Neurological diseases as primary gliopathies: a reassessment of neurocentrism

Diseases of the human brain are almost universally attributed to malfunction or loss of nerve cells. However, a considerable amount of work has, during the last decade, expanded our view on the role of astrocytes in CNS (central nervous system), and this analysis suggests that astrocytes contribute to both initiation and propagation of many (if not all) neurological diseases. Astrocytes provide metabolic and trophic support to neurons and oligodendrocytes. Here, we shall endeavour a broad overviewing of the progress in the field and forward the idea that loss of homoeostatic astroglial function leads to an acute loss of neurons in the setting of acute insults such as ischaemia, whereas more subtle dysfunction of astrocytes over periods of months to years contributes to epilepsy and to progressive loss of neurons in neurodegenerative diseases. The majority of therapeutic drugs currently in clinical use target neuronal receptors, channels or transporters. Future therapeutic efforts may benefit by a stronger focus on the supportive homoeostatic functions of astrocytes

Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy

Importance: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown. Objective: To test the association between pathogenic somatic variants in the hippocampus and MTLE. Design, Setting, and Participants: This case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy-associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022. Exposures: Drug-resistant MTLE. Main Outcomes and Measures: Presence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex. Results: Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9]; P =.01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11, SOS1, KRAS, BRAF, and NF1, all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism. Conclusions and Relevance: Hippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery

Clinical trials: from problem child to the driving force of medical advancement

Clinical trials are conducted to find better ways to prevent, screen for, diagnose or treat human disease. The development of clinical trials throughout history has built the foundation for ethically and scientifically robust research. As our healthcare needs have evolved, so have clinical trials and the standards by which they are run. Vanessa Raymont and colleagues explore the past, present and future of the clinical trial

Women in science: achievements and ambitions

International Women's Day will be celebrated on 8 March 2021. Much has changed in the modern world, but it is still a fact that women are underrepresented in many sectors; this is especially true in science and research. Colleagues from the Oxford Brain Health Clinical Trials Unit reflect on the historical contribution of women in STEM and what future challenges and successes may lay ahead

Rapid commentary: Ethical implications for clinical trialists and patients associated with COVID-19 research Delanerolle G, Rathod S, Elliot K, Ramakrishnan R, Thayanandan T, Sandle N, Haque N, Raymont V, Phiri P. Rapid commentary: Ethical implications for clinical trialists and patients associated with COVID-19 research

Pandemics disrupt clinical trials worldwide, with lasting effects on research. It can severely impact clinical trialists ability to conduct safe and ethically uncompromised trials. Hence, the mounting pressure results in ethically and morally distressing decisions faced by clinical trial professionals during pandemic situations. Whilst clinical trialists attempt to think about preparedness and responses during a pandemic, the need to have an ethical framework that has real-world applicability is imperative. Pandemics are a challenging time for all, however, the safety and access to support for clinical trialists and patients within clinical trials should be at the forefront for their organisations and the government

Artificial intelligence: a rapid case for advancement in the personalization of Gynaecology/Obstetric and Mental Health care

To evaluate and holistically treat the mental health sequelae and potential psychiatric comorbidities associated with obstetric and gynaecological conditions, it is important to optimize patient care, ensure efficient use of limited resources and improve health-economic models. Artificial intelligence applications could assist in achieving the above. The World Health Organization and global healthcare systems have already recognized the use of artificial intelligence technologies to address 'system gaps' and automate some of the more cumbersome tasks to optimize clinical services and reduce health inequalities. Currently, both mental health and obstetric and gynaecological services independently use artificial intelligence applications. Thus, suitable solutions are shared between mental health and obstetric and gynaecological clinical practices, independent of one another. Although, to address complexities with some patients who may have often interchanging sequelae with mental health and obstetric and gynaecological illnesses, 'holistically' developed artificial intelligence applications could be useful. Therefore, we present a rapid review to understand the currently available artificial intelligence applications and research into multi-morbid conditions, including clinical trial-based validations. Most artificial intelligence applications are intrinsically data-driven tools, and their validation in healthcare can be challenging as they require large-scale clinical trials. Furthermore, most artificial intelligence applications use rate-limiting mock data sets, which restrict their applicability to a clinical population. Some researchers may fail to recognize the randomness in the data generating processes in clinical care from a statistical perspective with a potentially minimal representation of a population, limiting their applicability within a real-world setting. However, novel, innovative trial designs could pave the way to generate better data sets that are generalizable to the entire global population. A collaboration between artificial intelligence and statistical models could be developed and deployed with algorithmic and domain interpretability to achieve this. In addition, acquiring big data sets is vital to ensure these artificial intelligence applications provide the highest accuracy within a real-world setting, especially when used as part of a clinical diagnosis or treatment

An evaluation of the mental health impact of SARS-CoV-2 on patients, general public and healthcare professionals: A systematic review and meta-analysis

Background: The global impact of COVID-19 pandemic continues to affect the lives of billions of people with recurrent waves. Healthcare systems are struggling to manage pre-existing patient care and recurring covid-19 demands. As a result, we evaluated the mental health impact using systematic review and meta-analysis. Methods: A comprehensive search was undertaken from April 2020 to 22nd January 2021 using multiple electronic databases. A systematic review protocol was developed and published on PROSPERO registration; CRD42020181481. A random-effects model was used to compute pooled estimates of anxiety, depression, PTSD, insomnia and suicidal thoughts. Findings: Our search yielded 11,295 studies and of those 287 met the inclusion criteria. The meta-analysis of 206 studies revealed minimal differences in prevalence of anxiety, depression, and PTSD among HCPs compared with the public during the pandemic but higher prevalence of suicidal thoughts/ideation or self-harm (11% vs 5.8%) and lower prevalence of wellbeing (28.2% vs 52.6%) among the public compared to HCPs. Interpretation: The pandemic has led to a high mental health burden especially amongst HCPs and higher suicidal ideation and lower wellbeing in general public which warrants further investigation and management globally. These findings highlight an emerging critical public health issue that requires urgent solutions