Mutation of Semaphorin-6A Disrupts Limbic and Cortical Connectivity and Models Neurodevelopmental Psychopathology

Psychiatric disorders such as schizophrenia and autism are characterised by cellular disorganisation and dysconnectivity across the brain and can be caused by mutations in genes that control neurodevelopmental processes. To examine how neurodevelopmental defects can affect brain function and behaviour, we have comprehensively investigated the consequences of mutation of one such gene, Semaphorin-6A, on cellular organisation, axonal projection patterns, behaviour and physiology in mice. These analyses reveal a spectrum of widespread but subtle anatomical defects in Sema6A mutants, notably in limbic and cortical cellular organisation, lamination and connectivity. These mutants display concomitant alterations in the electroencephalogram and hyper-exploratory behaviour, which are characteristic of models of psychosis and reversible by the antipsychotic clozapine. They also show altered social interaction and deficits in object recognition and working memory. Mice with mutations in Sema6A or the interacting genes may thus represent a highly informative model for how neurodevelopmental defects can lead to anatomical dysconnectivity, resulting, either directly or through reactive mechanisms, in dysfunction at the level of neuronal networks with associated behavioural phenotypes of relevance to psychiatric disorders. The biological data presented here also make these genes plausible candidates to explain human linkage findings for schizophrenia and autism

Epilepsy Benchmarks Area III: Improved Treatment Options for Controlling Seizures and Epilepsy-Related Conditions Without Side Effects.

The goals of Epilepsy Benchmark Area III involve identifying areas that are ripe for progress in terms of controlling seizures and patient symptoms in light of the most recent advances in both basic and clinical research. These goals were developed with an emphasis on potential new therapeutic strategies that will reduce seizure burden and improve quality of life for patients with epilepsy. In particular, we continue to support the proposition that a better understanding of how seizures are initiated, propagated, and terminated in different forms of epilepsy is central to enabling new approaches to treatment, including pharmacological as well as surgical and device-oriented approaches. The stubbornly high rate of treatment-resistant epilepsy-one-third of patients-emphasizes the urgent need for new therapeutic strategies, including pharmacological, procedural, device linked, and genetic. The development of new approaches can be advanced by better animal models of seizure initiation that represent salient features of human epilepsy, as well as humanized models such as induced pluripotent stem cells and organoids. The rapid advances in genetic understanding of a subset of epilepsies provide a path to new and direct patient-relevant cellular and animal models, which could catalyze conceptualization of new treatments that may be broadly applicable across multiple forms of epilepsies beyond those arising from variation in a single gene. Remarkable advances in machine learning algorithms and miniaturization of devices and increases in computational power together provide an enhanced opportunity to detect and mitigate seizures in real time via devices that interrupt electrical activity directly or administer effective pharmaceuticals. Each of these potential areas for advance will be discussed in turn

MicroRNA-335-5p suppresses voltage-gated sodium channel expression and may be a target for seizure control

There remains an urgent need for new therapies for treatment-resistant epilepsy. Sodium channel blockers are effective for seizure control in common forms of epilepsy, but loss of sodium channel function underlies some genetic forms of epilepsy. Approaches that provide bidirectional control of sodium channel expression are needed. MicroRNAs (miRNA) are small noncoding RNAs which negatively regulate gene expression. Here we show that genome-wide miRNA screening of hippocampal tissue from a rat epilepsy model, mice treated with the antiseizure medicine cannabidiol, and plasma from patients with treatment-resistant epilepsy, converge on a single target-miR-335-5p. Pathway analysis on predicted and validated miR-335-5p targets identified multiple voltage-gated sodium channels (VGSCs). Intracerebroventricular injection of antisense oligonucleotides against miR-335-5p resulted in upregulation of Scn1a, Scn2a, and Scn3a in the mouse brain and an increased action potential rising phase and greater excitability of hippocampal pyramidal neurons in brain slice recordings, consistent with VGSCs as functional targets of miR-335-5p. Blocking miR-335-5p also increased voltage-gated sodium currents and SCN1A, SCN2A, and SCN3A expression in human induced pluripotent stem cell-derived neurons. Inhibition of miR-335-5p increased susceptibility to tonic-clonic seizures in the pentylenetetrazol seizure model, whereas adeno-associated virus 9-mediated overexpression of miR-335-5p reduced seizure severity and improved survival. These studies suggest modulation of miR-335-5p may be a means to regulate VGSCs and affect neuronal excitability and seizures. Changes to miR-335-5p may reflect compensatory mechanisms to control excitability and could provide biomarker or therapeutic strategies for different types of treatment-resistant epilepsy

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Boolean affine approximation with binary decision diagrams

Selman and Kautz’s work on knowledge compilation has established how approximation (strengthening and/or weakening) of a propositional knowledgebase can be used to speed up query processing, at the expense of completeness. In the classical approach, the knowledge-base is assumed to be presented as a propositional formula in conjunctive normal form (CNF), and Horn functions are used to overand under-approximate it (in the hope that many queries can be answered efficiently using the approximations only). However, other representations are possible, and functions other than Horn can be used for approximations, as long as they have deductioncomputational properties similar to those of the Horn functions. Zanuttini has suggested that the class of affine Boolean functions would be especially useful in knowledge compilation and has presented various affine approximation algorithms. Since CNF is awkward for presenting affine functions, Zanuttini considers both a sets-of-models representation and the use of modulo 2 congruence equations. Here we consider the use of reduced ordered binary decision diagrams (ROBDDs), a representation which is more compact than the sets of models and which (unlike modulo 2 congruences) can express any source knowledge-base. We present an ROBDD algorithm to find strongest affine upper-approximations of a Boolean function and we argue its correctness.

The Brain Injury Screening Tool (BIST): Tool development, factor structure and validity.

Currently health care pathways (the combination and order of services that a patient receives to manage their injury) following a mild traumatic brain injury vary considerably. Some clinicians lack confidence in injury recognition, management and knowing when to refer. A clinical expert group developed the Brain Injury Screening Tool (BIST) to provide guidance on health care pathways based on clinical indicators of poor recovery. The tool aims to facilitate access to specialist services (if required) to improve longer term prognosis. The tool was developed using a three-step process including: 1) domain mapping; 2) item development and 3) item testing and review. An online retrospective survey of 114 adults (>16 years) who had experienced a mild brain injury in the past 10 years was used to determine the initial psychometric properties of the 15-item symptom scale of the BIST. Participants were randomised to complete the BIST and one of two existing symptom scales; the Rivermead Post-concussion Symptom Questionnaire (RPQ) or the Sports Concussion Assessment Test (SCAT-5) symptom scale to determine concurrent validity. Participant responses to the BIST symptom scale items were used to determine scale reliability using Cronbach's alpha. A principal components analysis explored the underlying factor structure. Spearman's correlation coefficients determined concurrent validity with the RPQ and SCAT-5 symptom scales. The 15 items were found to require a reading age of 6-8 years old using readability statistics. High concurrent validity was shown against the RPQ (r = 0.91) and SCAT-5 (r = 0.90). The BIST total symptom scale (α = 0.94) and the three factors identified demonstrated excellent internal consistency: physical/emotional (α = 0.90), cognitive (α = 0.92) and vestibular-ocular (α = 0.80). This study provides evidence to support the utility, internal consistency, factor structure and concurrent validity of the BIST. Further research is warranted to determine the utility of the BIST scoring criteria and responsiveness to change in patients

Building a supportive framework for brain research in Ireland: Inaugural position paper of the Irish Brain Council

The Irish Brain Council is an independent group of organisations which have come together to influence and impact upon brain research in Ireland. The purpose of the Irish Brain Council is to promote and advocate for brain research in Ireland. It aims to harness the expertise and experience of its membership to provide a platform for public outreach, legislative engagement and strategic partnership to foster a supportive environment for brain research that ensures Ireland's competitiveness in this area going forward and enables the attraction, retention and development of research initiatives in the understanding and treatment of brain conditions. This first inaugural position paper by the Irish Brain Council aims to outline the challenges and opportunities for brain research in this country and call for a supportive infrastructure to attract future investment, retain highly qualified personnel and ensure that research findings are effectively translated into better outcomes for people with brain conditions. Brain research was the initial focus of the European Brain Council (EBC) when it was launched 15 years ago; since then, however, the EBC has expanded into many other areas such as prevention, education, the patient's journey etc. The EBC has therefore recently adopted an alternative term ‘brain health’ in place of ‘brain research’, which is more holistic and more representative of their broader remit. For the remainder of this paper, we will use the term ‘brain health and research’ to mirror the aims of the EBC in the goals of the Irish Brain Council