Case Report: PAFAH1B1 Mutation and Posterior Band Heterotopia With Focal Temporal Lobe Epilepsy Treated by Responsive Neurostimulation

Subcortical band heterotopia (SBH), also known as double cortex syndrome, is a malformation of cortical development caused by inherited or somatic gene variants. We present a case of a young adult with posterior SBH and electroclinical features of focal neocortical temporal lobe epilepsy. Genomic blood analysis identified a pathogenic somatic mosaicism duplication variant of the PAFAH1B1 gene. Despite bilateral cortical MRI abnormalities, the interictal and ictal EEG findings indicated a focal epileptogenic region in the left posterior temporal region. Chronic responsive cortical neurostimulation across two four-contact depth electrodes placed 5mm on either side of the maximal interictal spiking identified during intraoperative electrocorticography resulted in a consistent 28%reduction in duration of electrographic seizures and as well as constricted propagation. Although electrographic seizures continued, the family reported no clinical seizures and a marked improvement in resistant behaviors. This observation supports that focal neocortical neuromodulation can control clinical seizures of consistently localized origin despite genetic etiology, bilateral structural brain abnormalities, and continuation of non-propagating electrographic seizures. We propose that a secondary somatic mutation may be the cause of the focal neocortical temporal lobe epilepsy

A Murine Model to Study Epilepsy and SUDEP Induced by Malaria Infection

One of the largest single sources of epilepsy in the world is produced as a neurological sequela in survivors of cerebral malaria. Nevertheless, the pathophysiological mechanisms of such epileptogenesis remain unknown and no adjunctive therapy during cerebral malaria has been shown to reduce the rate of subsequent epilepsy. There is no existing animal model of postmalarial epilepsy. In this technical report we demonstrate the first such animal models. These models were created from multiple mouse and parasite strain combinations, so that the epilepsy observed retained universality with respect to genetic background. We also discovered spontaneous sudden unexpected death in epilepsy (SUDEP) in two of our strain combinations. These models offer a platform to enable new preclinical research into mechanisms and prevention of epilepsy and SUDEP

A Murine Model to Study Epilepsy and SUDEP Induced by Malaria Infection.

One of the largest single sources of epilepsy in the world is produced as a neurological sequela in survivors of cerebral malaria. Nevertheless, the pathophysiological mechanisms of such epileptogenesis remain unknown and no adjunctive therapy during cerebral malaria has been shown to reduce the rate of subsequent epilepsy. There is no existing animal model of postmalarial epilepsy. In this technical report we demonstrate the first such animal models. These models were created from multiple mouse and parasite strain combinations, so that the epilepsy observed retained universality with respect to genetic background. We also discovered spontaneous sudden unexpected death in epilepsy (SUDEP) in two of our strain combinations. These models offer a platform to enable new preclinical research into mechanisms and prevention of epilepsy and SUDEP

The Bacterial and Viral Complexity of Postinfectious Hydrocephalus in Uganda

Postinfectious hydrocephalus (PIH), often following neonatal sepsis, is the most common cause of pediatric hydrocephalus world-wide, yet the microbial pathogens remain uncharacterized. Characterization of the microbial agents causing PIH would lead to an emphasis shift from surgical palliation of cerebrospinal fluid (CSF) accumulation to prevention. We examined blood and CSF from 100 consecutive cases of PIH and control cases of non-postinfectious hydrocephalus (NPIH) in infants in Uganda. Genomic testing was undertaken for bacterial, fungal, and parasitic DNA, DNA and RNA sequencing for viral identification, and extensive bacterial culture recovery. We uncovered a major contribution to PIH from Paenibacillus , upon a background of frequent cytomegalovirus (CMV) infection. CMV was only found in CSF in PIH cases. A facultatively anaerobic isolate was recovered. Assembly of the genome revealed a strain of P. thiaminolyticus . In mice, this isolate designated strain Mbale , was lethal in contrast with the benign reference strain. These findings point to the value of an unbiased pan-microbial approach to characterize PIH in settings where the organisms remain unknown, and enables a pathway towards more optimal treatment and prevention of the proximate neonatal infections. One Sentence Summary We have discovered a novel strain of bacteria upon a frequent viral background underlying postinfectious hydrocephalus in Uganda

Paenibacillus infection with frequent viral coinfection contributes to postinfectious hydrocephalus in Ugandan infants

Postinfectious hydrocephalus (PIH), which often follows neonatal sepsis, is the most common cause of pediatric hydrocephalus worldwide, yet the microbial pathogens underlying this disease remain to be elucidated. Characterization of the microbial agents causing PIH would enable a shift from surgical palliation of cerebrospinal fluid (CSF) accumulation to prevention of the disease. Here, we examined blood and CSF samples collected from 100 consecutive infant cases of PIH and control cases comprising infants with non-postinfectious hydrocephalus in Uganda. Genomic sequencing of samples was undertaken to test for bacterial, fungal, and parasitic DNA; DNA and RNA sequencing was used to identify viruses; and bacterial culture recovery was used to identify potential causative organisms. We found that infection with the bacterium Paenibacillus, together with frequent cytomegalovirus (CMV) coinfection, was associated with PIH in our infant cohort. Assembly of the genome of a facultative anaerobic bacterial isolate recovered from cultures of CSF samples from PIH cases identified a strain of Paenibacillus thiaminolyticus. This strain, designated Mbale, was lethal when injected into mice in contrast to the benign reference Paenibacillus strain. These findings show that an unbiased pan-microbial approach enabled characterization of Paenibacillus in CSF samples from PIH cases, and point toward a pathway of more optimal treatment and prevention for PIH and other proximate neonatal infections

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Association of cardiovascular disease and 10 other pre-existing comorbidities with COVID-19 mortality: A systematic review and meta-analysis

BACKGROUND: Estimating the risk of pre-existing comorbidities on coronavirus disease 2019 (COVID-19) mortality may promote the importance of targeting populations at risk to improve survival. This systematic review and meta-analysis aimed to estimate the association of pre-existing comorbidities with COVID-19 mortality. METHODS: We searched MEDLINE, SCOPUS, OVID, and Cochrane Library databases, and medrxiv.org from December 1st, 2019, to July 9th, 2020. The outcome of interest was the risk of COVID-19 mortality in patients with and without pre-existing comorbidities. We analyzed 11 comorbidities: cardiovascular diseases, hypertension, diabetes, congestive heart failure, cerebrovascular disease, chronic kidney disease, chronic liver disease, cancer, chronic obstructive pulmonary disease, asthma, and HIV/AIDS. Two reviewers independently extracted data and assessed the risk of bias. All analyses were performed using random-effects models and heterogeneity was quantified. RESULTS: Eleven pre-existing comorbidities from 25 studies were included in the meta-analysis (n = 65, 484 patients with COVID-19; mean age; 61 years; 57% male). Overall, the between-study heterogeneity was medium, and studies had low publication bias and high quality. Cardiovascular disease (risk ratio (RR) 2.25, 95% CI = 1.60–3.17, number of studies (n) = 14), hypertension (1.82 [1.43 to 2.32], n = 13), diabetes (1.48 [1.02 to 2.15], n = 16), congestive heart failure (2.03 [1.28 to 3.21], n = 3), chronic kidney disease (3.25 [1.13 to 9.28)], n = 9) and cancer (1.47 [1.01 to 2.14), n = 10) were associated with a significantly greater risk of mortality from COVID-19. CONCLUSIONS: Patients with COVID-19 with cardiovascular disease, hypertension, diabetes, congestive heart failure, chronic kidney disease and cancer have a greater risk of mortality compared to patients with COVID-19 without these comorbidities. Tailored infection prevention and treatment strategies targeting this high-risk population might improve survival

Sudden death in individuals with obstructive sleep apnoea: a systematic review and meta-analysis

Objectives Over 1 billion individuals worldwide experience some form of sleep apnoea, and this number is steadily rising. Obstructive sleep apnoea (OSA) can negatively influence one’s quality of life and potentially increase mortality risk. However, the association between OSA and mortality has not been reliably estimated. This meta-analysis estimates the risk of all-cause and cardiovascular mortality in individuals with OSA.Design Systematic review and meta-analysis.Data sources MEDLINE, Cochrane Library, Scopus and Joanna Briggs Institute Evidence-Based Practice databases were searched from inception through 1 January 2020.Eligibility criteria for selecting studies We included observational studies assessing the association of sudden deaths in individuals with and without OSA.Data extraction and synthesis Two independent reviewers (AES and ESH) extracted data and assessed the risk of bias using the Newcastle-Ottawa Scale quality assessment tool. Data were pooled using the random-effects models and reported as risk ratios (RRs) with 95% CIs. Heterogeneity was quantified with I2 statistic.Results We identified 22 observational studies (n=42 099 participants). The mean age was 62 years and 64% were men. OSA was associated with all-cause sudden death (RR=1.74, 95% CI: 1.44 to 2.10, I2=72%) and cardiovascular mortality (RR=1.94, 95% CI: 1.39 to 2.70, I2=32%). A marginally significant dose–response relationship between severity of OSA and the risk of death was observed (p for interaction=0.05): mild OSA (RR=1.16, 95% CI: 0.70 to 1.93), moderate OSA (RR=1.72, 95% CI: 1.11 to 2.67) and severe OSA (RR=2.87, 95% CI: 1.70 to 4.85). Meta-regression analysis showed that older age was a significant contributing factor in the relationship between OSA and mortality. The median study methodological quality was considered high.Conclusions OSA is a significant risk factor for all-cause mortality and cardiac mortality. Prevention and treatment strategies to optimise survival and quality of life in individuals with OSA are urgently needed.PROSPERO registration number CRD42020164941

Risk of suicidal ideation, suicide attempts, and suicide deaths in persons with sleep apnea: Protocol for a systematic review and meta-analysis.

AIM:To estimate the pooled prevalence and incidence of suicidal ideation, attempts, and deaths in people with sleep apnea. METHOD:We will identify epidemiological studies reporting the prevalence or incidence rate of suicide in people with sleep apnea. We will search the following databases: PubMed (MEDLINE), Scopus, Cochrane Library, OVID (HEALTH STAR), OVID (MEDLINE) and Joana Briggs Institute EBF Database. No age, geographical location, study-design or language limits will be applied. This protocol was developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines. Two reviewers (YY and YP) will independently screen citations, abstracts and will identify full-text articles for inclusion, extract data, and appraise the quality and bias of included studies. Discrepancies will be resolved by consulting with a third researcher (MC). Study quality will be assessed by the Newcastle-Ottawa Scale. The primary outcomes will be the overall prevalence or incidence of suicidal ideation, attempts and completion and the risk of suicide in people with sleep apnea. For pooling of the studies, we will use a random-effects model with a logit transformation. The DerSimonian and Laird (DL) random-effects method will be used to estimate the pooled inter-study variance. We will assess the between-study heterogeneity using I2 statistics, and Cochrane's Q statistic (significance level 75%), we will perform subgroup meta-analyses and conduct a meta-regression analysis to explore sources of study heterogeneity using study level median age, study-level proportions of race, gender, depression and quality scores. We will report effect estimates as suicide risk per 1000 individuals. Egger's test and funnel plots will be used to assess publication bias, and adjusted estimates using trim and fill methods will be reported if publication bias is suspected. ETHICS AND DISSEMINATION:No ethics clearance is required as no primary data will be collected. The results of this systematic review and meta-analysis will be presented at scientific conferences and published in a peer-review journal. The results may shed more light on the burden of suicide risk among individuals with sleep apnea and may guide future population-specific interventions. TRIAL REGISTRATION:PROSPERO registration number: CRD42020165404