The Intersection of Epigenetics and Metabolism in Trained Immunity.

The last few years have witnessed an increasing body of evidence that challenges the traditional view that immunological memory is an exclusive trait of the adaptive immune system. Myeloid cells can show increased responsiveness upon subsequent stimulation with the same or a different stimulus, well after the initial challenge. This de facto innate immune memory has been termed "trained immunity" and is involved in infections, vaccination and inflammatory diseases. Trained immunity is based on two main pillars: the epigenetic and metabolic reprogramming of cells. In this review we discuss the latest insights into the epigenetic mechanisms behind the induction of trained immunity, as well as the role of different cellular metabolites and metabolic networks in the induction, regulation and maintenance of trained immunity.

Alternating high-fat diet enhances atherosclerosis by neutrophil reprogramming.

Systemic immune responses caused by chronic hypercholesterolaemia contribute to atherosclerosis initiation, progression and complications1. However, individuals often change their dietary habits over time2, and the effects of an alternating high-fat diet (HFD) on atherosclerosis remain unclear. Here, to address this relevant issue, we developed a protocol using atherosclerosis-prone mice to compare an alternating versus continuous HFD while maintaining similar overall exposure periods. We found that an alternating HFD accelerated atherosclerosis in Ldlr-/- and Apoe-/- mice compared with a continuous HFD. This pro-atherogenic effect of the alternating HFD was also observed in Apoe-/-Rag2-/- mice lacking T, B and natural killer T cells, ruling out the role of the adaptive immune system in the observed phenotype. Discontinuing the HFD in the alternating HFD group downregulated RUNX13, promoting inflammatory signalling in bone marrow myeloid progenitors. After re-exposure to an HFD, these cells produced IL-1ß, leading to emergency myelopoiesis and increased neutrophil levels in blood. Neutrophils infiltrated plaques and released neutrophil extracellular traps, exacerbating atherosclerosis. Specific depletion of neutrophils or inhibition of IL-1ß pathways abolished emergency myelopoiesis and reversed the pro-atherogenic effects of the alternating HFD. This study highlights the role of IL-1ß-dependent neutrophil progenitor reprogramming in accelerated atherosclerosis induced by alternating HFD.

Chromosomal contact permits transcription between coregulated genes.

Transcription of coregulated genes occurs in the context of long-range chromosomal contacts that form multigene complexes. Such contacts and transcription are lost in knockout studies of transcription factors and structural chromatin proteins. To ask whether chromosomal contacts are required for cotranscription in multigene complexes, we devised a strategy using TALENs to cleave and disrupt gene loops in a well-characterized multigene complex. Monitoring this disruption using RNA FISH and immunofluorescence microscopy revealed that perturbing the site of contact had a direct effect on transcription of other interacting genes. Unexpectedly, this effect on cotranscription was hierarchical, with dominant and subordinate members of the multigene complex engaged in both intra- and interchromosomal contact. This observation reveals the profound influence of these chromosomal contacts on the transcription of coregulated genes in a multigene complex.

Long noncoding RNA CHROMR regulates antiviral immunity in humans.

Long noncoding RNAs (lncRNAs) have emerged as critical regulators of gene expression, yet their contribution to immune regulation in humans remains poorly understood. Here, we report that the primate-specific lncRNA CHROMR is induced by influenza A virus and SARS-CoV-2 infection and coordinates the expression of interferon-stimulated genes (ISGs) that execute antiviral responses. CHROMR depletion in human macrophages reduces histone acetylation at regulatory regions of ISG loci and attenuates ISG expression in response to microbial stimuli. Mechanistically, we show that CHROMR sequesters the interferon regulatory factor (IRF)-2-dependent transcriptional corepressor IRF2BP2, thereby licensing IRF-dependent signaling and transcription of the ISG network. Consequently, CHROMR expression is essential to restrict viral infection of macrophages. Our findings identify CHROMR as a key arbitrator of antiviral innate immune signaling in humans.

Trained immunity suppression determines kidney allograft survival.

The innate immune system plays an essential role in regulating the immune responses to kidney transplantation, but the mechanisms through which innate immune cells influence long-term graft survival are unclear. The current study highlights the vital role of trained immunity in kidney allograft survival. Trained immunity describes the epigenetic and metabolic changes that innate immune cells undergo following an initial stimulus, allowing them have a stronger inflammatory response to subsequent stimuli. We stimulated healthy peripheral blood mononuclear cells with pretransplant and posttransplant serum of kidney transplant patients and immunosuppressive drugs in an in vitro trained immunity assay and measured tumor necrosis factor and interleukin 6 cytokine levels in the supernatant as a readout for trained immunity. We show that the serum of kidney transplant recipients collected 1 week after transplantation can suppress trained immunity. Importantly, we found that kidney transplant recipients whose serum most strongly suppressed trained immunity rarely experienced graft loss. This suppressive effect of posttransplant serum is likely mediated by previously unreported effects of immunosuppressive drugs. Our findings provide mechanistic insights into the role of innate immunity in kidney allograft survival, uncovering trained immunity as a potential therapeutic target for improving graft survival.

Co-transport of the nuclear-encoded Cox7c mRNA with mitochondria along axons occurs through a coding-region-dependent mechanism.

Nuclear-encoded mitochondrial protein mRNAs have been found to be localized and locally translated within neuronal processes. However, the mechanism of transport for those mRNAs to distal locations is not fully understood. Here, we describe axonal co-transport of Cox7c with mitochondria. Fractionation analysis and single-molecule fluorescence in situ hybridization (smFISH) assay revealed that endogenous mRNA encoding Cox7c was preferentially associated with mitochondria in a mouse neuronal cell line and within mouse primary motor neuron axons, whereas other mRNAs that do not encode mitochondrial protein were much less associated. Live-cell imaging of MS2-tagged Cox7c mRNA further confirmed the preferential colocalization and co-transport of Cox7c mRNA with mitochondria in motor neuron axons. Intriguingly, the coding region, rather than the 3' untranslated region (UTR), was the key domain for the co-transport. Our results reveal that Cox7c mRNA can be transported with mitochondria along significant distances and that its coding region is a major recognition feature. This is consistent with the idea that mitochondria can play a vital role in spatial regulation of the axonal transcriptome at distant neuronal sites.

Comparative Efficacy of Medium and Soft Toothbrushes in Plaque Removal and Gingivitis Control.

BACKGROUND Regularly removing dental plaque is key to good oral hygiene and gingival health promotion. This study aimed to compare the effects of using soft and medium toothbrushes using the plaque index (PI), gingival index (GI), and bleeding on probing (BOP) index. MATERIAL AND METHODS A randomized parallel-group study design was used. Sixty-four participants were randomly assigned to 2 similar intervention groups (medium and soft toothbrush groups). The PI, GI, and BOP indexes were used. The median and median difference of PI, GI, and BOP were calculated. SPSS was used for data entry and analysis. Wilcoxon and Mann-Whitney U tests were used for data analysis. RESULTS The median scores of GI, PI, and BOP significantly decreased from 1.8, 1.7, and 2.0, respectively, before using medium toothbrushes to 0.0, 0.1, and 0.0, respectively, after using medium toothbrushes (all P<0.0001). Similarly, the median scores of GI, PI, and BOP significantly decreased from 2.0, 1.7, and 2.0, respectively, before using soft toothbrushes to 1.1, 0.9, and 1.0, respectively, after using soft toothbrushes (P<0.0001). The median differences in GI, PI, and BOP scores among those using medium toothbrushes were higher than the median differences among those using soft toothbrushes [(1.8 vs 0.9), (1.6 vs 0.8), and (2.0 vs 1.0), respectively]. These differences were statistically significant (P<0.0001). CONCLUSIONS This study concludes that medium and soft toothbrushes were effective in removing plaque and controlling gingivitis. Medium toothbrushes were more effective than soft toothbrushes in achieving these outcomes.

Morphological and Dimensional Analysis of the Nasopalatine Canal: Insights from Cone-Beam Computed Tomography Imaging in a Large Cohort.

BACKGROUND The nasopalatine canal (NPC), or incisive canal, is located in the midline of the palate, posterior to the maxillary central incisors. Its anatomy is important in prosthetic dentistry procedures. This study aimed to assess the anatomical morphology of the NPC according to age, sex, and dental status using cone-beam computed tomography (CBCT) in 335 patients. MATERIAL AND METHODS In this retrospective cross-sectional study, a total of 335 patients were recruited and categorized according to sex, age, and dental status. Individual CBCT images were analyzed in the sagittal, coronal, and axial planes. Also, we recorded the dimensions and morphological shape of the NPC and adjacent buccal bone plate (BBP) under standardized conditions. The associations between sex, age group, NPC shapes and types, and presence of central incisors were assessed. A significance level was set at P<0.05. RESULTS Mean labio-palatal and mediolateral measurements of the incisive foramen were 5.13±1.45 mm and 3.21±0.96 mm, whereas the mean diameter of Stenson foramen was 2.57±1.25 mm, and the total length of the NPC was 11.79±2.50 mm. Funnel, Y, and round-shaped canals were the most prevalent shapes of the NPC in sagittal, coronal, and axial planes. BBP was greater in men, with P=0.011, P=0.000, and P=0.001 at BBP1, BBP2, and BBP3, respectively. CONCLUSIONS NPC and BBP parameter values were slightly higher among male patients. NPC parameters increased with older age. The crest width of BBP decreased with older age and after missing maxillary central incisor teeth.

Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa.

The cause of autosomal-dominant retinitis pigmentosa (adRP), which leads to loss of vision and blindness, was investigated in families lacking a molecular diagnosis. A refined locus for adRP on Chr17q22 (RP17) was delineated through genotyping and genome sequencing, leading to the identification of structural variants (SVs) that segregate with disease. Eight different complex SVs were characterized in 22 adRP-affected families with >300 affected individuals. All RP17 SVs had breakpoints within a genomic region spanning YPEL2 to LINC01476. To investigate the mechanism of disease, we reprogrammed fibroblasts from affected individuals and controls into induced pluripotent stem cells (iPSCs) and differentiated them into photoreceptor precursor cells (PPCs) or retinal organoids (ROs). Hi-C was performed on ROs, and differential expression of regional genes and a retinal enhancer RNA at this locus was assessed by qPCR. The epigenetic landscape of the region, and Hi-C RO data, showed that YPEL2 sits within its own topologically associating domain (TAD), rich in enhancers with binding sites for retinal transcription factors. The Hi-C map of RP17 ROs revealed creation of a neo-TAD with ectopic contacts between GDPD1 and retinal enhancers, and modeling of all RP17 SVs was consistent with neo-TADs leading to ectopic retinal-specific enhancer-GDPD1 accessibility. qPCR confirmed increased expression of GDPD1 and increased expression of the retinal enhancer that enters the neo-TAD. Altered TAD structure resulting in increased retinal expression of GDPD1 is the likely convergent mechanism of disease, consistent with a dominant gain of function. Our study highlights the importance of SVs as a genomic mechanism in unsolved Mendelian diseases.

Super-beacons: Open-source probes with spontaneous tuneable blinking compatible with live-cell super-resolution microscopy.

Localization-based super-resolution microscopy relies on the detection of individual molecules cycling between fluorescent and non-fluorescent states. These transitions are commonly regulated by high-intensity illumination, imposing constrains to imaging hardware and producing sample photodamage. Here, we propose single-molecule self-quenching as a mechanism to generate spontaneous photoswitching. To demonstrate this principle, we developed a new class of DNA-based open-source super-resolution probes named super-beacons, with photoswitching kinetics that can be tuned structurally, thermally and chemically. The potential of these probes for live-cell compatible super-resolution microscopy without high-illumination or toxic imaging buffers is revealed by imaging interferon inducible transmembrane proteins (IFITMs) at sub-100 nm resolutions.

Impact of the COVID-19 Pandemic on Elderly Medical Admissions and Outcomes in a Tertiary Hospital in Northeastern Nigeria: A Comparative Retrospective Study.

BACKGROUND: The coronavirus infectious disease 2019 (COVID-19) has been shown to be more lethal in the elderly (>65 years), especially those with co-morbidities. This study examined the impact of the pandemic lockdown period on trends in elderly medical admissions and deaths. METHODOLOGY: This is a retrospective study of elderly medical admissions and deaths in the medical wards of a Nigerian hospital. Data for the months of March, April, May, June, and July of 2020 was compared to the same months before (2019) and after (2021). Analysis was done using STATA version 15.0. RESULTS: During the study period, two hundred and seventy-six elderly patients were admitted, with a mean age (±SD) of 73.4 ± 7.4 years. The most common diagnoses at admission were chronic kidney disease (CKD) (26.85%, n=74) and hypertensive heart disease (HHD) (21.7%, n=60). The highest admission was in 2021, with a total of 99 (35.9%). Overall, 60 mortalities were recorded, with a proportional mortality rate of 21.7%, which was highest in 2020 (25.0%) and lowest in 2021 (17.1%). There was no difference between the mortality rates of 2019 versus 2020 (P=0.82) and 2020 versus 2021(P=0.18). Sepsis (35.0%) and CKD (25.0%) were the major contributors in 2019. CONCLUSION: CKD and HHD were the most common diagnoses at admission, whereas sepsis, CKD, and CVD were the commonest causes of death. The Covid-19 pandemic did not significantly alter the elderly admission pattern in our setting.

CONTEXTE: Il a été démontré que la maladie infectieuse à coronavirus 2019 (COVID-19) est plus mortelle chez les personnes âgées (>65 ans), en particulier celles qui présentent des comorbidités. Cette étude a examiné l'impact de la période de verrouillage pandémique sur les tendances des admissions médicales et des décès de personnes âgées. MÉTHODOLOGIE: Il s'agit d'une étude rétrospective des admissions et des décès de personnes âgées dans les services médicaux d'un hôpital nigérian. Les données relatives aux personnes âgées pour les mois de mars, avril, mai, juin et juillet 2020 ont été comparées aux mêmes mois avant (2019) et après (2021). L'analyse a été réalisée à l'aide de STATA version 15.0. RÉSULTATS: Au cours de la période, deux cent soixante-seize patients âgés ont été admis, avec un âge moyen et un écart-type (ET) de 73,4 7,4 ans. Les diagnostics les plus fréquents à l'admission étaient l'insuffisance rénale chronique (IRC) (26,85 %, n=74) et la cardiopathie hypertensive (HHD) (21,7 %, n=60). Le nombre d'admissions le plus élevé a été enregistré en 2021, avec un total de 99 (35,9 %). Au total, 60 décès ont été enregistrés, avec un taux de mortalité proportionnel de 21,7 %, qui était le plus élevé en 2020 (25,0 %) et le plus faible en 2021 (17,1 %). Les preuves étaient insuffisantes pour montrer une différence entre les taux de mortalité de 2019 par rapport à 2020 (P=0,82) et de 2020 par rapport à 2021 (P=0,18). Le sepsis (35,0 %) et l'IRC (25,0 %) étaient les principaux facteurs de mortalité en 2019. CONCLUSION: L'IRC et l'HHD étaient les diagnostics les plus courants à l'admission, tandis que la septicémie, l'IRC et les MCV étaient les causes les plus fréquentes de décès. La pandémie de Covid-19 n'a pas modifié de manière significative le schéma d'admission des personnes âgées dans notre contexte. Mots clés: COVID-19, Personnes âgées, Mode d'admission, Mortalité.

Propolis mouthwash for preventing radiotherapy-induced mucositis in patients with nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is the most common head and neck cancer in Malaysia. The gold standard treatment of NPC is radiotherapy (RT), as NPC is a radiosensitive tumour. Although RT is successful in treating NPC, patients cannot avoid the resulting RT complications. Oral mucositis is the most frequently encountered debilitating complication of RT and has no specific preventive treatment. The aim of this study was to evaluate the efficacy and safety of a 2.5% propolis mouthwash for preventing RT-induced mucositis in patients with NPC. MATERIALS AND METHODS: The study was a prospective, double-arm, randomised control trial with intervention. The patients were randomly divided into an experimental group receiving propolis mouthwash and a placebo group receiving normal saline mouthwash. All patients were instructed to rinse their mouths with 7mL mouthwash three times daily for six weeks. The severity of oral mucositis was then evaluated by the World Health Organization Oral Toxicity Scale at the second, fourth, and sixth weeks of the study. RESULTS: In total, 17 patients completed the study: 10 patients used the propolis mouthwash and seven used the placebo mouthwash. The mean mucositis scores for the propolis mouthwash compared to the placebo at the second, fourth, and sixth weeks were 0.10 vs. 1.14, 0.50 vs. 2.00, and 1.20 vs. 2.86, respectively, and the differences between the two groups were statistically significant (p<0.001). CONCLUSION: A 2.5% propolis mouthwash was both safe and effective for reducing the severity of oral mucositis following RT for NPC.

Secondary Alcohol Dehydrogenases from Thermoanaerobacter pseudoethanolicus and Thermoanaerobacter brockii as Robust Catalysts.

Alcohol dehydrogenases (ADHs) are an important type of enzyme that have significant applications as biocatalysts. Secondary ADHs from Thermoanaerobacter pseudoethanolicus (TeSADH) and Thermoanaerobacter brockii (TbSADH) are well-known as robust catalysts. However, like most other ADHs, these enzymes suffer from their high substrate specificities (i. e., limited substrate scope), which to some extent restricts their use as biocatalysts. This minireview discusses recent efforts to expand the substrate scope and tune the enantioselectivity of TeSADH and TbSADH by using site-directed mutagenesis and directed evolution. Various examples of asymmetric synthesis of optically active alcohols using both enzymes are highlighted. Moreover, the unique thermal stability and organic solvent tolerance of these enzymes is illustrated by their concurrent inclusion with other interesting reactions to synthesize optically active alcohols and amines. For instance, TeSADH has been used in quantitative non-stereoselective oxidation of alcohols to deracemize alcohols via cyclic deracemization and in the racemization of enantiopure alcohols to accomplish a bienzymatic dynamic kinetic resolution.

Translation and validation of an epilepsy-screening questionnaire in three Nigerian languages.

OBJECTIVE: We describe the development, translation and validation of epilepsy-screening questionnaires in the three most popular Nigerian languages: Hausa, Igbo and Yoruba. METHODS: A 9-item epilepsy-screening questionnaire was developed by modifying previously validated English language questionnaires. Separate multilingual experts forward- and back-translated them to the three target languages. Translations were discussed with fieldworkers and community members for ethnolinguistic acceptability and comprehension. We used an unmatched affected-case versus unaffected-control design for the pilot study. Cases were people with epilepsy attending the tertiary hospitals where these languages are spoken. The controls were relatives of cases or people attending for other medical conditions. An affirmative response to any of the nine questions amounted to a positive screen for epilepsy. RESULTS: We recruited 153 (75 cases and 78 controls) people for the Hausa version, 106 (45 cases and 61 controls) for Igbo and 153 (66 cases and 87 controls) for the Yoruba. The sensitivity and specificity of the questionnaire were: Hausa (97.3% and 88.5%), Igbo (91.1% and 88.5%) and Yoruba (93.9% and 86.7%). The three versions reliably indicated epilepsy with positive predictive values of 85.9% (Hausa), 85.4% (Igbo) and 87.3% (Yoruba) and reliably excluded epilepsy with negative predictive values of 97.1% (Hausa), 93.1% (Igbo) and 95.1% (Yoruba). Positive likelihood ratios were all greater than one. CONCLUSIONS: Validated epilepsy screening questionnaires are now available for the three languages to be used for community-based epilepsy survey in Nigeria. The translation and validation process are discussed to facilitate usage and development for other languages in sub-Saharan Africa.

Enhancer-Derived lncRNAs Regulate Genome Architecture: Fact or Fiction?

How does the non-coding portion of the genome contribute to the regulation of genome architecture? A recent paper by Tan et al. focuses on the relationship between cis-acting complex-trait-associated lincRNAs and the formation of chromosomal contacts in topologically associating domains (TADs).

Topical Application of High-Dose Mesna Prevents Adhesion Formation: An Experimental Animal Study.

BACKGROUND: Adhesion formation is a common complication of abdominal surgeries. Mesna is a drug with fibrinolytic properties which has been used in surgical field to facilitate tissue dissection. The aim of this experimental animal study was to investigate the effect of mesna on prevention of intra-abdominal adhesion in rats. MATERIALS AND METHODS: Twenty-eight Wistar albino rats were used in the study. To create abdominal adhesion, cecum was abraded in all rats. No additional surgical procedure was performed other than adhesion in group 1 (only adhesion). In the other groups, rats were treated topically by administering 0.9% saline (group 2), 40 mg/kg mesna (group 3), and 400 mg/kg mesna (group 4). All rats were sacrificed on postoperative 21st day. Histopathological and macroscopic evaluations of adhesion formation were performed. RESULTS: Quantity of adhesion scores (P = 0.022), severity of adhesion scores (P = 0.041), total adhesion scores (P = 0.023), and histopathological adhesion grading scores (P < 0.001) were reduced by 400 mg/kg mesna. CONCLUSIONS: This is the first study for mesna on prevention of abdominal adhesion formation in rats. We concluded that dose-dependent reduction of adhesion was achieved by mesna. With future studies, topical administration of mesna during open abdominal surgeries may be used to prevent adhesion formation.

Enzymatic racemization of alcohols and amines: An approach for bi-enzymatic dynamic kinetic resolution.

Racemization is the key step to turn a kinetic resolution (KR), which suffers from the well-known drawback of being limited to a maximum yield of 50% with high enantiopurity, into a dynamic kinetic resolution (DKR) process. Enzyme-based racemization of enantiopure alcohols and amines has gained significant interest in recent years. This review covers recent advances in enzyme-based racemization approaches and their potential applications in bi-enzymatic DKR.

Induction of Rabies Virus Infection in Mice Brain may Up and Down Regulate Type II Interferon gamma via epigenetic modifications.

As feared and deadly human diseases globally, Rabies virus contrived mechanisms to escape early immune recognition via suppression of the interferon response. This study, preliminarily investigated whether Rabies virus employs epigenetic mechanism for the suppression of the interferon using the Challenge virus standard (CVS) strain and Nigerian street Rabies virus (SRV) strain. Mice were challenged with Rabies virus (RABV) infection, and presence of RABV antigen was assessed by direct fluorescent antibody test (DFAT). A real time quantitative Polymerase chain reaction (qRT-PCR) was used to measure the expression of type II interferon gamma (IFNG) and methylation specific quantitative PCR for methylation analysis of 1FNG promoter region. Accordingly, DNA methyltransferase (DNMT) and histone acetyltransferase (HAT) enzymes activities were determined. RABV antigen was detected in all infected samples. A statistically significant increase (p < 0.05) in mRNA level of IFNG was observed at the onset of the disease and a decrease as the disease progressed. An increase in methylation in the test groups from the control group was observed, with a fluctuation in methylation as the disease progressed. DNMT and HAT activities also agree with methylation as there was an observed increase activity in test group compared with control group. Similar fluctuation pattern was observed in both CVS and SRV groups as the disease progressed with HAT, being the most active proportionally. This study suggests that epigenetic modification via DNA methylation and histone acetylation may have played a role in the expression of type II interferon gamma in Rabies virus infection. Graphical abstract.

Epilepsy surgery in low- and middle-income countries: A scoping review.

BACKGROUND: Epilepsy surgery is an important treatment option for people with drug-resistant epilepsy. Surgical procedures for epilepsy are underutilized worldwide, but it is far worse in low- and middle-income countries (LMIC), and it is less clear as to what extent people with drug-resistant epilepsy receive such treatment at all. Here, we review the existing evidence for the availability and outcome of epilepsy surgery in LMIC and discuss some challenges and priority. METHODS: We used an accepted six-stage methodological framework for scoping reviews as a guide. We searched PubMed, Embase, Global Health Archives, Index Medicus for South East Asia Region (IMSEAR), Index Medicus for Eastern Mediterranean Region (IMEMR), Latin American & Caribbean Health Sciences Literature (LILACS), African Journal Online (AJOL), and African Index Medicus (AIM) to identify the relevant literature. RESULTS: We retrieved 148 articles on epilepsy surgery from 31 countries representing 22% of the 143 LMIC. Epilepsy surgery appears established in some of these centers in Asia and Latin America while some are in their embryonic stage reporting procedures in a small cohort performed mostly by motivated neurosurgeons. The commonest surgical procedure reported was temporal lobectomies. The postoperative seizure-free rates and quality of life (QOL) are comparable with those in the high-income countries (HIC). Some models have shown that epilepsy surgery can be performed within a resource-limited setting through collaboration with international partners and through the use of information and communications technology (ICT). The cost of surgery is a fraction of what is available in HIC. CONCLUSION: This review has demonstrated the availability of epilepsy surgery in a few LMIC. The information available is inadequate to make any reasonable conclusion of its existence as routine practice. Collaborations with international partners can provide an opportunity to bring high-quality academic training and technological transfer directly to surgeons working in these regions and should be encouraged.

Overall and cause-specific premature mortality in epilepsy: A systematic review.

BACKGROUND: We conducted a systematic review to ascertain the overall mortality and causes of premature mortality in epilepsy. METHODOLOGY: We searched PubMed and Embase to identify relevant articles reporting mortality in epilepsy. An assessment of the methodological quality and overall quality of evidence of the identified studies was done using appropriate checklists. We extracted data from these studies reporting measures of overall and cause-specific mortality in epilepsy. RESULTS: Sixty-three articles from fifty-six cohorts met the eligibility criteria, thirty-three population- or community-based and twenty-three hospital- or institutional-based studies. The majority of studies are from high-income countries (HIC). These studies reported overall excess mortality for people with epilepsy, with wide variability reported for population- or community-based studies and from low- and middle-income countries (LMIC). Twenty-seven articles from twenty-three cohorts reported measures of mortality for cause-specific mortality in epilepsy. People with epilepsy from HIC and LMIC have a higher risk of dying from various causes compared with the general population. Those in LMIC, however, have a particularly high chance of dying from external causes such as drowning and suicide. We observed a decrement over time in measures of overall and cause-specific mortality in cohorts. CONCLUSIONS: Despite the heterogeneity in reports, our findings support the suggestions that people with epilepsy have an increased risk of premature mortality from various causes. Further work is needed to elucidate the mechanisms, to determine biomarkers for predicting those at risk, and to understand the implications of counseling and preventive strategies.