Brain network changes after the first seizure: an insight into medication response?

After a first epileptic seizure, anti-seizure medications (ASMs) can change the likelihood of having a further event. This prospective study aimed to quantify brain network changes associated with taking ASM monotherapy. We applied graph theoretical network analysis to longitudinal resting-state functional MRI (fMRI) data from 28 participants who had recently experienced their first seizure. Participants were imaged before and during long-term ASM therapy, with a mean inter-scan interval of 6.9 months. After commencing ASM, we observed an increase in the clustering coefficient and a decrease in network path length. Brain changes after ASM treatment were most prominent in the superior frontoparietal and inferior fronto-temporal regions. Participants with recurrent seizures display the most pronounced network changes after ASM treatment. This study shows changes in brain network function after ASM administration, particularly in participants with recurrent seizures. Larger studies that ideally include control cohorts are required to understand further the connection between ASM-related brain network changes and longer-term seizure status.

Expression of Semaphorin3E/PlexinD1 in Human airway smooth muscle cells of COPD patients.

Semaphorin-3E (sema3E) is a member of axon guidance proteins that have emerged recently as essential regulators of cell migration and proliferation. It binds to plexinD1 with high affinity and is expressed in different cell types, including immune, cancer, and epithelial cells. Recent work in our lab has revealed a critical immunoregulatory role of sema3E in experimental allergic asthma; however, its role in COPD remains unclear. This study aimed to investigate the expression of sema3E and its receptor, plexinD1, in the airways of COPD patients and whether sema3E regulates airway smooth muscle (ASM) cell proliferation, a key feature of airway remodelling in COPD. We first demonstrate that human ASM cells obtained from COPD express sema3E and plexinD1 at both mRNA and protein levels. Also, bronchial sections from COPD patients displayed immunoreactivity of sema3E and its receptor plexinD1, suggestive of functional contribution of sema3E in airway remodeling. In contrast to ASM cells from healthy donors, sema3E did not inhibit the platelet-derived growth factor (PDGF) induced cell proliferation in ASM cells of COPD patients that were consistent with the binding of endogenous sema3E to its receptors on the cell surface and the expression and release of p61KDa-sema3E isoform. Our results support the sema3E-plexinD1 axis involvement in COPD airway smooth muscle remodelling.

Intravenous levetiracetam versus intravenous phenytoin as second Line treatment in pediatric convulsive status epilepticus- open label randomized controlled trial.

Background: Benzodiazepines (BZDs) are recommended as the initial therapy of choice in status epilepticus (SE). The age-old second-line treatment for BZD refractory convulsive SE is intravenous phenytoin (PHT) based predominantly on nonrandomized clinical trial data. We did this study to compare the efficacy and safety of intravenous levetiracetam (LEV) and PHT as second-line antiseizure medication (ASM) for children with SE. Methodology: A prospective, randomized controlled, open-label study was conducted in children 3 months to 15 years of age with SE in Pediatric Emergency. A total of 41 children were randomly allocated to either group 1 (Levetiracetam) or group 2 (Phenytoin) on the basis of computer-generated randomization. Children who were already on antiseizure medications, either LEV or PHT, or receiving these drugs outside for SE were excluded. Data analysis was done by SPSS V25. Results: The most common age group presenting with SE was 12 months to 5 years. Clinical cessation of seizure 5 minutes after the completion of drugs was 85% (17/20) in Levetiracetam group and 90.5% (19/21) in Phenytoin group. Recurrence of seizure within 24 hours was noted in 35% (7/20) in Levetiracetam group and 38.1% (8/21) in Phenytoin group. There was no statistically significant difference noted in both the groups in terms of seizure cessation, adverse events, and recurrence. Conclusion: The efficacy and safety of LEV were found to be comparable to those of PHT in controlling seizure as second-line ASM in SE.

Anti-seizure medication prescription preferences: a Moroccan multicenter study.

Background: The management of epilepsy is mainly based on antiseizure medications (ASMs). More than 20 ASMs have been introduced in clinical practice, providing a multitude of prescription choices. To date, there are no published data on the trends in ASMs prescriptions in Morocco. Therefore, we conducted a survey among practicing neurologists in seven tertiary referral hospitals in Morocco to study the current ASMs prescription preferences and their modifying factors. Methods: Our descriptive and analytical cross-sectional study was based on a survey sent between January and April 2022 to neurologists practicing in seven tertiary referral hospitals in Morocco. Information regarding the prescription of ASMs was collected using an exploitation form and analyzed using the SPSS version 13 software. Results: Based on questionnaire responses, our results showed that Valproic acid (96.3%) and Lamotrigine (59.8%) were the two most prescribed ASMs for generalized seizure types. For focal seizure types, Carbamazepine (98.8%) and Levetiracetam (34.1%) were the most commonly prescribed drugs, whereas for combined focal and generalized seizure types, the combination of Valproic acid and Carbamazepine (38.55%) was the most prescribed. Phenobarbital was the most commonly prescribed ASM for status epilepticus (40.2%). These prescription preferences were mainly due to seizure types, cost, health insurance coverage, years of experience, and additional epileptology training (p < 0.05). Conclusion: Our results show a shift in the prescription of ASMs in Morocco. Similar to many other countries, valproic acid and carbamazepine are considered the first-line treatments for generalized and focal seizure types. Some factors remain as major challenges in enhancing epilepsy management in Morocco.

Epilepsy and Anti-Seizure Medications: Secret Agents for Endocrine Disruption.

There is a reciprocal relationship between epilepsy and reproductive endocrine disorders. Seizures and anti-seizure medications (ASMs) can contribute to reproductive and endocrine dysfunction and reproductive dysfunction may exacerbate seizures. Epilepsy via neuroendocrine mechanisms affects the hypothalamic-pituitary-ovarian (HPO) axis, disrupting the regulation of gonadotropin secretion, and resulting in dystrophic effects on the ovaries and early menopause. Anti-seizure medications have endocrine-related side effects on sexual function and bone health. Long-term use of ASMs may result in menstrual irregularities, sexual dysfunction, anovulatory cycles, polycystic ovaries, and reduced fertility. Some ASMs also interfere with bone metabolism. Epilepsy patients treated with ASMs are at risk for bone loss and fractures. This article explores the endocrine and hormonal effects of seizures and ASMs.

Brain Region-Specific Expression Levels of Synuclein Genes in an Acid Sphingomyelinase Knockout Mouse Model: Correlation with Depression-/Anxiety-Like Behavior and Locomotor Activity in the Absence of Genotypic Variation.

Accumulating evidence suggests an involvement of sphingolipids, vital components of cell membranes and regulators of cellular processes, in the pathophysiology of both Parkinson's disease and major depressive disorder, indicating a potential common pathway in these neuropsychiatric conditions. Based on this interaction of sphingolipids and synuclein proteins, we explored the gene expression patterns of α-, ß-, and γ-synuclein in a knockout mouse model deficient for acid sphingomyelinase (ASM), an enzyme catalyzing the hydrolysis of sphingomyelin to ceramide, and studied associations with behavioral parameters. Normalized Snca, Sncb, and Sncg gene expression was determined by quantitative PCR in twelve brain regions of sex-mixed homozygous (ASM-/-, n = 7) and heterozygous (ASM+/-, n = 7) ASM-deficient mice, along with wild-type controls (ASM+/+, n = 5). The expression of all three synuclein genes was brain region-specific but independent of ASM genotype, with ß-synuclein showing overall higher levels and the least variation. Moreover, we discovered correlations of gene expression levels between brain regions and depression- and anxiety-like behavior and locomotor activity, such as a positive association between Snca mRNA levels and locomotion. Our results suggest that the analysis of synuclein genes could be valuable in identifying biomarkers and comprehending the common pathological mechanisms underlying various neuropsychiatric disorders.

Lamotrigine vs levetiracetam in female patients of childbearing age with juvenile absence epilepsy: A Bayesian reanalysis.

OBJECTIVE: Women of childbearing age with juvenile absence epilepsy (JAE) face treatment challenges due to limited access to safe and effective anti-seizure medications (ASMs). In a previous study we compared the effectiveness of levetiracetam (LEV) and lamotrigine (LTG) in women with idiopathic generalized epilepsy (IGE), highlighting a superiority of LEV in juvenile myoclonic epilepsy. In this study, we specifically reanalyzed, through a Bayesian approach and by expanding the previously published cohort, the comparative effectiveness of these ASMs as initial monotherapy in JAE. METHODS: We conducted a multicenter, retrospective, comparative effectiveness study on women of childbearing age diagnosed with JAE and prescribed LEV or LTG as the initial ASM. Inverse probability treatment weighting (IPTW) Bayesian Cox proportional hazard models were employed to evaluate treatment failure (TF) due to ineffectiveness and ASM retention. The patients' center of provenance and year of prescription were considered as random effect factors. Posterior probabilities and relative log-risk distribution were computed, and the distribution of posterior draws was analyzed to assess the evidence supporting LTG superiority over LEV. RESULTS: Of 123 patients, those treated with LTG (n = 67) demonstrated lower TF and higher ASM retention than those treated with LEV (n = 56), with the IPTW-weighted Bayesian Cox proportional hazards model showing a 99.2% posterior probability of LTG being superior on TF and a 99.5% probability on ASM retention. Additional analyses on ≥50% and ≥75% seizure reduction through IPTW-weighted Bayesian logistic regression largely confirmed these findings, whereas the two ASMs did not show evident differences in terms of seizure freedom. The two ASMs showed comparable safety profiles, with only a minority of patients discontinuing treatment due to side effects. SIGNIFICANCE: Bayesian reanalysis supports LTG as first-line monotherapy for JAE in women of childbearing age, emphasizing the importance of individualized treatment strategies in women with IGE. This study underscores the value of Bayesian methods in refining clinical research and treatment decisions.

Effect of Antiseizure Medication on the Salience Network in Patients with Epilepsy with Generalized Tonic-Clonic Seizures Alone.

This study aimed to investigate the effects of antiepileptic drugs on salience network regions in patients with epilepsy with generalized tonic-clonic seizures alone (EGTCSa). A retrospective observational case-control study was performed on 40 patients diagnosed with epilepsy with EGTCSa and 40 healthy age-matched controls. In LORETA, a voxel-by-voxel analysis between regions from the salience network was performed for both hemispheres, specifically between the anterior cingulate (BA 32 and BA 24) and the sublobar insula (BA 13). Subsequently, a Wilcoxon rank-sum test (the Mann-Whitney U test) was conducted for the equality of medians in the transformation matrix. A comparison was then made between each region of interest as defined by the salience network and the controls. Marked differences were found in the brain regions assessed in patients with EGTCSa treated with valproic acid and carbamazepine compared to the control group; few differences in patients treated with levetiracetam; and no difference was found in the group without treatment compared with those in the control group. These results suggest that ASMs can influence cognitive processes, which provide novel insights toward understanding the neural mechanisms underlying the effects of ASMs administration.

Bromide: the good, the bad, and the ugly of the oldest antiseizure medication.

Bromide is the first effective antiseizure medication used in human medicine since the XIX century. Initially met with skepticism, bromide quickly gained enthusiasm within the medical field until being largely replaced by newer antiseizure medications with significantly fewer adverse effects in people. In veterinary medicine, bromide continues to be used in the management of epileptic patients for over 30 years, yet adverse effects can impact owners and patients alike. We sought to provide the general practitioner and veterinary neurologist with insightful information on both the positive and negative attributes of bromide, explore factors that may influence its desirability as an antiseizure medication in specific veterinary cases and elucidate its current role in modern epilepsy treatment for veterinary patients. It's also our endeavor to discuss the current use as an alternative or add-on with other known antiseizure medications and potential future studies that might enhance our understanding and use of this medication.

Comparative analysis of Sarcopenia in hospitalized elderly: exploring the impact of liver cirrhosis.

The progressive aging of the population has led to a rise in geriatric pathologies, with sarcopenia, characterized by muscle mass and function loss, becoming a crucial prognostic indicator. This study investigates sarcopenia in elderly hospitalized patients with advanced chronic liver disease (cirrhotic) and non-liver disease patients, comparing their prevalence and exploring correlations with anthropometric and biochemical factors. The cohort of 115 patients, including 50 cirrhotic and 65 non-cirrhotic individuals, exhibited significant comorbidities and a mean age of 78.4 years. Cirrhotic patients presented distinct laboratory parameters indicating liver damage. Applying European Working Group on Sarcopenia in Older People criteria, probable sarcopenia prevalence was similar in cirrhotic (62%) and non-cirrhotic (63%) patients. Stratifying probable sarcopenia into confirmed sarcopenia and dynapenia revealed no significant differences between populations. Correlation analyses demonstrated positive associations between Appendicular Skeletal Muscle Mass (ASM) and anthropometric parameters, malnutrition risk, and grip strength. In cirrhotic patients, muscle mass inversely correlated with liver damage. Odds ratio analysis highlighted the Mini Nutritional Assesment's (MNA) significant predictive capability for sarcopenia. ROC curve analysis affirmed MNA and biochemical markers' combined use, such as transferrin, albumin, total cholesterol, lymphocyte count and C-reactive protein as a strong predictor. Despite limitations, such as a small sample size, this study underscores the significance of thorough sarcopenia screening in elderly hospitalized patients, especially those with cirrhosis. Indeed, individuals with end-stage liver disease are particularly susceptible to sarcopenia. A more personalized approach utilizing tools like MNA and biochemical markers could prove beneficial. Further research is warranted to validate these findings and inform clinical interventions.

Characterization of anti-seizure medication reduction and discontinuation rates following epilepsy surgery.

OBJECTIVE: Many patients pursue epilepsy surgery with the hope of reducing or stopping anti-seizure medications (ASMs), in addition to reducing their seizure frequency and severity. While ASM decrease is primarily driven by surgical outcomes and patient preferences, preoperative estimates of meaningful ASM reduction or discontinuation are uncertain, especially when accounting for the various forking paths possible following intracranial EEG (iEEG), including resection, neuromodulation, or even the absence of further surgery. Here, we characterize in detail the ASM reduction in a large cohort of patients who underwent iEEG, facilitating proactive, early counseling for a complicated cohort considering surgical treatment. METHODS: We identified a multi-institutional cohort of patients who underwent iEEG between 2001 and 2022, with a minimum of two years follow-up. The total number of ASMs prescribed immediately prior to surgery, choice of investigation modality, and subsequent surgical treatment were extracted for each patient. Primary endpoints included decreases in ASM counts from preoperative baseline to various follow-up intervals. RESULTS: A total of 284 patients were followed for a median of 6.0 (range 2,22) years after iEEG surgery. Patients undergoing resection saw an average reduction of âˆ¼ 0.5 ASMs. Patients undergoing neuromodulation saw no decrease and trended towards requiring increased ASM usage during long-term follow-up. Only patients undergoing resection were likely to completely discontinue all ASMs, with an increasing probability over time approaching âˆ¼ 10 %. Up to half of resection patients saw ASM decreases, which was largely stable during long-term follow-up, whereas only a quarter of neuromodulation patients saw a reduction, though their ASM reduction decreased over time. CONCLUSIONS: With the increasing use of stereotactic EEG and non-curative neuromodulation procedures, realistic estimates of ASM reduction and discontinuation should be considered preoperatively. Almost half of patients undergoing resective surgery can expect to reduce their ASMs, though only a tenth can expect to discontinue ASMs completely. If reduction is not seen early, it likely does not occur later during long-term follow-up. Less than a third of patients undergoing neuromodulation can expect ASM reduction, and instead most may require increased usage during long-term follow-up.

Uses of antiseizure medication among pregnant women with epilepsy and risk of adverse obstetric outcomes: A group-based trajectory analysis.

OBJECTIVE: This study was undertaken to examine the association between different patterns of antiseizure medication (ASM) use during pregnancy and adverse obstetric outcomes (preterm birth, low birth weight [LBW], and small for gestational age [SGA]). METHODS: This retrospective cohort study used the Birth Certificate Application and National Health Insurance data in Taiwan (January 1, 2004 through December 31, 2018). We retrieved weekly ASM among pregnant women with epilepsy who were prepregnancy chronic users and used group-based trajectory modeling to identify distinct patterns of use. Logistic regressions were adopted to examine the association between patterns of ASM use and risk of preterm birth, LBW, and SGA. In addition, we revealed postnatal ASM utilization pattern among these prepregnancy chronic users as an exploratory study. RESULTS: Of 2175 pregnant women with epilepsy, we identified four patterns of ASM use during pregnancy: frequent and continuous (64.87%), frequent but discontinuous (7.08%), intermittent (19.72%), and intermittent and discontinuous users (8.32%). Compared to frequent and continuous users, the adjusted odds ratios for preterm birth in frequent but discontinuous, intermittent, and intermittent and discontinuous users were .83 (95% confidence interval [CI] = .47-1.48), .71 (95% CI = .47-1.05), and .88 (95% CI = .52-1.49), respectively. Similar results were observed for LBW and SGA. In the exploratory study, we found that most of our study subjects maintained the same patterns before and after delivery. SIGNIFICANCE: After considering duration and timing of exposure, our study did not find an association between four distinct patterns of ASM use and adverse obstetric outcomes among women with epilepsy. The findings suggested that optimal seizure control could be received for pregnant women with epilepsy after evaluating the risks and benefits.

ß-Tocotrienol Decreases PDGF-BB-Induced Proliferation and Migration of Human Airway Smooth Muscle Cells by Inhibiting RhoA and Reducing ROS Production.

BACKGROUND: Tocotrienols exhibit antioxidant and anti-inflammatory activities. RhoA, a small GTPase protein, plays a crucial role in regulating contractility in airway smooth muscle (ASM). Previous studies have demonstrated that γ-tocotrienols reduce ASM proliferation and migration by inhibiting the activation of RhoA. In this present study, we investigate the effect of another vitamin E isoform, ß-tocotrienols, on human ASM cell proliferation and migration stimulated by platelet-derived growth factor-BB (PDGF-BB). METHODS: Human ASM cells were pre-treated with ß-tocotrienol prior to being stimulated with PDGF-BB to induce ASM cell proliferation and migration. The proliferation and migration of PDGF-BB-induced human ASM cells were assessed using colorimetric and transwell migration assays. The intracellular ROS assay kit was employed to quantify reactive oxygen species (ROS) in human ASM cells. Additionally, we explored the effect of ß-tocotrienols on the signaling pathways involved in PDGF-BB-induced ASM proliferation and migration. RESULTS: ß-tocotrienol inhibited PDGF-BB-induced ASM cell proliferation and migration by reducing RhoA activation and ROS production. However, in this present study, ß-tocotrienol did not affect the signaling pathways associated with cyclin D1, phosphorylated Akt1, and ERK1/2. CONCLUSIONS: In conclusion, the inhibition of RhoA activation and ROS production by ß-tocotrienol, resulting in the reduction in human ASM proliferation and migration, suggests its potential as a treatment for asthma airway remodeling.

Effluent quality improvement in sequencing batch reactor-based wastewater treatment processes using advanced control strategies.

The treatment of wastewater is highly challenging due to large fluctuations in flowrates, pollutants, and variable influent water compositions. A sequencing batch reactor (SBR) and modified SBR cycle-step-feed process (SSBR) configuration are studied in this work to effectively treat municipal wastewater while simultaneously removing nitrogen and phosphorus. To control the amount of dissolved oxygen in an SBR, three axiomatic control strategies (proportional integral (PI), fractional proportional integral (FPI), and fuzzy logic controllers) are presented. Relevant control algorithms have been designed using plant data with the models of SBR and SSBR based on ASM2d framework. On comparison, FPI showed a significant reduction in nutrient levels and added an improvement in effluent quality. The overall effluent quality is improved by 0.86% in FPI in comparison with PI controller. The SSBR, which was improved by precisely optimizing nutrient supply and aeration, establishes a delicate equilibrium. This refined method reduces oxygen requirements while reliably sustaining important biological functions. Focusing solely on the FPI controller's performance in terms of total air volume consumption, the step-feed SBR mechanism achieves an excellent 11.04% reduction in consumption.

Evaluating bexicaserin for the treatment of developmental epileptic encephalopathies.

INTRODUCTION: Developmental epileptic encephalopathies (DEEs) pose significant challenges due to their refractory nature and limited treatment options. Despite advancements in genetic understanding, effective therapies targeting underlying pathophysiology are lacking. Serotoninergic dysfunction has been implicated in epilepsy, sparking interest in serotonin as a therapeutic target. AREA COVERED: This article explores the potential of bexicaserin, a selective 5-HT2C receptor agonist, as an adjunctive antiseizure medication in DEEs. Bexicaserin is thought to modulate GABAergic neurotransmission, suppressing central hyperexcitability. Preclinical studies demonstrate its efficacy across various seizure models. Clinical trials, including the Pacific Study, reveal promising results in reducing motor seizures. However, challenges such as adverse effects and treatment discontinuation underscore the need for further investigation. EXPERT OPINION: The efficacy of 5-HT2C serotoninergic agonists, validated in preclinical and clinical studies, highlights serotonin's role in DEEs. Bexicaserin offers new therapeutic possibilities, potentially synergizing with existing antiseizure medications. Polypharmacotherapy, targeting distinct pathways, may enhance therapeutic outcomes. Monitoring pharmacological interactions and addressing central nervous system comorbidities are crucial for optimizing treatment strategies. Further research is needed to elucidate bexicaserin's mechanisms and potential antiepileptogenic effects.

Status epilepticus management in patients with brain tumors. A cohort study.

PURPOSE: Status epilepticus (SE) represents a neurological emergency with significant morbidity and mortality. SE in patients with primary brain tumors received only limited attention to date; detailed analysis of treatment flow is lacking, especially as compared to other SE causes. This study aims to describe the frequency and treatment flow of tumor-related SE and compare it to other SE etiologies. METHODS: Retrospective cohort study based on an institutional SE registry (SERCH) comprising adult SE (excluding post-anoxic causes), treated between January 2013 and December 2022, comparing SE management, frequency of refractory SE, and clinical outcome, among four patients' groups stratified by SE etiology: Non-neoplastic, Gliomas, Brain metastases, Other brain tumors. RESULTS: We analyzed 961 episodes in 831 patients (Non-neoplastic: 649, Gliomas: 85, Metastases: 77, Other brain tumors: 20). Although tumor-patients presented more often with focal episodes and less consciousness impairment than non-neoplastic patients, administration of benzodiazepines as first-line treatment (>75% across all groups), and utilization of second-line ASM were similar across groups. Treatment adequacy was marginally higher in glioma patients compared to the non-neoplastic population (p: 0.049), while refractory SE was comparable in all groups (p: 0.269). No significant differences in clinical outcomes were observed (mortality: non-neoplastic (89/649, 13.7%), glioma (8/85, 9.4%), metastases (14/77, 18.2%), other tumors (5/20, 25.0%), p: 0.198; non-neoplastic vs. glioma, p: 0.271) CONCLUSION: Tumor-associated SE represents 1/5 of all SE episodes, and is managed similarly to other SE causes. Treatment responsiveness and short-term clinical outcomes also exhibit comparable results.

PYRIDOXINE-dependent epilepsy (PDE): An observational study of neonatal cases on the role of pyridoxine in patients treated with standard anti-seizure medications.

BACKGROUND: The main objective of this study was to evaluate the neurological consequences of delayed pyridoxine administration in patients diagnosed with Pyridoxin Dependent Epilepsies (PDE). MATERIALS AND METHODS: We reviewed 29 articles, comprising 52 genetically diagnosed PDE cases, ensuring data homogeneity. Three additional cases were included from the General Pediatric Operative Unit of San Marco Hospital. Data collection considered factors like age at the first seizure's onset, EEG reports, genetic analyses, and more. Based on the response to first-line antiseizure medications, patients were categorized into four distinct groups. Follow-up evaluations employed various scales to ascertain neurological, cognitive, and psychomotor developments. RESULTS: Our study includes 55 patients (28 males and 27 females), among whom 15 were excluded for the lack of follow-up data. 21 patients were categorized as "Responder with Relapse", 11 as "Resistant", 6 as "Pyridoxine First Approach", and 2 as "Responders". The neurological outcome revealed 37,5 % with no neurological effects, 37,5 % showed complications in two developmental areas, 15 % in one, and 10 % in all areas. The statistical analysis highlighted a positive correlation between the time elapsed from the administration of pyridoxine after the first seizure and worse neurological outcomes. On the other hand, a significant association was found between an extended latency period (that is, the time that elapsed between the onset of the first seizure and its recurrence) and worse neurological outcomes in patients who received an unfavorable score on the neurological evaluation noted in a subsequent follow-up. CONCLUSIONS: The study highlights the importance of early recognition and intervention in PDE. Existing medical protocols frequently overlook the timely diagnosis of PDE. Immediate administration of pyridoxine, guided by a swift diagnosis in the presence of typical symptoms, might improve long-term neurological outcomes, and further studies should evaluate the outcome of PDE neonates promptly treated with Pyridoxine.

The social and environmental responsibility of informal artisanal and small-scale mining in Ghana: An Akan philosophical perspective.

Informal artisanal and small-scale mining (ASM) continues to grow globally, raising both challenges and opportunities in terms of economic, social, and environmental impacts. The ASM literature explores the formalization and transfer of corporate social responsibility (CSR) practices from larger firms as the pathway to minimize negative impacts and maximize benefits. But we know very little about environmental and social responsibilities of informal mining operations (and informal economy actors in general, who are often portrayed as devoid of these responsibilities). This paper aims to theorize and empirically explore principles and practices of social and environmental responsibility in informal mining. We combine elements of relational stakeholder theory with Ghana's Akan philosophy to develop our theoretical framework. Through a qualitative research process involving thematic analysis - of field notes from field observations and 81 interviews with ASM miners, community leaders/residents and executive members of Small-Scale Mining Association-Prestea Branch in Ghana - and pattern-matching technique, we find that: a) informal ASM is culturally and relationally motivated to be socially and environmentally responsible, b) there is a model of informal social and environmental responsibility (ISER) that is characterized by commonality, solidarity, tradition, and human-nature interdependencies, and c) social and environmental responsibilities are interpreted in a distinctive, non-Western way and comply with two main informal norms: gifting for social responsibilities and taboos for environmental responsibility. We conclude by suggesting that governments should collaborate with traditional authorities to promote ISER practices as cultural norms.

Genetic heterogeneity in epilepsy and comorbidities: insights from Pakistani families.

BACKGROUND: Epilepsy, a challenging neurological condition, is often present with comorbidities that significantly impact diagnosis and management. In the Pakistani population, where financial limitations and geographical challenges hinder access to advanced diagnostic methods, understanding the genetic underpinnings of epilepsy and its associated conditions becomes crucial. METHODS: This study investigated four distinct Pakistani families, each presenting with epilepsy and a spectrum of comorbidities, using a combination of whole exome sequencing (WES) and Sanger sequencing. The epileptic patients were prescribed multiple antiseizure medications (ASMs), yet their seizures persist, indicating the challenging nature of ASM-resistant epilepsy. RESULTS: Identified genetic variants contributed to a diverse range of clinical phenotypes. In the family 1, which presented with epilepsy, developmental delay (DD), sleep disturbance, and aggressive behavior, a homozygous splice site variant, c.1339-6 C > T, in the COL18A1 gene was detected. The family 2 exhibited epilepsy, intellectual disability (ID), DD, and anxiety phenotypes, a homozygous missense variant, c.344T > A (p. Val115Glu), in the UFSP2 gene was identified. In family 3, which displayed epilepsy, ataxia, ID, DD, and speech impediment, a novel homozygous frameshift variant, c.1926_1941del (p. Tyr643MetfsX2), in the ZFYVE26 gene was found. Lastly, family 4 was presented with epilepsy, ID, DD, deafness, drooling, speech impediment, hypotonia, and a weak cry. A homozygous missense variant, c.1208 C > A (p. Ala403Glu), in the ATP13A2 gene was identified. CONCLUSION: This study highlights the genetic heterogeneity in ASM-resistant epilepsy and comorbidities among Pakistani families, emphasizing the importance of genotype-phenotype correlation and the necessity for expanded genetic testing in complex clinical cases.

Antiseizure medication and SUDEP - a need for unifying methodology in research.

The risk of sudden unexpected death in epilepsy (SUDEP) increases with the frequency of generalized tonic-clonic seizures. Carbamazepine (CBZ) and lamotrigine (LTG) have been suggested to increase the risk. However, the prevailing viewpoint is that the choice of antiseizure medication (ASM) does not influence the occurrence. We have explored the approach to addressing this question in relevant studies to evaluate the validity of the conclusions reached. A systematic search was performed in PubMed to identify all controlled studies on SUDEP risk in individuals on CBZ or LTG. Studies were categorized according to whether idiopathic generalized epilepsy (IGE) or females were considered separately, and whether data were adjusted for seizure frequency. Eight studies on CBZ and six studies on LTG were identified. For CBZ, one study showed a significantly increased risk of SUDEP without adjustment for seizure frequency. Another study found significantly increased risk after statistical adjustment for seizure frequency and one study found increased risk with high blood levels. Five other studies found no increase in risk. For LTG, one study showed a significantly increased risk in patients with IGE as opposed to focal epilepsy, and another study showed a significantly increased risk in females. None of the subsequent studies on LTG and none of the studies on CBZ considered females with IGE separately. Taken together the available studies suggest that LTG, and possibly CBZ, may increase occurrence of SUDEP when used in females with IGE. Additional studies with sub-group analysis of females with IGE are needed.