A quality of care assessment for women of childbearing potential with epilepsy in Bhutan: An observational study.

BACKGROUND & OBJECTIVE: In lower-middle income countries such as Bhutan, the treatment gap for epilepsy is over 50% as compared to a treatment gap of less than 10% in high-income countries. We aim to analyze the quality of epilepsy care for women of childbearing potential in Bhutan using the Quality Indicators in Epilepsy Treatment (QUIET) tool, and to assess the usefulness of the tool's section for women with active epilepsy (WWE) in the Bhutanese setting. METHODS: A prospective convenience cohort was enrolled in Thimphu, Paro, Punakha, and Wangdue, Kingdom of Bhutan, in 2022. Bhutanese women of childbearing potential at the time of enrollment (18-44 years old) were evaluated for the diagnosis of active epilepsy and underwent a structured survey-based interview with Bhutanese staff. Participants were surveyed on their epilepsy, pregnancy, and antiseizure medicine (ASM) histories. The clinical history and quality of epilepsy care of adult WWE were assessed using a section of the QUIET tool for women, an instrument originally developed by the U.S. Department of Veterans Affairs to analyze the quality of epilepsy care for American adults. RESULTS: There were 82 Bhutanese WWE of childbearing potential, with mean age of 30.6 years at enrollment (range 18-44, standard deviation (SD) 6.6) and mean age of 20.3 years at epilepsy diagnosis (range 3-40, SD 8.0)). 39 % (n = 32) had a high school or above level of education, and 42 % (n = 34) were employed. 35 % (n = 29) reported a seizure within the prior week, and 88 % (n = 72) reported a seizure within the prior year. 49 % (n = 40) of participants experienced > 100 lifetime seizures. All but one participant took antiseizure medications (ASMs). At enrollment, participants presently took no (n = 1), one (n = 3), two (n = 37), three (n = 25), four (n = 11), or over five (n = 5) ASMs. The most common ASMs taken were levetiracetam (n = 40), phenytoin (n = 27), carbamazepine (n = 23), phenobarbital (n = 22), and sodium valproate (n = 20). 61 % of all WWE took folic acid. Of the 40 previously pregnant WWE, eight (20 %) took folic acid during any time of their pregnancy. 35 % (n = 29) used betel nut (doma, quid) and 53 % (n = 21) of pregnant WWE used betel nut during pregnancy. CONCLUSIONS: Based on data about WWE participants' ASM, supplement, and substance use, our study identified the high use of first generation ASMs (including valproate), frequently in polytherapy, and betel nut use as treatment gaps in women of childbearing potential age with active epilepsy in Bhutan. To address these gaps for locations such as Bhutan, we propose modifications to the QUIET tool's "Chronic Epilepsy Care for Women" section.

Riluzole-induced apoptosis in osteosarcoma is mediated through Yes-associated protein upon phosphorylation by c-Abl Kinase.

Our lab has previously demonstrated Riluzole to be an effective drug in inhibiting proliferation and inducing apoptosis in both human and mouse osteosarcoma. Yes-associated protein is a transcription co-activator, known to be involved in cell proliferation or apoptosis depending on its protein partner. In the present study we investigated the role of YAP in apoptosis in osteosarcoma, we hypothesized that YAP may be activated by Riluzole to induce apoptosis in osteosarcoma. By knocking down the expression of YAP, we have demonstrated that Riluzole failed to induce apoptosis in YAP deficient osteosarcoma cells. Riluzole caused translocation of YAP from the cytoplasm to the nucleus, indicating YAP's role in apoptosis. Both Riluzole-induced phosphorylation of YAP at tyrosine 357 and Riluzole-induced apoptosis were blocked by inhibitors of c-Abl kinase. In addition, knockdown of c-Abl kinase prevented Riluzole-induced apoptosis in LM7 cells. We further demonstrated that Riluzole promoted interaction between YAP and p73, while c-Abl kinase inhibitors abolished the interaction. Subsequently, we demonstrated that Riluzole enhanced activity of the Bax promoter in a luciferase reporter assay and enhanced YAP/p73 binding on endogenous Bax promoter in a ChIP assay. Our data supports a novel mechanism in which Riluzole activates c-Abl kinase to regulate pro-apoptotic activity of YAP in osteosarcoma.

Riluzole: A neuroprotective drug with potential as a novel anti­cancer agent (Review).

Riluzole, a glutamate release inhibitor, has been in use for the treatment of amyotrophic lateral sclerosis for over two decades since its approval by the Food and Drug Administration. Recently, riluzole has been evaluated in cancer cells and indicated to block cell proliferation and/or induce cell death. Riluzole has been proven effective as an anti­neoplastic drug in cancers of various tissue origins, including the skin, breast, pancreas, colon, liver, bone, brain, lung and nasopharynx. While cancer cells expressing glutamate receptors frequently respond to riluzole treatment, numerous types of cancer cell lacking glutamate receptors unexpectedly responded to riluzole treatment as well. Riluzole was demonstrated to interfere with glutamate secretion, growth signaling pathways, Ca2+ homeostasis, glutathione synthesis, reactive oxygen species generation and integrity of DNA, as well as autophagic and apoptotic pathways. Of note, riluzole is highly effective in inducing cell death in cisplatin­resistant lung cancer cells. Furthermore, riluzole pretreatment sensitizes glioma and melanoma to radiation therapy. In addition, in triple­negative breast cancer, colorectal cancer, melanoma and glioblastoma, riluzole has synergistic effects in combination with select drugs. In an effort to highlight the therapeutic potential of riluzole, the current study reviewed the effect and outcome of riluzole treatment on numerous cancer types investigated thus far. The mechanism of action and the various molecular pathways affected by riluzole are discussed.

Contraception, pregnancy, and peripartum experiences among women with epilepsy in Bhutan.

INTRODUCTION: Reports on the reproductive health of women with epilepsy (WWE) in low- and middle-income countries (LMICs) are limited. Bhutan is a lower income country with a high estimated prevalence of epilepsy and no out-of-pocket payment requirements for health visits or medications. METHODS: We developed a 10-category survey to interview WWE ages 20-59 years in the Kingdom of Bhutan to understand their contraceptive use and peripartum experiences. WWE were recruited from 2016-2017 from an existing epilepsy cohort and their reproductive health data were merged with epilepsy and socioeconomic data obtained from initial clinical evaluations performed between 2014 and 2016. RESULTS: Of the 134 WWE eligible for the study, 94 were reachable and there was 1 refusal to participate (response rate 99% among reachable WWE; 69% of all WWE in the cohort). Of the 93 WWE (median age 27 years, range 20-52), 50 (54%) reported prior pregnancies. Of the entire cohort, 55 women responded on contraception: 26 (47%) WWE had never used contraception in their lifetime. Of the 29 WWE who had ever used contraception, the most commonly reported form was male condoms (14/29, 48%), followed by depot medroxyprogesterone acetate injections (13/29, 45%), and intrauterine devices (5/29, 17%). Sixty-three percent of WWE recalled receiving information on family planning (31 of 49). Of the 50 WWE with prior pregnancies, 37 of 46 (80%) used folic acid; 6 WWE reported commencing it in the first trimester while 29 WWE began supplementation in the second trimester. Primary school education or higher was associated with folic acid supplementation during pregnancy (26/29 vs. 11/17, p=0.040). Epilepsy affected at least one of the pregnancies in 38 of the cases (76%) with an average of 2.3 pregnancies per woman). There was a total of 86 pregnancies and an average inter-pregnancy interval of 3.5 years. Ninety-five percent of women attended prenatal care (36/38), 22% had at least one miscarriage (8/37), 14% had at least one pre-term delivery (5/36), and 21% had Caesarean sections (8/38). Seventeen of 38 (45%) of WWE had seizures during pregnancy. A majority of WWE (97%, 37 of 38) with a prior pregnancy reported breastfeeding their infant. CONCLUSIONS: Nearly half of Bhutanese WWE did not use contraception; among those who used it, male condoms were most common but 11% were at risk of potential drug-drug interactions between oral contraception and enzyme-inducing antiepileptic drugs. Bhutanese WWE had a high rate of prenatal visits. Folic acid was prescribed in most pregnant WWE but the majority began supplementation in the second trimester. The number of pregnancies in WWE in Bhutan (2.3 per woman) was comparable to the number of children per women in Bhutan (2.3). Breastfeeding was practiced almost universally. Points of intervention may include pre-conception initiation of folic acid, optimization of dosing of AEDs with contraceptives, guidelines for peripartum seizure treatment, and establishment of a prospective registry for WWE and their offspring.