Cannabis-based magistral formulation is highly effective as an adjuvant treatment in drug-resistant focal epilepsy in adult patients: an open-label prospective cohort study.

INTRODUCTION: The safety and efficacy of a formulation high in cannabidiol (CBD) and low in ∆9-tetrahydrocannabinol (THC) to treat drug-resistant epilepsy have been examined previously in children, but not in adult population. The aim of this study was to evaluate whether CBD-rich oil, as an add-on treatment to conventional antiepileptic drugs, was effective, safe, and well-tolerated in adults with drug-resistant focal epilepsy (DRFE). METHODS: An open-label, prospective cohort, single-center in adult patients with DRFE, were receiving stable doses of antiepileptic drugs (AEDs). A cannabis based-magistral formulation (CBMF) (100 mg/ml CBD and THC <1.9 mg/ml) was administrated 0.1 ml sublingually every 12 hours, up-titrated weekly. The primary outcome was to establish a reduction in seizures frequency >50% at 12 weeks. Adverse-drug reactions monitoring was done. p-value <0.05 was statistically significant. RESULTS: Between August 2020 and July 2022, 44 (38.6%) patients completed >3 months of follow-up. The median daily dose of CBD was 200 mg, that of THC was 4 mg, and that of CBD per kilogram of weight was 3.7 mg. The median number of seizures per month before CBD treatment was 11, and after CBD treatment was 2.5 (p<0.001). A reduction in seizures >50% at 12 week was achieved in 79.5% of the patients. The median percentage change in seizure frequency per month was 84.1% at 12 weeks. Five patients reported any adverse-drug reactions. CONCLUSION: The CBMF is a highly effective and safety therapy to treat adult patients with DRFE. The reduction in seizures frequency is maintained over time.

Dethreading of Tetraalkylsuccinamide-Based [2]Rotaxanes for Preparing Benzylic Amide Macrocycles.

The dethreading of a series of succinamide-based [2]rotaxanes bearing benzylic amide macrocycles is reported herein. These transformations proceeded quantitatively either under flash vacuum pyrolysis, conventional heating, or microwave irradiation. Studying the size complementarity of the stoppers at the ends of the thread and the cavity of the macrocycle allowed us to set up the best substituents for implementing the extrusion of the thread from the interlocked precursors. A variety of (1)H NMR kinetic experiments were carried out in order to evaluate the rate constants of the dethreading process, the half-life times of the rotaxanes, and the influence of temperature and solvents on these processes. The use of dibutylamino groups as stoppers yielded the rotaxane precursor in a reasonable yield and allowed the quantitative deslipping of the rotaxane. The overall process, including the rotaxane formation and its further dethreading, has been exploited for preparing benzylic amide macrocycles enhancing, in most cases, the results of the classical (2 + 2) condensation and other reported stepwise syntheses. The kinetics of the dethreading process is fairly sensitive to the electronic effects of the substituents on the isophthalamide unit or to the electronic nature of the pyridine rings through a conformational equilibrium expanding or contracting the cavity of the interlocked precursor.

Cost-Effectiveness Analysis Comparing QuantiFERON-TB Gold Plus Test and Tuberculin Skin Test for the Diagnosis of Latent Tuberculosis Infection in Immunocompetent Subjects in Colombia.

OBJECTIVES: To determine the cost-effectiveness of the QuantiFERON-TB Gold Plus (QFT-Plus) test versus the tuberculin skin test in diagnosing latent tuberculosis infection in immunocompetent subjects in the context of the Colombian healthcare system. METHODS: A hypothetical cohort of 2000 immunocompetent adults vaccinated with Bacillus Calmette-Guérin at birth who are asymptomatic for tuberculosis disease was simulated and included in a decision tree over a horizon of <1 year. The direct healthcare costs related to tests, antituberculosis treatment, and medical care were considered, and diagnostic performance was used as a measure of effectiveness. The incremental cost-effectiveness ratio (ICER) was estimated, and univariate deterministic and probabilistic sensitivity analyses were carried out using 5000 simulations. The currency was the US dollar for the year 2022, with a cost-effectiveness threshold of $6666 USD (1 gross domestic product per capita for 2022). RESULTS: QFT-Plus was cost-effective with an ICER of $5687 USD for each correctly diagnosed case relative to a threshold of $6666 USD. In the deterministic analysis, QFT-Plus was cost-effective in half of the proposed scenarios. The variable that most affected the ICER was the prevalence of latent tuberculosis and test sensitivities. In the probabilistic analysis, QFT-Plus was cost-effective in 54.74% of the simulated scenarios, and tuberculin skin test was dominant in 13.84%. CONCLUSIONS: The study provides evidence of the cost-effectiveness of QFT-Plus compared with the tuberculin skin test in diagnosing latent tuberculosis infection in immunocompetent adults in the Colombian context.

Cost-Utility Analysis Comparing Ocrelizumab Versus Rituximab in the Treatment of Relapsing-Remitting Multiple Sclerosis: The Colombian Perspective.

OBJECTIVES: This study aimed to determine the cost-utility of ocrelizumab versus rituximab in patients with RRMS, from the perspective of the Colombian healthcare system. METHODOLOGY: Cost-utility study based on a Markov model, with a 50-year horizon and payer perspective. The currency was the US dollar for the year 2019, with a cost-effectiveness threshold of $5180 defined for Colombian health system. The model used annual cycles according to the health status determined by the disability scale. Direct costs were considered, and the incremental cost-effectiveness ratio per 1 quality-adjusted life-year (QALY) gained was used as the outcome measure. A discount rate of 5% was applied to costs and outcomes. Multiple one-way deterministic sensitivity analyses and 10 000 Monte Carlo simulation were conducted. RESULTS: For the treatment of patients with RRMS, ocrelizumab versus rituximab had an incremental cost-effectiveness ratio of $73 652 for each QALY gained. After 50 years, 1 subject treated with ocrelizumab earns 4.8 QALYs >1 subject treated with rituximab, but at a higher cost of $521 759 versus $168 752, respectively. Ocrelizumab becomes a cost-effective therapy if its price is discounted > 86% or if there is a high willingness to pay. CONCLUSIONS: Ocrelizumab was not a cost-effective drug as compared with rituximab in treating patients with RRMS in Colombia.

Multiple sclerosis coverage in the written media of a low prevalence country.

BACKGROUND: Awareness in the community is an important factor across a wide range of diseases and the communication media have an important role in its promotion. However, misinformation and misguide may take place heightening the expectations of people affected by chronic conditions such as multiple sclerosis (MS). This study explores media coverage of MS in a low prevalence country. METHODS: We identified the most important written media at national and local levels and performed a search in their digital archives and social media with the words "Multiple Sclerosis". The articles found were categorized as relevant, and non-relevant. We describe the total number, number of relevant and non-relevant articles published every year, since the earliest found until 2018. We identified the topics covered by the relevant articles and described their distribution and performed a quality evaluation of their content. RESULTS: We reviewed the archives of 20 sources. A total of 976 articles where MS was mentioned were reviewed (relevant: 143 [14.6%]; non-relevant: 833 [85.4%]). We observed a steady increase in the annual publication rate, from the first in 1991 up to 107 in 2018. The most frequent covered topic was disease modifying therapies and MS itself, and the least documented topic was rehabilitation. Most of the relevant articles had low quality scores. CONCLUSION: The media coverage of different topics MS has risen steadily since its first appearance in the early nineties. This should be encouraged, but caution should be held so misinformation is not propagated. We call for the public to discuss misleading information with their healthcare providers.

Disease modifying therapies in multiple sclerosis: cost-effectiveness systematic review.

OBJECTIVE: To identify and describe cost-effectiveness studies that  evaluate disease modifying therapies in the context of relapsing- remitting multiple sclerosis. METHOD: A systematic review of the literature was carried out by  searching MEDLINE, Embase, the Cochrane Library, LILACS, the Tufts  Medical Center Cost-Effectiveness Analysis Registry, the National Health  Service Economic Evaluation Database and Open Grey. The search was  performed in January 2018 and covered articles published between  January 2010 and December 2017. The studies reviewed were payer- perspective cost-effectiveness analyses for interferon beta-1a, interferon beta-1b, glatiramer acetate, teriflunomide, fingolimod, dimethyl  fumarate, natalizumab, alemtuzumab and rituximab. The Quality of  Health Economic Studies instrument was used to determine the quality  of the studies reviewed. Risk of bias was assessed without a  standardized tool. An analysis was made of direct costs, quality- adjusted life-years and the incremental cost-effectiveness ratio. Data  extraction and evaluation of information were conducted separately by  each author. RESULTS: Four hundred one references were found; nine studies were included. A great degree of variability was identified for several  methodological aspects. Two studies that applied the incremental cost- effectiveness ratio (cost) showed no first-line therapy to be cost- effective. A third study demonstrated dominance of interferon beta-1b  over placebo (USD -315,109.45) and a fourth paper showed dominance  of teriflunomide over interferons and glatiramer acetate (USD - 121,840.37). As regards second-line therapies, dimethyl fumarate was  cost-effective in a study that compared it to glatiramer acetate and  interferon beta-1a and it was dominant in another study that compared  it with glatiramer acetate (USD -158,897.93) and fingolimod (USD - 92,988.97). In the third line of treatment, one study showed  natalizumab to be cost-effective as compared with fingolimod, and  another study showed alemtuzumab to be dominant over fingolimod  (USD -49,221). A third trial demonstrated alemtuzumab to be dominant over natalizumab (USD -1,656,266.07). Many of the trials have  sponsorship bias. Eight of the trials received a high QHES score. CONCLUSIONS: The present paper shows that cost-effectiveness studies have high levels of methodological variability, some of them  reaching contradictory results. As a result, it is not possible to  determine which disease- modifying therapy is really cost-effective in  the context of relapsingremitting multiple sclerosis.

Objetivo: Identificar y describir los estudios de costo-efectividad que evalúan las terapias modificadoras de la enfermedad en esclerosis  múltiple recurrente-remitente.Método: Revisión sistemática de la literatura en MEDLINE, Embase,  Cochrane Library, LILACS, Tufts Medical Center cost-effectiveness  analysis registry, National Health Service economic evaluation database  y Open Grey; búsqueda limitada entre enero de 2010 y diciembre de  2017, se ejecutó en enero de 2018. Se incluyeron modelos de costo- efectividad con perspectiva de pagador para interferón beta-1a,  interferón beta-1b, acetato de glatiramero, teriflunomida, fingolimod,  dimetilfumarato, natalizumab, alemtuzumab y rituximab. La  herramienta Quality of Health Economic Studies fue usada para  determinar la calidad de los estudios, el sesgo se evaluó sin una  herramienta estandarizada, dada su no existencia. Se analizaron costos directos, años de vida ajustados por calidad y la razón de costo- efectividad incremental. La extracción de los datos y la evaluación de la  información se realizaron por cada autor de forma independiente.Resultados: Se encontraron 401 referencias, se incluyeron nueve  estudios; hubo variabilidad en múltiples aspectos metodológicos. Según  la razón de costo-efectividad incremental (costo), dos trabajos  mostraron que ninguna terapia de primera línea fue costo-efectiva, un  tercer estudio reporta al interferón beta-1b como dominante sobre  placebo (­315.109,45 dólar estadounidense [US$]) y un cuarto artículo  expone a teriflunomida como dominante sobre interferones y acetato de glatiramero (­121.840,37 US$). Respecto a las terapias de segunda  línea, dimetil fumarato fue costoefectivo en un estudio comparado con  acetato de glatiramero e interferón beta-1a y fue dominante en otro  trabajo frente a acetato de glatiramero (­158.897,93 US$) y fingolimod  (­92.988,97 US$). En la tercera línea de tratamiento, natalizumab fue  costo-efectivo sobre fingolimod en un artículo, y alemtuzumab fue  dominante contra fingolimod (­49.221 US$) en un segundo estudio. En  un tercer ensayo el alemtuzumab fue dominante sobre natalizumab (­ 1.656.266,07 US$). Muchos estudios tuvieron sesgo de patrocinador.  Ocho artículos obtuvieron alta puntuación de calidad con la herramienta  Quality of Health Economic Studies.Conclusiones: Este trabajo demuestra que existe una gran variabilidad metodológica entre los estudios de costo-efectividad, y  algunos de ellos tienen resultados contradictorios. No es posible  determinar qué terapia modificadora de la enfermedad en esclerosis  múltiple recurrente-remitente es costo-efectiva.

Bilateral Calcification of the Meckel Cave Causing Hemicrania Continua.

This case report describes a woman with bilateral orbital and frontal throbbing pain with stabbing exacerbations and dystrophic calcification of dura mater and arachnoid granulations.

Myelopathy secondary to human T-lymphotropic virus and Treponema pallidum infection: case report.

Introduction: The human T-lymphotropic virus has been associated with human disease, affecting CD4+ T, CD8+ T, and B lymphocytes. It can cause T-cell leukemia/lymphoma and HTLV-associated myelopathy. Case presentation: A 31-year-old woman was admitted after 2 months of cramps, paraparesis, and fecal/urinary incontinence. She was diagnosed with neurosyphilis according to the cerebrospinal fluid analysis. Despite treatment with crystalline penicillin there was no recovery, and anti-HTLV-1/2 tests were positive; therefore, the diagnosis of HTLV-associated myelopathy was made. The patient rejected glucocorticoid treatment; baclofen and carbamazepine were used to treat spasticity and cramps, respectively. The patient has not had progression. Discussion: HTLV-associated myelopathy is generated by an exaggerated inflammatory response in the central nervous system with clonal expansion of CD4+ T and CD8+ T lymphocytes. There is not a specific and useful treatment; glucocorticoids can reduce inflammation, but do not improve clinical functional outcomes. There is a high prevalence of syphilis and human T-lymphotropic virus co-infection in tropical countries; however, myelopathy as the first clinical manifestation is unusual. The treatment of neurosyphilis could reduce the inflammation into the central nervous system and could decrease the progression of sequelae. This is the first case of myelopathy secondary to viral and treponemal co-infection confirmed in Colombia.

Fludarabine-Induced Posterior Reversible Encephalopathy Syndrome in a Pediatric Patient With ß-Thalassemia: Case Report and Literature Review.

Posterior reversible encephalopathy syndrome is a disorder of reversible subcortical vasogenic brain edema in the context of different diseases or exposure to cytotoxic drugs such as fludarabine. We present the case of a pediatric patient with ß-thalassemia who develops a fludarabine-induced posterior reversible encephalopathy while he received an induction regimen to achieve an allogenic hematopoietic cell transplantation. The clinical presentation consists in altered mental state, headache, status epilepticus, visual disturbance, and hypertension. His treatment was carried out with the suspension of the medication and the control of hypertension and status epilepticus; the final outcome was positive without additional complications. There are published reports about fludarabine toxicity in the central nervous system with different doses of the drug in different clinical context. We also made a review of the literature available and conclude that fludarabine is not an extraordinary cause of posterior reversible encephalopathy syndrome.

Photoswitchable interlocked thiodiglycolamide as a cocatalyst of a chalcogeno-Baylis-Hillman reaction.

En route to a photoswitchable interlocked catalyst we have proved the ability of thiodiglycolamide to act as a template in the formation of hydrogen-bonded [2]rotaxanes. X-ray diffraction studies reveal the shielding of the sulfide atom by the macrocycle. A series of molecular shuttles are described as having an isomerizable fumaramide and thiodiglycolamide binding sites for controlling the relative ring position at will. By employing these systems as photoregulated catalysts, the TiCl4-mediated chalcogeno-Morita-Baylis-Hillman reaction is tested. In the presence of the maleamide shuttle, in which the sulfide function is encapsulated by the macrocycle, a complete loss in control of the geometry of the produced aldol is observed. The E-aldol adduct is predominantly obtained when the photoisomerized fumaramide shuttle, in which the sulfide function is exposed, is used.

Síndrome de vasoconstricción cerebral reversible inducido por maniobra de Valsalva: Reporte de caso y revisión de la literatura / Valsalva maneuver induced-reversible cerebral vasoconstriction syndrome: Case report and literature review

RESUMEN El síndrome de vasoconstricción cerebral reversible es una entidad clínico-radiológica caracterizada por la presentación de cefalea severa de inicio hiperagudo tipo "trueno", con o sin signos y síntomas neurológicos adicionales en relación a una vasoconstricción arterial cerebral segmentaria que resuelve espontáneamente a los 3 meses. Por la superposición de las manifestaciones clínicas con otras entidades nosológicas, y por los múltiples factores etiológicos asociados, el diagnóstico se convierte en un reto; es imperativo realizarlo de forma temprana para la instauración de un tratamiento adecuado y la prevención de complicaciones. Se presenta el caso clínico de una paciente en quien se documentó como etiología la realización repetitiva de la maniobra de Valsalva sin otro factor concomitante, se exponen las intervenciones realizadas y se hace una revisión narrativa del tema con énfasis en el diagnóstico diferencial.

SUMMARY Reversible cerebral vasoconstriction syndrome is a clinical-radiological entity characterized by severe and hyperacute onset-thunderclap headache, with or without additional neurological signs and symptoms in relation to a segmental cerebral arterial vasoconstriction that resolves spontaneously at around 3 months. Its clinical manifestations are similar to other diseases, and additionally there are multiple associated etiological factors; early diagnosis becomes a challenge, but is essential to establish proper treatment and prevent complications. We present the case of a female patient in whom the repetitive performance of the Valsalva maneuver without another concomitant factor was documented as etiology, the interventions performed are presented and a narrative review of the topic is made with emphasis on differential diagnosis.