Predicting toxicity properties through machine learning

It is currently known that the high power of a drug does not fully determine its efficacy. Several properties must also be considered, including absorption, distribution, metabolism, excretion and toxicity [8]. These are the ADME-Tox properties, which are fundamental in the discovery of new effective and safe drugs. Since ignoring these properties is the main cause of failure in the development of new drugs, it is understandable that some techniques arise, such as machine learning, which apply some predictor variables as molecular characteristics to obtain models to determine some of these ADME-Tox properties. In silico models are booming because of the exorbitant expenses involved in discovering a new drug using traditional trial-and-error methods [2], and they have proven to be an effective approach to increase efficiency in drug discovery and development processes. The objective of this study is to analyze the best current machine learning techniques for predicting toxicity as an ADME-Tox property

Lifestyle and cardiovascular mortality in menopausal women: a population-based cohort study

Introduction and objectives: There are models for cardiovascular risk prediction in the general population, but the prediction of risk in postmenopausal women has not been specifically studied. This study aimed to determine the association of lifestyle habits and chronic diseases with cardiovascular risk in menopausal women, as well as to build a risk scale. Methods: Retrospective population-based cohort study using data from the 2011 National Health Survey of Spain as a data source, Women 50 years were included. The characteristics that best defined the life habits of the study women were collected, as well as their health status and self-reported medical history at the time of the survey. Follow-up data on all-cause mortality were obtained from participants from 2011 to 2017. Results: A total of 5953 women 50 years of age were included, with a mean age of 66.4 11.4 years. The incidence of cardiovascular mortality in the follow-up period was 4%. Vegetable consumption less than 1 time/week (HR, 1.758), smoking (HR, 1.816) or excess hours of sleep ( 9 h/day, HR, 1.809), or o have main daily activity sitting most of the time (HR, 2.757) were related to cardiovascular mortality. The predictive model presents an honest C-index in test sample of 0.8407 (95%CI, 0.8025-0.8789). Conclusions: Life habits such as the consumption of vegetables, daily main activity, sleeping hours or smoking are risk factors for cardiovascular mortality of great relevance among menopausal women. A simple 6-year self-reported risk scale with high predictive capacity is provide

HPLC-PDA METHOD FOR THE QUANTIFICATION OF PARACETAMOL IN PLASMA: APPLICATION TO PK/PD STUDIES WITH ARTHRITIC RATS

Objective: To develop and validate an easy, rapid, sensitive and selective high-performance liquid chromatography with photodiode diode-array (HPLC-PDA) detection method for quantification of paracetamol and to demonstrate its application in a pharmacokinetic–pharmacodynamic study with arthritic rats.Methods: Paracetamol was separated from plasma samples (50-100 µl) by a single protein precipitation step, prior to HPLC-PDA detection. The separation was performed on a Knauer Eurospher II, C18 column 5 µm, 150 × 4.6 mm. The mobile phase comprised a mixture of water: methanol (75:25) and the flow rate was 1.1 ml/min. The detection wavelength was set at 245 nm. All analyses were carried out at room temperature (25 °C). Pharmacodynamics data were obtained with a gout-type pain model in rats.Results: The method was linear within a range of 0.2-200 µg/ml (R2≥0.99). The intra-day and inter-day precision and accuracy expressed as coefficient of variation and relative error, respectively were below 10%. The lower limit of quantification was 0.2 µg/ml. Plasma samples were stable at least for 5 w at ‒20° C.Conclusion: The validated method is sensitive, precise, accurate and specific as other more complex high-performance liquid chromatographic methods coupled to mass spectrometry (HPLC-MS), using small plasma samples (50-100 µl) and with a short time analysis (<5 min). The method was successfully applied to a pharmacokinetic-pharmacodynamic study of paracetamol in arthritic rats.Â

Diagnóstico coproparasitológico de fascioliasis en ovinos y caprinos de Boavita, Boyacá (Colombia)

The aim of this study was to establish the prevalence of Fasciola hepatica through coprological analysis and to identify risk factors associated with the presentation of the parasite in sheep and goats in the municipality of Boavita, Boyacá. The study was observational, descriptive, cross-sectional with simple random sampling. Faecal samples were taken from 297 sheep and 337 goats to identify parasite eggs. The general prevalence was 8.0% (51/634), being 9.1% for sheep and 7.1% for goats. The prevalence in sheep was higher in males (14.8%) than in females (8.5%), likewise, sheep less than one year old (9.3%) and Criolla (11.1%) presented the highest prevalence. In goats, the prevalence was higher in females (7.3%) than in males (5.6%), and those less than one year old (10.5%) and the Alpine breed (8%) presented the greater prevalence. No significant statistical association was found between females and males. The Creole breed was established as a risk factor for sheep.El objetivo del estudio fue establecer la prevalencia de Fasciola hepatica mediante análisis coprológico e identificar factores de riesgo asociados a la presentación del parásito en ovinos y caprinos del municipio de Boavita, Boyacá. El estudio fue observacional, descriptivo de corte transversal con muestreo aleatorio simple. Se tomaron muestras de materia fecal a 297 ovinos y 337 caprinos para identificar los huevos del parásito. La prevalencia general fue de 8.0% (51/634), siendo de 9.1% para ovejas y de 7.1% para cabras. La prevalencia en ovinos fue mayor en machos (14.8%) que en hembras (8.5%); asimismo, los ovinos menores a un año (9.3%) y de Criolla (11.1%) presentaron las prevalencias más altas. En las cabras, la prevalencia fue mayor en hembras (7.3%) que en machos (5.6%), y los menores a un año (10.5%) y de la raza Alpina (8%) presentaron las prevalencias más altas. No se encontró asociación estadística significativa entre hembras y machos. La raza Criolla se estableció como factor de riesgo para los ovinos

Eventos adversos posteriores a la vacunación contra COVID-19: un estudio de corte transversal

Los datos disponibles de farmacovigilancia de las vacunas contra la COVID-19 en Latinoamérica son limitados. El objetivo de este estudio fue determinar la frecuencia de los eventos adversos posteriores a la vacunación (EAPV) con la primera y la segunda dosis contra la COVID-19 en estudiantes de medicina de Cali (Colombia), en el 2021. Se realizó un estudio observacional descriptivo de corte transversal en adultos voluntarios que habían recibido al menos una dosis de la vacuna BNT162b2 de Pfizer-BioNTech, y que respondieron una encuesta electrónica. De los invitados, 292 adultos con una mediana de edad de 21 años (RIC: 20-22) aceptaron participar. El 95% de ellos recibió dos dosis y el 5% una dosis, el 64,4% eran mujeres y el 76,37% reportó al menos un EAPV, todos de severidad leve. El dolor en el sitio de inyección, con un 73,6%, fue el evento más reportado. Lo siguieron EAPV sistémicos como fatiga, sueño y cefalea, con el 56,8%, 46,9% y 38,6%, respectivamente, los cuales se presentaron en mayor proporción después de la segunda dosis. Con significancia estadística, las mujeres presentaron una odds ratio de exposición mayor para dolor en el sitio de inyección y escalofríos con (OR = 1,89; IC 95%: 1,07-3,33; p = 0,01) y (OR = 3,03; IC 95%: 1,63-5,88; p = 0,0002), respectivamente, en comparación con los hombres. Otras condiciones clínicas y demográficas evaluadas no tuvieron asociación significativa con el desarrollo de eventos. Por lo tanto, en esta población, al menos un EAPV se presentó en tres de cada cuatro vacunados con BNT162b2; el dolor en el sitio de inyección, la fatiga, el sueño y el dolor de cabeza, fueron los más frecuentes. Las mujeres presentaron EAPV con más frecuencia y los EAPV sistémicos se presentaron en mayor proporción para ambos sexos tras la segunda dosis. No obstante, todos los EAPV reportados fueron leves y de corta duración

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

*Shared first authorship (Dominguez-V M, Sampson J, Seppälä T)PURPOSE: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. METHODS: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. RESULTS: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. CONCLUSION: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.Peer reviewe

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2

Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants : a Prospective Lynch Syndrome Database report

Purpose To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants. Methods The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages. Results Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively. Conclusion Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.Peer reviewe