Towards Understanding Tenofovir Disposition: MALDI-Imaging and Pharmacogenetics

The emergence of HIV pre-exposure prophylaxis, applying antiretroviral drugs toward prevention of infection by human immunodeficiency virus in uninfected individuals, reveals a promising avenue toward decreasing the number of annual new HIV infections worldwide. The nucleotide reverse transcriptase inhibitor tenofovir, along with the nucleoside reverse transcriptase inhibitor emtricitabine, currently make up the FDA-approved regimen for pre-exposure prophylaxis. Intracellular phosphorylation of both tenofovir and emtricitabine is necessary to generate nucleotide triphosphate analogs that would competitively inhibit HIV reverse transcriptase. Kinases demonstrated to phosphorylate tenofovir to the intermediate tenofovir monophosphate and then to the active anabolite tenofovir monophosphate have been shown to be expressed in HIV-susceptible tissues. Adenylate kinase 2 phosphorylates tenofovir to tenofovir monophosphate in peripheral blood mononuclear cells, vaginal, and colorectal tissues. In colorectal tissues, creatine kinase, muscle was found to phosphorylate tenofovir monophosphate to tenofovir diphosphate. The two kinases pyruvate kinase, muscle and pyruvate kinase, liver and red blood cell were shown to yield tenofovir diphosphate in peripheral blood mononuclear cells and vaginal tissue. These four kinases were sequenced for genetic variants that could affect tenofovir activation. In a clinical study spread across the three geographic regions Bangkok, Thailand, Cape Town, South Africa, and New York City, USA, 103 previously unreported variants across the kinases AK2, CKM, PKM and PKLR were detected. Of 505 individuals, 19 individuals (3.7% frequency) were found to be carrying variants that were predicted to be deleterious and probably damaging. In emtricitabine activation, we put forward four candidate kinases that would yield the nucleotide triphosphate analog emtricitabine triphosphate. Emtricitabine requires three phosphorylation steps to become pharmacologically active. Deoxycytidine kinase and thymidine kinase 1 are proposed to phosphorylate emtricitabine to emtricitabine-monophosphate. To generate emtricitabine-diphosphate, cytidine monophosphate kinase 1 is suggested to phosphorylate emtricitabine-monophosphate. To form the competitive HIV reverse transcriptase inhibitor emtricitabine triphosphate, phosphoglycerate kinase 1 was identified as a candidate kinase. In a clinical study, we identified 17 previously unreported genetic variants of these kinases. Additionally, to further understand tenofovir and emtricitabine disposition in tissue, a matrix-assisted laser desorption/ionization coupled to mass spectrometry method was developed. This method aims to image tenofovir, emtricitabine, and the corresponding phosphorylated anabolites of each drug in an effort to better understand drug distribution in HIV susceptible tissues. Taken together, development of the imaging technology and application of next-generation sequencing to identify variants in kinases proposed to activate nucleos(t)ide reverse transcriptase inhibitors aim to allow for explanations of inter-individual variability of pre-exposure prophylaxis efficacy

Knowledge Infrastructure Requirements for Computable Biomedical Knowledge (CBK)

Purpose: Platforms for computable biomedical knowledge are rapidly emerging to accelerate the application of biomedical knowledge into practice. At an inaugural Mobilizing Computable Biomedical Knowledge (MCBK) working meeting held in Ann Arbor, MI on October 18 & 19, 2017, the group took important early steps to: Engage critical dialogue on how to effectively develop and govern platforms for machine-executable biomedical knowledge to improve health and to build a pre-competitive computable biomedical knowledge community. This conference was significant for advancing work in areas that require computable knowledge to translate biomedical insights for better health: Learning Health Systems, Open Biomedical Science, and Clinical Decision Support. Participants explored what will be required to shape and sustain a community focused on making computable biomedical knowledge FAIR: Findable, Accessible, Interoperable and Reusable. Participants discussed biomedical computable knowledge in the context of four, overarching themes, one of which included Knowledge Infrastructure Requirements for Computable Biomedical Knowledge.https://deepblue.lib.umich.edu/bitstream/2027.42/140738/1/Knowledge Infrastructure Requirements for Computable Biomedical Knowledge (CBK) Briefing Paper.pdf-1Description of Knowledge Infrastructure Requirements for Computable Biomedical Knowledge (CBK) Briefing Paper.pdf : Briefing Pape

The origins of dengue and chikungunya viruses in Ecuador following increased migration from Venezuela and Colombia

This work was funded by the Armed Forces Health Surveillance Branch (AFHSB) and its Global Emerging Infections Surveillance (GEIS) Section, FY2018 ProMIS ID P0108_18_WR.Background: In recent years, Ecuador and other South American countries have experienced an increase in arboviral diseases. A rise in dengue infections was followed by introductions of chikungunya and Zika, two viruses never before seen in many of these areas. Furthermore, the latest socioeconomic and political instability in Venezuela and the mass migration of its population into the neighboring countries has given rise to concerns of infectious disease spillover and escalation of arboviral spread in the region. Results: We performed phylogeographic analyses of dengue (DENV) and chikungunya (CHIKV) virus genomes sampled from a surveillance site in Ecuador in 2014-2015, along with genomes from the surrounding countries. Our results revealed at least two introductions of DENV, in 2011 and late 2013, that initially originated from Venezuela and/or Colombia. The introductions were subsequent to increases in the influx of Venezuelan and Colombian citizens into Ecuador, which in 2013 were 343% and 214% higher than in 2009, respectively. However, we show that Venezuela has historically been an important source of DENV dispersal in this region, even before the massive exodus of its population, suggesting already established paths of viral distribution. Like DENV, CHIKV was introduced into Ecuador at multiple time points in 2013-2014, but unlike DENV, these introductions were associated with the Caribbean. Our findings indicated no direct CHIKV connection between Ecuador, Colombia, and Venezuela as of 2015, suggesting that CHIKV was, at this point, not following the paths of DENV spread. Conclusion: Our results reveal that Ecuador is vulnerable to arbovirus import from many geographic locations, emphasizing the need of continued surveillance and more diversified prevention strategies. Importantly, increase in human movement along established paths of viral dissemination, combined with regional outbreaks and epidemics, may facilitate viral spread and lead to novel virus introductions. Thus, strengthening infectious disease surveillance and control along migration routes and improving access to healthcare for the vulnerable populations is of utmost importance.Publisher PDFPeer reviewe

Frequency of gastronintestinal parasite of dogs in public parks in two neighboring municipalities of state of Mexico

Artículo científicoLa contaminación de suelos por parásitos gastrointestinales representa un problema mundial y un riesgo a la salud. Objetivo. Determinar la presencia de parásitos en heces de perros en los parques públicos del área. Materiales y métodos. Se recolectaron muestras de heces en 27 parques públicos de Metepec y Toluca Estado de México, mismos que se procesaron con 3 técnicas parasitológicas; 81.4% de los parques públicos resultaron positivos a parásitos gastrointestinales, con una frecuencia global de muestras del 16.5%. El porcentaje de parasitosis con potencial zoonótico fue de 81.3%; Toxocara spp, Ancylostoma spp y Giardia spp fueron las especies zoonóticas identificadas. Conclusiones. Los resultados indican que los parques de la zona conurbada de Toluca representan un problema de salud pública importante al ser una fuente de parásitos gastrointestinales zoonóticos de perro

Evaluación y comparación del estado de desarrollo de los patrones motores identificación de las partes, equilibrio, tomar la pelota, salto y caída de estudiantes de 4° Básico de dos colegios de la Región Metropolitana

Tesis (Profesor de Educación Física para la Enseñanza Básica, Licenciado en Educación)En el siguiente estudio se presentará el análisis del desarrollo motor de niños cursando cuarto básico de dos colegios de la comuna de Santiago; La Escuela Particular Guillermo Matta, que tiene dos horas de Educación física y el colegio The Mayflower school, que posee más de cuatro horas de clase a la semana. Este tiene como objetivo principal, analizar si la cantidad de horas semanales influye directamente en los patrones motores de Salto y caída, identificación de las partes del cuerpo, atrapar el balón y la tabla de equilibrio. Para esto, se aplicó el test adaptado de Jack Capon, el cual consiste en medir el desarrollo motriz de los niños de entre 6 y 14 años. Este test categoriza a los sujetos en tres estadios diferentes. (Inicial, elemental y maduro). Se entiende por estadio inicial el no cumplimiento del ejercicio solicitado, el estadio elemental se define como un desarrollo inmaduro de la tarea solicitada y el estadio maduro es la realización del movimiento de la forma correcta. Con los resultados de este test, se observa que, a mayor cantidad de horas semanales, mayor es el desarrollo motriz de los alumnos. como se puede evidenciar en los datos adquiridos, existe una diferencia de desarrollo entre ambos colegios, se evidencia que, en tres de las cuatro pruebas totales, el colegio The Mayflower School consigue una mayor cantidad de alumnos en el estadio maduro

Recommendations of the Colombian association of coloproctology for management of colorectal cancer during the COVID-19 pandemic

La pandemia por el coronavirus 2 del síndrome respiratorio agudo severo (SARS-CoV-2), (coronavirus disease-19 [COVID-19]), ha alterado por completo toda la realidad mundial con repercusiones económicas, sociales y grandes compromisos de los sistemas de salud. La enfermedad ha afectado a todos los países en los 5 continentes; y en nuestro país, desde el primer caso, se han venido tomando medidas para prepararnos mejor ante esta crisis. Pese a que se trata de un virus respiratorio, se ha documentado su presencia en diferentes tejidos y órganos de los seres humanos. Aunque la presentación clínica en su mayoría tiene síntomas leves, se sabe que un porcentaje importante tiene manifestaciones graves que pueden llevar a complicaciones graves y la muerte. El cáncer colorrectal es un tumor prevalente en nuestra población y obliga a tener una mejor preparación para tratarlo durante este período. Desde la Asociación Colombiana de Coloproctología, basados en los diferentes reportes de la literatura, en las recomendaciones de las diferentes asociaciones internacionales y en nuestra propia experiencia, se realiza una revisión del cáncer colorrectal durante la pandemia de COVID-19 y se comparten algunas recomendaciones para el manejo de los pacientes con esta patología revisando las diferentes opciones de manejo según la presentación de la enfermedad.The economic and social repercussions and the enormous commitment required of health care systems by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic (coronavirus disease [COVID-19]) has completely altered world reality. The disease has affected all countries on all five continents. In Colombia, from diagnosis of the very first case, measures have been taken to better prepare ourselves for this crisis. Although it is a respiratory virus, its presence in various human tissues and organs has been documented. Despite the fact that its clinical presentation is most often in the form of mild symptoms, a significant percentage of those infected have severe manifestations that can lead to serious complications and death. Colorectal cancer is a prevalent tumor in our population, and this pandemic forces to prepare ourselves better to treat it during this period. The Colombian Coloproctology Association has reviewed reports in the literature and recommendations of various international associations and on our own experience with colorectal cancer during the COVID-19 pandemic. We present our recommendations for management of patients with this pathology and review management options according to disease presentation

Tyrannobdella rex N. Gen. N. Sp. and the Evolutionary Origins of Mucosal Leech Infestations

BACKGROUND: Leeches have gained a fearsome reputation by feeding externally on blood, often from human hosts. Orificial hirudiniasis is a condition in which a leech enters a body orifice, most often the nasopharyngeal region, but there are many cases of leeches infesting the eyes, urethra, vagina, or rectum. Several leech species particularly in Africa and Asia are well-known for their propensity to afflict humans. Because there has not previously been any data suggesting a close relationship for such geographically disparate species, this unnerving tendency to be invasive has been regarded only as a loathsome oddity and not a unifying character for a group of related organisms. PRINCIPAL FINDINGS: A new genus and species of leech from Perú was found feeding from the nasopharynx of humans. Unlike any other leech previously described, this new taxon has but a single jaw with very large teeth. Phylogenetic analyses of nuclear and mitochondrial genes using parsimony and Bayesian inference demonstrate that the new species belongs among a larger, global clade of leeches, all of which feed from the mucosal surfaces of mammals. CONCLUSIONS: This new species, found feeding from the upper respiratory tract of humans in Perú, clarifies an expansion of the family Praobdellidae to include the new species Tyrannobdella rex n. gen. n. sp., along with others in the genera Dinobdella, Myxobdella, Praobdella and Pintobdella. Moreover, the results clarify a single evolutionary origin of a group of leeches that specializes on mucous membranes, thus, posing a distinct threat to human health

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks