A finite element study comparing Advansync® and Twin Block in mandibular anterior repositioning.

OBJECTIVE: This study aims to utilize the finite element method (FEM) to compare the dentoalveolar and mandibular effects associated with anterior mandibular repositioning using AdvanSync® (ADV) and Twin Block (TB). METHODS: A patient with Class II skeletal malocclusion and mandibular retrognathism was selected. A TB appliance was subsequently applied. Computed Tomography (CT) scans were acquired at the beginning of treatment (T1) and 8 months later (T2). Concurrently, a numerical TB model was validated through FEM simulations, which were compared with the T2 results. The ADV appliance was virtually simulated to evaluate stress and deformation on the condyle, symphysis, first lower molar and lower central incisors. RESULTS: Both simulations demonstrated significant mandibular advancement. However, ADV led to less incisor proclination and more molar intrusion compared to TB. ADV exhibited increased stress in the lower molar area, while TB had higher stress in the lower incisor region. Stress and deformations in the condyle and mandibular symphysis were similar in both simulations, with the highest stress observed at the condylar neck and the lowest at the upper pole of the condylar head. CONCLUSIONS: Both appliances achieved similar levels of mandibular advancement, with greater proclination of the lower central incisors and more widespread distribution of stress and molar intrusion when using ADV compared to TB.

Investigation of the Effect of Lasmiditan on the Pharmacokinetics of P-Glycoprotein and Breast Cancer Resistance Protein Substrates.

Lasmiditan is an in vitro inhibitor of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux transporters. We aimed to confirm predictions from physiologically based pharmacokinetic models of lasmiditan, and assess the safety and tolerability of rosuvastatin and dabigatran co-administered with lasmiditan. In this open-label, post-marketing drug-drug interaction, phase 1 clinical trial, eligible participants were adults aged 21-70 years with a body mass index of 18.5-35.0 kg/m2 . Part 1 (P-gp, 150 mg dabigatran etexilate with 200 mg lasmiditan) and part 2 (BCRP, 10 mg rosuvastatin with 200 mg lasmiditan) employed similar designs: a single dose of probe substrate administered on day -2 with pharmacokinetic evaluation; 1-week washout; lasmiditan administered on days 8 and 9 alone; lasmiditan co-administered with a single dose of probe substrate on day 10, with pharmacokinetic evaluation of probe substrate and lasmiditan. Sixty-six participants were included in part 1 and 30 participants were included in part 2. Following dabigatran co-administration with lasmiditan, versus dabigatran alone, 90% confidence intervals for geometric least-squares (LS) mean ratios of area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-∞ ) and maximum observed drug concentration (Cmax ) were not contained within the non-effect boundaries (0.80 to 1.25). Dabigatran AUC0-∞ increased by 25% and Cmax increased by 22%. The median time of maximum observed drug concentration (tmax ) for dabigatran was 2.0 to 3.0 hours. Following rosuvastatin co-administration with lasmiditan, versus rosuvastatin alone, 90%CIs for geometric LS mean ratios of AUC0-∞ and Cmax were contained within non-effect boundaries (0.80-1.25). Rosuvastatin AUC0-∞ increased by 15% and Cmax increased by 7%. The median tmax for rosuvastatin was 4.0 hours. Results suggest that lasmiditan has a weak effect on P-gp substrates and no clinically relevant effect on BCRP substrates.

Prevalencia y caracterización de las neoplasias malignas en personas viviendo con VIH en Colombia

Introducción: En el síndrome de inmunodeficiencia adquirida las neoplasias han jugado un papel preponderante, y con el advenimiento del tratamiento antirretroviral (TAR), la infección por VIH se ha transformado en una enfermedad crónica, siendo los tumores malignos una causa importante de morbilidad y mortalidad. Objetivo: Describir las características demográficas, clínicas y de laboratorio de las personas que viven con VIH (PVVIH) y han sido diagnosticadas con cáncer en Colombia y comparar los grupos de neoplasias definitorias y no definitorias de Sida. Métodos: Revisión multicéntrica retrospectiva, en la que se recolectó y analizó datos relacionados con la infección por VIH y de diagnóstico de cáncer y tipo. Incluyó PVVIH diagnosticadas con neoplasias malignas atendidas en 23 centros de atención de pacientes con VIH en 11 ciudades de Colombia desde 1986 hasta 2018. Resultados: En 23.189 pacientes, se identificaron 650 casos de malignidad (prevalencia de 2,8 % [IC de 95%: 2,6-2,9]). La neoplasia definitoria de Sida (NDS) sigue siendo el tipo de cáncer prevalente (71,1%), las neoplasias malignas más frecuentes fueron sarcoma de Kaposi (n: 330; 50,8%), linfoma no Hodgkin (n: 110; 16,9%), cáncer de piel (n: 48; 7,4%) y linfoma de Hodgkin (n: 25; 3,8%). Los pacientes con NDS tenían más probabilidades de ser HSH y estar en un estadio CDC 3, un recuento de linfocitos T CD4 < 200/μL y una carga viral del VIH ≥ 50 copias/mL al momento del diagnóstico de malignidad. Las personas con neoplasias no definitorias de Sida (NNDS) eran significativamente mayores y tenían más probabilidades de ser fumadores. Conclusiones: Estos hallazgos son relevantes considerando la creciente carga de cáncer en las PVVIH que envejecen y las causas cambiantes de morbilidad y mortalidad. La presentación tardía a la atención del VIH y el retraso en el inicio del TAR son probablemente factores que contribuyen al cambio más lento hacia NNDS en comparación con las regiones de altos ingresos donde hay un acceso más rápido y temprano al TAR. El conocimiento de las tendencias epidemiológicas actuales y el perfil del cáncer en las PVVIH es fundamental para mejorar los esfuerzos de prevención y tratamiento del cáncer en el contexto de la atención integral del VIH.

Background: In the acquired immunodeficiency syndrome, neoplasms have played a preponderant role, and with the advent of antiretroviral treatment (ART), HIV has become a chronic disease, with malignant tumors being an important cause of morbidity and mortality. Aim: To describe the demographic, clinical, and laboratory characteristics of people living with HIV (PLHIV) who have been diagnosed with cancer in Colombia and to compare the groups of AIDS-defining (ADC) and non-AIDS-defining neoplasms (NADC). Methods: Retrospective, multicenter study that included people living with HIV/AIDS (PLHIV) diagnosed with malignancies treated at 23 HIV care centers located in 11 Colombian cities from 1986 to 2018. Data related to HIV infection and cancer diagnosis were collected and analyzed. Results: Among 23,189 patients, 650 malignancy cases were identified (prevalence of 2.8% [95% CI 2.6-2.9]). AIDS-defining neoplasm remains the most prevalent type of cancer (71.1%), The most frequent individual malignancies were Kaposi sarcoma (n: 330; 50.8%), non-Hodgkin lymphoma (n: 110; 16.9%), skin cancer (n: 48; 7.4%), and Hodgkin lymphoma (n: 25; 3.8%). Compared people with NADC, with ADC were more likely to be MSM and have a CDC HIV stage 3, CD4 T cell count < 200/μL, and HIV viral load ≥ 50 copies/mL at the time of malignancy diagnosis. PLHIV and with NADC were significantly older and were more likely to be smokers. Conclusions: These findings are relevant considering the increasing burden of cancer in the aging PLHIV and the changing causes of morbidity and mortality. Late presentation to HIV care and delayed ART initiation are likely factors contributing to the slower shift toward NADCs compared with high-income regions where access to ART is better. Knowledge of the current epidemiological trends and profile of cancer in PLWHA is critical to improve cancer prevention and treatment efforts in the context of comprehensive HIV care.

Pandemic play moderates the relation between caregiver stress and child emotional distress in contexts of economic adversity.

It is well-established that caregiver stress is linked to increased emotional distress among children, and recent evidence highlights similar associations between caregiver and child emotional well-being during the coronavirus (COVID-19) pandemic. Examining protective factors and coping mechanisms that are associated with resiliency in the face of pandemic-related stress can highlight potential strategies that may help children adapt to other unexpected hardships outside of a global pandemic. Previous research found that playing about the pandemic moderated an association between caregiver stress and children's emotional distress. However, few studies have explored "pandemic play" among children from low-income households, where pandemic-related stressors were often exacerbated. In the present study, 72 caregivers of Head Start preschoolers between 3 and 6 years of age were surveyed between late 2020 and early 2021. Results revealed that 32% of children engaged in pandemic play frequently. Caregiver stress was positively associated with child emotional distress, but only among children who did not engage in pandemic play frequently. These findings support the idea that child-directed play may be a developmentally appropriate and accessible coping mechanism to reduce the emotional burden of stressful events on children, regardless of economic context.

Prediction of the Renal Organic Anion Transporter 1 (OAT1)- Mediated Drug Interactions for LY404039, the Active Metabolite of Pomaglumetad Methionil.

PURPOSE: The objective of this work was to demonstrate that clinical OAT1-mediated DDIs can be predicted using physiologically based pharmacokinetic (PBPK) modeling. METHODS: LY404039 is a metabotropic glutamate receptor 2/3 agonist and the active moiety of the prodrug pomaglumetad methionil (LY2140023). After oral administration, pomaglumetad methionil is rapidly taken up by enterocytes via PEPT1 and once absorbed, converted to LY404039 via membrane dehydropeptidase 1 (DPEP1). LY404039 is renally excreted by both glomerular filtration and active secretion and in vitro studies showed that the active secretion of LY404039 was mediated by the organic anion transporter 1 (OAT1). Both clinical and in vitro data were used to build a PBPK model to predict OAT1-mediated DDIs. RESULTS: In vitro inhibitory potencies (IC50) of the known OAT inhibitors, probenecid and ibuprofen, were determined to be 4.00 and 2.63 µM, respectively. Subsequently, clinical drug-drug interaction (DDI) study showed probenecid reduced the renal clearance of LY404039 by 30 to 40%. The PBPK bottom-up model, predicted a renal clearance that was approximately 20% lower than the observed one. The middle-out model, using an OAT1 relative activity factor (RAF) of 3, accurately reproduced the renal clearance of LY404039 and pharmacokinetic (PK) changes of LY404039 in the presence of probenecid. CONCLUSIONS: OAT1- mediated DDIs can be predicted using in vitro measured IC50 and PBPK modeling. The effect of ibuprofen was predicted to be minimal (AUC ratio of 1.15) and not clinically relevant.

Identification of CD8+ T cell subsets that normalize in early-treated people living with HIV receiving antiretroviral therapy.

BACKGROUND: Although combined antiretroviral therapy (cART) has decreased the mortality associated with HIV infection, complete immune reconstitution is not achieved despite viral suppression. Alterations of CD8+ T cells and some of their subpopulations, such as interleukin (IL)-17-producing cells, are evidenced in treated individuals and are associated with systemic inflammation and adverse disease outcomes. We sought to evaluate if different CD8+ T cell subsets are differentially normalized during a clinical follow-up of people living with HIV (PLWH) receiving suppressive cART. METHODS: We explored the changes in the frequencies, activation/exhaustion phenotypes (HLA-DR, CD38, PD-1, and TIM-3), and function (total and HIV-specific cells expressing CD107a, perforin, granzyme B, interferon [IFN]-γ and IL-17) of CD8+ T cells from early-treated PLWH receiving cART in a 1-year follow-up, using a multidimensional flow cytometry approach. RESULTS: Despite continuous cART-induced viral suppression and recovery of CD4+ T cells, after a 1-year follow-up, the CD8+ T cell counts, CD4:CD8 ratio, PD-1 expression, and IL-17 production by CD8+ T cells exhibited incomplete normalization compared with seronegative controls. However, the proportion of CD8+ T cells with an exhausted phenotype (co-expressing PD-1 andTIM-3), and cells co-expressing cytotoxic molecules (Perforin and Granzyme B), reached normalization. CONCLUSIONS: Although suppressive cART achieves normalization of CD4+ T cell counts, only particular subsets of CD8+ T cells are more rapidly normalized in PLWH receiving cART, which could be routinely used as biomarkers for therapy efficiency in these patients.

Onicomatricoma: puntos clínicos claves de una enfermedad infrecuente / Onychomatricoma: Key clinical points of an unfrequented disease

Resumen Introducción: el onicomatricoma es un tumor fibroepitelial originado en la matriz ungular, es infrecuente y suele presentarse alrededor de la quinta y sexta década de la vida. Métodos: se presenta el caso de un paciente masculino de 57 años, sin antecedentes patológicos, quien consultó por una lesión no dolorosa en la uña del tercer dedo de la mano derecha. Al examen físico presentaba cromoniquia amarilla longitudinal, estrías blanquecinas y hemorragias en astilla. Se realizó onicectomía y matricectomía proximal y se envió el especimen resecado a estudio histopatológico. Resultados: el examen histopatológico reportó una lesión fibroepitelial, con invaginaciones del epitelio y ausencia de la capa granulosa. En el estroma se observaban células ondulantes y fusocelulares acompañadas de mastocitos. Se realizaron tinciones de inmunohistoquímica, confirmando el diagnóstico de onicomatricoma, variante micropapilifera. Conclusiones: debido a los múltiples diagnósticos diferenciales de esta condición, es importante para el dermatólogo familiarizarse con la clínica, hallazgos dermatoscópicos y manejo de esta entidad.

Abstract Introduction: onychomatricoma is a fibroepithelial tumor originating in the nail matrix, it is infrequent and usually presents around the fifth and sixth decades of life. Methods: we present the case of a 57-year-old male patient, without relevant past medical history, who complained of a non-painful lesion in the nail of the third finger of the right hand. Physical exam revealed longitudinal yellow chromonychia, whitish striae, and splinter hemorrhages. Onychectomy and proximal matricectomy were performed and the resected specimen was sent for histopathological study. Results: the histopathological study reported a fibroepithelial lesion, with invaginations of the epithelium and absence of the granular layer. Undulating and spindle cell cells accompanied by mast cells were observed in the stroma. Immunohistochemical staining was performed, confirming the diagnosis of onychomatricoma, micropapiliferum variant. Conclusions: due to the multiple differential diagnoses of this condition, it´s important for the dermatologist to become familiar with the clinic, dermoscopic findings and management of this entity.

DPP4 Promotes Human Endothelial Cell Senescence and Dysfunction via the PAR2-COX-2-TP Axis and NLRP3 Inflammasome Activation.

BACKGROUND: Abnormal accumulation of senescent cells in the vessel wall leads to a compromised vascular function contributing to vascular aging. Soluble DPP4 (dipeptidyl peptidase 4; sDPP4) secretion from visceral adipose tissue is enhanced in obesity, now considered a progeric condition. sDPP4 triggers vascular deleterious effects, albeit its contribution to vascular aging is unknown. We aimed to explore sDPP4 involvement in vascular aging, unraveling the molecular pathway by which sDPP4 acts on the endothelium. METHODS: Human endothelial cell senescence was assessed by senescence-associated ß-galactosidase assay, visualization of DNA damage, and expression of prosenescent markers, whereas vascular function was evaluated by myography over human dissected microvessels. In visceral adipose tissue biopsies from a cohort of obese patients, we explored several age-related parameters in vitro and ex vivo. RESULTS: By a common mechanism, sDPP4 triggers endothelial cell senescence and endothelial dysfunction in isolated human resistance arteries. sDPP4 activates the metabotropic receptor PAR2 (protease-activated receptor 2), COX-2 (cyclooxygenase 2) activity, and the production of TXA2 (thromboxane A2) acting over TP (thromboxane receptor) receptors (PAR2-COX-2-TP axis), leading to NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3) inflammasome activation. Obese patients exhibited impaired microarterial functionality in comparison to control nonobese counterparts. Importantly, endothelial dysfunction in obese patients positively correlated with greater expression of DPP4, prosenescent, and proinflammatory markers in visceral adipose tissue nearby the resistance arteries. Moreover, when DPP4 activity or sDPP4-induced prosenescent mechanism was blocked, endothelial dysfunction was restored back to levels of healthy subjects. CONCLUSIONS: These results reveal sDPP4 as a relevant mediator in early vascular aging and highlight its capacity activating main proinflammatory mediators in the endothelium that might be pharmacologically tackled.

Diseno del trabajo, bienestar y salud mental: Revision de literatura / Work Design, Well-being, and Mental Health: Literature Review

Resumen. El presente texto aporta al conocimiento sobre la relación entre diseno del trabajo, bienestar y salud mental. Realizamos una revisión de las publicaciones más recientes en relación con las variables estudiadas para ofrecer una sintesis de los principales conceptos, modelos teóricos y la evidencia empirica que explican la relación. Efectuamos la búsqueda en cuatro bases de datos: Web of Science, Springer, Ebsco y Pro-Quest en las que identificamos N = 11,878 artículos sobre Work design (N = 4,332), Job Desgin (N = 4,854) y Job Demands-Resources (N = 2,692). Destacamos los modelos de características del trabajo y de demandas-recursos laborales, para promover el bienestar y salud mental de los trabajadores. Analizamos la importancia de integrar las variables a nivel práctico, en relación con las unidades de análisis individual, grupal y organizacional; así como la necesidad de tener en cuenta la variedad de ocupaciones, cargos y la forma en que sus empleados se interrelacionan.

Abstract. This text contributes to the knowledge about the relationship between work design, well-being and mental health. We review the most recent publications concerning the variables studied to offer a synthesis of the main concepts, theoretical models and the empirical evidence that explain the relationship. We searched four databases: Web of Science, Springer, Ebsco and Pro-Quest, in which we identified N = 11,878 articles on Work design (N = 4,332), Job design (N = 4,854) and Job Demands-Resources (N = 2,692). We highlight the models of job characteristics and job-demand resources, to promote the well-being and mental health of workers. We discuss the importance of integrating the variables at a practical level, about the individual, group and organizational units of analysis; as well as the need to take into account the variety of occupations, positions and how their employees interact.

Synthesis and Preclinical Characterization of LY3154885, a Human Dopamine D1 Receptor Positive Allosteric Modulator with an Improved Nonclinical Drug-Drug Interaction Risk Profile.

Results from recently completed clinical studies suggest the dopamine D1 receptor positive allosteric modulator (PAM) mevidalen (1) could offer unique value for lewy body dementia (LBD) patients. In nonclinical assessments, 1 was mainly eliminated by CYP3A4-mediated metabolism, therefore at the risk of being a victim of drug-drug interactions (DDI) with CYP3A4 inhibitors and inducers. An effort was initiated to identify a new D1 PAM with an improved DDI risk profile. While attempts to introduce additional metabolic pathways mediated by other CYP isoforms failed to provide molecules with an acceptable profile, we discovered that the relative contribution of CYP-mediated oxidation and UGT-mediated conjugation could be tuned to reduce the CYP3A4-mediated victim DDI risk. We have identified LY3154885 (5), a D1 PAM that possesses similar in vitro and in vivo pharmacologic properties as 1, but is metabolized mainly by UGT, predicting it could potentially offer lower victim DDI risk in clinic.

Síncope como manifestación clínica del bloqueo aurículo-ventricular paroxístico y respuesta al implante de marcapasos bicameral / Syncope as a clinical manifestation of paroxysmal atrioventricular block and response to bicameral pacemaker implantation

Resumen El síncope es el principal síntoma que presentan los pacientes con bloqueo aurículo-ventricular completo paroxístico y puede obedecer a una serie de etiologías intrínsecas o extrínsecas. Los bloqueos son causa de disfunción importante, con alta carga de morbilidad, incluso en pacientes sin cardiopatía isquémica o anomalía estructural de base. Se presenta el caso de una paciente con corazón estructuralmente normal, quien ingresó para estudio de síncope y durante el monitoreo Holter de 24 horas se documentó bloqueo aurículo-ventricular completo paroxístico, por lo cual se procedió al implante de un marcapasos bicameral, con muy buena respuesta a la intervención. Los bloqueos aurículo-ventricular completos pueden ser paroxísticos o permanentes y la única forma de diferenciarlos son los hallazgos electrocardiográficos. Es muy importante realizar el diagnóstico de bloqueo aurículo-ventricular completo, bien sea paroxístico o definitivo, porque el único tratamiento es el implante de un dispositivo de estimulación eléctrica cardíaca.

Abstract Syncope is the main symptom presented by patients with paroxysmal complete atrioventricular block, and it may be due to several intrinsic or extrinsic etiologies. AV blocks are a major cause of dysfunction, with a high burden of disease, even in patients without ischemic heart disease or underlying structural abnormality. The case of a patient with a structurally normal heart is presented, who was admitted for a syncope study and during a 24-hour Holter monitoring, a paroxysmal complete AV block was documented, which led to the implantation of a bicameral pacemaker and had a very good response to the procedure. Complete AV blocks can be paroxysmal or permanent, and the only way to differentiate them is by electrocardiographic findings. It is very important to make the diagnosis of complete AV block, either paroxysmal or permanent, because the only treatment is the implantation of a cardiovascular implantable electronic device.

Development and Application of a Mechanistic Population Modeling Approach to Describe Abemaciclib Pharmacokinetics.

Abemaciclib is an oral anticancer drug that inhibits cyclin dependent kinases 4 and 6 and is metabolized by cytochrome P450 3A in the intestines and liver to active metabolites. The objectives were (1) to develop a mechanistic model to characterize the pharmacokinetics (PK) of the active moieties and investigate the effect of patient factors and (2) apply the model to dat from two phase III breast cancer trials of abemaciclib in combination with endocrine therapy. To develop the model, data from seven phase I studies and two phase II studies including 421 patients with cancer and 65 healthy individuals were pooled for nonlinear mixed effects modeling. The PK was similar between patients and healthy subjects, and the effects of diarrhea, formulation, race, and patient covariates on exposure were negligible. Application of the model confirmed its predictive performance and that abemaciclib PK did not change when coadministered with endocrine therapy.

Ruptura de vena cava inferior secundaria a uso de sonda de ecografía intracardiaca tratada de manera exitosa con balón de alta distensibilidad / Inferior vena cava rupture associated with the use of an intracardiac echocardiography probe and successfully treated with a high-compliance balloon

Resumen La ruptura de la vena cava inferior durante los procedimientos de intervencionismo percutáneo es una complicación infrecuente que se asocia con alta tasa de mortalidad aunque sea detectada a tiempo y se realice reparo quirúrgico, el cual es hoy el estándar de manejo. No existen hasta el momento casos reportados de manejo percutáneo de perforación de la vena cava durante procedimientos de electrofisiología. Se describe el caso de una paciente llevada a aislamiento eléctrico de venas pulmonares para el manejo de fibrilación auricular paroxística, en quien, durante el procedimiento, se produjo perforación accidental de la vena cava inferior con la sonda de ecocardiografía intracardiaca, la cual fue tratada exitosamente mediante el uso de un balón de alta distensibilidad con lo que se logró adecuada hemostasia sin necesidad de intervención quirúrgica. Se considera que el uso de un balón de alta distensibilidad puede ser una herramienta útil en el control del sangrado asociado a lesiones vasculares iatrogénicas, y que por consiguiente todo intervencionista debería tener presente.

Abstract Rupture of the inferior vena cava during percutaneous intervention procedures is an uncommon complication. It is associated with a high rate of mortality, even when it is detected at the time and the current standard management, surgical repair is performed. At present there are no cases reported of the percutaneous management of a vena cava perforation during electrophysiology procedures. The case is described of a patient subjected to electric ablation of pulmonary veins for the management of paroxysmal atrial fibrillation. During the procedure there was an accidental rupture of the inferior vena cava with the echocardiography cardiac catheter. She was successfully treated using a high-compliance balloon, with adequate haemostasis being achieved without surgical intervention. The use of a high-compliance balloon is considered as a useful tool in the control of bleeding associated with iatrogenic vascular injuries, and for this reason all interventionist should be aware of it.

Predicting Clinical Effects of CYP3A4 Modulators on Abemaciclib and Active Metabolites Exposure Using Physiologically Based Pharmacokinetic Modeling.

Abemaciclib, a selective inhibitor of cyclin-dependent kinases 4 and 6, is metabolized mainly by cytochrome P450 (CYP)3A4. Clinical studies were performed to assess the impact of strong inhibitor (clarithromycin) and inducer (rifampin) on the exposure of abemaciclib and active metabolites. A physiologically based pharmacokinetic (PBPK) model incorporating the metabolites was developed to predict the effect of other strong and moderate CYP3A4 inhibitors and inducers. Clarithromycin increased the area under the plasma concentration-time curve (AUC) of abemaciclib and potency-adjusted unbound active species 3.4-fold and 2.5-fold, respectively. Rifampin decreased corresponding exposures 95% and 77%, respectively. These changes influenced the fraction metabolized via CYP3A4 in the model. An absolute bioavailability study informed the hepatic and gastric availability. In vitro data and a human radiolabel study determined the fraction and rate of formation of the active metabolites as well as absorption-related parameters. The predicted AUC ratios of potency-adjusted unbound active species with rifampin and clarithromycin were within 0.7- and 1.25-fold of those observed. The PBPK model predicted 3.78- and 7.15-fold increases in the AUC of the potency-adjusted unbound active species with strong CYP3A4 inhibitors itraconazole and ketoconazole, respectively; and 1.62- and 2.37-fold increases with the concomitant use of moderate CYP3A4 inhibitors verapamil and diltiazem, respectively. The model predicted modafinil, bosentan, and efavirenz would decrease the AUC of the potency-adjusted unbound active species by 29%, 42%, and 52%, respectively. The current PBPK model, which considers changes in unbound potency-adjusted active species, can be used to inform dosing recommendations when abemaciclib is coadministered with CYP3A4 perpetrators.

Physiologically-Based Pharmacokinetic Models for Evaluating Membrane Transporter Mediated Drug-Drug Interactions: Current Capabilities, Case Studies, Future Opportunities, and Recommendations.

Physiologically-based pharmacokinetic (PBPK) modeling has been extensively used to quantitatively translate in vitro data and evaluate temporal effects from drug-drug interactions (DDIs), arising due to reversible enzyme and transporter inhibition, irreversible time-dependent inhibition, enzyme induction, and/or suppression. PBPK modeling has now gained reasonable acceptance with the regulatory authorities for the cytochrome-P450-mediated DDIs and is routinely used. However, the application of PBPK for transporter-mediated DDIs (tDDI) in drug development is relatively uncommon. Because the predictive performance of PBPK models for tDDI is not well established, here, we represent and discuss examples of PBPK analyses included in regulatory submission (the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Agency (PMDA)) across various tDDIs. The goal of this collaborative effort (involving scientists representing 17 pharmaceutical companies in the Consortium and from academia) is to reflect on the use of current databases and models to address tDDIs. This challenges the common perceptions on applications of PBPK for tDDIs and further delves into the requirements to improve such PBPK predictions. This review provides a reflection on the current trends in PBPK modeling for tDDIs and provides a framework to promote continuous use, verification, and improvement in industrialization of the transporter PBPK modeling.

Calidad de vida de pacientes con diabetes tipo 2 en Colombia. Revisión sistemática y metaanálisis acumulativo / Quality of Life of Patients with Type 2 Diabetes in Colombia. Systematic Review and Cumulative Meta-analysis

Resumen Antecedentes: La calidad de vida (CV) relacionada con la salud es un indicador de desempeño de los sistemas sanitarios; no obstante, se desconoce su estado en personas con diabetes tipo 2, lo que limita la implementación y evaluación de intervenciones dirigidas a mejorar su salud. Objetivo: Identificar los dominios más afectados en la CV de pacientes con diabetes tipo 2. Método: Búsqueda sistemática en las bases de datos LILACS, Pubmed, Embase y Google Académico, de estudios observacionales que midieron de manera cuantitativa la CV de pacientes con diabetes tipo 2, sin importar la comorbilidad o estado funcional, en el contexto ambulatorio u hospitalario en Colombia. Para identificar los dominios más afectados se realizó un metaanálisis acumulativo de estudios observacionales que midieron la CV con los Cuestionarios de Salud SF-36 (Short Form-36) y SF-8 (Short Form-8), y se realizó un modelo de efectos aleatorios que permitió la estimación de las medias como medida de efecto combinado. Resultados: Se identificaron siete artículos, de los cuales cuatro fueron incluidos en la síntesis cuantitativa. Los dominios de la CV de los pacientes con diabetes tipo 2 más afectados según los Cuestionarios SF-36 y SF-8 fueron salud general 49,7 (IC 95%: 37,3 a 62,0), rol físico 53,6 (IC 95%: 35,6 a 71,6) y función física 53,8 (IC 95%: 34,8 a 72,8). Conclusión: Los programas preventivos y de atención a personas con diabetes tipo 2 deben enfocarse en un manejo integral que contribuya al mejoramiento de su CV relacionada con su salud.

Abstract Background: The quality of life related to health is an indicator performance of health system; however, its condition in people with type 2 diabetes is unknown, which limits the implementation and evaluation of interventions aimed at improving their health. Objectives: To identify the most affected domains in the quality of life in people with 2 type diabetes. Methods: Systematic search in LILACS, Pubmed, Embase and Google Scholar data bases for observational studies that measure quantitatively the quality of life for patients with diabetes type 2, despite comorbidity or functional status, in the ambulatory or hospital setting in Colombia. In order to identify the most affected domains, it was carried out a cumulative meta-analysis of observational studies aimed to measure life quality through the Health Questionnaires SF-36 (Short Form-36) and SF-8 (Short Form-8), and also, a Random effects model was conducted, which allowed the average as a measure of combined effect. Results: Seven articles were identified, of which four were included in the quantitative synthesis, the most affected domains according to SF-36 and SF-8 were general health 49.7 (95% CI: 37.3 to 62.0), physical role 53.6 (95% CI: 35.6 to 71.6), physical function 53.8 (95% CI: 34.8 to 72.8). Conclusion: Preventive and care programs for people with type 2 diabetes should focus on comprehensive management that contributes to quality of life improvement concerned health. It is still required to expand the investigation to account for the results in people's health.

Taponamiento pericárdico asociado a minoxidil: un diagnóstico olvidado / Pericardial tamponade associated with minoxidil: a forgotten diagnosis

Resumen El derrame pericárdico es una acumulación excesiva de líquido en el espacio pericárdico, el cual se ha asociado al empleo crónico de minoxidil desde principios de su uso clínico; este es formulado comúnmente a pacientes con hipertensión arterial de difícil control y con enfermedad renal crónica asociada, por su efecto vasodilatador arterial y poco efecto sobre la circulación venosa. Se expone el caso de un paciente quien presentó clínica sugestiva de derrame pericárdico, el cual fue confirmado por imágenes (rayos X, tomografía y ecocardiografía) y quien además se encontraba en tratamiento de hemodiálisis crónica por enfermedad renal crónica secundaria a síndrome nefrótico. En la literatura existen algunos reportes de casos similares, pero no hay estudios con datos concluyentes que permitan establecer un porcentaje claro de asociación ni la causa de esta enfermedad. Con este reporte de caso se busca aumentar la sospecha diagnóstica de esta asociación para que otros clínicos tengan este posible diagnóstico en mente, una vez se hayan descartado otras etiologías adicionales y puedan suspender a tiempo la medicación a fin de evitar desenlaces catastróficos como el taponamiento pericárdico.

Abstract Pericardial effusion is an excessive accumulation of fluid in the pericardial space and has been associated with the long-term use of minoxidil from the beginning of its clinical use. It is commonly prescribed to patients with difficult to control arterial hypertension and associated chronic kidney disease due to it arterial vasodilator effects and little effect of the venous circulation. A case is presented on a patient who had a clinical picture suggestive of a pericardial effusion, which was confirmed by imaging tests (X-ray, tomography, and cardiac ultrasound). She was also on long-term haemodialysis treatment due to chronic kidney disease secondary to a nephrotic syndrome. There are reports of similar cases in the literature, but there are no studies with conclusive data that may help to establish a clear percentage association or the cause of the disease. This case report seeks to increase the diagnostic suspicion of this association so that other clinicians may have this possible diagnosis in mind, once they have ruled out any other. They can then stop the medication on time in order to prevent catastrophic outcomes like pericardiac tamponade.

Evaluación y manejo del riesgo cardiovascular en infección por VIH. Consenso de expertos ACIN / Evaluation and management of cardiovascualr risk in VIH infection: Expert consensus of ACIN (Colombian Association of Infectious Diseases)

Los pacientes con infección por VIH tienen una mayor incidencia de eventos cardiovasculares en comparación con la población general; los factores que contribuyen al incremento del riesgo de eventos cardiovasculares son la prevalencia de factores de riesgo cardiovascular tradicionales (FRCV), la infección por VIH que condiciona tanto un proceso de inflamación crónica como alteración de la función endotelial y la exposición a los antirretrovirales. Los factores que deben ser objeto de intervención son los FRCV tradicionales, en especial la alta tasa de fumadores entre este grupo de pacientes, la tamización y tratamiento de HTA, el síndrome metabólico y el acceso temprano a la terapia antirretroviral con medicamentos con mayor perfil de seguridad . Esta guía pretende proveer información y recomendaciones en el ámbito nacional acerca de la relación entre la infección por VIH/SIDA (Síndrome de Inmunodeficiencia Adquirida), uso de antirretrovirales y riesgo cardiovascular.

Patients with VIH infection have greater risk for cardiovascular diseases compared to general population. Risk factors that increase the frequency of cardiovascular events are: presence of cardiovascular traditional risk factors, chronic inflammation by HIV that impairs endothelial function and the exposure to antiretrovirals. The factors that should be the target for intervention are the traditional know cardiovascular factors such, especially high rate of smokers, screening and treatment for hypertension, metabolic syndrome and early access to HAART. The present guidelines provides information about the use of antiretrovirals in patients with HIV and its relation with cardiovascular risk.