Impact of thermo-mechanical skin treatment on refraction and keratometry in patients with dry eye disease and the implications for cataract surgery.

PURPOSE: To determine the changes in keratometry measurements and refraction in patients having the thermo-mechanical periorbital skin treatment, Tixel®, to treat dry eye disease (DED). METHODS: A multi-centre, prospective, non-masked study was conducted. DED patients were recruited in 3 international centres and were evaluated in 5 visits separated by an interval of 2 weeks except for the last visit which took place after 18 weeks from visit 1. The same clinical examination was performed at all visits: OSDI questionnaire, tear stability, keratometry, best corrected visual acuity and refraction. Tixel® treatment was applied at the first 3 visits. RESULTS: 89 participants (24 males/65 females; mean age: 55.0 ± 14.2 years) were included: 20 presented moderate DED symptoms and 69 severe DED symptoms. Significant differences were found for the spherocylindrical refraction (vector analysis) between visit 1 and visits 2 and 3. Following cumulative analysis, 11.86 % and 16.94 % of participants had more than 0.5 dioptre (D) change in mean keratometry and keratometric astigmatism, respectively, at 3 months post-treatment. A total of 5.40 % had a sphere and cylinder change greater than 0.50D and 16.21 % had the axis changed more than 10 degrees (vector analysis). These changes were particularly significant in patients with severe DED symptoms. CONCLUSIONS: Keratometry readings and refraction can change following thermo-mechanical skin treatment for DED, especially in those patients with severe DED symptoms. This should be considered as potential errors in intraocular lens calculations may be induced.

Short-Term Efficacy of Ophthalmic Cyclosporine: A 0.1% Cationic Emulsion in Dry Eye Patients Assessed Under Controlled Environment.

INTRODUCTION: To evaluate the short-term efficacy of cyclosporine A (CsA)-0.1% cationic emulsion (CE) in patients with dry eye disease (DED) and mitigation of the inflammatory flares triggered by desiccating stress environments. METHODS: A single-center non-randomized clinical trial was performed at a tertiary care setting. Twenty patients with DED treated with CsA 0.1% CE were exposed to a normal controlled environment (NCE) (23 °C, 50% relative humidity) and an adverse controlled environment (ACE) (23 °C, 10% relative humidity, 0.43 m/s localized airflow) during baseline and the 1- and 3-month visits. Patients underwent the following evaluations: conjunctival hyperemia and staining, corneal fluorescein staining (CFS) using the Oxford and Cornea and Contact Lens Research Unit (CCLRU) scale, meibomian gland (MG) secretion quality, Dry Eye Questionnaire-5, Symptom Assessment in Dry Eye (SANDE II), and Change in Dry Eye Symptoms Questionnaire. Multivariate models were adjusted for statistical analysis. RESULTS: Nineteen women and one man (mean age, 58.9 ± 12.3 years) completed the study. All symptom questionnaires, CFS, conjunctival hyperemia and staining, and MG secretion quality improved (p ≤ 0.003) with 1 month of treatment; improvements were maintained after 3 months (p ≤ 0.02), except for SANDE II (p ≥ 0.07). The CFS worsening (total CCLRU) after baseline ACE exposure (from 8.6 to 10.1) was higher, although not significant (p = 0.64), compared with 1 month (from 5.4 to 5.8) and 3 months (from 5.0 to 5.9) after treatment. CONCLUSION: Topical CsA-0.1% CE improved DED signs and symptoms after 1 month of treatment under controlled environmental conditions. Future studies should confirm the benefit of CsA-0.1% CE in desiccating stress environments. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04492878.

Analysis of the mucosal chemokines CCL28, CXCL14, and CXCL17 in dry eye disease: An in vitro and clinical investigation.

Mucosal chemokines have antimicrobial properties and play an important role in mucosal immunity. However, little is known about their expression on the ocular surface. This study aimed to analyze the expression of the mucosal chemokines CCL28, CXCL14 and CXCL17 in corneal and conjunctival epithelial cells under in vitro dry eye (DE) conditions, and in conjunctival samples from healthy subjects and DE patients. Human corneal epithelial cells (HCE) and immortalized human conjunctival epithelial cells (IM-HConEpiC) were incubated under hyperosmolar (400-500 mOsM) or inflammatory (TNF-α 25 ng/mL) conditions for 6 h and 24 h to measure CCL28, CXCL14, and CXCL17 gene expression by RT-PCR and their secretion by immunobead-based analysis (CCL28, CXCL14) and ELISA (CXCL17). Additionally, twenty-seven DE patients and 13 healthy subjects were included in this study. DE-related questionnaires (OSDI, mSIDEQ and NRS) evaluated symptomatology. Ocular surface integrity was assessed using vital staining. Tactile sensitivity was measured with Cochet-Bonnet esthesiometer, and mechanic and thermal (heat and cold) sensitivity using Belmonte's non-contact esthesiometer. Subbasal nerve plexus and dendritic cell density were analyzed by in vivo confocal microscopy. Conjunctival cells from participants were collected by impression cytology to measure mucosal chemokines gene expression by RT-PCR. Our results showed that HCE and IM-HConEpiC cells increased CCL28, CXCL14, and CXCL17 secretion under hyperosmolar conditions. The gene expression of CCL28 was significantly upregulated in conjunctival samples from DE patients. CCL28 expression correlated positively with symptomatology, corneal staining, heat sensitivity threshold, and dendritic cell density. CXCL14 expression correlated positively with age, ocular pain, conjunctival staining, tactile sensitivity, and image reflectivity. CXCL17 expression correlated positively with corneal staining. These results suggest that corneal and conjunctival epithelial cells could be a source of CCL28, CXCL14, and CXCL17 on the ocular surface and that CCL28 might be involved in DE pathogenesis.

Aplicación de un modelo farmacocinético poblacional para el seguimiento de pacientes en tratamiento con dolutegravir: estudio piloto

Introducción: a pesar de los avances en tratamiento antirretroviral, existe la posibilidad de que personas que viven con el virus de la inmunodeficiencia humana (VIH) experimenten falla terapéutica vinculada a múltiples factores que impactan en la respuesta al fármaco. Objetivos: evaluar la utilidad de aplicar un modelo farmacocinético en pacientes con diagnóstico de VIH en tratamiento con dolutegravir para el análisis de las concentraciones plasmáticas experimentales. Adicionalmente, se pretende identificar potenciales interacciones farmacológicas, evaluar adherencia y fallo terapéutico. Material y método: se realizó un estudio piloto transversal y observacional en pacientes VIH tratados con dolutegravir que incluyó la dosificación de la concentración plasmática, evaluación de adherencia mediante el cuestionario simplificado de adherencia a la medicación (SMAQ) y retiro de medicación. Se utilizó un modelo poblacional referenciado en la bibliografía para la predicción de concentraciones de dolutegravir en cada paciente y se compararon con las concentraciones experimentales. Resultados: fueron incluidos en el estudio 21 pacientes. Al cotejar las concentraciones plasmáticas experimentales con la simulación farmacocinética se encontraron diferencias para 12 pacientes, las cuales se explican por posibles interacciones farmacológicas, mala adherencia u otros factores que afectan la farmacocinética. Se detectó 38% de no adherencia de acuerdo con SMAQ y 23% de acuerdo con el retiro de medicación. Conclusiones: se expone el rol potencial de los modelos farmacocinéticos para la interpretación de concentraciones plasmáticas y se genera la necesidad de avanzar en este tipo de estudios para el establecimiento de rango terapéutico y aplicabilidad clínica.

Introduction: Despite advances in antiretroviral treatment, there is a possibility that people living with HIV may experience treatment failure linked to multiple factors that impact drug response. Objective: To evaluate the usefulness of applying a pharmacokinetic model in patients diagnosed with HIV undergoing treatment with dolutegravir for the analysis of experimental plasma concentrations. Additionally, the aim is to identify potential drug interactions, assess adherence, and therapeutic failure. Method: A cross-sectional, observational pilot study was conducted in HIV patients treated with dolutegravir, which included plasma concentration dosing, assessment of adherence using the Simplified Medication Adherence Questionnaire (SMAQ), and medication withdrawal. A population-based model referenced in the literature was used to predict dolutegravir concentrations in each patient and these were compared with experimental concentrations. Results: Twenty-one patients were included in the study. When comparing experimental plasma concentrations with pharmacokinetic simulation, differences were found for 12 patients, which can be explained by possible drug interactions, poor adherence, or other factors affecting pharmacokinetics. Non-adherence was detected in 38% according to the SMAQ and 23% according to medication withdrawal. Conclusions: The potential role of pharmacokinetic models in the interpretation of plasma concentrations is highlighted, emphasizing the need to advance in this type of studies to establish therapeutic ranges and clinical applicability.

Introdução: Apesar dos avanços no tratamento antirretroviral, existe a possibilidade de que pessoas que vivem com HIV experimentem falha terapêutica ligada a múltiplos fatores que impactam na resposta ao medicamento. Objetivos: Avaliar a utilidade da aplicação de um modelo farmacocinético em pacientes com diagnóstico de HIV em tratamento com dolutegravir para análise de concentrações plasmáticas experimentais. Além disso, pretende-se identificar potenciais interações medicamentosas, avaliar a adesão e a falha terapêutica. Método: Um estudo piloto observacional transversal foi conduzido em pacientes HIV tratados com dolutegravir que incluiu dosagem de concentração plasmática, avaliação de adesão usando o questionário simplificado de adesão à medicação (SMAQ) e retirada da medicação. Um modelo populacional referenciado na literatura foi utilizado para prever as concentrações de dolutegravir em cada paciente e compará-las com as concentrações experimentais. Resultados: 21 pacientes foram incluídos no estudo. Ao comparar as concentrações plasmáticas experimentais com a simulação farmacocinética, foram encontradas diferenças em 12 pacientes, que são explicadas por possíveis interações medicamentosas, má adesão ou outros fatores que afetam a farmacocinética. Foram detectadas 38% de não adesão segundo o SMAQ e 23% segundo retirada da medicação. Conclusões: Fica exposto o papel potencial dos modelos farmacocinéticos para a interpretação das concentrações plasmáticas e gera-se a necessidade de avançar neste tipo de estudos para estabelecer a faixa terapêutica e a aplicabilidade clínica.

Living Lab Data of Patient Needs and Expectations for eHealth-Based Cardiac Rehabilitation in Germany and Spain From the TIMELY Study: Cross-Sectional Analysis.

BACKGROUND: The use of eHealth technology in cardiac rehabilitation (CR) is a promising approach to enhance patient outcomes since adherence to healthy lifestyles and risk factor management during phase III CR maintenance is often poorly supported. However, patients' needs and expectations have not been extensively analyzed to inform the design of such eHealth solutions. OBJECTIVE: The goal of this study was to provide a detailed patient perspective on the most important functionalities to include in an eHealth solution to assist them in phase III CR maintenance. METHODS: A guided survey as part of a Living Lab approach was conducted in Germany (n=49) and Spain (n=30) involving women (16/79, 20%) and men (63/79, 80%) with coronary artery disease (mean age 57 years, SD 9 years) participating in a structured center-based CR program. The survey covered patients' perceived importance of different CR components in general, current usage of technology/technical devices, and helpfulness of the potential features of eHealth in CR. Questionnaires were used to identify personality traits (psychological flexibility, optimism/pessimism, positive/negative affect), potentially predisposing patients to acceptance of an app/monitoring devices. RESULTS: All the patients in this study owned a smartphone, while 30%-40% used smartwatches and fitness trackers. Patients expressed the need for an eHealth platform that is user-friendly, personalized, and easily accessible, and 71% (56/79) of the patients believed that technology could help them to maintain health goals after CR. Among the offered components, support for regular physical exercise, including updated schedules and progress documentation, was rated the highest. In addition, patients rated the availability of information on diagnosis, current medication, test results, and risk scores as (very) useful. Of note, for each item, except smoking cessation, 35%-50% of the patients indicated a high need for support to achieve their long-term health goals, suggesting the need for individualized care. No major differences were detected between Spanish and German patients (all P>.05) and only younger age (P=.03) but not sex, education level, or personality traits (all P>.05) were associated with the acceptance of eHealth components. CONCLUSIONS: The patient perspectives collected in this study indicate high acceptance of personalized user-friendly eHealth platforms with remote monitoring to improve adherence to healthy lifestyles among patients with coronary artery disease during phase III CR maintenance. The identified patient needs comprise support in physical exercise, including regular updates on personalized training recommendations. Availability of diagnoses, laboratory results, and medications, as part of a mobile electronic health record were also rated as very useful. TRIAL REGISTRATION: ClinicalTrials.gov NCT05461729; https://clinicaltrials.gov/study/NCT05461729.

Drug Exposure During Pregnancy: A Case-Control Study from a Primary Care Database.

Objective: Drug exposure during pregnancy is frequent, even more during first trimester as pregnant women might not be aware of their condition. We used available electronic health records (EHRs) to describe the use of medications during the first trimester in pregnant women and to compare drug exposure between those women who had an abortion (either elective or spontaneous) compared to those who had live births. Materials and Methods: Case-control study of abortions, either elective or spontaneous (cases), and live birth pregnancies (controls) in Sistema d'Informació per al Desenvolupament de la Investigació en Atenció Primària (Catalan Primary Health electronic health records) from 2012 to 2020. Exposure to drugs during first trimester of pregnancy was considered to estimate the association with abortion by conditional logistic regression and adjusted by health conditions and other drugs exposure. Results: Sixty thousand three hundred fifty episodes of abortions were matched to 118,085 live birth pregnancy episodes. Cases had higher rates of alcohol intake (9.9% vs. 7.2%, p < 0.001), smoking (4.5% vs. 3.6%, p < 0.001), and previous abortions (9.9% vs. 7.8%, p < 0.001). Anxiety (30.3% and 25.1%, p < 0.001), respiratory diseases (10.6% and 9.2%, p < 0.001), and migraine (8.2% and 7.3%, p < 0.001), for cases and controls, respectively, were the most frequent baseline conditions. Cases had lower rate of drug exposure, 40,148 (66.5%) versus 80,449 (68.1%), p < 0.001. Association with abortion was found for systemic antihistamines (adjusted odds ratio [ORadj] 1.23, 95% confidence interval [CI] 1.19-1.27), antidepressants (ORadj 1.11, 95% CI 1.06-1.17), anxiolytics (ORadj 1.31, 95% CI 1.26-1.73), and nonsteroidal anti-inflammatory drugs (ORadj 1. 63, 95% CI 1.59-1.67). Conclusions: These high rates of drug exposures during the first trimester of pregnancy highlights the relevance of informed prescription to women with childbearing potential.

Human Data on Pharmacokinetic Interactions of Cannabinoids: A Narrative Review.

Concomitant use of cannabinoids with other drugs may result in pharmacokinetic drug-drug interactions, mainly due to the mechanism involving Phase I and Phase II enzymes and/or efflux transporters. Cannabinoids are not only substrates but also inhibitors or inducers of some of these enzymes and/or transporters. This narrative review aims to provide the available information reported in the literature regarding human data on the pharmacokinetic interactions of cannabinoids with other medications. A search on Pubmed/Medline, Google Scholar, and Cochrane Library was performed. Some studies were identified with Google search. Additional articles of interest were obtained through cross-referencing of published literature. All original research papers discussing interactions between cannabinoids, used for medical or recreational/adult-use purposes, and other medications in humans were included. Thirty-two studies with medicinal or recreational/adult-use cannabis were identified (seventeen case reports/series, thirteen clinical trials, and two retrospective analyses). In three of these studies, a bidirectional pharmacokinetic drug-drug interaction was reported. In the rest of the studies, cannabinoids were the perpetrators, as in most of them, concentrations of cannabinoids were not measured. In light of the widespread use of prescribed and non-prescribed cannabinoids with other medications, pharmacokinetic interactions are likely to occur. Physicians should be aware of these potential interactions and closely monitor drug levels and/or responses. The existing literature regarding pharmacokinetic interactions is limited, and for some drugs, studies have relatively small cohorts or are only case reports. Therefore, there is a need for high-quality pharmacological studies on cannabinoid-drug interactions.

Drug-Drug Interaction Between Cannabidiol, Cyclosporine, and Mycophenolate Mofetil: A Case Report.

Kidney transplantation remains the optimal therapy for many patients with end-stage kidney disease (ESKD). Chronic pain is one of the most common and distressing symptoms among patients with ESKD, and its treatment is a complex and challenging task to accomplish. The benefits of cannabidiol (CBD) in chronic pain treatment have been reported recently. Cannabidiol is metabolized by cytochrome P450, mainly CYP3A4 and CYP2C19, and can also undergo direct conjugation via UDP-glucuronosyltransferase enzymes, with a growing body of evidence suggesting it is also a potent inhibitor or inducer of these pathways. Cannabidiol was also found to be a potent inhibitor of carboxylesterases in vitro. Because cytochrome P450 enzymes and carboxylesterases are also responsible for the clearance and activation of immunosuppressants, respectively, drug-drug interactions are likely to occur. Here, we report a pharmacokinetic drug interaction between CBD and cyclosporine and mycophenolate mofetil in a patient with ESKD with a kidney transplantation. It is thus crucial to take into account these interactions and monitor drug levels to avoid drug toxicity or a lack of efficacy. This study is in accordance with the guidelines of the Declaration of Helsinki and the Declaration of Istanbul.

Gene expression changes in conjunctival cells associated with contact lens wear and discomfort.

PURPOSE: This study aimed to analyze the differences in the expression of pain-related genes in conjunctival epithelial cells among symptomatic contact lens (CL) wearers (SCLWs), asymptomatic CL wearers (ACLWs), and non-CL wearers (non-CLWs). METHODS: For this study, 60 participants (20 non-CLWs, 40 CLWs) were enrolled. The CLW group comprised 20 ACLWs and 20 SCLWs according to the Contact Lens Dry Eye Questionnaire short form©. Conjunctival cells were collected using impression cytology, and RNA was isolated and used to determine the expression levels of 85 human genes involved in neuropathic and inflammatory pain. The effects of CL wear and discomfort were evaluated using mixed-effects ANOVA with partially nested fixed-effects model. Gene set enrichment analysis was performed to assign biological meaning to sets of differentially expressed genes. RESULTS: Six genes (CD200, EDN1, GRIN1, PTGS1, P2RX7, and TNF) were significantly upregulated in CLWs compared to non-CLWs. Eleven genes (ADORA1, BDKRB1, CACNA1B, DBH, GRIN1, GRM1, HTR1A, PDYN, PTGS1, P2RX3, and TNF) were downregulated in SCLWs compared to ACLWs. These genes were mainly related to pain, synaptic transmission and signaling, ion transport, calcium transport and concentration, and cell-cell signaling. CONCLUSIONS: CL wear modified the expression of pain- and inflammation-related genes in conjunctival epithelial cells. These changes may be in part, along with other mechanisms, responsible for CL discomfort in SCLWs.

Estimating the direct costs of oral cancer in Spain: a retrospective hospital data analysis

Background: Studies on the costs incurred from cancer in Spain are scarce and have focused on the most prevalent types such as colorectal, breast, and lung cancer. The aim of this study was to calculate the direct costs associated with the diagnostic, treatment and follow-up procedures for oral cancer in Spain. Material and methods: Applying a bottom-up approach, we retrospectively analyzed the medical records of a cohort of 200 patients with oral cancer (C00-C10), diagnosed and treated in Spain between 2015 and 2017. For each patient, we collected their age, sex, degree of medical impairment (American Society of Anesthesiologists [ASA] classification), tumor extent (TNM classification), relapses and survival during the first 2 years of follow-up. The final calculation of the costs is expressed in absolute values in euros as the percentage of the gross domestic product per capita and in international dollars (I$). Results: The total cost per patient rose to €16,620 (IQR, €13,726; I$11,634), and the total direct cost at the national level was €136,084,560 (I$95,259,192). The mean cost for oral cancer represented 65.1% of the gross domestic product per capita. The costs for the diagnostic and therapeutic procedures were determined by the ASA grade, tumor size, lymph node infiltration and presence of metastases. Conclusions: The direct costs for oral cancer are considerable compared with other types of cancer. In terms of gross domestic product, the costs were similar to those of countries neighboring Spain, such as Italy and Greece. The main determinants of this economic burden were the patient's degree of medical impairment and tumor extent. (AU)

Drug exposure during pregnancy in primary care: an algorithm and observational study from SIDIAP database, Catalunya, Spain.

OBJECTIVES: To develop an algorithm to identify pregnancy episodes in women at childbearing age using SIDIAP (Information System for the Improvement of Research in Primary Care) data (Catalunya, Spain).To describe drugs dispensed during gestation. DESIGN: Construction of an algorithm to identify all pregnancy episodes occurred from January 2011 to June 2020 in women aged 12-50. The variables used to create the algorithm include first day of last menstrual period, reasons for pregnancy termination and diagnoses registered in the primary healthcare records. Population-based cohort study including the pregnancy episodes identified by the algorithm. SETTING: Catalonia, Spain. PARTICIPANTS: All women aged 12-50 with at least one pregnancy episode occurred during January 2011-June 2020. INTERVENTIONS: No interventions performed. PRIMARY AND SECONDARY OUTCOME MEASURES: Identification of pregnancy episodes through an algorithm and description of drug exposure. RESULTS: We identified 327 865 pregnancy episodes in 250 910 people with a mean age of 31.3 years. During the study period, 83.4% of the episodes were exposed to at least one drug. The most frequent groups dispensed were iron preparations (48% of pregnancy episodes), iodine therapy (40.2%), analgesics and antipyretics (28%), penicillins (19.8%), vitamin B12 plus folic acid (19.7%) and non-steroidal anti-inflammatory drugs (NSAIDs, 15.1%). The supplements were more frequently dispensed at least twice, and the drugs for acute conditions were mainly dispensed only once during the pregnancy episode. CONCLUSIONS: We developed an algorithm to automatically identify the pregnancy periods in SIDIAP.We described prescription drugs used during pregnancy. The most used ones were supplements, analgesics, NSAID or antibiotics.SIDIAP might be an efficient database to study drug safety during pregnancy and the consequences of drug use in the offspring. TRIAL REGISTRATION NUMBER: EUPAS37675.

Fracture risk after deprescription of bisphosphonates: Application of real-world data in primary care / Riesgo de fractura después de la desprescripción de bifosfonatos: aplicación de real-world data en atención primaria

Purpose: To compare the effect of discontinuing bisphosphonate treatment on fracture risk in postmenopausal women at high versus low risk of fracture. Design: Retrospective, longitudinal and population-based cohort study. Setting: Barcelona City Primary Care. Catalan Health Institute. Participants: All women attended by primary care teams who in January 2014 had received bisphosphonate treatment for at least five years were included and followed for another five years. Intervention: Patients were classified according to their risk of new fractures, defined as those who had a history of osteoporotic fracture and/or who received treatment with an aromatase inhibitor, and the continuity or deprescription of the bisphosphonate treatment was analyzed over fiver year follow-up. Main measurements: The cumulative incidence of fractures and the incidence density were calculated and analyzed using logistic regression and Cox models. Results: We included 3680 women. There were no significant differences in fracture risk in high-risk women who discontinued versus continued bisphosphonate treatment (hazard ratio [HR] 1.17, 95% confidence interval [CI] 0.87–1.58 for total osteoporotic fractures). However, discontinuers at low risk had a lower incidence of fracture than continuers. This difference was significant for vertebral fractures (HR 0.64, 95% CI 0.47–0.88) and total fractures (HR 0.77, 95% CI 0.64–0.92). Conclusion: Our results suggest that deprescribing bisphosphonates in women who have already received five years of treatment does not increase fracture risk. In low-risk women, continuing this treatment might could even favor the appearance of new osteoporotic fractures.(AU)

Objetivo: Comparar el efecto de la desprescripción de bifosfonatos sobre el riesgo de fractura en mujeres posmenopáusicas con alto y bajo riesgo de fractura. Diseño: Estudio de cohortes retrospectivo, longitudinal y de base poblacional. Emplazamiento: Atención primaria Barcelona. Institut Català de la Salut. Participantes: Se incluyeron todas las mujeres atendidas por los equipos de atención primaria que a enero de 2014 habían recibido tratamiento con bifosfonatos durante al menos cinco años. Intervención: Se clasificó a las pacientes según su riesgo de nuevas fracturas, definido como presencia de antecedentes de fractura osteoporótica y/o tratamiento con un inhibidor de la aromatasa, y se analizó la continuidad o desprescripción del tratamiento con bifosfonatos a lo largo de cinco años de seguimiento. Mediciones principales: La incidencia acumulada de fracturas y la densidad de incidencia se calcularon y analizaron mediante regresión logística y modelos de Cox. Resultados: Se incluyeron 3.680 mujeres. No hubo diferencias significativas en el riesgo de fractura en mujeres de alto riesgo que desprescribieron el bisfosfonato comparado con aquellas que continuaron (hazard ratio [HR] 1,17, intervalo de confianza [IC] de 95% 0,87-1,58 para fracturas osteoporóticas totales). Sin embargo, los que discontinuaron con bajo riesgo tuvieron una menor incidencia de fractura que los que continuaron. Esta diferencia fue significativa para fracturas vertebrales (HR 0,64, IC 95% 0,47-0,88) y fracturas totales (HR 0,77, IC 95% 0,64-0,92). Conclusiones: Nuestros resultados sugieren que la desprescripción de bifosfonatos en mujeres que ya han recibido cinco años de tratamiento no aumenta el riesgo de fractura. En mujeres de bajo riesgo, la continuación de este tratamiento podría incluso favorecer la aparición de nuevas fracturas osteoporóticas.(AU)

Fracture risk after deprescription of bisphosphonates: Application of real-world data in primary care.

PURPOSE: To compare the effect of discontinuing bisphosphonate treatment on fracture risk in postmenopausal women at high versus low risk of fracture. DESIGN: Retrospective, longitudinal and population-based cohort study. SETTING: Barcelona City Primary Care. Catalan Health Institute. PARTICIPANTS: All women attended by primary care teams who in January 2014 had received bisphosphonate treatment for at least five years were included and followed for another five years. INTERVENTION: Patients were classified according to their risk of new fractures, defined as those who had a history of osteoporotic fracture and/or who received treatment with an aromatase inhibitor, and the continuity or deprescription of the bisphosphonate treatment was analyzed over fiver year follow-up. MAIN MEASUREMENTS: The cumulative incidence of fractures and the incidence density were calculated and analyzed using logistic regression and Cox models. RESULTS: We included 3680 women. There were no significant differences in fracture risk in high-risk women who discontinued versus continued bisphosphonate treatment (hazard ratio [HR] 1.17, 95% confidence interval [CI] 0.87-1.58 for total osteoporotic fractures). However, discontinuers at low risk had a lower incidence of fracture than continuers. This difference was significant for vertebral fractures (HR 0.64, 95% CI 0.47-0.88) and total fractures (HR 0.77, 95% CI 0.64-0.92). CONCLUSION: Our results suggest that deprescribing bisphosphonates in women who have already received five years of treatment does not increase fracture risk. In low-risk women, continuing this treatment might could even favor the appearance of new osteoporotic fractures.

Quantitative systems pharmacology Model to characterize valproic acid-induced hyperammonemia and the effect of L-carnitine supplementation.

Valproic acid (VPA) is a short-chain fatty acid widely prescribed in the treatment of seizure disorders and epilepsy syndromes, although its therapeutic value may be undermined by its toxicity. VPA serious adverse effects are reported to have a significant and dose-dependent incidence, many associated with VPA-induced hyperammonemia. This effect has been linked with reduced levels of carnitine; an endogenous compound involved in fatty acid's mitochondrial ß-oxidation by facilitation of its entrance via the carnitine shuttle. High exposure to VPA can lead to carnitine depletion causing a misbalance between the intra-mitochondrial ß-oxidation and the microsomal ω-oxidation, a pathway that produces toxic metabolites such as 4-en-VPA which inhibits ammonia elimination. Moreover, a reduction in carnitine levels might be also related to VPA-induced obesity and lipids disorder. In turn, L-carnitine supplementation (CS) has been recommended and empirically used to reduce VPA's hepatotoxicity. The aim of this work was to develop a Quantitative Systems Pharmacology (QSP) model to characterize VPA-induced hyperammonemia and evaluate the benefits of CS in preventing hyperammonemia under both chronic treatment and after VPA overdosing. The QSP model included a VPA population pharmacokinetics model that allowed the prediction of total and unbound concentrations after single and multiple oral doses considering its saturable binding to plasma proteins. Predictions of time courses for 2-en-VPA, 4-en-DPA, VPA-glucuronide, carnitine, ammonia and urea levels, and for the relative change in fatty acids, Acetyl-CoA, and glutamate reflected the VPA induced changes and the efficacy of the treatment with L-carnitine. The QSP model was implemented to give a rational basis for the L-carnitine dose selection to optimize CS depending on VPA dosage regime and to assess the currently recommended L-carnitine rescue therapy after VPA overdosing. Results show that a L-carnitine dose equal to the double of the VPA dose using the same interdose interval would maintain the ammonia levels at baseline. The QSP model may be expanded in the future to describe other adverse events linked to VPA-induced changes in endogenous compounds.

Seguridad del paciente: análisis de la prescripción en adultos mayores de una policlínica de salud mental del Hospital Vilardebó, Uruguay / Patient safety: analysis of prescriptions in older adults in a Mental Health Outpatient Clinic at Vilardebó Hospital, Uruguay / Segurança do paciente: análise da prescrição em idosos de uma Policlínica de Saúde Mental do Hospital Vilardebó, Uruguai

Introducción: los pacientes con 65 años o más, por su condición fisiológica, tienen mayor probabilidad de estar expuestos a reacciones adversas a medicamentos. Algunos riesgos están asociados a la carga anticolinérgica de la medicación, y otros al perfil de seguridad de cada uno de los fármacos. Objetivo: realizar un análisis de los tratamientos farmacológicos para los pacientes ≥65 años y su posible implicancia en la clínica, por los riesgos potenciales debido a reacciones adversas. Método: se realizó un estudio descriptivo, transversal, observacional, naturalístico, del tratamiento farmacológico de los pacientes ≥65 años de la policlínica del Hospital Vilardebó, entre mayo y agosto de 2021. Se calculó la carga anticolinérgica de los tratamientos y se efectuó una comparación de dicha carga con la de una muestra de pacientes menores de 65 años. Resultados: 356 pacientes (83,0%) ≥65 años tenían un riesgo alto de tener algún efecto por su carga anticolinérgica y este riesgo fue similar a los pacientes menores de 65 años. Un total de 344 pacientes estaban en tratamiento con alguna benzodiazepina, destacándose el uso de flunitrazepam (47,6%) y clonazepam (32,6%). A 289 pacientes (67,4%) se le prescribió algún antipsicótico y nueve pacientes estaban con más de dos antipsicóticos. Dos pacientes estaban en tratamiento con imipramina y 49 pacientes recibían algún antiparkisoniano. Conclusiones: los pacientes mayores de 65 años están expuestos a riesgos altos de padecer reacciones adversas a medicamentos como consecuencia de una alta carga anticolinérgica (similar a la de la población más joven estudiada) y de una acentuada polifarmacia. Además, se deberían evitar algunas prácticas, como la prescripción de ciertos tipos de benzodiacepinas, así como minimizar el uso de imipramina y antiparkisonianos. Es necesario buscar estrategias de formación que disminuyan o minimicen este potencial riesgo que repercute adversamente en la salud de los pacientes.

Summary: Introduction: patients aged 65 years or older are at increased risk for exposure to adverse drug reactions because of their physiological status. Some risks are associated with the anticholinergic burden of medication, and others with the safety profile of each drug. Objective: to perform an analysis of pharmacological treatments for patients aged 65 years old or older and their possible clinical implications, given the potential risks of adverse drug reactions. Method: a descriptive, cross-sectional, observational, naturalistic, observational study of the pharmacological treatment of users aged 65 years old or older of the outpatient service at Vilardebó Hospital, between May and August 2021, was performed. A calculation was made of the anticholinergic burden of treatments and a comparison of this burden was made with a sample of patients under 65 years of age. Results: 356 patients (83.0%) ≥ 65 years old were at high risk of having some kind of effect from their anticholinergic burden and this risk was similar to patients younger than 65 years. A total of 344 patients were in treatment with a benzodiazepine. The prescription of flunitrazepam (47.6%) and clonazepam (32.6%) stood out. While 289 patients (67.4%) were in treatment with an antipsychotic, 9 patients were on more than 2 antipsychotics. Two patients were on imipramine and 49 patients were in treatment with some antiparkinsonian drugs. Conclusions: patients older than 65 years old are exposed to a high risk of suffering adverse drug reactions as a consequence of a high anticholinergic load (similar to that of the younger population studied) and a marked polypharmacy. In addition, some practices should be avoided, such as the prescription of certain types of benzodiazepines used in this population, as well as minimizing the use of imipramine and antiparkinsonian drugs. It is necessary to look for training strategies to minimize this potential risk that adversely affects the health of patients.

Introdução: pacientes com 65 anos ou mais, devido à sua condição fisiológica, estão mais propensos a serem expostos a reações adversas a medicamentos. Alguns riscos estão associados à carga anticolinérgica do fármaco e outros ao perfil de segurança de cada um dos medicamentos. Objetivo: realizar uma análise dos tratamentos farmacológicos para pacientes ≥ 65 anos de idade e sua possível implicação clínica, devido aos riscos potenciais decorrentes de reações adversas. Método: foi realizado um estudo descritivo, transversal, observacional, naturalístico do tratamento farmacológico de pacientes ≥ 65 anos da Policlínica Hospitalar de Vilardebó, entre maio e agosto de 2021. A carga anticolinérgica dos tratamentos foi calculada e foi feita uma comparação com a de uma amostra de pacientes com menos de 65 anos. Resultados: 356 pacientes (83,0%) ≥ 65 anos apresentaram alto risco de ter algum efeito devido à sua carga anticolinérgica e esse risco foi semelhante aos pacientes com menos de 65 anos. Um total de 344 pacientes estava em tratamento com algum benzodiazepínico, com destaque para o uso de flunitrazepam (47,6%) e clonazepam (32,6%). 289 pacientes (67,4%) receberam algum antipsicótico e 9 pacientes estavam tomando mais de 2 antipsicóticos. Dois pacientes estavam sendo tratados com imipramina e 49 estavam recebendo um antiparkisoniano. Conclusões: pacientes com mais de 65 anos estão expostos a um alto risco de sofrer reações adversas a medicamentos em decorrência de uma carga anticolinérgica elevada (semelhante à da população mais jovem estudada) e de uma polifarmácia acentuada. Além disso, algumas práticas devem ser evitadas, como a prescrição de determinados tipos de benzodiazepínicos que são utilizados nessa população, além de minimizar o uso de imipramina e antiparkinsonianos. É necessário buscar estratégias de formação que reduzam ou minimizem esse risco potencial que afeta negativamente a saúde dos pacientes.

Effect of a single vectored thermal pulsation treatment of Meibomian gland dysfunction patients under controlled environmental conditions.

To assess the prophylactic effect of LipiFlow treatment in Meibomian gland dysfunction (MGD) patients exposed to an adverse environmental humidity. MGD patients were exposed to normal (23 °C; 50% relative humidity; 30 min) and adverse (23 °C; 10% relative humidity; 2 h) controlled environments consecutively during baseline and follow-up visits (3, 6, and 12 months) after a single LipiFlow treatment. Ocular Surface Disease Index (OSDI), lipid layer thickness (LLT), fluorescein tear break-up time (TBUT), corneal and conjunctival staining, change in dry eye symptoms questionnaire (CDES-Q), and Meibomian gland yielding liquid secretion (MGYLS), were assessed. Linear mixed-effects and cumulative logit mixed models were fitted to assess the effect of the LipiFlow treatment over time and within the controlled environments. Seventeen females and 4 males (59.6 ± 9.4 years) completed the study. LLT and TBUT did not vary significantly (p > 0.05) after LipiFlow treatment. OSDI, corneal and conjunctival staining, and MGYLS scores were improved (p ≤ 0.01) 12 months after treatment. After the adverse exposure, corneal staining increased at all visits (p = 0.01), and there was no significant improvement in CDES-Q scores after LipiFlow treatment (p ≥ 0.07). One LipiFlow treatment improved objective and subjective outcomes in MGD disease for at least one year. Further studies are needed to support that LipiFlow might also help as an adjuvant to avoid acute flares against an adverse environmental humidity.

Is contact lens discomfort related to meibomian gland morphology?

PURPOSE: To examine the relationship between contact lens (CL) discomfort and meibomian gland (MG) morphology assessed by a semi-objective software in subjects without an alteration of MG function (meibum quality and expressibility). METHODS: Nineteen symptomatic (CLDEQ-8 ≥ 12) CL wearers, 19 asymptomatic (CLDEQ-8 < 12) wearers, and 22 non-wearers were recruited. Upper and lower eyelid meibography images were taken and the following parameters were analysed using a semi-objective software in the central 2/3 of each eyelid: number of MG, number of partial MG, percentage of MG loss and percentage of tortuosity. One-way ANOVA or Kruskal-Wallis H test were used for comparisons among groups. The relationships between CLDEQ-8 and MG morphology parameters were analysed using the Spearman correlation coefficient and multivariable linear regression models. RESULTS: No significant differences were found among groups in the MG morphology of the upper or lower eyelids. In all CL wearers, a significant correlation with CLDEQ-8 was found in the upper eyelid for the number of MG (rho = 0.47, p = 0.003). In symptomatic wearers, significant correlations with CLDEQ-8 were found in the lower eyelid for the number of partial MG (rho = 0.49, p = 0.03) and the percentage of partial MG (rho = 0.61, p = 0.005). In all CL wearers, multivariable models were fitted to explain CLDEQ-8 score including the number of MG, the number of partial MG and the percentage of MG loss from the lower eyelid (R2 = 0.19; p = 0.007), and the number of MG from the upper eyelid (R2 = 0.19; p = 0.001). In symptomatic wearers, a model was fitted including the percentage of MG loss from the lower eyelid (R2 = 0.30; p = 0.016). CONCLUSIONS: Alterations of MG morphology, without clinically apparent alteration of MG function, can be involved in causing CL discomfort and influence the degree of symptoms. The differences in findings between eyelids indicate the need to monitor both eyelids, especially the lower one, in CL wearers.

Tissue Drug Concentration.

Blood flow enables the delivery of oxygen and nutrients to the different tissues of the human body. Drugs follow the same route as oxygen and nutrients; thus, drug concentrations in tissues are highly dependent on the blood flow fraction delivered. Although the free drug concentration in blood correlates with pharmacodynamics, the pharmacodynamics of a drug is primarily commanded by the drug concentrations in the aqueous spaces of bodily tissues. However, the concentrations of the drug are not homogeneous throughout the tissues, and they rarely reflect the free drug concentration in the blood. This heterogeneity is due to differences in the blood flow fraction delivered to the tissues and membrane transporters, efflux pumps, and metabolic enzymes. The rate of drug elimination from the body (systemic elimination) depends more on the driving force of drug elimination than on the free concentration of the drug at the site from which the drug is being eliminated. In fact, the actual free drug concentration in the tissues results from the balance between the input and output rates. In the present paper, we develop a theoretical concept regarding solute partition between intravascular and extravascular spaces; discuss experimental research on aqueous/non-aqueous solute partitioning and clinical research on microdialysis; present hypotheses to predict in-vivo elimination using parameters of in-vitro metabolism.

Inflammation-related molecules in tears of patients with chronic ocular pain and dry eye disease.

The purpose of this study was to analyze inflammation- and pain-related molecules in tears of patients suffering from chronic ocular pain associated with dry eye (DE) and/or a previous corneal refractive surgery (RS). Based on history, symptomatology, and clinical signs, the subjects (n = 180, 51.0 ± 14.7 years, 118 females, 62 males) in this cross-sectional study were assigned to one of five groups: DE and chronic ocular pain after RS (P/DE-RS, n = 52); asymptomatic subjects, i.e., without DE and chronic ocular pain, after RS (A-RS, n = 30); DE and chronic ocular pain without previous RS (P/DE-nonRS, n = 31); DE, no pain, and no previous RS (DE-nonRS, n = 35); and asymptomatic subjects with no previous RS (controls, n = 32). The tear concentrations of 20 cytokines and substance P (SP) were analyzed by immunobead-based assay and enzyme-linked immunosorbent assay, respectively. We found that tear levels of interleukin (IL)-10 and SP were increased in the RS groups. There were significant differences in IL-8/CXCL8 among the five groups. Nerve growth factor (NGF) tear levels were significantly higher in P/DE-RS than in DE-nonRS and controls. IL-9 had the highest percentage of detection in the P/DE-RS and P/DE-nonRS groups, while macrophage inflammatory protein (MIP)-1α, IL-2, and interferon (IFN)-γ were higher in the P/DE-RS, A-RS, and P/DE-nonRS groups. IL-17A was detected only in the A-RS group. Moderate correlations were observed in the A-RS, P/DE-nonRS, DE-nonRS and controls groups. A positive correlation was obtained between growth related oncogene concentration and tear break-up time (rho = 0.550; p = 0.012), while negative correlation was found between monocyte chemoattractant protein-3/CCL7 and conjunctival staining (rho = -0.560; p = 0.001), both in the A-RS group. IL-10 correlated positively with ocular pain intensity (rho = 0.513; p = 0.003) in the P/DE-nonRS group. Regulated on Activation Normal T Cell Expressed and Secreted/CCL5 correlated negatively with conjunctival staining (rho = -0.545; p = 0.001) in the DE-nonRS group. SP correlated negatively with corneal staining (rho = -0.559; p = 0.001) in the controls. In conclusion, chronic ocular pain was associated with higher IL-9 tear levels. IL-10, SP, MIP-1α/CCL3, IL-2, and IFN-γ were associated with previous RS. Higher levels of IL-8/CXCL8, MIP-1α/CCL3, IL-2, and IFN-γ were associated with DE-related inflammation, while NGF levels were related to chronic ocular pain and DE in RS patients. These findings suggest that improved knowledge of tear cytokines and neuromodulators will lead to a more nuanced understanding of how these molecules can serve as biomarkers of chronic ocular pain, leading to better therapeutic and disease management decisions.

The role of efflux transporters and metabolizing enzymes in brain and peripheral organs to explain drug-resistant epilepsy.

Drug-resistant epilepsy has been explained by different mechanisms. The most accepted one involves overexpression of multidrug transporters proteins at the blood brain barrier and brain metabolizing enzymes. This hypothesis is one of the main pharmacokinetic reasons that lead to the lack of response of some antiseizure drug substrates of these transporters and enzymes due to their limited entrance into the brain and limited stay at the sites of actions. Although uncontrolled seizures can be the cause of the overexpression, some antiseizure medications themselves can cause such overexpression leading to treatment failure and thus refractoriness. However, it has to be taken into account that the inductive effect of some drugs such as carbamazepine or phenytoin not only impacts on the brain but also on the rest of the body with different intensity, influencing the amount of drug available for the central nervous system. Such induction is not only local drug concentration but also time dependent. In the case of valproic acid, the deficient disposition of ammonia due to a malfunction of the urea cycle, which would have its origin in an intrinsic deficiency of L-carnitine levels in the patient or by its depletion caused by the action of this antiseizure drug, could lead to drug-resistant epilepsy. Many efforts have been made to change this situation. In order to name some, the administration of once-daily dosing of phenytoin or the coadministration of carnitine with valproic acid would be preferable to avoid iatrogenic refractoriness. Another could be the use of an adjuvant drug that down-regulates the expression of transporters. In this case, the use of cannabidiol with antiseizure properties itself and able to diminish the overexpression of these transporters in the brain could be a novel therapy in order to allow penetration of other antiseizure medications into the brain.