Production of bacterial cellulose tubes for biomedical applications: Analysis of the effect of fermentation time on selected properties.

Biosynthesis of bacterial cellulose (BC) in cylindrical oxygen permeable molds allows the production of hollow tubular structures of increasing interest for biomedical applications (artificial blood vessels, ureters, urethra, trachea, esophagus, etc.). In the current contribution a simple set-up is used to obtain BC tubes of predefined dimensions; and the effects of fermentation time on the water holding capacity, nanofibrils network architecture, specific surface area, chemical purity, thermal stability, mechanical properties, and cell adhesion, proliferation and migration of BC tubes are systematically analysed for the first time. The results reported highlight the role of culture time on key properties of the BC tubes produced, with significant differences arising from the denser and more compact fibril arrangements generated at longer fermentation intervals.

Anharmonic Origin of the Giant Thermal Expansion of NaBr.

All phonons in a single crystal of NaBr are measured by inelastic neutron scattering at temperatures of 10, 300, and 700 K. Even at 300 K, the phonons, especially the longitudinal-optical phonons, show large shifts in frequencies and show large broadenings in energy owing to anharmonicity. Ab initio computations are first performed with the quasiharmonic approximation (QHA) in which the phonon frequencies depend only on V and on T only insofar as it alters V by thermal expansion. This QHA is an unqualified failure for predicting the temperature dependence of phonon frequencies, even 300 K, and the thermal expansion is in error by a factor of 4. Ab initio computations that include both anharmonicity and quasiharmonicity successfully predict both the temperature dependence of phonons and the large thermal expansion of NaBr. The frequencies of longitudinal-optical phonon modes decrease significantly with temperature owing to the real part of the phonon self-energy from explicit anharmonicity originating from the cubic anharmonicity of nearest-neighbor NaBr bonds. Anharmonicity is not a correction to the QHA predictions of thermal expansion and thermal phonon shifts but dominates the behavior.

Homenaje a los farmacéuticos en la pandemia COVID-19 / Homage to pharmacists in the COVID-19 pandemic

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Síndrome de apneas-hipopneas del sueño: ¿hay diferencias en las formas de presentación y características clínicas según la edad de los pacientes? / OSA: are there differences in the forms of presentation and clinical characteristics according to the age of the patients?

Antecedentes y objetivo. El síndrome de apneas-hipopneas del sueño (SAHS) puede tener unas características clínicas propias dependiendo de la edad y es importante profundizar en el conocimiento de estas para afrontar el creciente aumento en la actividad asistencial en algunos grupos de edad. Materiales y métodos. Estudio observacional transversal retrospectivo, en una población de 2.087 pacientes remitidos a una unidad especializada en trastornos respiratorios del sueño por sospecha de SAHS, para analizar las características clínicas, antropométricas y de los estudios de sueño; dividiendo la población en tres grupos etarios: jóvenes, edad media y ancianos. Resultados. Hemos encontrado un predominio superior de hombres en los tres grupos, con un porcentaje de mujeres más elevado a medida que aumenta la edad. Salvo la dislipemia, el resto de comorbilidades encontradas han sido superiores en los ancianos. Respecto a los síntomas de SAHS más relevantes no encontramos diferencias significativas en los tres grupos. El índice de masa corporal (IMC) no difiere en los tres grupos y, en el grupo de mediana edad, este parámetro se correlaciona con un perfil glucídico y lipídico más desfavorable, cosa que no sucede en los ancianos. A diferencia del IMC, la cintura y el índice cintura-cadera (ICC) aumentan a medida que lo hace la edad. En los pacientes jóvenes, pero no en los ancianos, las alteraciones oximétricas propias del SAHS se correlacionan con marcadores bioquímicos de riesgo metabólico y cardiovascular

Background and objectives. Obstructive sleep apnea (OSA) can have its own clinical characteristics depending on age and it is important to improve our knowledge of these characteristics will allow us to cope with the increase in health care of some age groups. Material and Methods. Retrospective cross-sectional observational study in 2.087 patients referred to a Unit specialized in Sleep Respiratory Disorders due to suspicion of OSA in order to analyze the clinical, anthropometric and sleep characteristics, dividing the population into three age groups: young people, middle age and elderly. Results. We found a higher percentage of men than women in all the groups. The percentage of women increases with the age. All comorbidities, except dyslipemia, were more predominant in the elderliest group. Regarding the most relevant symptoms of OSA, we did not find significant differences in the three groups. The body mass index (BMI) does not differ in the three groups and, in the middle age group, this parameter correlates with a worse glucidic and lipid profile, something that does not happen in the elderly group. Unlike BMI, the waist and waist-hip ratio (WHR) increase as age does. In younger patients, but not in the elderly, the oximetric alterations characteristic of OSA are correlated with biochemical markers of metabolic and cardiovascular risk. Conclusions. There are some differential aspects in the clinical presentation of OSA and its consequences, depending on the age of the patients

Toll-Like Receptors as Therapeutic Targets in Central Nervous System Tumors.

In recent years, progress has been made in understanding the pathological, genetic, and molecular heterogeneity of central nervous system (CNS) tumors. However, improvements in risk classification, prognosis, and treatment have not been sufficient. Currently, great importance has been placed to the tumor microenvironment and the immune system, which are very important components that influence the establishment and development of tumors. Toll-like receptors (TLRs) are innate immunite system sensors of a wide variety of molecules, such as those associated with microorganisms and danger signals. TLRs are expressed on many cells, including immune cells and nonimmune cells such as neurons and cancer cells. In the tumor microenvironment, activation of TLRs plays dual antitumoral (dendritic cells, cytotoxic T cells, and natural killer cells activation) and protumoral effects (tumor cell proliferation, survival, and resistance to chemotherapy) and constitutes an area of opportunities and challenges in the development of new therapeutic strategies. Several clinical trials have been carried out, and others are currently in process; however, the results obtained to date have been contradictory and have not led to a definitive position about the use of TLR agonists in adjuvant therapy during the treatment of central nervous system (CNS) tumors. In this review, we focus on recent advances in TLR agonists as immunotherapies for treatment of CNS tumors.

Impact of pretransplant CMV-specific T-cell immune response in the control of CMV infection after solid organ transplantation: a prospective cohort study.

INTRODUCTION: Although solid organ transplant (SOT) recipients with pretransplant serology for cytomegalovirus (CMV-R+) are considered at intermediate risk for CMV infection post transplantation, CMV infection remains a major cause of morbidity in this population. We prospectively characterized whether having pretransplant CMV-specific cellular immunity is independently associated with controlling infection after transplantation in R + SOT recipients. METHODS: A prospective cohort of consecutive R + SOT recipients that received pre-emptive treatment for CMV infection was monitored after transplantation and variables were recorded during the follow-up. The cytomegalovirus-specific T-cell immune response was characterized by intracellular cytokine staining and viral loads determined using real-time PCR. RESULTS: One hundred and thirty-five R + SOT recipients were included (67 kidney, 64 liver, four liver-kidney). Only one-third of the patients (42; 31.85%) had CMV-specific T-cell immunity (CD8+CD69+INF-γ+ T cells >0.25%) before transplantation. Patients with negative pretransplant immunity had more CMV infection (49, 52.7% vs. 15, 35.7%; p 0.07) and received more antiviral therapy than those with immunity (32, 34.4% vs. 6, 14.3%, p 0.016). Having CMV specific immunity was an independent factor for protection from developing viraemia ≥2000 IU/mL (OR 0.276, 95% CI 0.105-0.725, p < 0.01) and lower administration of treatment (OR 0.398, 95% CI 0.175-0.905, p 0.028). Only patients with no pretransplant CMV-specific T-cell response were diagnosed with CMV-disease (8, 8.6% vs. 0, 0%, p 0.05). DISCUSSION: Our results show that having a pretransplant CMV specific T-cell response may be associated with a lower rate of CMV viraemia and less antiviral treatment after transplantation; however, more prospective studies are needed to confirm these findings.

Reflexiones sobre el infradiagnóstico y la primoinfección por VIH / Reflections on underdiagnosis and primary HIV infection

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Normas 2017 de contención de infecciones por gérmenes productores de carbapenemasas del Hospital Nacional de Itauguá, Paraguay / 2017 regulations for the containment of carbapenemase-producing infections of the National Hospital of Itauguá, Paraguay

La carbapenemasa es una enzima producida por varias especies bacterianas, capaz de inactivar un grupo de antibióticos: los carbapenemes. El riesgo radica, además de la dificultad para el tratamiento de las infecciones resistentes a estos antibióticos, en su fácil diseminación entre especies bacterianas, entre pacientes y entre pacientes y contactos (familiares, personal de salud, etc.) Su sigla KPC se generalizó desde el primer caso se dio en la Klebsiella pneumoniae. Se publican Normas que tienen el objetivo de prevenir y controlar la colonización e infección de pacientes con gérmenes productores de carbapenemasa (tipo KPC-NDM etc.) en el Hospital Nacional.

Carbapenemase is an enzyme produced by several bacterial species, capable of inactivating a group of antibiotics: carbapenems. In addition to the difficulty in treating infections resistant to these antibiotics, the risk lies in their easy spread among bacterial species, between patients and between patients and contacts (family members, health personnel, etc.). Its initials KPC was generalized since the first case that occurred in Klebsiella pneumoniae. Guidelines that aim to prevent and control the colonization and infection of patients with carbape

Disfunción endotelial medida con flujimetría láser-doppler en pacientes con Síndrome de apneas-hipopneas del sueño. Efecto del tratamiento con presión positiva continua en la vía aérea / Endothelial dysfunction measured with a Laser-Doppler flowmetry in patients with sleep apnea-hypopnea syndrome. The effecto ftreatment with continuous positive airway pressure

INTRODUCCIÓN: El SAHS se relaciona con el desarrollo de enfermedades cardiovasculares, con un aumento de la mortalidad de los pacientes que lo padecen. Dentro del espectro de la afectación cardiovascular, cada día se reconoce como más importante la disfunción endotelial. MATERIAL Y MÉTODOS: Estudio prospectivo de pacientes diagnosticados de SAHS mediante poligrafía respiratoria con indicación de CPAP. La función endotelial se ha valorado mediante la técnica no invasiva de flujimetría láser-doppler, realizada de manera basal y tras 3 meses de tratamiento con CPAP. RESULTADOS: Hemos observado una correlación significativa entre los parámetros oximétricos de la poligrafía respiratoria y algunos parámetros de la flujimetría basal. Además, hemos encontrado un aumento significativo en el valor del área bajo la curva y una disminución del valor de la pendiente de la flujimetría láser doppler (que indica mejoría de la función endotelial) tras la realización del tratamiento con CPAP durante 3 meses

INTRODUCTION: Sleep apnea-hypopnea syndrome (SAHS) is linked to the development of cardiovascular diseases, with increased mortality among these patients. Within the range of cardiovascular affections, the importance of endothelial dysfunction is evermore recognized. MATERIAL AND METHODS: Prospective studies in patients with SAHS using respiratory polygraph with continuous positive airway pressure (CPAP). Endothelial function has been assessed using non-invasive Laser-Doppler Flowmetry, both basal and after 3 months of treatment with CPAP. RESULTS: A significant correlation was observed between the respiratory polygraph oximetry parameters and certain basal flowmeter parameters. Moreover, a significant increase in the value of the area under the curve(AUC) and a decrease in the slope of the Laser-Doppler flowmetry was seen (thus indicating an improvement of endothelial function) after a 3-month treatment with CPAP

Estudio de la función muscular periférica y de la capacidad de ejercicio en pacientes con síndrome de apneas hipopneas del sueño / Peripheral muscle function study and the exercise capacity in patients with Sleep Apnea Syndrome

El objetivo del estudio fue evaluar la composición corporal, la función muscular y la capacidad de ejercicio en pacientes con Síndrome de Apneas-Hipopneas del Sueño (SAHS) moderado-severo. Material y métodos: Se trata de un estudio observacional descriptivo. Se realizó una poligrafía domiciliaria a 25 pacientes, de los que 16 fueron diagnosticados de SAHS moderado severo (IAH >15) constituyendo el grupo de estudio, mientras que el resto (IAH< 5), formaron el grupo control. Se evaluó la fuerza muscular periférica mediante test de una repetición máxima, 1RM, la capacidad de ejercicio mediante test de esfuerzo cardiopulmonar, se realizó un test de marcha de 6 min, se calculó la composición corporal y valoró la calidad de vida mediante el cuestionario SF36. Resultados: Nuestros hallazgos principales mostraron que los pacientes con SAHS tenían un menor VO2max de p50 (p25-p75) 19,6 [15,7 - 23,7] vs grupo control 26,2 [18 - 29,1] (n.s.) y menor Wmax (carga máxima alcanzada durante el esfuerzo) 69,5 [53,2 - 77,5] vs 81 [72,7 - 90,7] p = 0,029. Menor fuerza muscular periférica 1RM hombros 32 [22 - 38] vs 34 [19 - 40,5] (n.s), 1RM cuádriceps 33 [22,5 - 48,5] vs 36 [20 - 42,5] (n.s.) y menor distancia recorrida en test 6 min 579 [524 - 613,5] vs 594 [552,7 - 623,7], (n.s.). Los pacientes SAHS tenían mayor grasa corporal con un peso graso en Kg 31,25 (23,1 - 44,2) vs 21,4 (18,5 - 28,5) P = 0,015. Conclusiones: En nuestro grupo de pacientes con SAHS, se demuestra una peor tolerancia al ejercicio en comparación con pacientes sanos con características antropométricas similares. Esto no parece estar relacionado con la fuerza muscular de las extremidades, sino que podría deberse a otros factores, como la obesidad e incluso el desentrenamiento

The aim of the study was to assess body composition, muscle function and exercise capacity in patients with moderate to severe Obstructive Sleep Apnea (OSA). Methods: This is an observational descriptive study. A home sleep monitoring was performed in 25 patients. 16 were diagnosed with moderate-severe (AHI >15) SAHS and constituted the study group, whereas the rest (AHI< 5) formed the control group. Peripheral muscle strength was assessed with the one repetition maximum (1RM) test, exercise capacity by means of a cardiopulmonary exercise test and the 6 minutes walking test; body composition was calculated by impedanciometry, and quality of life was assessed with the SF36 questionnaire. Results: Our main findings showed that patients with OSA had lower VO2max of P50 (P25- P75) 19.6 [15.7 - 23.7] vs control group 26.2 [18 - 29.1] (ns), and lower Wmax 69.5 [53.2 - 77.5] vs 81 [72.7 - 90.7] p = 0.029. OSA patients had lower peripheral muscle strength: 1RM shoulders 32 [22 - 38] vs 34 [19 - 40.5] (ns), 1RM quadriceps 33 [22.5 - 48.5] vs 36 [20 - 42.5] (ns), and less distance in 6 min walking test 579 [524 - 613.5] vs 594 [552.7 - 623.7] (ns). The OSA patients had a greater body fat weight 31.25 (23.1 - 44.2) vs 21.4 (18.5 - 28.5) P = 0.015. Conclusions: Our patients with OSA demonstrated a worse exercise tolerance compared to healthy patients with similar anthropometric characteristics. This does not appear to be related to muscle strength in the limbs, but could be due to other factors such as obesity and even detraining

[Effect of antidiabetes treatment adjustment at discharge on 30-day outcomes of patients with diabetes mellitus presenting to an emergency department with hypoglycemia]. / Efecto del ajuste del tratamiento al alta en los resultados a 30 días en los pacientes diabéticos atendidos por hipoglucemia en un servicio de urgencias hospitalario.

BACKGROUND: To determine if antidiabetes treatment adjustment at discharge from an Emergency Department(ED) is associated with 30-day outcomes in patients with diabetes mellitus presenting to the ED with hypoglycemia. METHODS: Retrospective cohort observational study. Patients with diabetes mellitus presenting to the ED with hypoglycemia directly discharged from the ED between 2012-2014 were included. Primary outcome was a 30-day composite adverse event(mortality or revisiting). RESULTS: A total of 203 patients were included with a mean age of 69.7 (SD 18.9), mainly type 2 diabetics.Hypoglycemia was the primary diagnosis in 162(79%) of patients and antidiabetes treatment was adjusted at discharge in 98 (48%) of cases. Non-adjustment of antidiabetes treatment at ED discharge was an independent factor associated with a 30-day adverse event (OR=2.8; CI 95%=1.34-5.93; p=0.006). CONCLUSIONS: Non-adjustment of antidiabetes treatment at discharge in patients with diabetes mellitus presenting to the ED with hypoglycemia could be an independent factor of suffering a 30-day adverse event.

Efecto del ajuste del tratamiento al alta en los resultados a 30 días en los pacientes con diabetes mellitus atendidos por hipoglucemia en un servicio de urgencias hospitalario / Effect of antidiabetes treatment adjustment at discharge on 30-day outcomes of patients with diabetes mellitus presenting to an emergency department with hypoglycemia

Fundamento: Determinar si ajustar el tratamiento antidiabético al alta se relaciona con los resultados a 30 días en los pacientes con diabetes mellitus atendidos por hipoglucemia en un servicio de urgencias (SU). Método: Estudio observacional de cohorte retrospectivo. Se incluyeron todos los pacientes con diabetes mellitus con hipoglucemia dados del alta desde SU entre 2012-2014. La variable resultado fue un evento adverso por cualquier causa a los 30 días. Resultados: El estudio se realizó en 203 pacientes con edad media de 69,7(DE 18,9) mayoritariamente con diabetes mellitus tipo 2. El diagnóstico de hipoglucemia fue principal en 162 (79%) y se realizó ajuste terapéutico en 98 (48%) casos. El no ajuste de tratamiento fue un factor independiente asociado con un evento adverso a los 30 días (OR=2,82; IC 95%=1,34-5,93; p=0,006). Conclusiones: No ajustar el tratamiento antidiabético al alta del SU podría ser un factor independiente de sufrir un resultado adverso a los 30 días en los pacientes con diabetes mellitus que presentaron hipoglucemia en un SU (AU)

Background: To determine if antidiabetes treatment adjustment at discharge from an Emergency Department (ED) is associated with 30-day outcomes in patients with diabetes mellitus presenting to the ED with hypoglycemia. Methods: Retrospective cohort observational study. Patients with diabetes mellitus presenting to the ED with hypoglycemia directly discharged from the ED between 2012-2014 were included. Primary outcome was a 30-day composite adverse event (mortality or revisiting). Results: A total of 203 patients were included with a mean age of 69.7 (SD18.9), mainly type 2 diabetics. Hypoglycemia was the primary diagnosis in 162 (79%) of patients and antidiabetes treatment was adjusted at discharge in 98 (48%) of cases. Non-adjustment of antidiabetes treatment at ED discharge was an independent factor associated with a 30-day adverse event (OR=2.8; CI 95%=1.34-5.93; p=0.006). Conclusions: Non-adjustment of antidiabetes treatment at discharge in patients with diabetes mellitus presenting to the ED with hypoglycemia could be an independent factor of suffering a 30-day adverse event (AU)

Strong inflammatory response and Th1-polarization profile in children with acute lymphoblastic leukemia without apparent infection.

Children with acute lymphoblastic leukemia (ALL) often present fever. Febrile states are usually associated with infectious processes that generate an inflammatory response involving various molecules, including cytokines. However, an inflammatory response may also occur in the absence of infection. We hypothesized that the levels of inflammatory cytokines are increased in children with ALL without apparent infection. The serum levels of 13 cytokines in 99 patients with ALL and 48 non-oncological patients without apparent infection were measured using multiplex analyte profiling technology (Luminex®). The concentration of circulating pro-inflammatory cytokines associated with fever was similar between patients with ALL and fever at diagnosis and those without fever. The levels of tumor necrosis factor α, interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1 (MCP-1) and IL-10 were higher in patients with ALL vs. the control group (P<0.05). Moreover, the levels of the T helper 1 (interferon­Î³ and IL-12) cytokines were higher in patients with ALL vs. the control group. Transforming growth factor ß was lower in patients with ALL vs. the control group (P<0.05). The levels of IL-1ß, IL-2, IL-4, IL-13, and IL-17 were similar in the two groups. Our results indicate that the circulating levels of seven of the important studied cytokines are elevated in patients with newly diagnosed ALL without apparent infection, reflecting a strong and deregulated inflammatory state in this disease, with a Th1-polarization profile.

Nueva metodología de evaluación del Holter basada en los sistemas dinámicos y la geometría fractal: confirmación de su aplicabilidad a nivel clínico / New methodology in Holter evaluation based on dynamics systems and fractal geometry: confirmation of its applicability at clinical level

Introducción: La teoría de sistemas dinámicos establece medidas cuantitativas de evolución de los sistemas mediante la construcción de atractores. Medidas de ocupación espacial de atractores cardiacos en el espacio fractal de Box Counting diferenciaron normalidad y enfermedad crónica de enfermedad aguda. Objetivo: Aplicar la metodología desarrollada para evaluar matemáticamente el estado cardiaco de Holter con diferentes patologías, confirmando la aplicabilidad de esta metodología para la detección de dinámicas agudas mediante medidas de concordancia estadística respecto al Gold Standard. Metodología: Se analizaron 170 Holter, incluyendo normales, crónicos y en estado agudo. Se construyeron simulaciones de la totalidad de la dinámica basada en número de latidos y frecuencia mínima y máxima cada hora durante 21 horas, para construir atractores en el espacio de fases. Se calculó la dimensión fractal de los atractores evaluando su ocupación espacial en el espacio de Box Counting, estableciendo cuáles corresponden a normalidad y enfermedad aguda de acuerdo con resultados matemáticos previos. Se comparó el diagnóstico matemático con el diagnóstico convencional del Holter, tomado como Gold Standard, estableciendo valores de sensibilidad, especificidad y coeficiente Kappa. Resultados: La dimensión fractal no logró evidenciar diferencias cuantitativas mientras que la metodología detectó en todos los casos dinámicas normales y en estado agudo independientemente de la patología, logrando valores de sensibilidad, especificidad, valor predictivo positivo y negativo de 100%, y coeficiente Kappa de 1. Conclusiones: Se confirmó la capacidad de la metodología físico-matemática para detectar dinámicas agudas independientemente de la patología asociada, confirmando una auto-organización acausal de la dinámica del sistema cuya evaluación permite establecer medidas de aplicabilidad clínica.

Introduction: Dynamic systems theory provides quantitative measures of evolution of systems by building attractors. Spatial occupation measures of cardiac attractors in fractal Box Counting space differentiated normality and chronic disease from acute illness. Objective: To apply the developed methodology to evaluate mathematically the cardiac status of Holter with different pathologies, confirming the applicability of this methodology for the detection of acute dynamic by statistical measures of agreement regarding the Gold Standard. Methodology: 170 Holter, including normal, chronic and in acute states were evaluated. Simulations were constructed the entire dynamic based on the number of beats and the minimum and maximum frequencies every hour for 21 hours, to build attractors in the phase space. The fractal dimension of attractors is calculated, evaluating the spatial occupation in the Box Counting space, establishing which corresponds to normal setting and acute disease in accordance with previous mathematical results. Mathematical diagnosis was compared with conventional diagnostic Holter, taken as the Gold Standard, setting sensitivity, specificity, positive and negative predictive value and Kappa coefficient. Results: The fractal dimension failed to show quantitative differences while the methodology detected in all cases normal dynamics and acute state independently of the disease, achieving sensitivity, specificity, positive and negative predictive value of 100% and a Kappa 1. Conclusions: the ability of the physical-mathematical methodology to detect acute dynamic regardless of the associated pathology was confirmed, as well as an acausal self-organization of the system dynamics, which allows for assessment of clinical applicability measures.

Adherence to oral anticoagulants in patients with atrial fibrillation-a population-based retrospective cohort study linking health information systems in the Valencia region, Spain: a study protocol.

INTRODUCTION: Adherence to oral anticoagulation (OAC) treatment, vitamin K antagonists or new oral anticoagulants, is an essential element for effectiveness. Information on adherence to OAC in atrial fibrillation (AF) and the impact of adherence on clinical outcomes using real-world data barely exists. We aim to describe the patterns of adherence to OAC over time in patients with AF, estimate the associated factors and their impact on clinical events, and assess the same issues with conventional measures of primary and secondary adherence-proportion of days covered (PDC) and persistence-in routine clinical practice. METHODS AND ANALYSIS: This is a population-based retrospective cohort study including all patients with AF treated with OAC from 2010 to date in Valencia, Spain; data will be obtained from diverse electronic records of the Valencia Health Agency. PRIMARY OUTCOME MEASURE: adherence trajectories. SECONDARY OUTCOMES: (1) primary non-adherence; (2) secondary adherence: (a) PDC, (b) persistence. Clinical outcomes: hospitalisation for haemorrhagic or thromboembolic events and death during follow-up. ANALYSIS: (1) description of baseline characteristics, adherence patterns (trajectory models or latent class growth analysis models) and conventional adherence measures; (2) logistic or Cox multivariate regression models, to assess the associations between adherence measures and the covariates, and logistic multinomial regression models, to identify characteristics associated with each trajectory; (3) Cox proportional hazard models, to assess the relationship between adherence and clinical outcomes, with propensity score adjustment applied to further control for potential confounders; (4) to estimate the importance of different healthcare levels in the variations of adherence, logistic or Cox multilevel regression models. ETHICS AND DISSEMINATION: This study has been approved by the corresponding Clinical Research Ethics Committee. We plan to disseminate the project's findings through peer-reviewed publications and presentations at relevant health conferences. Policy reports will also be prepared in order to promote the translation of our findings into policy and clinical practice.