Factor B Inhibition with Iptacopan in Recurrent C3 Glomerulopathy Following Kidney Transplant: A Report of Two Cases.

C3 glomerulopathy is a rare disease caused by fluid phase dysregulation of the alternative complement pathway. Currently, treatment depends on clinical and histological severity and includes nephroprotection, unspecific immunosuppression, and terminal complement blockers (C5), without having an etiological treatment approved. C3 glomerulopathy has high recurrence rates after kidney transplantation with a high risk of graft loss. Fortunately, new molecules are being developed that specifically target the proximal alternative complement pathway, such as iptacopan, a factor B inhibitor that showed promising results in native kidneys and cases of transplant recurrence in a phase 2 clinical trial. We present 2 "real-world" cases of C3 glomerulopathy recurrence in kidney allografts treated with iptacopan, with initial excellent clinical response and safety profile, especially with early introduction. We also present follow-up biopsies that showed no C3 deposition during factor B inhibition. Our cases suggest that proximal blockade of the alternative complement pathway can be effective and safe in the treatment of C3 glomerulopathy recurrence in kidney transplantation, bringing other questions such as dual blockade (eg, in C3 and C5), the optimal patient profile to benefit from factor B inhibition or treatment duration and its potential use in other forms of membranoproliferative glomerulonephritis (eg, immune complex-mediated).

Drug Cost Avoidance Resulting from Participation in Clinical Trials: A 10-Year Retrospective Analysis of Cancer Patients with Solid Tumors.

The objective of this single-center retrospective study was to describe the clinical characteristics of adult patients with solid tumors enrolled in cancer clinical trials over a 10-year period (2010-2019) and to assess drug cost avoidance (DCA) associated with sponsors' contributions. The sponsors' contribution to pharmaceutical expenditure was calculated according to the actual price (for each year) of pharmaceutical specialties that the Vall d'Hebron University Hospital (HUVH) would have had to bear in the absence of sponsorship. A total of 2930 clinical trials were conducted with 10,488 participants. There were 140 trials in 2010 and 459 in 2019 (228% increase). Clinical trials of high complexity phase I and basket trials accounted for 34.3% of all trials. There has been a large variation in the pattern of clinical research over the study period, whereas, in 2010, targeted therapy accounted for 79.4% of expenditure and cytotoxic drugs for 20.6%; in 2019, immunotherapy accounted for 68.4%, targeted therapy for 24.4%, and cytotoxic drugs for only 7.1%. A total of four hundred twenty-one different antineoplastic agents were used, the variability of which increased from forty-seven agents in 2010, with only seven of them accounting for 92.8% of the overall pharmaceutical expenditure) to three hundred seventeen different antineoplastic agents in 2019, with thirty-three of them accounting for 90.6% of the overall expenditure. The overall expenditure on antineoplastic drugs in clinical care patients not included in clinical trials was EUR 120,396,096. The total cost of antineoplastic drugs supplied by sponsors in a clinical trial setting was EUR 107,306,084, with a potential DCA of EUR 92,662,609. Overall, clinical trials provide not only the best context for the progress of clinical research and healthcare but also create opportunities for reducing cancer care costs.

Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma.

PURPOSE: B-cell maturation antigen (BCMA)-chimeric antigen receptor T-cells (CART) improve results obtained with conventional therapy in the treatment of relapsed/refractory multiple myeloma. However, the high demand and expensive costs associated with CART therapy might prove unsustainable for health systems. Academic CARTs could potentially overcome these issues. Moreover, response biomarkers and resistance mechanisms need to be identified and addressed to improve efficacy and patient selection. Here, we present clinical and ancillary results of the 60 patients treated with the academic BCMA-CART, ARI0002h, in the CARTBCMA-HCB-01 trial. PATIENTS AND METHODS: We collected apheresis, final product, peripheral blood and bone marrow samples before and after infusion. We assessed BCMA, T-cell subsets, CART kinetics and antibodies, B-cell aplasia, cytokines, and measurable residual disease by next-generation flow cytometry, and correlated these to clinical outcomes. RESULTS: At cut-off date March 17, 2023, with a median follow-up of 23.1 months (95% CI, 9.2-37.1), overall response rate in the first 3 months was 95% [95% confidence interval (CI), 89.5-100]; cytokine release syndrome (CRS) was observed in 90% of patients (5% grades ≥3) and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in 2 patients (3%). Median progression-free survival was 15.8 months (95% CI, 11.5-22.4). Surface BCMA was not predictive of response or survival, but soluble BCMA correlated with worse clinical outcomes and CRS severity. Activation marker HLA-DR in the apheresis was associated with longer progression-free survival and increased exhaustion markers correlated with poorer outcomes. ARI0002h kinetics and loss of B-cell aplasia were not predictive of relapse. CONCLUSIONS: Despite deep and sustained responses achieved with ARI0002h, we identified several biomarkers that correlate with poor outcomes.

Additive and Lithographic Manufacturing of Biomedical Scaffold Structures Using a Versatile Thiol-Ene Photocurable Resin.

Additive and lithographic manufacturing technologies using photopolymerisation provide a powerful tool for fabricating multiscale structures, which is especially interesting for biomimetic scaffolds and biointerfaces. However, most resins are tailored to one particular fabrication technology, showing drawbacks for versatile use. Hence, we used a resin based on thiol-ene chemistry, leveraging its numerous advantages such as low oxygen inhibition, minimal shrinkage and high monomer conversion. The resin is tailored to applications in additive and lithographic technologies for future biofabrication where fast curing kinetics in the presence of oxygen are required, namely 3D inkjet printing, digital light processing and nanoimprint lithography. These technologies enable us to fabricate scaffolds over a span of six orders of magnitude with a maximum of 10 mm and a minimum of 150 nm in height, including bioinspired porous structures with controlled architecture, hole-patterned plates and micro/submicro patterned surfaces. Such versatile properties, combined with noncytotoxicity, degradability and the commercial availability of all the components render the resin as a prototyping material for tissue engineers.

Significance of clinical-immunological patterns and diagnostic yield of biopsies in microscopic polyangiitis and granulomatosis with polyangiitis.

BACKGROUND: Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are the two major antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). OBJECTIVES: To characterize a homogenous AAV cohort and to assess the impact of clinicopathological profiles and ANCA serotypes on clinical presentation and prognosis. Clinical differences in GPA patients according to ANCA serotype and the diagnostic yield for vasculitis of biopsies in different territories were also investigated. RESULTS: This retrospective study (2000-2021) included 152 patients with AAV (77 MPA/75 GPA). MPA patients (96.1% myeloperoxidase [MPO]-ANCA and 2.6% proteinase 3 [PR3]-ANCA) presented more often with weight loss, myalgia, renal involvement, interstitial lung disease (ILD), cutaneous purpura, and peripheral nerve involvement. Patients with GPA (44% PR3-ANCA, 33.3% MPO, and 22.7% negative/atypical ANCA) presented more commonly with ear, nose, and throat and eye/orbital manifestations, more relapses, and higher survival than patients with MPA. GPA was the only independent risk factor for relapse. Poor survival predictors were older age at diagnosis and peripheral nerve involvement. ANCA serotypes differentiated clinical features in a lesser degree than clinical phenotypes. A mean of 1.5 biopsies were performed in 93.4% of patients in different territories. Overall, vasculitis was identified in 80.3% (97.3% in MPA and 61.8% in GPA) of patients. CONCLUSIONS: The identification of GPA presentations associated with MPO-ANCA and awareness of risk factors for relapse and mortality are important to guide proper therapeutic strategies in AAV patients. Biopsies of different affected territories should be pursued in difficult-to-diagnose patients based on their significant diagnostic yield.

Academic challenges on advanced therapy medicinal products' development: a regulatory perspective.

Advanced therapy medicinal products (ATMPs) are becoming the new kid on the block for the treatment of a variety of indications with promising results. Despite the academic contribution to the basic and clinical research of ATMPs, undertaking a full product development process is extraordinarily challenging and demanding for academic institutions. Meeting regulatory requirements is probably the most challenging aspect of academic development, considering the limited experience and resources compared with pharmaceutical companies. This review aims to outline the key aspects to be considered when developing novel ATMPs from an academic perspective, based on the results of our own experience and interaction with the Spanish Agency of Medicines and Medical Devices (AEMPS) and European Medicine Agency (EMA) related to a number of academic ATMP initiatives carried out at our center during the last 5 years. Emphasis is placed on understanding the regulatory requirements during the early phases of the drug development process, particularly for the preparation of a Clinical Trial Application. Academic centers usually lack expertise in product-related documentation (such as the Investigational Medicinal Product Dossier), and therefore, early interaction with regulators is crucial to understand their requirements and receive guidance to comply with them. Insights are shared on managing quality, nonclinical, clinical, and risk and benefit documentation, based on our own experience and challenges. This review aims to empower academic and clinical settings by providing crucial regulatory knowledge to smooth the regulatory journey of ATMPs.

The academic point-of-care anti-CD19 chimeric antigen receptor T-cell product varnimcabtagene autoleucel (ARI-0001 cells) shows efficacy and safety in the treatment of relapsed/refractory B-cell non-Hodgkin lymphoma.

Varnimcabtagene autoleucel (var-cel) is an academic anti-CD19 chimeric antigen receptor (CAR) product used for the treatment of non-Hodgkin lymphoma (NHL) in the CART19-BE-01 trial. Here we report updated outcomes of patients with NHL treated with var-cel. B-cell recovery was compared with patients with acute lymphoblastic leukaemia (ALL). Forty-five patients with NHL were treated. Cytokine release syndrome (any grade) occurred in 84% of patients (4% grade ≥3) and neurotoxicity in 7% (2% grade ≥3). The objective response rate was 73% at Day +100, and the 3-year duration of response was 56%. The 3-year progression-free and overall survival were 40% and 52% respectively. High lactate dehydrogenase was the only covariate with an impact on progression-free survival. The 3-year incidence of B-cell recovery was lower in patients with NHL compared to ALL (25% vs. 60%). In conclusion, in patients with NHL, the toxicity of var-cel was manageable, while B-cell recovery was significantly prolonged compared to ALL. This trial was registered as NCT03144583.

Sociodemographic inequalities in cardiovascular risk factors among adolescents from indigenous areas in Chiapas, Mexico.

This study was aimed to determine the prevalence of cardiovascular risk factors among different sociodemographic groups of adolescents from indigenous communities in Chiapas, Mexico. A cross-sectional prevalence study was performed in urban and rural communities in the Tzotzil-Tzeltal and Selva regions of Chiapas. A sample of 253 adolescents was studied, of whom 48% were girls and 52% were boys. A descriptive analysis of quantitative variables was performed using measures of central tendency and dispersion. The prevalence of cardiovascular risk factors stratified by sex, geographical area, years of schooling, and ethnicity of the mothers was estimated. The prevalence of cardiovascular risk factors was analyzed in relation to the sociodemographic characteristics of the study population. Low HDL-c (51%) was the predominant cardiovascular risk factor. Girls had a higher prevalence of abdominal obesity, hypertriglyceridemia, and borderline total cholesterol than boys. High diastolic blood pressure was more prevalent in boys. Adolescents from urban areas had a higher prevalence of overweight/obesity and insulin resistance than adolescents from rural areas. The prevalence of overweight/obesity and abdominal obesity was higher in adolescents whose mothers had ≥ 7 years of schooling compared with adolescents with less educated mothers. Differences by maternal ethnicity also influenced the prevalence of insulin resistance. Among the main findings, this study associated sociodemographic and geographical inequalities with cardiovascular risk factors. Promoting a healthy lifestyle for this young population is absolutely necessary to prevent cardiovascular diseases in adulthood.

Do the Outcomes of Clinical Efficacy Trials Matter in Regulatory Decision-Making for Biosimilars?

BACKGROUND: There is an increasing body of evidence supporting a more flexible approach in clinical data requirements for the approval of more complex biosimilar substances such as monoclonal antibodies (mAbs). OBJECTIVE: The aim of this paper is to further analyse the role of quality/chemistry, manufacturing and controls (CMC) and clinical data for the conclusion on biosimilarity and the decision on marketing authorisation (MA). METHODS: In the present study, we analysed the MA applications (MAAs) of all 33 mAbs and three fusion proteins evaluated by the European Medicines Agency (EMA) between July 2012 and November 2022 with special emphasis on all submitted rituximab (four products) and trastuzumab (seven products) biosimilar candidates, including withdrawn applications. For the two withdrawn applications, the comparative efficacy trials suggested biosimilarity, but the quality/CMC package was not accepted by EMA. We therefore investigated whether a negative MAA outcome could have been predicted based on the evidence generated in the quality/CMC packages, regardless of clinical trial data. For this purpose, we reviewed the respective European Public Assessment Reports (EPARs) or withdrawal assessment reports, and the first regulatory assessments for all these 36 MAAs (i.e. day 120 of the centralized procedure), which are not publicly available. During EMA review, where significant issues are identified which would preclude a marketing authorisation, these issues are raised as questions to the applicant and are classified as major objections (MO). RESULTS: In 67% of cases, the outcome of the quality and clinical assessment was the same, i.e. both the quality and clinical assessments either supported approval or did not support approval. In 11% of cases, MO were identified in the quality part of the submission but not in the clinical data. In 22% of cases, MO were raised on the clinical data package but not on the quality data. However, we found no instance where seemingly negative clinical data, including failed efficacy trials, led to a negative overall decision. In each instance, the failure to confirm similar clinical performance in all investigated aspects was eventually viewed as not being related to the biosimilar per se but as being due to imbalances in the trial arms, immaturity of secondary endpoint results, change in the reference product, or even chance findings. Furthermore, when performing an in-depth analysis of the quality and clinical packages of trastuzumab and rituximab biosimilars, we found that in no case were clinical trial data necessary to resolve residual uncertainties regarding the quality part. CONCLUSION: The results further support the argument that sufficient evidence for biosimilarity can be obtained from a combination of analytical and functional testing and pharmacokinetic studies which may also generate immunogenicity data. This calls into question the usefulness of comparative efficacy studies for the purposes of regulatory decision-making when approving biosimilar mAbs and fusion proteins.

Use of Drugs in Clinical Practice and the Associated Cost of Cancer Treatment in Adult Patients with Solid Tumors: A 10-Year Retrospective Cohort Study.

BACKGROUND: Cancer is one of the leading causes of morbidity and mortality in the world. Its growing incidence and prevalence, as well as the advances in diagnostic and treatment tools, motivate an open debate about the economic burden it may place on health systems and have raised concerns about access to this technological innovation. There is a lack of information on the detailed costs of pharmacological treatment of cancer in our health setting. In this context, it is necessary to know the use of drugs in cancer treatment in conditions of real clinical practice. A real-word, evidence-based retrospective cohort study was conducted at Vall d'Hebron University Hospital (VHUH), the largest hospital complex in Catalonia, Spain, in order to determine the use of drugs and the associated cost in real clinical practice for the treatment of solid tumors in adult patients attended at this institution over 10 years (2010-2019). METHODS: This was a single-center retrospective cohort study of adult cancer patients attended in clinical practice at the Medical Oncology Department of VHUH between 1 January 2010 and 31 December 2019. Data of prescription, preparation, and cost of antineoplastic treatments were analyzed by pharmacological class (cytotoxic drugs, immunotherapy, targeted therapy, radiopharmaceuticals, and others), by antineoplastic agent, and by type of tumor. The number of patients and the pharmaceutical expenditure corresponding to all these subgroups were recorded. The cost per patient in each tumor location was also calculated. RESULTS: The study population included 13,209 patients with an overall pharmaceutical antineoplastic expenditure of EUR 120,396,097, increasing from 7.67% in relation to the total HUVH pharmaceutical expenditure in 2010 to 12.82% in 2019. By pharmacological class, the specific weight of the cost of targeted therapy is relevant (75.22% of pharmaceutical antineoplastic expenditure, 21.3% of patients) compared to the group of conventional cytotoxics (17.25% of pharmaceutical antineoplastic expenditure, 76.37% of patients), while immunotherapy has represented the largest relative increase, from 5% in 2014 to 12% in 2019. Eight targeted therapy drugs represented 50% of the costs of the targeted therapy drug class (palbociclib, trastuzumab, pertuzumab, bevacizumab, nivolumab, cetuximab, pembrolizumab, and trastuzumab emtansine). Eleven tumor sites accounted for 90% of the expenditure in 71% of all patients. Breast cancer had the highest expenditure during the study period (EUR 34,332,210) and at each individual year. Melanoma showed the highest increase, with 9.7% of total pharmaceutical antineoplastic expenditure in 2019 (2% of patients), representing a paradigm of the rising costs of cancer treatment due to the incorporation of new high-cost therapies. The average annual cost per patient was highly variable depending on the pathology. There was a growing increase in costs per patient in most tumor locations, particularly in patients with melanoma (from EUR 1922 in 2010 to EUR 37,020 in 2019), prostate cancer (from EUR 2992 in 2010 to EUR 14,118 in 2019), and non-small cell lung cancer (from EUR 3545 in 2010 to EUR 8371 in 2019). The relevance of the difference in monthly cost per patient that has been identified for the different intrinsic subtypes in breast cancer patients during 2019 (HER2+ EUR 2661/month, Luminal EUR 881/month, Triple negative EUR 386/month) makes us consider suggesting differentiated reimbursement rates for certain clinical conditions. Finally, support treatment with antiemetic drugs, erythropoietin stimulating agents, granulocyte-colony stimulating factor (G-CSF), and bone resorption inhibitors has involved a cost of EUR 5,751,910, which represents 4.6% of the overall pharmacological cost of cancer treatment. CONCLUSION: This study provides detailed insights on the oncological pharmaceutical expenditure for the treatment for solid tumors in the VHUH, based on real cost information from our hospital practice and for all antineoplastic therapies and types of solid tumors. This type of information on all the different types of cancer can be useful to better understand the economic burden of the disease and can be decisive for allocating public resources and funds for research, especially in those areas where information is scarce and therefore where further studies are needed. The contribution to knowledge of the cost of oncology therapy is of great value due to its realism and scope.

Unknown adverse drug reactions from spontaneous reports in a hospital setting: characterization, follow-up, and contribution to the pharmacovigilance system.

Introduction: Post-marketing identification and report of unknown adverse drug reactions (ADRs) are crucial for patient safety. However, complete information on unknown ADRs seldom is available at the time of spontaneous ADR reports and this can hamper their contribution to the pharmacovigilance system. Methods: In order to characterize the seriousness and outcome of unknown ADRs at the time of report and at follow-up, and analyze their contribution to generate pharmacovigilance regulatory actions, a retrospective observational study of those identified in the spontaneous ADR reports of patients assisted at a hospital (January, 2016-December, 2021) was carried out. Information on demographic, clinical and complementary tests was retrieved from patients' hospital medical records. To evaluate the contribution to pharmacovigilance system we reviewed the European Union SmPCs, the list of the pharmacovigilance signals discussed by the Pharmacovigilance Risk Assessment Committee, and its recommendations reports on safety signals. Results: A total of 15.2% of the spontaneous reported cases during the study contained at least one unknown drug-ADR pair. After exclusions, 295 unknown drug-ADR pairs were included, within them the most frequently affected organs or systems were: skin and subcutaneous tissue (34, 11.5%), hepatobiliary disorders (28, 9.5%), cardiac disorders (28, 9.5%) and central nervous system disorders (27, 9.2%). The most frequent ADRs were pemphigus (7, 2.4%), and cytolytic hepatitis, sudden death, cutaneous vasculitis and fetal growth restriction with 6 (2%) each. Vaccines such as covid-19 and pneumococcus (68, 21.3%), antineoplastics such as paclitaxel, trastuzumab and vincristine (39, 12.2%) and immunosuppressants such as methotrexate and tocilizumab (35, 11%) were the most frequent drug subgroups involved. Sudden death due to hydroxychloroquine alone or in combination (4, 1.4%) and hypertransaminasemia by vincristine (n = 3, 1%) were the most frequent unknown drug-ADR pairs. A total of 269 (91.2%) of them were serious. Complementary tests were performed in 82.7% of unknown-ADR pairs and helped to reinforce their association in 18.3% of them. A total of 18 (6.1%) unknown drug-ADR pairs were evaluated by the EMA, in 8 (2.7%) the information was added to the drug's SmPC and in 1 case the risk prevention material was updated. Conclusion: Identification and follow-up of unknown ADRs can be of great relevance for patient safety and for the enrichment of the pharmacovigilance system.

Increasing the Stability of Isolated and Dense High-Aspect-Ratio Nanopillars Fabricated Using UV-Nanoimprint Lithography.

Structural anti-reflective coating and bactericidal surfaces, as well as many other effects, rely on high-aspect-ratio (HAR) micro- and nanostructures, and thus, are of great interest for a wide range of applications. To date, there is no widespread fabrication of dense or isolated HAR nanopillars based on UV nanoimprint lithography (UV-NIL). In addition, little research on fabricating isolated HAR nanopillars via UV-NIL exists. In this work, we investigated the mastering and replication of HAR nanopillars with the smallest possible diameters for dense and isolated arrangements. For this purpose, a UV-based nanoimprint lithography process was developed. Stability investigations with capillary forces were performed and compared with simulations. Finally, strategies were developed in order to increase the stability of imprinted nanopillars or to convert them into nanoelectrodes. We present UV-NIL replication of pillars with aspect ratios reaching up to 15 with tip diameters down to 35 nm for the first time. We show that the stability could be increased by a factor of 58 when coating them with a 20 nm gold layer and by a factor of 164 when adding an additional 20 nm thick layer of SiN. The coating of the imprints significantly improved the stability of the nanopillars, thus making them interesting for a wide range of applications.

A Data Driven Approach to Support Tailored Clinical Programs for Biosimilar Monoclonal Antibodies.

Biosimilar monoclonal antibodies (mAbs) have been approved in the European Union since 2013 and have been demonstrated to reduce healthcare costs and to expand patient access. Biosimilarity is mainly established on the basis of demonstrated similarity of relevant quality attributes (QAs), determined by comprehensive physiochemical and functional analyses, and demonstration of bioequivalence. In addition, comparative efficacy/safety studies have been requested for all approved biosimilar mAbs so far, although the European Medicines Agency (EMA) Guidelines state that such confirmatory clinical trials may not be necessary in specific circumstances. In order to evaluate the degree of analytical similarity, how residual uncertainty regarding biosimilarity was resolved, and the value of clinical data, we analyzed the quality and clinical data packages for authorized adalimumab (7 products) and bevacizumab (5 products) biosimilars. The percentage of biosimilar batches meeting the similarity range for QAs, as defined by the biosimilar manufacturer based on a comprehensive characterization of the EU reference product (RP), was determined and clinical data were reviewed. Our analyses show that QAs of approved adalimumab and bevacizumab biosimilars have varying concordance with the EU-RP similarity range. In this study, we found that clinical efficacy data played a limited role in addressing quality concerns. Therefore, we encourage a regulatory review of the standards for clinical data requirements for mAb and fusion protein biosimilars. This study outlines a quality data driven approach for facilitating tailored clinical programs for biosimilars.

Thrombotic microangiopathy in patients with malignant hypertension.

BACKGROUND: Thrombotic microangiopathy (TMA) is a complication of malignant hypertension (mHTN) attributed to high blood pressure (BP). However, no studies have investigated in patients with mHTN of different aetiologies whether the presence of TMA is associated with specific causes of mHTN. METHODS: We investigated the presence of TMA (microangiopathic haemolytic anaemia and thrombocytopenia) in a large and well-characterized cohort of 199 patients with mHTN of different aetiologies [primary HTN 44%, glomerular diseases 16.6%, primary atypical haemolytic uraemic syndrome (aHUS) 13.1%, renovascular HTN 9.5%, drug-related HTN 7%, systemic diseases 5.5%, endocrine diseases 4.5%]. Outcomes of the study were kidney recovery and kidney failure. RESULTS: Patients with TMA [40 cases (20.1%)] were younger, were more likely female and had lower BP levels and worse kidney function at presentation. Their underlying diseases were primary aHUS (60%), drug-related mHTN (15%), glomerular diseases [all of them immunoglobulin A nephropathy (IgAN); 10%], systemic diseases (10%) and primary HTN (5%). The presence of TMA was 92.3% in primary aHUS, 42.9% in drug-related HTN, 36.4% in systemic diseases, 12.1% in glomerular diseases and 2.3% in primary HTN. No patient with renovascular HTN or mHTN caused by endocrine diseases developed TMA, despite BP levels as high as patients with TMA. A higher proportion of TMA patients developed kidney failure as compared with patients without TMA (56.4% versus 38.9%, respectively). CONCLUSIONS: The presence of TMA in patients with mHTN should guide the diagnosis towards primary aHUS, drug-related mHTN, some systemic diseases and IgAN, while it is exceptional in other causes of mHTN.

Sociodemographic inequalities in cardiovascular risk factors among adolescents from indigenous areas in Chiapas, Mexico / Desigualdades sociodemográficas como factores de riesgo cardiovascular para adolescentes de zonas indígenas de Chiapas, México / Desigualdades sociodemográficas como fatores de risco cardiovascular para adolescentes de áreas indígenas de Chiapas, México

Abstract: This study was aimed to determine the prevalence of cardiovascular risk factors among different sociodemographic groups of adolescents from indigenous communities in Chiapas, Mexico. A cross-sectional prevalence study was performed in urban and rural communities in the Tzotzil-Tzeltal and Selva regions of Chiapas. A sample of 253 adolescents was studied, of whom 48% were girls and 52% were boys. A descriptive analysis of quantitative variables was performed using measures of central tendency and dispersion. The prevalence of cardiovascular risk factors stratified by sex, geographical area, years of schooling, and ethnicity of the mothers was estimated. The prevalence of cardiovascular risk factors was analyzed in relation to the sociodemographic characteristics of the study population. Low HDL-c (51%) was the predominant cardiovascular risk factor. Girls had a higher prevalence of abdominal obesity, hypertriglyceridemia, and borderline total cholesterol than boys. High diastolic blood pressure was more prevalent in boys. Adolescents from urban areas had a higher prevalence of overweight/obesity and insulin resistance than adolescents from rural areas. The prevalence of overweight/obesity and abdominal obesity was higher in adolescents whose mothers had ≥ 7 years of schooling compared with adolescents with less educated mothers. Differences by maternal ethnicity also influenced the prevalence of insulin resistance. Among the main findings, this study associated sociodemographic and geographical inequalities with cardiovascular risk factors. Promoting a healthy lifestyle for this young population is absolutely necessary to prevent cardiovascular diseases in adulthood.

Resumen: El objetivo de este estudio fue estimar la prevalencia de los factores de riesgo cardiovascular entre diferentes grupos sociodemográficos de adolescentes de comunidades indígenas de Chiapas, México. Se realizó un estudio transversal de prevalencia en comunidades urbanas y rurales de las regiones Tzotzil-Tzeltal y Selva, en Chiapas. Participó una muestra de 253 adolescentes, en la cual el 48% eran niñas y el 52% niños. Se realizó un análisis descriptivo de las variables cuantitativas utilizando medidas de tendencia central y dispersión. Se estimó la prevalencia de los factores de riesgo cardiovascular, estratificados por sexo, área geográfica, nivel de estudios y etnia de las madres. Se analizó la prevalencia de los factores de riesgo cardiovascular con relación a las características sociodemográficas de la población estudiada. El HDL-c bajo (51%) fue el factor de riesgo cardiovascular predominante. Se observó una mayor prevalencia de obesidad abdominal, hipertrigliceridemia y colesterol total en las niñas que en los niños. La alta presión arterial diastólica prevaleció en los niños. Los adolescentes del área urbana tuvieron una mayor prevalencia de sobrepeso/obesidad y resistencia a la insulina que los del área rural. La prevalencia de sobrepeso/obesidad y obesidad abdominal fue mayor en los adolescentes cuyas madres tenían nivel de estudios ≥ 7 años que aquellos cuyas madres tenían bajo nivel de estudios. Las diferencias en la etnicidad materna también influyeron en la prevalencia de resistencia a la insulina. Entre las principales conclusiones de este estudio, se destacan las desigualdades sociodemográficas y geográficas entre los factores de riesgo cardiovascular. La promoción de un estilo de vida saludable entre la población joven es lo indicado para prevenir las enfermedades cardiovasculares en la edad adulta.

Resumo: O objetivo deste estudo foi determinar a prevalência de fatores de risco cardiovascular entre diferentes grupos sociodemográficos de adolescentes de comunidades indígenas em Chiapas, México. Foi realizado um estudo transversal de prevalência em comunidades urbanas e rurais das regiões de Tzotzil-Tzeltal e Selva de Chiapas. Foi estudada uma amostra de 253 adolescentes, sendo 48% meninas e 52% meninos. Foi realizada uma análise descritiva das variáveis quantitativas por meio de medidas de tendência central e dispersão. Foram estimadas as prevalências de fatores de risco cardiovascular, estratificadas por sexo, área geográfica, escolaridade e etnia das mães. A prevalência dos fatores de risco cardiovascular foi analisada em relação às características sociodemográficas da população estudada. O HDL-c baixo (51%) foi o fator de risco cardiovascular predominante. Prevalências mais elevadas de obesidade abdominal, hipertrigliceridemia e colesterol total limítrofe foram mais observadas em meninas do que em meninos. A pressão arterial diastólica elevada prevaleceu nos meninos. Adolescentes da área urbana apresentaram prevalências de sobrepeso/obesidade e resistência à insulina maiores do que os da área rural. A prevalência de sobrepeso/obesidade e obesidade abdominal foi maior nos adolescentes cujas mães possuíam escolaridade ≥ 7 anos do que naqueles indivíduos cujas mães tinham baixa escolaridade. As diferenças de etnia das mães também foram observadas na prevalência de resistência à insulina. Dentre as principais conclusões, foram encontradas, neste estudo, desigualdades sociodemográficas e geográficas entre fatores de risco cardiovascular. Promover estilos de vida saudáveis entre a população jovem é o ideal para prevenir doenças cardiovasculares na vida adulta.

Driver Take-Over Behaviour Study Based on Gaze Focalization and Vehicle Data in CARLA Simulator.

Autonomous vehicles are the near future of the automobile industry. However, until they reach Level 5, humans and cars will share this intermediate future. Therefore, studying the transition between autonomous and manual modes is a fascinating topic. Automated vehicles may still need to occasionally hand the control to drivers due to technology limitations and legal requirements. This paper presents a study of driver behaviour in the transition between autonomous and manual modes using a CARLA simulator. To our knowledge, this is the first take-over study with transitions conducted on this simulator. For this purpose, we obtain driver gaze focalization and fuse it with the road's semantic segmentation to track to where and when the user is paying attention, besides the actuators' reaction-time measurements provided in the literature. To track gaze focalization in a non-intrusive and inexpensive way, we use a method based on a camera developed in previous works. We devised it with the OpenFace 2.0 toolkit and a NARMAX calibration method. It transforms the face parameters extracted by the toolkit into the point where the user is looking on the simulator scene. The study was carried out by different users using our simulator, which is composed of three screens, a steering wheel and pedals. We distributed this proposal in two different computer systems due to the computational cost of the simulator based on the CARLA simulator. The robot operating system (ROS) framework is in charge of the communication of both systems to provide portability and flexibility to the proposal. Results of the transition analysis are provided using state-of-the-art metrics and a novel driver situation-awareness metric for 20 users in two different scenarios.

Reinforcement Learning-Based Autonomous Driving at Intersections in CARLA Simulator.

Intersections are considered one of the most complex scenarios in a self-driving framework due to the uncertainty in the behaviors of surrounding vehicles and the different types of scenarios that can be found. To deal with this problem, we provide a Deep Reinforcement Learning approach for intersection handling, which is combined with Curriculum Learning to improve the training process. The state space is defined by two vectors, containing adversaries and ego vehicle information. We define a features extractor module and an actor-critic approach combined with Curriculum Learning techniques, adding complexity to the environment by increasing the number of vehicles. In order to address a complete autonomous driving system, a hybrid architecture is proposed. The operative level generates the driving commands, the strategy level defines the trajectory and the tactical level executes the high-level decisions. This high-level decision system is the main goal of this research. To address realistic experiments, we set up three scenarios: intersections with traffic lights, intersections with traffic signs and uncontrolled intersections. The results of this paper show that a Proximal Policy Optimization algorithm can infer ego vehicle-desired behavior for different intersection scenarios based only on the behavior of adversarial vehicles.

Safety of Drugs Used during the First Wave of COVID-19: A Hospital-Registry-Based Study.

The emergency of the coronavirus disease 2019 (COVID-19) pandemic led to the off-label use of drugs without data on their toxicity profiles in patients with COVID-19, or on their concomitant use. Patients included in the COVID-19 Patient Registry of a tertiary hospital during the first wave were analyzed to evaluate the adverse drug reactions (ADRs) with the selected treatments. Twenty-one percent of patients (197 out of 933) had at least one ADR, with a total of 240 ADRs. Patients with ADRs were more commonly treated with multiple drugs for COVID-19 infection than patients without ADRs (p < 0.001). They were younger (median 62 years vs. 70.1 years; p < 0.001) and took less medication regularly (69.5% vs. 75.7%; p = 0.031). The most frequent ADRs were gastrointestinal (67.1%), hepatobiliary (10.8%), and cardiac disorders (3.3%). Drugs more frequently involved included lopinavir/ritonavir (82.2%), hydroxychloroquine (72.1%), and azithromycin (66.5%). Although most ADRs recovered without sequelae, fatal cases were described, even though the role of the disease could not be completely ruled out. In similar situations, efforts should be made to use the drugs in the context of clinical trials, and to limit off-label use to those drugs with a better benefit/risk profile in specific situations and for patients at high risk of poor disease prognosis.

Efficacy and safety of hydroxychloroquine in healthcare professionals with mild SARS-CoV-2 infection: Prospective, non-randomized trial.

OBJECTIVES: To assess the efficacy and safety of hydroxychloroquine (HCQ) compared with no treatment in healthcare workers with mild SARS-CoV-2 infection. METHODS: Prospective, non-randomized study. All health professionals with confirmed COVID-19 between April 7 and May 6, 2020, non-requiring initial hospitalization were asked to participate. Patients who accepted treatment were given HCQ for five days (loading dose of 400mg q12h the first day followed by200mg q12h). Control group included patients with contraindications for HCQ or who rejected treatment. Study outcomes were negative conversion and viral dynamics of SARS-CoV-2, symptoms duration and disease progression. RESULT: Overall, 142 patients were enrolled: 87 in treatment group and 55 in control group. The median age was 37 years and 75% were female, with few comorbidities. There were no significant differences in time to negative conversion of PCR between both groups. The only significant difference in the probability of negative conversion of PCR was observed at day 21 (18.7%, 95%CI 2.0-35.4). The decrease of SARS-CoV-2 viral load during follow-up was similar in both groups. A non significant reduction in duration of some symptoms in HCQ group was observed. Two patients with HCQ and 4 without treatment developed pneumonia. No patients required admission to the Intensive Care Unit or died. About 50% of patients presented mild side effects of HCQ, mainly diarrhea. CONCLUSIONS: Our study failed to show a substantial benefit of HCQ in viral dynamics and in resolution of clinical symptoms in health care workers with mild COVID-19.

Efficacy and safety of hydroxychloroquine in healthcare professionals with mild SARS-CoV-2 infection: Prospective, non-randomized trial / Eficacia y seguridad de hidroxicloroquina en profesionales sanitarios con infección leve por SARS-CoV-2: Estudio prospectivo y no aleatorio

Objectives: To assess the efficacy and safety of hydroxychloroquine (HCQ) compared with no treatment in healthcare workers with mild SARS-CoV-2 infection. Methods: Prospective, non-randomized study. All health professionals with confirmed COVID-19 between April 7 and May 6, 2020, non-requiring initial hospitalization were asked to participate. Patients who accepted treatment were given HCQ for five days (loading dose of 400mg q12h the first day followed by200mg q12h). Control group included patients with contraindications for HCQ or who rejected treatment. Study outcomes were negative conversion and viral dynamics of SARS-CoV-2, symptoms duration and disease progression. Result: Overall, 142 patients were enrolled: 87 in treatment group and 55 in control group. The median age was 37 years and 75% were female, with few comorbidities. There were no significant differences in time to negative conversion of PCR between both groups. The only significant difference in the probability of negative conversion of PCR was observed at day 21 (18.7%, 95%CI 2.0–35.4). The decrease of SARS-CoV-2 viral load during follow-up was similar in both groups. A non significant reduction in duration of some symptoms in HCQ group was observed. Two patients with HCQ and 4 without treatment developed pneumonia. No patients required admission to the Intensive Care Unit or died. About 50% of patients presented mild side effects of HCQ, mainly diarrhea. Conclusions: Our study failed to show a substantial benefit of HCQ in viral dynamics and in resolution of clinical symptoms in health care workers with mild COVID-19.(AU)

Objetivos: Evaluar la eficacia y seguridad de hidroxicloroquina (HCQ), en comparación con la ausencia de tratamiento en los profesionales sanitarios con infección leve por SARS-CoV-2. Métodos: Estudio prospectivo y no aleatorio. Se solicitó su participación a todos los profesionales sanitarios con diagnóstico confirmado de COVID-19, entre el 7 de abril y el 6 de mayo de 2020, que no requirieron hospitalización inicial. Los pacientes que aceptaron el tratamiento recibieron HCQ durante cinco días (dosis de carga de 400 mg cada 12 h el primer día, y a continuación 200 mg cada 12 h). El grupo control incluyó pacientes con contraindicaciones de HCQ, o que rechazaron el tratamiento. Los resultados del estudio fueron conversión negativa y dinámica viral de SARS-CoV-2, duración de los síntomas y progresión de la enfermedad. Resultados: En total se incluyeron 142 pacientes: 87 en el grupo de tratamiento, y 55 en el grupo control. La edad media fue de 37 años, y el 75% fueron mujeres, con pocas comorbilidades. No existieron diferencias significativas en cuanto al tiempo transcurrido hasta la conversión negativa de la PCR entre ambos grupos. La única diferencia significativa en cuanto a la probabilidad de negativización de la PCR se observó el día 21 (18,7%, IC 95% 2-35,4). El descenso de la carga viral de SARS-CoV-2 durante el seguimiento fue similar en ambos grupos. Se observó una reducción no significativa de la duración de algunos síntomas en el grupo HCQ. Dos pacientes con HCQ y cuatro sin tratamiento desarrollaron neumonía. Ningún paciente requirió ingreso en la Unidad de Cuidados Intensivos, ni hubo fallecidos. Cerca del 50% de los pacientes presentó efectos secundarios leves de HCQ, principalmente diarrea. Conclusiones: Nuestro estudio no reflejó un beneficio sustancial de HCQ, en cuanto a dinámica viral y resolución de los síntomas clínicos en los profesionales sanitarios con infección leve por COVID-19.(AU)