Impact of a geriatric intervention based on the Comprehensive Geriatrics Assessment on avoidable admissions in older patients at risk evaluated in the Emergency Department.

OBJECTIVE: To know the impact of a geriatric intervention based on the Comprehensive Geriatric Assessment (CGA) on avoidable admissions in older patients at risk evaluated in the Emergency Department. METHOD: Prospective observational unicenter study. We included patients, from October 1, 2018 to January 31, 2020, over 75 years who were attended at the Emergency Department with a Triage Risk Screening Tool (TRST) score≥2. All patients were evaluated by a geriatrician through the CGA. The reasons for going to the Emergency room were collected and also the main intervention carried out by Geriatrics, whether admission or discharge was indicated and whether the admission was avoidable. We did a cost analysis calculating this by (bed/day×average stay×number of admissions avoided). RESULTS: We included 260 patients, 66% were women and the mean age was 86 years. 73.5% patients had polypharmacy, the mean Charlson index was 2.5 (5.6). 63.3% were independent for walking and 20.8% independent for basic activities of daily living. 59% had cognitive impairment. 91.5% lived at home. The most frequent reason for visiting the Emergency room was decline of general state in 22% and the most frequent intervention carried out by Geriatrics was assistance in the decision making process in 35.4% followed by referral to a preferential outpatient geriatric care circuit in 32.7%. Other interventions carried out by Geriatrics was assistance in clarifying diagnosis (4.2%), assistance in pharmacological adjustment (8.5%), referral to a standard geriatric care pathway (13.1%), telephone follow-up (4.2%) and/or coordination with Social Services for care planning (11.2%). Including all patients, 29.2% required hospital admission and 70.8% were discharged. 40% admissions were avoided, which meant more than 540 thousand euros saved. CONCLUSIONS: A standardized CGA coordinated by Geriatrics in older patients at risk of suffering adverse events in the Emergency room reduces admissions and costs, so it should therefore be established as a recommendation of good clinical practice.

Atorvastatin before percutaneous coronary intervention: A systematic review and meta-analysis.

Atorvastatin is widely recommended for long-term secondary prevention in STEMI patients with no contraindication. Although high-dose atorvastatin has been shown to reduce important patient outcomes such as MACE, there is still doubt that high-dose atorvastatin could have the same protective effect in patients undergoing PCI in the short and long term. We searched the following electronic databases: Scopus, Web of Science, MEDLINE, EMBASE, and Cochrane Central considering studies that enrolled adult patients with a confirmed diagnosis of STEMI or NSTEMI undergoing PCI. The intervention must have been atorvastatin alone compared to a placebo, standard care, or a different atorvastatin dose. A total of (n = 11) studies were included in the quantitative analysis. Information on (N = 5,399) patients was available; 2,654 were assigned to receive high-dose atorvastatin therapy, and 2,745 comprised the control group. High-dose atorvastatin pre-loading significantly reduced MACE at one month of follow-up (RR: 0.78; 95% CI: 0.67-0.91; p = 0.014) in both STEMI and NSTEMI. All-cause mortality was reduced in patients with STEMI (RR: 0.28; 95% CI: 0.10-0.81; p = 0.029). The quality of the body of evidence was rated overall as moderate. Patients presenting with STEMI or NSTEMI benefit from high-dose atorvastatin pre-loading before PCI by reducing MACE at 30 days. The use of high-dose atorvastatin in STEMI patients reduced all-cause mortality. The beneficial effects of atorvastatin pre-loading are limited to 30 days post-PCI.

Impacto y características de la gripe nosocomial a lo largo de 10 temporadas en un hospital universitario de tercer nivel / Impact and characteristics of hospital-acquired influenza over 10 seasons in a third-level university hospital

Objetivos: Analizar las características de los pacientes con gripe nosocomial, compararlas con las de los enfermos con diagnóstico de gripe comunitaria para estudiar posibles diferencias e identificar posibles factores de riesgo asociados a este tipo de gripe. Pacientes y métodos: Estudio observacional, transversal y retrospectivo de los pacientes hospitalizados con diagnóstico microbiológico de gripe en un hospital universitario de tercer nivel durante 10 temporadas, de 2009 a 2019. Se definió como gripe nosocomial aquella infección cuyos síntomas comenzaron 72 h después del ingreso hospitalario y se analizó su incidencia, características y consecuencias. Resultados: Se incluyó a un total de 1.260 pacientes hospitalizados con diagnóstico microbiológico de gripe, de los cuales 110 (8,7%) fueron nosocomiales. Los pacientes con gripe adquirida en el hospital eran más jóvenes (71,74±16,03 años; p=0,044), tuvieron una estancia hospitalaria mayor (24,25±20,25 días; p<0,001), tenían con mayor frecuencia antecedentes de enfermedades pulmonares crónicas (p=0,010), inmunodeficiencias (p<0,001) y se asociaron con mayor desarrollo de sobreinfección bacteriana (p<0,001), distrés respiratorio (p=0,003) e ingreso en la unidad de cuidados intensivos (UCI) (p<0,001). En el análisis por regresión logística multivariante se identificaron como factores de riesgo independientes: inmunodeficiencia (ORa=2,33; IC 95%: 1,47-3,60); ingreso en UCI (ORa=4,29; IC 95%: 2,23-10,91); desarrollo de sobreinfección bacteriana (ORa=1,64; IC 95%: 1,06-2,53) y de distrés respiratorio (ORa=3,88; IC 95%: 1,23-12,23).Conclusiones: La gripe nosocomial es más frecuente en los pacientes con antecedentes de inmunodeficiencia. Además, los enfermos con gripe hospitalaria tienen un riesgo aumentado de sobreinfección bacteriana, ingreso en UCI y desarrollo de distrés respiratorio.(AU)

Objectives: To analyze the characteristics of patients with nosocomial flu, to compare them with patients with community-acquired influenza to study possible differences and to identify possible risk factors associated with this type of flu. Patients and methodsObservational, cross-sectional and retrospective study of hospitalized patients with a microbiological confirmation of influenza in a third-level university hospital over 10seasons, from 2009 to 2019. Nosocomial influenza was defined as that infection whose symptoms began 72h after hospital admission, and its incidence, characteristics and consequences were further analyzed. Results: A total of 1260 hospitalized patients with a microbiological diagnosis of influenza were included, which 110 (8.7%) were nosocomial. Patients with hospital-acquired influenza were younger (71.74±16.03 years, P=0.044), had a longer hospital stay (24.25±20.25 days, P<0.001), had more frequently a history of chronic pulmonary pathologies (P=0.010), immunodeficiency (P<0.001), and were associated with greater development of bacterial superinfection (P<0.001), respiratory distress (P=0.003), and admission to the intensive care unit (ICU) (P<0.001). In the multivariate logistic regression analysis, the following characteristics were identified as independent risk factors: immunodeficiency (ORa=2.33; 95% CI: 1.47-3.60); ICU admission (ORa=4.29; 95% CI: 2.23-10.91); bacterial superinfection (ORa=1.64; 95% CI: 1.06-2.53) and respiratory distress (ORa=3.88; 95% CI: 1.23-12.23). Conclusions: Nosocomial influenza is more common in patients with a history of immunodeficiency. In addition, patients with hospital-acquired influenza had an increased risk of bacterial superinfection, admission to the ICU, and development of respiratory distress.(AU)

Carotid atherosclerosis in the first five years since rheumatoid arthritis diagnosis: a cross sectional study.

BACKGROUND: Systemic inflammation, documented before rheumatoid arthritis (RA) diagnosis, is associated with accelerated atherosclerosis. We aimed to compare the prevalence of carotid plaque (CP) in RA patients in the first five years since diagnosis and healthy controls, and to determine disease characteristics associated with the presence of subclinical atherosclerosis in RA patients. METHODS: This was a cross-sectional study. We recruited 60 RA patients in the first five years since diagnosis and 60 matched healthy controls. Carotid ultrasound was performed to detect the presence of CP and measure carotid-intima media thickness (cIMT). Subclinical atherosclerosis was considered as the presence of CP and/or increased cIMT. Distribution was evaluated with the Kolmogorov-Smirnov test. Comparisons were made with Chi-square or Fisher's exact test for qualitative variables and Student's t or Mann-Whitney's U test for quantitative variables. A p-value < 0.05 was considered significant. RESULTS: There were no differences in the demographic characteristics between RA patients and controls. The mean disease duration was 2.66 ± 1.39 years. A higher prevalence of CP (30.0% vs. 11.7%, p = 0.013), bilateral CP (18.3% vs. 3.3%, p = 0.008), increased cIMT (30.0% vs. 6.7%, p = 0.001), and subclinical atherosclerosis (53.3% vs. 18.3%, p = < 0.001) was found in RA patients. RA patients with subclinical atherosclerosis were older (56.70 years vs. 50.00 years, p = 0.002), presented a higher prevalence of dyslipidemia (53.1% vs. 14.3%, p = 0.002), and higher prevalence of classification in moderate-high disease activity category measured by DAS28-CRP (68.8% vs. 35.7%, p = 0.010). The latter variable persisted independently associated with subclinical atherosclerosis in the binary logistic regression (OR 6.11, 95% CI 1.51-24.70, p = 0.011). CONCLUSIONS: In the first five years since diagnosis, higher prevalence of subclinical atherosclerosis, including CP was found in RA patients. Carotid ultrasound should be considered part of the systematic CVR evaluation of RA at the time of diagnosis.

Tumor glómico del espacio masticatorio que imita patología mandibular / Glomus tumour of the masticatory space mimicking oral mandibular pathology

El tumor glómico es una neoplasia mesenquimal derivada de la célula muscular lisa modificada del aparato glómico. Solo se han descrito 39 casos en la cavidad oral. Una mujer de 32 años presentó dolor intenso e hipoestesia en el área del nervio mandibular. El examen físico oral reveló un abultamiento suave sensible a la palpación. La ortopantomografía mostró una imagen radiolúcida y bien definida en la rama mandibular que sugiere un trastorno óseo. Sin embargo, el TC y el angio-TC mostraron una lesión hipervascular en el espacio masticatorio derecho. Se optó por un abordaje quirúrgico intraoral de la lesión. El análisis histopatológico mostró una positividad difusa y fuerte para la vimentina. La actina del músculo liso, la actina específica del músculo y la cadena pesada de miosina del músculo liso también fueron positivas, pero la inmunorreactividad para los marcadores varió en extensión e intensidad entre las diferentes áreas tumorales. Calponina mostró inmunotinción focal y débil. El índice de proliferación (Ki67-MIB1) fue inferior al 1 %.Basado en estos hallazgos morfológicos e inmunohistoquímicos, el tumor se diagnosticó como un tumor glómico (tipo sólido). Esta primera descripción de un tumor glómico en el espacio masticatorio nos hace incluirlo en el diagnóstico diferencial de las neoplasias en esta área. (AU)

Glomus tumour is a mesenchymal neoplasm from modified smooth muscle cell of the glomus apparatus. Only 39 cases have been reported in the oral cavity. A 32-year-old female presented with intense pain and hypoaestesia in the mandibular nerve area. Oral physical examination revealed a soft bulging tender to palpation. Orthopantomography showed a radiolucent, well-defined image in the mandibular ramus suggesting an osseous disorder. However, CT and angio-CT showed a hypervascular lesion in the right masticatory space. An intraoral surgical approach to the lesion was chosen. Histopathological analysis showed diffuse and strong positivity for vimentin. Smooth muscle actin, muscle specific actin, and smooth muscle myosin heavy-chain were also positive, but immunoreactivity for markers varied in extension and intensity between different tumour areas. Calponin showed focal and weak immunostaning. Proliferation index (Ki67-MIB1) was less than 1 %.Based on these morphological and immunohistochemical findings, the tumour was diagnosed as a glomus tumour (solid type). This first description of a glomus tumour in the masticatory space makes us include it in the differential diagnosis of neoplasms in this area. (AU)

MSIMEP: Predicting microsatellite instability from microarray DNA methylation tumor profiles.

Deficiency in DNA MMR activity results in tumors with a hypermutator phenotype, termed microsatellite instability (MSI). Beyond its utility in Lynch syndrome screening algorithms, today MSI has gained importance as predictive biomarker for various anti-PD-1 therapies across many different tumor types. Over the past years, many computational methods have emerged to infer MSI using either DNA- or RNA-based approaches. Considering this together with the fact that MSI-high tumors frequently exhibit a hypermethylated phenotype, herein we developed and validated MSIMEP, a computational tool for predicting MSI status from microarray DNA methylation tumor profiles of colorectal cancer samples. We demonstrated that MSIMEP optimized and reduced models have high performance in predicting MSI in different colorectal cancer cohorts. Moreover, we tested its consistency in other tumor types with high prevalence of MSI such as gastric and endometrial cancers. Finally, we demonstrated better performance of both MSIMEP models vis-à-vis a MLH1 promoter methylation-based one in colorectal cancer.

Implementation of a centralized pharmacovigilance system in academic pan-European clinical trials: Experience from EU-Response and conect4children consortia.

Setting-up a high quality, compliant and efficient pharmacovigilance (PV) system in multi-country clinical trials can be more challenging for academic sponsors than for companies. To ensure the safety of all participants in academic studies and that the PV system fulfils all regulations, we set up a centralized PV system that allows sponsors to delegate work on PV. This initiative was put in practice by our Inserm-ANRS MIE PV department in two distinct multinational European consortia with 19 participating countries: conect4children (c4c) for paediatrics research and EU-Response for Covid-19 platform trials. The centralized PV system consists of some key procedures to harmonize the complex safety processes, creation of a local safety officer (LSO) network and centralization of all safety activities. The key procedures described the safety management plan for each trial and how tasks were shared and delegated between all stakeholders. Processing of serious adverse events (SAEs) in a unique database guaranteed the full control of the safety data and continuous evaluation of the risk-benefit ratio. The LSO network participated in efficient regulatory compliance across multiple countries. In total, there were 1312 SAEs in EU-Response and 83 SAEs in c4c in the four trials. We present here the lessons learnt from our experience in four clinical trials. We managed heterogeneous European local requirements and implemented efficient communication with all trial teams. Our approach builds capacity for PV that can be used by multiple academic sponsors.

Impact and characteristics of hospital-acquired influenza over 10 seasons in a third-level university hospital.

OBJECTIVES: To analyze the characteristics of patients with nosocomial flu, to compare them with patients with community-acquired influenza to study possible differences and to identify possible risk factors associated with this type of flu. PATIENTS AND METHODS: Observational, cross-sectional and retrospective study of hospitalized patients with a microbiological confirmation of influenza in a third-level university hospital over 10 seasons, from 2009 to 2019. Nosocomial influenza was defined as that infection whose symptoms began 72h after hospital admission, and its incidence, characteristics and consequences were further analyzed. RESULTS: A total of 1260 hospitalized patients with a microbiological diagnosis of influenza were included, which 110 (8.7%) were nosocomial. Patients with hospital-acquired influenza were younger (71.74±16.03 years, P=0.044), had a longer hospital stay (24.25±20.25 days, P<0.001), had more frequently a history of chronic pulmonary pathologies (P=0.010), immunodeficiency (P<0.001), and were associated with greater development of bacterial superinfection (P<0.001), respiratory distress (P=0.003), and admission to the intensive care unit (ICU) (P<0.001). In the multivariate logistic regression analysis, the following characteristics were identified as independent risk factors: immunodeficiency (ORa=2.33; 95% CI: 1.47-3.60); ICU admission (ORa=4.29; 95% CI: 2.23-10.91); bacterial superinfection (ORa=1.64; 95% CI: 1.06-2.53) and respiratory distress (ORa=3.88; 95% CI: 1.23-12.23). CONCLUSIONS: Nosocomial influenza is more common in patients with a history of immunodeficiency. In addition, patients with hospital-acquired influenza had an increased risk of bacterial superinfection, admission to the ICU, and development of respiratory distress.

Carotid atherosclerosis in the first five years since rheumatoid arthritis diagnosis: a cross sectional study

Abstract Background Systemic inflammation, documented before rheumatoid arthritis (RA) diagnosis, is associated with accelerated atherosclerosis. We aimed to compare the prevalence of carotid plaque (CP) in RA patients in the first five years since diagnosis and healthy controls, and to determine disease characteristics associated with the presence of subclinical atherosclerosis in RA patients. Methods This was a cross-sectional study. We recruited 60 RA patients in the first five years since diagnosis and 60 matched healthy controls. Carotid ultrasound was performed to detect the presence of CP and measure carotidintima media thickness (cIMT). Subclinical atherosclerosis was considered as the presence of CP and/or increased cIMT. Distribution was evaluated with the Kolmogorov-Smirnov test. Comparisons were made with Chi-square or Fisher's exact test for qualitative variables and Student's t or Mann-Whitney's U test for quantitative variables. A p-value < 0.05 was considered significant. Results There were no differences in the demographic characteristics between RA patients and controls. The mean disease duration was 2.66 ± 1.39 years. A higher prevalence of CP (30.0% vs. 11.7%, p = 0.013), bilateral CP (18.3% vs. 3.3%, p = 0.008), increased cIMT (30.0% vs. 6.7%, p = 0.001), and subclinical atherosclerosis (53.3% vs. 18.3%, p = < 0.001) was found in RA patients. RA patients with subclinical atherosclerosis were older (56.70 years vs. 50.00 years, p = 0.002), presented a higher prevalence of dyslipidemia (53.1% vs. 14.3%, p = 0.002), and higher prevalence of classification in moderate-high disease activity category measured by DAS28-CRP (68.8% vs. 35.7%, p = 0.010). The latter variable persisted independently associated with subclinical atherosclerosis in the binary logistic regression (OR 6.11, 95% CI 1.51-24.70, p = 0.011). Conclusions In the first five years since diagnosis, higher prevalence of subclinical atherosclerosis, including CP was found in RA patients. Carotid ultrasound should be considered part of the systematic CVR evaluation of RA at the time of diagnosis.

Laboratory Cross-Comparison and Ring Test Trial for Tumor BRCA Testing in a Multicenter Epithelial Ovarian Cancer Series: The BORNEO GEICO 60-0 Study.

Germline and tumor BRCA testing constitutes a valuable tool for clinical decision-making in the management of epithelial ovarian cancer (EOC) patients. Tissue testing is able to identify both germline (g) and somatic (s) BRCA variants, but tissue preservation methods and the widespread implementation of NGS represent pre-analytical and analytical challenges that need to be managed. This study was carried out on a multicenter prospective GEICO cohort of EOC patients with known gBRCA status in order to determine the inter-laboratory reproducibility of tissue sBRCA testing. The study consisted of two independent experimental approaches, a bilateral comparison between two reference laboratories (RLs) testing 82 formalin-paraffin-embedded (FFPE) EOC samples each, and a Ring Test Trial (RTT) with five participating clinical laboratories (CLs) evaluating the performance of tissue BRCA testing in a total of nine samples. Importantly, labs employed their own locally adopted next-generation sequencing (NGS) analytical approach. BRCA mutation frequency in the RL sub-study cohort was 23.17%: 12 (63.1%) germline and 6 (31.6%) somatic. Concordance between the two RLs with respect to BRCA status was 84.2% (gBRCA 100%). The RTT study distributed a total of nine samples (three commercial synthetic human FFPE references, three FFPE, and three OC DNA) among five CLs. The median concordance detection rate among them was 64.7% (range: 35.3-70.6%). Analytical discrepancies were mainly due to the minimum variant allele frequency thresholds, bioinformatic pipeline filters, and downstream variant interpretation, some of them with consequences of clinical relevance. Our study demonstrates a wide range of concordance in the identification and interpretation of BRCA sequencing data, highlighting the relevance of establishing standard criteria for detecting, interpreting, and reporting BRCA variants.

Vascular smooth muscle ion channels in essential hypertension.

Hypertension is a highly prevalent chronic disease and the major risk factor for cardiovascular diseases, the leading cause of death worldwide. Hypertension is characterized by an increased vascular tone determined by the contractile state of vascular smooth muscle cells that depends on intracellular calcium levels. The interplay of ion channels determine VSMCs membrane potential and thus intracellular calcium that controls the degree of contraction, vascular tone and blood pressure. Changes in ion channels expression and function have been linked to hypertension, but the mechanisms and molecular entities involved are not completely clear. Furthermore, the literature shows discrepancies regarding the contribution of different ion channels to hypertension probably due to differences both in the vascular preparation and in the model of hypertension employed. Animal models are essential to study this multifactorial disease but it is also critical to know their characteristics to interpret properly the results obtained. In this review we summarize previous studies, using the hypertensive mouse (BPH) and its normotensive control (BPN), focused on the identified changes in the expression and function of different families of ion channels. We will focus on L-type voltage-dependent Ca2+ channels (Cav1.2), canonical transient receptor potential channels and four different classes of K+ channels: voltage-activated (Kv), large conductance Ca2+-activated (BK), inward rectifiers (Kir) and ATP-sensitive (KATP) K+ channels. We will describe the role of these channels in hypertension and we will discuss the importance of integrating individual changes in a global context to understand the complex interplay of ion channels in hypertension.

Lipin-1-derived diacylglycerol activates intracellular TRPC3 which is critical for inflammatory signaling.

Exposure to Gram-negative bacterial LPS exacerbates host immune responses and may lead to sepsis, a life-threatening condition. Despite its high mortality and morbidity, no drugs specifically directed to treating sepsis are currently available. Using human cell genetic depletion, pharmacological inhibition, live-cell microscopy and organelle-targeted molecular sensors we present evidence that the channel TRPC3 is activated intracellularly during macrophage exposure to LPS and is essential for Ca2+ release from internal stores. In this manner, TRPC3 participates in cytosolic Ca2+ elevations, activation of the transcription factor NF-κB and cytokine upregulation. We also report that TRPC3 is activated by diacylglycerol generated by the phosphatidic acid phosphatase lipin-1. In accord with this, lipin-1-deficient cells exhibit reduced Ca2+ responses to LPS challenge. Finally, pharmacological inhibition of TRPC3 reduces systemic inflammation induced by LPS in mice. Collectively, our study unveils a central component of LPS-triggered Ca2+ signaling that involves intracellular sensing of lipin-1-derived DAG by TRPC3, and opens new opportunities for the development of strategies to treat LPS-driven inflammation.

Optimizing ECG to detect echocardiographic left ventricular hypertrophy with computer-based ECG data and machine learning.

BACKGROUND: Left ventricular hypertrophy detected by echocardiography (Echo-LVH) is an independent predictor of mortality. Integration of the Philips DXL-16 algorithm into the electrocardiogram (ECG) extensively analyses the electricity of the heart. Machine learning techniques such as the C5.0 could lead to a new decision tree criterion to detect Echo-LVH. OBJECTIVES: To search for a new combination of ECG parameters predictive of Echo-LVH. The final model is called the Cardiac Hypertrophy Computer-based model (CHCM). METHODS: We extracted the 458 ECG parameters provided by the Philips DXL-16 algorithm in patients with Echo-LVH and controls. We used the C5.0 ML algorithm to train, test, and validate the CHCM. We compared its diagnostic performance to validate state-of-the-art criteria in our patient cohort. RESULTS: We included 439 patients and considered an alpha value of 0.05 and a power of 99%. The CHCM includes T voltage in I (≤0.055 mV), peak-to-peak QRS distance in aVL (>1.235 mV), and peak-to-peak QRS distance in aVF (>0.178 mV). The CHCM had an accuracy of 70.5% (CI95%, 65.2-75.5), a sensitivity of 74.3%, and a specificity of 68.7%. In the external validation cohort (n = 156), the CHCM had an accuracy of 63.5% (CI95%, 55.4-71), a sensitivity of 42%, and a specificity of 82.9%. The accuracies of the most relevant state-of-the-art criteria were: Romhilt-Estes (57.4%, CI95% 49-65.5), VDP Cornell (55.7%, CI95%47.6-63.7), Cornell (59%, CI95%50.8-66.8), Dalfó (62.9%, CI95%54.7-70.6), Sokolow Lyon (53.9%, CI95%45.7-61.9), and Philips DXL-16 algorithm (54.5%, CI95%46.3-62.5). CONCLUSION: ECG computer-based data and the C5.0 determined a new set of ECG parameters to predict Echo-LVH. The CHCM classifies patients as Echo-LVH with repolarization abnormalities or LVH with increased voltage. The CHCM has a similar accuracy, and is slightly more sensitive than the state-of-the-art criteria.

Anti-Inflammatory Effect of Tacrolimus/Hydroxypropyl-ß-Cyclodextrin Eye Drops in an Endotoxin-Induced Uveitis Model.

BACKGROUND: Uveitis is an infrequent disease which constitutes a major cause of ocular morbidity. Correct management is essential, being corticosteroids its cornerstone. In case of contraindication to corticosteroids or treatment failure, the use of topical tacrolimus (TAC) could be an alternative which has already demonstrated safety and effectiveness in other ocular pathologies. However, TAC eye drops are not marketed, thus their elaboration must be carried out in Hospital Pharmacy Departments (HPDs). METHODS: 32 Sprague-Dawley rats were divided into 4 groups of 8 rats each: (a) untreated healthy rats (Healthy); (b) untreated Endotoxin-Induced Uveitis model-rats (EIU); (c) EIU-rats treated with standard treatment of dexamethasone ophthalmic drops (DXM) and (d) EIU-rats treated with TAC-hydroxypropyl-ß-cyclodextrin eye drops previously developed by our group (TAC-HPßCD). The mRNA expression levels of IL-6, IL-8, MIP-1α and TNF-α, quantitative analysis of leucocytes in aqueous humor and histological evaluation were performed. RESULTS: TAC-HPßCD eye drops demonstrated to reduce ocular inflammation, expression of IL-6, TNF-α, MIP-1α and leukocyte infiltration in aqueous humor. CONCLUSIONS: TAC-HPßCD eye drops showed beneficial effect in EIU model in rats, positioning as an alternative for uveitis treatment in case of corticosteroids resistance or intolerance.

Development and Characterization of Inhaled Ethanol as a Novel Pharmacological Strategy Currently Evaluated in a Phase II Clinical Trial for Early-Stage SARS-CoV-2 Infection.

Inhaled administration of ethanol in the early stages of COVID-19 would favor its location on the initial replication sites, being able to reduce the progression of the disease and improving its prognosis. Before evaluating the efficacy and safety of this novel therapeutic strategy in humans, its characterization is required. The developed 65° ethanol formulation is stable at room temperature and protected from light for 15 days, maintaining its physicochemical and microbiological properties. Two oxygen flows have been tested for its administration (2 and 3 L/min) using an automated headspace gas chromatographic analysis technique (HS-GC-MS), with that of 2 L/min being the most appropriate one, ensuring the inhalation of an ethanol daily dose of 33.6 ± 3.6 mg/min and achieving more stable concentrations during the entire treatment (45 min). Under these conditions of administration, the formulation has proven to be safe, based on histological studies of the respiratory tracts and lungs of rats. On the other hand, these results are accompanied by the first preclinical molecular imaging study with radiolabeled ethanol administered by this route. The current ethanol formulation has received approval from the Spanish Agency of Medicines and Medical Devices for a phase II clinical trial for early-stage COVID-19 patients, which is currently in the recruitment phase (ALCOVID-19; EudraCT number: 2020-001760-29).

Diagnostic utility of the electrocardiographic left ventricular hypertrophy criteria in specific populations.

BACKGROUND: Several electrocardiographic (ECG) criteria have been validated for the diagnosis of left ventricular hypertrophy (LVH); the majority in Caucasian subjects from Europe and North America. Diagnostic utility of ECG criteria to detect LVH has never been established in our population; nonetheless they are frequently used. OBJECTIVE: To evaluate the diagnostic utility of different LVH ECG criteria in a Northern Mexican population and to determine the effect of gender, age, body mass index (BMI), hypertension and ischaemic heart disease (IHD) on their performance. METHODS: We conducted an observational, case-control study in patients divided according to the presence of LVH in an echocardiogram (Echo). We calculated the accuracy, sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of 22 ECG criteria. RESULTS: Four hundred thirty-two patients were studied (202 had LVH). The Dalfó criterion (ECG18. SV3 + RaVL) had the best diagnostic performance with a Se of 56%, Sp of 71.3%, PPV 62.9%, NPV 65% and a diagnostic accuracy (95%CI) of 64.1% (59.5-68.6). This criterion had the highest accuracy in both genders, in all BMI, in older patients (>60 years) and in those with positive Echo ischaemic heart disease (IHD); it also performed well in patients with history of IHD and in hypertensive patients. VDP Cornell had the best accuracy in patients less than 60 years old, and in patients with non-ischaemic findings by Echo. CONCLUSIONS: The Dalfó criteria had the overall best accuracy in the detection of LVH, and specific populations.

3D Printed Tacrolimus Rectal Formulations Ameliorate Colitis in an Experimental Animal Model of Inflammatory Bowel Disease.

The aim of this study was to fabricate novel self-supporting tacrolimus suppositories using semisolid extrusion 3-dimensional printing (3DP) and to investigate their efficacy in an experimental model of inflammatory bowel disease. Blends of Gelucire 44/14 and coconut oil were employed as lipid excipients to obtain suppository formulations with self-emulsifying properties, which were then tested in a TNBS (2,4,6-trinitrobenzenesulfonic acid) induced rat colitis model. Disease activity was monitored using PET/CT medical imaging; maximum standardized uptake values (SUVmax), a measure of tissue radiotracer accumulation rate, together with body weight changes and histological assessments, were used as inflammatory indices to monitor treatment efficacy. Following tacrolimus treatment, a significant reduction in SUVmax was observed on days 7 and 10 in the rat colon sections compared to non-treated animals. Histological analysis using Nancy index confirmed disease remission. Moreover, statistical analysis showed a positive correlation (R2 = 71.48%) between SUVmax values and weight changes over time. Overall, this study demonstrates the effectiveness of 3D printed tacrolimus suppositories to ameliorate colitis and highlights the utility of non-invasive PET/CT imaging to evaluate new therapies in the preclinical area.

Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial.

Importance: Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with moderate disease is unknown. Objective: To determine the efficacy of 5 or 10 days of remdesivir treatment compared with standard care on clinical status on day 11 after initiation of treatment. Design, Setting, and Participants: Randomized, open-label trial of hospitalized patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation >94%) enrolled from March 15 through April 18, 2020, at 105 hospitals in the United States, Europe, and Asia. The date of final follow-up was May 20, 2020. Interventions: Patients were randomized in a 1:1:1 ratio to receive a 10-day course of remdesivir (n = 197), a 5-day course of remdesivir (n = 199), or standard care (n = 200). Remdesivir was dosed intravenously at 200 mg on day 1 followed by 100 mg/d. Main Outcomes and Measures: The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group. Results: Among 596 patients who were randomized, 584 began the study and received remdesivir or continued standard care (median age, 57 [interquartile range, 46-66] years; 227 [39%] women; 56% had cardiovascular disease, 42% hypertension, and 40% diabetes), and 533 (91%) completed the trial. Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group. On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; 95% CI, 1.09-2.48; P = .02). The clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (P = .18 by Wilcoxon rank sum test). By day 28, 9 patients had died: 2 (1%) in the 5-day remdesivir group, 3 (2%) in the 10-day remdesivir group, and 4 (2%) in the standard care group. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients compared with standard care. Conclusions and Relevance: Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance. Trial Registration: ClinicalTrials.gov Identifier: NCT04292730.

Elastin-like recombinamer-based devices releasing Kv1.3 blockers for the prevention of intimal hyperplasia: An in vitro and in vivo study.

Coronary artery disease (CAD) is the most common cardiovascular disorder. Vascular surgery strategies for coronary revascularization (either percutaneous or open) show a high rate of failure because of restenosis of the vessel, due to phenotypic switch of vascular smooth muscle cells (VSMCs) leading to proliferation and migration. We have previously reported that the inhibition of Kv1.3 channel function with selective blockers represents an effective strategy for the prevention of restenosis in human vessels used for coronary angioplasty procedures. However, delivery systems for controlled release of these drugs have not been investigated. Here we tested the efficacy of several formulations of elastin like recombinamers (ELRs) hydrogels to deliver the Kv1.3 blocker PAP-1 in various restenosis models. The dose and time course of PAP-1 release from ELRs click hydrogels was able to inhibit human VSMC proliferation in vitro as well as remodeling of human vessels in organ culture and restenosis in in vivo models. We conclude that this combination of active compound and advanced delivery method could improve the outcomes of vascular surgery in patients. STATEMENT OF SIGNIFICANCE: Vascular surgery strategies for coronary revascularization show a high rate of failure, because of occlusion (restenosis) of the vessel, due to vascular smooth muscle cells proliferation and migration. We have previously reported that blockers of Kv1.3 channels represent an effective anti-restenosis therapy, but delivery systems for their controlled release have not being explored. Here we tested the efficacy of several formulations of elastin like recombinamers (ELRs) hydrogels to deliver the Kv1.3 blocker PAP-1 in various restenosis models, both in vivo and in vitro, and also in human vessels. We demonstrated that combination of active compound and advanced delivery method could improve the outcomes of vascular surgery in patients.