Effect of the combination of bumetanide plus chlorthalidone on hypertension and volume overload in patients with chronic kidney disease stage 4-5 KDIGO without renal replacement therapy: a double-blind randomized HEBE-CKD trial.

BACKGROUND: The co-administration of loop diuretics with thiazide diuretics is a therapeutic strategy in patients with hypertension and volume overload. The aim of this study was to assess the efficacy and safety of treatment with bumetanide plus chlorthalidone in patients with chronic kidney disease (CKD) stage 4-5 KDIGO. METHODS: A double-blind randomized study was conducted. Patients were randomized into two groups: bumetanide plus chlorthalidone group (intervention) and the bumetanide plus placebo group (control) to evaluate differences in TBW, ECW and ECW/TBW between baseline and 30 Days of follow-up. Volume overload was defined as 'bioelectrical impedance analysis as fluid volume above the 90th percentile of a presumed healthy reference population. The study's registration number was NCT03923933. RESULTS: Thirty-two patients with a mean age of 57.2 ± 9.34 years and a median estimated glomerular filtration rate (eGFR) of 16.7 ml/min/1.73 m2 (2.2-29) were included. There was decreased volume overload in the liters of total body water (TBW) on Day 7 (intervention: -2.5 vs. control: -0.59, p = 0.003) and Day 30 (intervention: -5.3 vs. control: -0.07, p = 0.016); and in liters of extracellular water (ECW) on Day 7 (intervention: -1.58 vs. control: -0.43, p < 0.001) and Day 30 (intervention: -3.05 vs. control: -0.15, p < 0.000). There was also a decrease in systolic blood pressure on Day 7 (intervention: -18 vs. control: -7.5, p = 0.073) and Day 30 (intervention: -26.1 vs. control: -10, p = 0.028) and in diastolic blood pressure on Day 7 (intervention: -8.5 vs. control: -2.25, p = 0.059) and Day 30 (intervention: -13.5 vs. control: -3.4, p = 0.018). CONCLUSION: In CKD stage 4-5 KDIGO without renal replacement therapy, bumetanide in combination with chlorthalidone is more effective in treating volume overload and hypertension than bumetanide with placebo.

CARDIOMETABOLIC RISK FACTORS ASSOCIATED WITH RENAL FUNCTION IN APPARENTLY HEALTHY YOUNG STUDENTS: A CROSS-SECTIONAL STUDY.

BACKGROUND: Cardiometabolic risk factors (CMRFs) appear decades before developing chronic kidney disease (CKD) in adulthood. OBJECTIVE: The objective of the study was to identify the prevalence and association between CMRFs and kidney function in apparently healthy young adults (18-25 years old). METHODS: We included 5531 freshman year students. Data collected on CMRFs included central obesity, high body mass index (hBMI >25), blood pressure, glycemia, lipids, uric acid (UA >6.8 mg/dL), and insulin. Glomerular filtration rate (GFR) was estimated by CKD-Epidemiology Collaboration formula. We used logistic regression and a log linear for odds ratio (OR) (95% confidence level) and probabilities. RESULTS: The presence of any CMRF was observed in 78% (4312) of individuals; GFR ≥120/130 mL/min/1.73 m2sc was found in 33%, GFR <90 mL/min/1.73 m2sc in 3%, and proteinuria in 3%. Factors associated with high GFR were hBMI (OR 1.3 [1.14, 1.47]), UA (OR 0.2 [0.15, 0.26]), high-density lipoprotein (HDL) (OR 1.4 [1.2, 1.6]), and insulin resistance (OR 1.3 [1.05, 1.7]). CMRF associated with low GFR was UA (OR 1.8 [1.3, 2.6]), low-density lipoprotein cholesterol (OR 1.66 [1.05, 2.6]), and proteinuria (OR 3.4 [2.07, 5.7]). Proteinuria was associated with high UA (OR 1.59 [1.01, 2.5]) and hypercholesterolemia (OR 1.8 [1.03, 3.18]). The sole presence of hBMI+UA predicted low GFR with p = 0.6 and hBMI+UA+low HDL predicted proteinuria with p = 0.55. CONCLUSIONS: CMRFs were highly prevalent among this freshman student population and were associated with proteinuria and GFR abnormalities. Future studies should focus on public health programs to prevent or delay the development of CKD.

Marital functioning and treatment outcome in couples undergoing assisted reproduction.

AIM: To investigate the relationship between the quality of marital functioning and communication, individual psychological symptomatology, and pregnancy achievement in couples undergoing assisted reproduction. BACKGROUND: The results concerning marital functioning and the feasibility of pregnancy yield contradictory outcomes and the quality of the relationship of the couple undergoing assisted reproduction has not been analysed from systemic models. Our hypothesis is that when undergoing assisted reproduction treatment (ART), the couple's functioning and communication will be related to the pregnancy rate. DESIGN: This study employs a cross-sectional design with couples receiving ART. METHODS: Spanish heterosexual couples (N = 185) completed the self-report instruments. The data were collected from 2010 - 2015. All the couples completed at least one treatment process, or at least 1 year had gone by since beginning the treatment. RESULTS: The association between couple relationship quality and the individual psychological symptomatology experienced during the assisted reproduction process was confirmed in men and women. Although both members of the couple experienced an increase of symptomatology, only men's symptomatology was statistically significantly linked to pregnancy achievement. CONCLUSION: It is necessary to support the couple from the assisted reproduction centres, promoting cohesion, flexibility, and communication in the relationship. The intervention process should also be understood from a systemic perspective; that is, considering dyadic transactions as a systemic unit. Two aspects seem to be especially relevant for clinical nurses in ART: (a) the man's role is crucial for treatment success; (b) the woman's communication is crucial to the process.

Management and outcome of children and adolescents with non-medulloblastoma CNS embryonal tumors in Spain: room for improvement in standards of care.

Non-medulloblastoma CNS embryonal tumors (former PNET/Pineoblastomas) are aggressive malignancies with poor outcome that have been historically treated with medulloblastoma protocols. The purpose of this study is to present a tumor-specific, real-world data cohort of patients with CNS-PNET/PB to analyze quality indicators that can be implemented to improve the outcome of these patients. Patients 0-21 years with CNS-PNET treated in eight large institutions were included. Baseline characteristics, treatment and outcome [progression-free and overall survival (PFS and OS respectively)] were analyzed. From 2005 to 2014, 43 patients fulfilled entry criteria. Median age at diagnosis was 3.6 years (range 0.0-14.7). Histology was pineoblastoma (9%), ependymoblastoma (5%), ETANTR (7%) and PNET (77%). Median duration of the main symptom was 2 weeks (range 0-12). At diagnosis, 28% presented with metastatic disease. Seventeen different protocols were used on frontline treatment; 44% had gross total resection, 42% craniospinal radiotherapy, 86% chemotherapy, and 33% autologous hematopoietic stem cell transplantation (aHSCT). Median follow-up for survivors was 3.5 years (range 1.7-9.3). 3-year PFS was 31.9% (95% CI 17-47%) and OS 35.1% (95% CI 20-50%). Age, extent of resection and radiotherapy were prognostic of PFS and OS in univariate analysis (p < 0.05). Our series shows a dismal outcome for CNS-PNET, especially when compared to patients included in clinical trials. Establishing a common national strategy, implementing referral circuits and collaboration networks, and incorporating new molecular knowledge into routine clinical practice are accessible measures that can improve the outcome of these patients.

[Liver transplantation as treatment for acetaminophen poisoning]. / Trasplante hepático como tratamiento de intoxicación por paracetamol.

Acetaminophen is a commonly used analgesic and antipyretic drug, which has experienced an increase in its consumption in recent years in our environment. There has also been an increase in the number of accidental and intentional overdoses that were treated by the health system. Its toxicity is dose-dependent and can cause fulminant liver failure, becoming one of the main reasons for liver transplantation in English-speaking countries. The case of a 28-year-old woman with a history of major depression and five previous suicide attempts, who deliberately ingested a significant amount of paracetamol tablets, is here presented. She developed fulminant liver failure and metabolic acidosis, for which she underwent an emergency liver transplant due to the severity of her condition, from which she evolved favorably. The decision to perform a liver transplant in serious cases like this and under a condition of severe psychiatric vulnerability is challenging and must be carefully considered. This particular case illustrates the importance of multidisciplinary care including psychiatric evaluation in patients with acetaminophen poisoning.

El paracetamol es una droga analgésica y antipirética comúnmente utilizada, que ha experimentado un aumento en su consumo en los últimos años en nuestro medio. También se ha observado un incremento en el número de sobredosis accidentales e intencionales que fueron atendidas por el sistema de salud. Su toxicidad es dosis dependiente y puede causar falla hepática fulminante, convirtiéndose en una de las principales razones de trasplante hepático en países angloparlantes. Se presenta el caso de una mujer de 28 años con antecedentes de depresión mayor y cinco intentos de suicidio previos, quien ingirió deliberadamente una cantidad significativa de comprimidos de paracetamol. Desarrolló una falla hepática fulminante y acidosis metabólica, por lo que fue sometida a un trasplante hepático de emergencia debido a la gravedad de su condición evolucionando favorablemente. La decisión de realizar un trasplante hepático en casos graves como este y bajo una condición de vulnerabilidad psiquiátrica grave, es un desafío y debe considerarse cuidadosamente. Este caso en particular ilustra la importancia de la atención multidisciplinaria incluyendo la evaluación psiquiátrica en pacientes con intoxicación por paracetamol.

Overlap Syndrome of Diffuse Systemic Sclerosis, Sjögren Syndrome, and ANCA-Associated Renal-Limited Vasculitis: Three Entities in One Patient - Case Report.

Introduction: The presence of three different entities in a single patient is usually of clinical interest and mostly anecdotal. The overlap of systemic sclerosis (SSc), Sjögren syndrome (SS), and ANCA-associated renal-limited vasculitis has been reported only once previously. Case Presentation: A 61-year-old female was evaluated at consultation with 2 years of symptomatology, presenting cardboard-like skin, sclerodactyly, limited oral opening, and dry skin and eyes. She was admitted for progressive renal failure (serum creatinine, 5.5 mg/dL). Her serology work-up showed positive anti-SCL-70, anti-Ro, anti-La, anti-MPO, and antinuclear antibodies. Renal biopsy was performed and confirmed histological findings for SSc, SS, and ANCA-associated vasculitis with active extracapillary glomerulonephritis with fibrous predominance (EUVAS-Berden sclerotic class), active tubulointerstitial nephritis, focal tubular injury, and moderate chronic arteriolopathy. Treatment with 6 monthly doses of methylprednisolone and cyclophosphamide was established. At the last follow-up, the patient maintained a stable serum creatinine level of 2.6 mg/dL and had decreased proteinuria, no erythrocyturia, and no requirement for renal replacement therapy. Conclusion: Systemic sclerosis is a rare autoimmune disease; nevertheless, overlap with Sjögren syndrome is relatively common, although its association with ANCA vasculitis is anecdotal. Diagnostic integration presents a challenge for nephrologists to define the prognosis and a specific treatment.

Electroacupuncture efficacy in diabetic polyneuropathy: Study protocol for a double-blinded randomized controlled multicenter clinical trial.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is the most common complication of type 2 diabetes mellitus (T2DM); its diagnosis and treatment are based on symptomatic improvement. However, as pharmacological therapy causes multiple adverse effects, the implementation of acupunctural techniques, such as electroacupuncture (EA) has been suggested as an alternative treatment. Nonetheless, there is a lack of scientific evidence, and its mechanisms are still unclear. We present the design and methodology of a new clinical randomized trial, that investigates the effectiveness of EA for the treatment of DPN. METHODS: This study is a four-armed, randomized, controlled, multicenter clinical trial (20-week intervention period, plus 12 weeks of follow-up after concluding intervention). A total of 48 T2DM patients with clinical signs and symptoms of DPN; and electrophysiological signs in the Nerve Conduction Study (NCS); will be treated by acupuncture specialists in outpatient units in Mexico City. Patients will be randomized in a 1:1 ratio to one of the following four groups: (a) short fibre DPN with EA, (b) short fibre DPN with sham EA, (c) axonal DPN with EA and (d) axonal DPN with sham EA treatment. The intervention will consist of 32 sessions, 20 min each, per patient over two cycles of intervention of 8 weeks each and a mid-term rest period of 4 weeks. The primary outcome will be NCS parameters, and secondary outcomes will include DPN-related symptoms and pain by Michigan Neuropathy Screening Instrument (MNSI), Michigan Diabetic Neuropathy Score (MDNS), Dolour Neuropatique Score (DN-4), Semmes-Westein monofilament, Numerical Rating Scale (NRS) for pain assessment, and the 36-item Short Form Health Survey (SF-36). To measure quality of life and improve oxidative stress, the inflammatory response; and genetic expression; will be analysed at the beginning and at the end of treatment. DISCUSSION: This study will be conducted to compare the efficacy of EA versus sham EA combined with conventional diabetic and neuropathic treatments if needed. EA may improve NCS, neuropathic pain and symptoms, oxidative stress, inflammatory response, and genetic expression, and it could be considered a potential coadjutant treatment for the management of DPN with a possible remyelinating effect. TRIAL REGISTRATION: ClinicalTrials.gov. NCT05521737 Registered on 30 August 2022. International Clinical Trials Registry Platform (ICTRP) ISRCTN97391213 Registered on 26 September 2022 [2b].

Characterisation of pks15/1 in clinical isolates of Mycobacterium tuberculosis from Mexico.

Tuberculosis (TB) is an infectocontagious respiratory disease caused by members of the Mycobacterium tuberculosis complex. A 7 base pair (bp) deletion in the locus polyketide synthase (pks)15/1 is described as polymorphic among members of the M. tuberculosis complex, enabling the identification of Euro-American, Indo-Oceanic and Asian lineages. The aim of this study was to characterise this locus in TB isolates from Mexico. One hundred twenty clinical isolates were recovered from the states of Veracruz and Estado de Mexico. We determined the nucleotide sequence of a ± 400 bp fragment of the locus pks15/1, while genotypic characterisation was performed by spoligotyping. One hundred and fifty isolates contained the 7 bp deletion, while five had the wild type locus. Lineages X (22%), LAM (18%) and T (17%) were the most frequent; only three (2%) of the isolates were identified as Beijing and two (1%) EAI-Manila. The wild type pks15/1 locus was observed in all Asian lineage isolates tested. Our results confirm the utility of locus pks15/1 as a molecular marker for identifying Asian lineages of the M. tuberculosis complex. This marker could be of great value in the epidemiological surveillance of TB, especially in countries like Mexico, where the prevalence of such lineages is unknown.

Neuroprotection of Thioredoxin1 in the Brain.

Thioredoxin1 (Trx1) is a ubiquitous antioxidant protein that regulates the cell's redox status. Trx1's thiol redox activity protects neurons from various physiological processes that cause neuronal damage and neurodegeneration, including oxidative stress, apoptosis, and inflammation. Several studies have found that direct or indirect Trx1 regulation has neuroprotective effects in the brain, protecting against, preventing, or delaying neurodegenerative processes or brain traumas. This review focuses on the term neuroprotection, Trx1 localization, and expression in the brain, as well as its modulation concerning its neuroprotective effect in both animal and clinical models of ischemia, hypoxia, hemorrhage, traumatic brain injury, epilepsy, Alzheimer's disease, and Parkinson's disease.

The effect of thioredoxin-1 in a rat model of traumatic brain injury depending on diurnal variation.

INTRODUCTION: Traumatic brain injury (TBI) is a public health concern with limited treatment options because it causes a cascade of side effects that are the leading cause of hospital death. Thioredoxin is an enzyme with neuroprotective properties such as antioxidant, antiapoptotic, immune response modulator, and neurogenic, among others; it has been considered a therapeutic target for treating many disorders. METHODS: The controlled cortical impact (CCI) model was used to assess the effect of recombinant human thioredoxin 1 (rhTrx1) (1 µg/2 µL, intracortical) on rats subjected to TBI at two different times of the light-dark cycle (01:00 and 13:00 h). We analyzed the food intake, body weight loss, motor coordination, pain perception, and histology in specific hippocampus (CA1, CA2, CA3, and Dental Gyrus) and striatum (caudate-putamen) areas. RESULTS: Body weight loss, reduced food intake, spontaneous pain, motor impairment, and neuronal damage in specific hippocampus and striatum regions are more evident in rats subjected to TBI in the light phase than in the dark phase of the cycle and in groups that did not receive rhTrx1 or minocycline (as positive control). Three days after TBI, there is a recovery in body weight, food intake, motor impairment, and pain, which is more pronounced in the rats subjected to TBI at the dark phase of the cycle and those that received rhTrx1 or minocycline. CONCLUSIONS: Knowing the time of day a TBI occurs in connection to the neuroprotective mechanisms of the immune response in diurnal variation and the usage of the Trx1 protein might have a beneficial therapeutic impact in promoting quick recovery after a TBI.

Changes in lactate dehydrogenase on admission throughout the COVID-19 pandemic and possible impacts on prognostic capability.

Introduction: The enzyme lactate dehydrogenase (LDH) is a good marker of general hyperinflammation correlated with mortality for COVID-19, and is therefore used in prognosis tools. In a current COVID-19 clinical randomized trial (CRT), the blood level of LDH was selected as an inclusion criterion. However, LDH decreased during the pandemic; hence, the impact of this decrease on the prognostic value of LDH for mortality was evaluated. Methods: Data on LDH levels in 843 patients were obtained and analyzed. Relative risk, standard error and receiver operating characteristic curves were calculated for two cutoff values. Results: Relative risk lost validity and the area under the curve narrowed by trimester during the pandemic. Conclusion: The progressive decrease in LDH impacted the capacity to predict mortality in COVID-19. More studies are needed to validate this finding and its implications.

Immune disease risk variants regulate gene expression dynamics during CD4+ T cell activation.

During activation, T cells undergo extensive gene expression changes that shape the properties of cells to exert their effector function. Understanding the regulation of this process could help explain how genetic variants predispose to immune diseases. Here, we mapped genetic effects on gene expression (expression quantitative trait loci (eQTLs)) using single-cell transcriptomics. We profiled 655,349 CD4+ T cells, capturing transcriptional states of unstimulated cells and three time points of cell activation in 119 healthy individuals. This identified 38 cell clusters, including transient clusters that were only present at individual time points of activation. We found 6,407 genes whose expression was correlated with genetic variation, of which 2,265 (35%) were dynamically regulated during activation. Furthermore, 127 genes were regulated by variants associated with immune-mediated diseases, with significant enrichment for dynamic effects. Our results emphasize the importance of studying context-specific gene expression regulation and provide insights into the mechanisms underlying genetic susceptibility to immune-mediated diseases.

[Factors associated to pulmonary tuberculosis in patients with diabetes mellitus from Veracruz, México]. / Factores asociados a tuberculosis pulmonar en pacientes con diabetes mellitus de Veracruz, México.

In Mexico, 20% of cases of tuberculosis (TB) are associated with diabetes mellitus (DM). However, the behavior of the factors related to this comorbidity is unknown, so the aim of this study was to estimate the risk factors and outcome for TB-DM in a population from the state of Veracruz, Mexico. We developed a double-design study: cases and controls for the estimation of risk factors, and a retrospective cohort for the outcome factors. The populations surveyed were 67 patients with the comorbidity TB-DB and 109 with TB. The risk factors for tuberculosis in the diabetic population studied were: age ≥ 35 with an OR of 2.5 (95% CI: 1.4-4.3) and IMC ≥ 25 with an OR of 8.5 (95% CI: 3.1-23.3). According to the outcome variables, the patients with TB-DM showed an increased risk of 2.8 (95% CI: 2.2-3.4) for the development of drug resistance against tuberculosis. In conclusion, age and overweight are important risk factors, and drug resistance is an important outcome factor for the binomial TB-DM in the population from Veracruz. This information will have important effects on the development of surveillance programs against TB, with emphasis on the characteristics of the diabetic population.

Epromoters function as a hub to recruit key transcription factors required for the inflammatory response.

Gene expression is controlled by the involvement of gene-proximal (promoters) and distal (enhancers) regulatory elements. Our previous results demonstrated that a subset of gene promoters, termed Epromoters, work as bona fide enhancers and regulate distal gene expression. Here, we hypothesized that Epromoters play a key role in the coordination of rapid gene induction during the inflammatory response. Using a high-throughput reporter assay we explored the function of Epromoters in response to type I interferon. We find that clusters of IFNa-induced genes are frequently associated with Epromoters and that these regulatory elements preferentially recruit the STAT1/2 and IRF transcription factors and distally regulate the activation of interferon-response genes. Consistently, we identified and validated the involvement of Epromoter-containing clusters in the regulation of LPS-stimulated macrophages. Our findings suggest that Epromoters function as a local hub recruiting the key TFs required for coordinated regulation of gene clusters during the inflammatory response.

Looking for Crumbs in the Obesity Forest: Anti-obesity Interventions and Obesity-Associated Cardiometabolic Traits in the Mexican Population. History and Systematic Review With Meta-Analyses.

Mexicans and Mexican Americans share culture, genetic background, and predisposition for chronic complications associated with obesity and diabetes making imperative efficacious treatments and prevention. Obesity has been treated for centuries focused-on weight loss while other treatments on associated conditions like gout, diabetes (T2D), and hypertriglyceridemia. To date, there is no systematic review that synthesizes the origin of obesity clinics in Mexico and the efforts to investigate treatments for obesity tested by randomized clinical trials (RCT). We conducted systematic searches in Pubmed, Scopus, and Web of Science to retrieve anti-obesity RCT through 2019 and without an inferior temporal limit. The systematic review included RCT of anti-obesity treatments in the Mexican adult population, covering alternative medicine, pharmacological, nutritional, behavioral, and surgical interventions reporting metabolism-associated traits such as BMI, weight, waist circumference, triglycerides, glucose, among others. Only the studies with at least 3 months of treatment were included in the meta-analyses in order to reduce placebo effects. We found 634 entries, after removal of duplicates and screening the studies based on eligibility criteria, we analyzed 43 national, and 2 multinational-collaborative studies. Most of the national studies had small sample sizes, and the implemented strategies do not have replications in the population. The nutrition/behavioral interventions were difficult to blind, and most studies have medium-to-high risk of bias. Nutritional/behavioral interventions and medications showed effects on BMI, waist circumference, and blood pressure. Simple measures like pure water instead of sweet beverages decrease triglycerides and systolic blood pressure. Dark chocolate showed the highest effect for BMI and high blood pressure, and treatment with insulin increased weight in those with T2D. The study of obesity in Mexico has been on-going for more than four decades, the interest on RCT just increased until this millennium, but with small sample sizes and lack of replication. The interventions affect different cardiometabolic associated traits, which should be analyzed in detail in the population living near the Mexico-U.S. border; therefore, bi-national collaboration is desirable to disentangle the cultural effects on this population's treatment response. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020221436, identifier: CRD42020221436.

Crystal structures of Triosephosphate Isomerases from Taenia solium and Schistosoma mansoni provide insights for vaccine rationale and drug design against helminth parasites.

Triosephosphate isomerases (TPIs) from Taenia solium (TsTPI) and Schistosoma mansoni (SmTPI) are potential vaccine and drug targets against cysticercosis and schistosomiasis, respectively. This is due to the dependence of parasitic helminths on glycolysis and because those proteins elicit an immune response, presumably due to their surface localization. Here we report the crystal structures of TsTPI and SmTPI in complex with 2-phosphoglyceric acid (2-PGA). Both TPIs fold into a dimeric (ß-α)8 barrel in which the dimer interface consists of α-helices 2, 3, and 4, and swapping of loop 3. TPIs from parasitic helminths harbor a region of three amino acids knows as the SXD/E insert (S155 to E157 and S157 to D159 in TsTPI and SmTPI, respectively). This insert is located between α5 and ß6 and is proposed to be the main TPI epitope. This region is part of a solvent-exposed 310-helix that folds into a hook-like structure. The crystal structures of TsTPI and SmTPI predicted conformational epitopes that could be used for vaccine design. Surprisingly, the epitopes corresponding to the SXD/E inserts are not the ones with the greatest immunological potential. SmTPI, but not TsTPI, habors a sole solvent exposed cysteine (SmTPI-S230) and alterations in this residue decrease catalysis. The latter suggests that thiol-conjugating agents could be used to target SmTPI. In sum, the crystal structures of SmTPI and TsTPI are a blueprint for targeted schistosomiasis and cysticercosis drug and vaccine development.

[Consenso experto en tiempos de COVID-19: aplicaciones del método Delphi en materia de salud].

La epidemia de COVID-19 ha modificado la cultura de la comunicación. La solución para los problemas de salud puede ser asertiva cuando es consensuada. El método Delphi es una herramienta de consenso que emplea rondas de listas de preguntas para recopilar información del conocimiento de un panel de expertos que analizan planteamientos y posibles soluciones a problemas. Se basa en la premisa de que, con la libertad del anonimato, la inteligencia combinada mejora el juicio individual y captura la opinión colectiva experta. El proceso del método es muy flexible, pues las rondas de preguntas pueden realizarse de manera presencial o remota. En este artículo se describe cómo implementar el método Delphi convencional en tiempos de confinamiento, y se analizan la utilidad y las limitaciones del método para su uso por expertos en salud para la resolución de problemas de tratamiento, diagnóstico o administrativos. Las tecnologías actuales para recolectar los datos permiten gran flexibilidad en el formato de los cuestionarios y facilitan la recopilación de la opinión experta. Gracias a su adaptabilidad, el método Delphi se está convirtiendo en una estrategia popular que involucra los ámbitos cualitativo y cuantitativo.

RSAT variation-tools: An accessible and flexible framework to predict the impact of regulatory variants on transcription factor binding.

Gene regulatory regions contain short and degenerated DNA binding sites recognized by transcription factors (TFBS). When TFBS harbor SNPs, the DNA binding site may be affected, thereby altering the transcriptional regulation of the target genes. Such regulatory SNPs have been implicated as causal variants in Genome-Wide Association Study (GWAS) studies. In this study, we describe improved versions of the programs Variation-tools designed to predict regulatory variants, and present four case studies to illustrate their usage and applications. In brief, Variation-tools facilitate i) obtaining variation information, ii) interconversion of variation file formats, iii) retrieval of sequences surrounding variants, and iv) calculating the change on predicted transcription factor affinity scores between alleles, using motif scanning approaches. Notably, the tools support the analysis of haplotypes. The tools are included within the well-maintained suite Regulatory Sequence Analysis Tools (RSAT, http://rsat.eu), and accessible through a web interface that currently enables analysis of five metazoa and ten plant genomes. Variation-tools can also be used in command-line with any locally-installed Ensembl genome. Users can input personal collections of variants and motifs, providing flexibility in the analysis.

Nanotransportadores activos de cannabinoides para el tratamiento de la aterosclerosis / Active cannabinoid nanocarriers for the treatment of atherosclerosis

Con la intención de vehiculizar fármacos cannabinoides (agonistas CB2) de forma selectiva hacia la placa de ateroma, se han obtenido nanopartículas biocompatibles y biodegradables. Para ello, las nanopartículas PEGyladas, han sido funcionalizadas con un péptido capaz de unirse selectivamente a proteínas endoteliales de adhesión sobreexpresadas en la placa aterosclerótica (vascular cell adhesion molecule 1, VCAM-1). Las partículas han sido caracterizadas fisicoquímicamente, in vitro en cultivos celulares e in vivo en un modelo animal de aterosclerosis (ratones deficientes en apolipoproteína E, ApoE-/-), demostrando un óptimo control espacio-temporal de la liberación del cannabinoide y una respuesta farmacológica superior. Dado que los fármacos agonistas CB2 presentan alta lipofilia y baja disponibilidad, la introducción de nanosistemas selectivos para la vehiculización de estos fármacos antiaterogénicos, mejoraría su biodisponibilidad y eficacia.El trabajo presentado muestra parte de los resultados obtenidos de un proyecto previo. Estos resultados nos han avalado para la concesión de una nueva ayuda de financiación para abordar una estrategia más avanzada que implica la introducción de elementos de diagnóstico y de un fitocannabinoide. (AU)

In order to selectively deliver cannabinoid drugs (CB2 agonists) to the atherosclerotic plaque, biocompatible and biodegradable nanoparticles have been obtained. For this purpose, the PEGylated nanoparticles have been functionalized with a peptide capable of selectively binding to endothelial adhesion proteins overexpressed in the atherosclerotic plaque (vascular cell adhesion molecules 1, VCAM-1). The particles have been characterized physicochemically, in vitro in cell cultures and in vivo in an animal model of atherosclerosis (apolipoprotein E-deficient ApoE-/- mice), demonstrating optimal spatiotemporal control of cannabinoid release and superior pharmacological response. Given that CB2 agonist drugs present high lipophilicity and low availability, the introduction of selective nanosystems for the vehiculation of these antiatherogenic drugs would improve their bioavailability and efficacy.The work presented shows part of the results obtained from a previous project. These results have supported us for the award of a new funding grant to address a more advanced strategy involving the introduction of diagnostic elements and a phytocannabinoid. (AU)

The effect size of type 2 diabetes mellitus on tuberculosis drug resistance and adverse treatment outcomes.

OBJECTIVE: To evaluate the effect size of type 2 diabetes mellitus (T2DM) on tuberculosis (TB) treatment outcomes and multi drug resistance (MDR). METHODS: A cohort with 507 individuals with diagnosed TB included 183 with coexistence of T2DM and TB (TB-T2DM). Participants were identified at the time of TB diagnosis and followed during the course of TB treatment. Then we computed relative risks and adjustments by Cox proportional hazards for outcome variables (drug resistance, death, relapse, treatment failure), and the size of their effect as Cohen's-d. RESULTS: Patients with TB-T2DM were more likely to remain positive for acid-fast bacilli after two months of anti-TB treatment RR = [2.01 (95% CI: 1.3, 3.1)], to have drug resistant (DR) [OR 3.5 (95% CI: 1.8, 6.7)] and multi-drug resistant (MDR) TB [OR 3.5 (95% CI: 1.8, 7.1)]. The Cohen's-d for DR or MDR in T2DM was 0.69 when compared with non-DM subjects. The T2DM patients had higher odds of resistance to isoniazid (OR 3.9, 95% CI: 2.01, 7.9), rifampicin (OR 3.4, 95% CI: 1.6, 7.2) and pyrazinamide (OR 9.4, 95% CI: 2.8, 25.6), and their effect sizes were ≥0.67. Patients with TB-T2DM (versus no DM) were more likely to present with MDR TB (HR 3.1; 95% CI: 1.7, 5.8; p < 0.001), treatment failure (HR 2.04; 95% CI: 1.07, 3.8; p = 0.02) and relapse (HR 1.86; 95% CI: 1.09, 3.1; p = 0.02), with effect size ≥0.34. CONCLUSION: T2DM showed a substantial contribution to the presence of DR or MDR-TB and to adverse clinical outcomes during and after TB treatment. Our findings support the importance for routine screening of T2DM among newly-diagnosed TB patients in order to stratify them for immediate DR assessment, and highlight the need for clinical trials to evaluate variations to the standard TB treatment in TB-T2DM to prevent adverse treatment outcomes.