Does geographic availability of alcohol influence drinking in adolescents? A systematic review of literature associations.

BACKGROUND: The role of alcohol geographic availability in influencing adolescent drinking has been debated. However, clear literature consensus has not been reached. OBJECTIVE: To provide a systematic review of the associations between geographic availability of alcohol outlets measured through different methodologies and drinking outcomes in adolescents. METHODS: We conducted a systematic search (PubMed/SCOPUS/Web of Science) for articles exploring associations between alcohol availability and adolescent drinking before 2023. Original articles written in English that evaluated adolescent populations (10-19 years old), included at least one quantitative alcohol consumption outcome and its relationship with geographic availability of alcohol, and declared no conflicts of interest were selected for the review. A quality assessment of the selected articles was made using the Newcastle-Ottawa Scale and descriptive analyses were carried out to summarize results. RESULTS: Thirty-one articles were reviewed (19 cross-sectional and 12 longitudinal studies), which included a total of 507336 participants. Alcohol availability was positively related to drinking prevalence and risky patterns in 53.3% and 60.5% of associations, respectively. Individual-level covariates, the type of alcohol outlets measured and the different methodological approaches to measure outlet density were related to differences in the direction and magnitude of these associations. CONCLUSION: Just over half of the studies in this review demonstrate a positive association between alcohol availability and adolescent alcohol consumption with no negative associations reported. The review highlights the mix of methodological approaches that are used, which made it difficult to conduct joint analyses. Additional research is needed to explore the appropriateness, effectiveness and reliability of these methods within various contexts.

Emerging Role of Extracellular Vesicles as Biomarkers in Neurodegenerative Diseases and Their Clinical and Therapeutic Potential in Central Nervous System Pathologies.

The emerging role of extracellular vesicles (EVs) in central nervous system (CNS) diseases is gaining significant interest, particularly their applications as diagnostic biomarkers and therapeutic agents. EVs are involved in intercellular communication and are secreted by all cell types. They contain specific markers and a diverse cargo such as proteins, lipids, and nucleic acids, reflecting the physiological and pathological state of their originating cells. Their reduced immunogenicity and ability to cross the blood-brain barrier make them promising candidates for both biomarkers and therapeutic agents. In the context of CNS diseases, EVs have shown promise as biomarkers isolable from different body fluids, providing a non-invasive method for diagnosing CNS diseases and monitoring disease progression. This makes them useful for the early detection and monitoring of diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, where specific alterations in EVs content can be detected. Additionally, EVs derived from stem cells show potential in promoting tissue regeneration and repairing damaged tissues. An evaluation has been conducted on the current clinical trials studying EVs for CNS diseases, focusing on their application, treatment protocols, and obtained results. This review aims to explore the potential of EVs as diagnostic markers and therapeutic carriers for CNS diseases, highlighting their significant advantages and ongoing clinical trials evaluating their efficacy.

Pembrolizumab Plus Carboplatin and Paclitaxel as First-Line Therapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (KEYNOTE-B10): A Single-Arm Phase IV Trial.

PURPOSE: Standard-of-care first-line treatment for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is pembrolizumab plus platinum and fluorouracil (FU). However, FU is associated with potential challenges (continuous 4-day infusion, high administration costs, and cardiovascular and gastrointestinal toxicities), creating a clinical need for alternative chemotherapy combinations. We evaluated the efficacy and safety of first-line pembrolizumab plus carboplatin and paclitaxel for R/M HNSCC in the open-label, single-arm, phase IV KEYNOTE-B10 study (ClinicalTrials.gov identifier: NCT04489888). METHODS: Eligible adults had previously untreated, histologically or cytologically confirmed R/M HNSCC regardless of PD-L1 status, measurable disease per RECIST v1.1 by blinded independent central review (BICR), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received pembrolizumab 200 mg intravenously once every 3 weeks for ≤35 cycles and carboplatin AUC 5 mg/mL/min intravenously once every 3 weeks for ≤6 cycles and investigator's choice of paclitaxel 100 mg/m2 on days 1 and 8 or 175 mg/m2 on day 1, intravenously once every 3 weeks. The primary end point was objective response rate per RECIST v1.1 by BICR. RESULTS: Between October 27, 2020, and April 29, 2022, 149 patients were screened and 101 received treatment. As of February 20, 2023, the median follow-up was 18.9 months (range, 9.1-27.0). At this final analysis, 49 (49%) of 101 patients had an objective response (95% CI, 38.4 to 58.7), including seven patients (7%) with a confirmed complete response. Of the 101 treated patients, grade 3-5 and serious treatment-related adverse events occurred in 76 (75%) and 27 (27%), respectively. There were no new safety signals. CONCLUSION: Pembrolizumab plus carboplatin and paclitaxel showed promising antitumor activity and a manageable safety profile in first-line R/M HNSCC, suggesting this combination may be an alternative option for this patient population.

Extracellular Vesicles as Mediators of Neuroinflammation in Intercellular and Inter-Organ Crosstalk.

Neuroinflammation, crucial in neurological disorders like Alzheimer's disease, multiple sclerosis, and hepatic encephalopathy, involves complex immune responses. Extracellular vesicles (EVs) play a pivotal role in intercellular and inter-organ communication, influencing disease progression. EVs serve as key mediators in the immune system, containing molecules capable of activating molecular pathways that exacerbate neuroinflammatory processes in neurological disorders. However, EVs from mesenchymal stem cells show promise in reducing neuroinflammation and cognitive deficits. EVs can cross CNS barriers, and peripheral immune signals can influence brain function via EV-mediated communication, impacting barrier function and neuroinflammatory responses. Understanding EV interactions within the brain and other organs could unveil novel therapeutic targets for neurological disorders.

Tigecycline Opposes Bortezomib Effect on Myeloma Cells Decreasing Mitochondrial Reactive Oxygen Species Production.

Multiple myeloma is an incurable plasma cell malignancy. Most patients end up relapsing and developing resistance to antineoplastic drugs, like bortezomib. Antibiotic tigecycline has activity against myeloma. This study analyzed tigecycline and bortezomib combination on cell lines and plasma cells from myeloma patients. Apoptosis, autophagic vesicles, mitochondrial mass, mitochondrial superoxide, cell cycle, and hydrogen peroxide were studied by flow cytometry. In addition, mitochondrial antioxidants and electron transport chain complexes were quantified by reverse transcription real-time PCR (RT-qPCR) or western blot. Cell metabolism and mitochondrial activity were characterized by Seahorse and RT-qPCR. We found that the addition of tigecycline to bortezomib reduces apoptosis in proportion to tigecycline concentration. Supporting this, the combination of both drugs counteracts bortezomib in vitro individual effects on the cell cycle, reduces autophagy and mitophagy markers, and reverts bortezomib-induced increase in mitochondrial superoxide. Changes in mitochondrial homeostasis and MYC upregulation may account for some of these findings. These data not only advise to avoid considering tigecycline and bortezomib combination for treating myeloma, but caution on the potential adverse impact of treating infections with this antibiotic in myeloma patients under bortezomib treatment.

Using photovoice to generate policy recommendations to improve the alcohol urban environment: A participatory action research project.

The place where we live, work and play may influence our alcohol drinking behaviours. This study aimed to present local policy recommendations on urban determinants for alcohol consumption prevention in a low-income and a high-income area of Madrid (Spain) using a participatory action research method, with photovoice and nominal group techniques. Participants (n = 26) engaged in a photovoice project initiated a process of critical reflection by discussing and analysing their alcohol environment based on photographs they took themselves. At the end of six week group discussion sessions, participants identified 33 themes related to their alcohol environment. They later met to translate the final categories into urban policy recommendations using a logical framework approach. Then, with a nominal group, they prioritized these recommendations based on time, impact, feasibility, and cost. Finally, participants produced a total of 61 policy recommendations for the improvement of the alcohol environment, highlighting the need for researcher-community collaborations when designing public health interventions.

Role of miR-15a-5p and miR-199a-3p in the inflammatory pathway regulated by NF-κB in experimental and human atherosclerosis.

BACKGROUND: Cardiovascular diseases (CVDs) prevalence has significantly increased in the last decade and atherosclerosis development is the main trigger. MicroRNAs (miRNAs) are non-coding RNAs that negatively regulate gene expression of their target and their levels are frequently altered in CVDs. METHODS: By RT-qPCR, we analysed miR-9-5p, miR-15a-5p, miR-16-5p and miR-199a-3p levels in aorta from apolipoprotein knockout (ApoE-/- ) mice, an experimental model of hyperlipidemia-induced atherosclerosis, and in human aortic and carotid atherosclerotic samples. By in silico studies, Western blot analysis and immunofluorescence studies, we detected the targets of the altered miRNAs. RESULTS: Our results show that miR-15a-5p and miR-199a-3p are significantly decreased in carotid and aortic samples from patients and mice with atherosclerosis. In addition, we found an increased expression in targets of both miRNAs that participate in the inflammatory pathway of nuclear factor kappa B (NF-κB), such as IKKα, IKKß and p65. In human vein endothelial cells (HUVECs) and vascular smooth muscle cells (VSMCs), the overexpression of miR-15a-5p or miR-199a-3p decreased IKKα, IKKß and p65 protein levels as well as NF-κB activation. On the other hand, miR-15a-5p and miR-199a-3p overexpression reduced ox-LDL uptake and the inflammation regulated by NF-κB in VSMCs. Moreover, although miR-15a-5p and miR-199a-3p were significantly increased in exosomes from patients with advanced carotid atherosclerosis, only in the ROC analyses for miR-15a-5p, the area under the curve was 0.8951 with a p value of .0028. CONCLUSIONS: Our results suggest that the decrease of miR-199a-3p and miR-15a-5p in vascular samples from human and experimental atherosclerosis could be involved in the NF-κB activation pathway, as well as in ox-LDL uptake by VSMCs, contributing to inflammation and progression atherosclerosis. Finally, miR-15a-5p could be used as a novel diagnostic biomarker for advanced atherosclerosis.

Increased let-7d-5p in non-alcoholic fatty liver promotes insulin resistance and is a potential blood biomarker for diagnosis.

BACKGROUND AND AIMS: The molecular mechanisms driving non-alcoholic fatty liver disease (NAFLD) are poorly understood; however, microRNAs might play a key role in these processes. We hypothesize that let-7d-5p could contribute to the pathophysiology of NAFLD and serve as a potential diagnostic biomarker. METHODS: We evaluated let-7d-5p levels and its targets in liver biopsies from a cross-sectional study including patients with NAFLD and healthy donors, and from a mouse model of NAFLD. Moreover, the induction of let-7d-5p expression by fatty acids was evaluated in vitro. Further, we overexpressed let-7d-5p in vitro to corroborate the results observed in vivo. Circulating let-7d-5p and its potential as a NAFLD biomarker was determined in isolated extracellular vesicles from human plasma by RT-qPCR. RESULTS: Our results demonstrate that hepatic let-7d-5p was significantly up-regulated in patients with steatosis, and this increase correlated with obesity and a decreased expression of AKT serine/threonine kinase (AKT), insulin-like growth factor 1 (IGF1), IGF-I receptor (IGF1R) and insulin receptor (INSR). These alterations were corroborated in a NAFLD mouse model. In vitro, fatty acids increased let-7d-5p expression, and its overexpression decreased AKT, IGF-IR and IR protein expression. Furthermore, let-7d-5p hindered AKT phosphorylation in vitro after insulin stimulation. Finally, circulating let-7d-5p significantly decreased in steatosis patients and receiver operating characteristic (ROC) analyses confirmed its utility as a diagnostic biomarker. CONCLUSIONS: Our results highlight the emerging role of let-7d-5p as a potential therapeutic target for NAFLD since its overexpression impairs hepatic insulin signalling, and also, as a novel non-invasive biomarker for NAFLD diagnosis.

Alterations in the immune system persist after one year of convalescence in severe COVID-19 patients.

Introduction: Severe COVID-19 originates a myriad of alterations in the immune system during active disease, especially in the T and NK cell compartments, but several studies in the last year have unveiled some alterations that persist in convalescence. Although most of the studies follow the participants for a short recovery time, studies following patients up to three or six months still find alterations. We aimed at evaluating changes in the NK, T and B cell compartments after severe COVID-19 in participants with a median recovery time of eleven months. Methods: Eighteen convalescent of severe COVID-19 (CSC), 14 convalescent of mild COVID-19 (CMC) and nine controls were recruited. NKG2A, NKG2C, NKG2D and the activating receptor NKp44 were evaluated in NKbright, NKdim and NKT subpopulations. In addition, CD3 and CD19 were measured and a basic biochemistry with IL-6 levels was obtained. Results: CSC participants showed lower NKbright/NKdim ratio, higher NKp44 expression in NKbright subpopulations, higher levels of serum IL-6, lower levels of NKG2A+ T lymphocytes and a trend to a lower expression of CD19 in B lymphocytes compared to controls. CMC participants showed no significant alterations in the immune system compared to controls. Conclusions: These results are concordant with previous studies, which find alterations in CSC weeks or months after resolution of the symptoms, and point to the possibility of these alterations lasting one year or more after COVID-19 resolution.

A SARS-CoV-2 full genome sequence of the B.1.1 lineage sheds light on viral evolution in Sicily in late 2020.

To investigate the influence of geographic constrains to mobility on SARS-CoV-2 circulation before the advent of vaccination, we recently characterized the occurrence in Sicily of viral lineages in the second pandemic wave (September to December 2020). Our data revealed wide prevalence of the then widespread through Europe B.1.177 variant, although some viral samples could not be classified with the limited Sanger sequencing tools used. A particularly interesting sample could not be fitted to a major variant then circulating in Europe and has been subjected here to full genome sequencing in an attempt to clarify its origin, lineage and relations with the seven full genome sequences deposited for that period in Sicily, hoping to provide clues on viral evolution. The obtained genome is unique (not present in databases). It hosts 20 single-base substitutions relative to the original Wuhan-Hu-1 sequence, 8 of them synonymous and the other 12 encoding 11 amino acid substitutions, all of them already reported one by one. They include four highly prevalent substitutions, NSP12:P323L, S:D614G, and N:R203K/G204R; the much less prevalent S:G181V, ORF3a:G49V and N:R209I changes; and the very rare mutations NSP3:L761I, NSP6:S106F, NSP8:S41F and NSP14:Y447H. GISAID labeled this genome as B.1.1 lineage, a lineage that appeared early on in the pandemic. Phylogenetic analysis also confirmed this lineage diagnosis. Comparison with the seven genome sequences deposited in late 2020 from Sicily revealed branching leading to B.1.177 in one branch and to Alpha in the other branch, and suggested a local origin for the S:G118V mutation.

Extracellular vesicles from mesenchymal stem cells reduce neuroinflammation in hippocampus and restore cognitive function in hyperammonemic rats.

Chronic hyperammonemia, a main contributor to hepatic encephalopathy (HE), leads to neuroinflammation which alters neurotransmission leading to cognitive impairment. There are no specific treatments for the neurological alterations in HE. Extracellular vesicles (EVs) from mesenchymal stem cells (MSCs) reduce neuroinflammation in some pathological conditions. The aims were to assess if treatment of hyperammonemic rats with EVs from MSCs restores cognitive function and analyze the underlying mechanisms. EVs injected in vivo reach the hippocampus and restore performance of hyperammonemic rats in object location, object recognition, short-term memory in the Y-maze and reference memory in the radial maze. Hyperammonemic rats show reduced TGFß levels and membrane expression of TGFß receptors in hippocampus. This leads to microglia activation and reduced Smad7-IkB pathway, which induces NF-κB nuclear translocation in neurons, increasing IL-1ß which alters AMPA and NMDA receptors membrane expression, leading to cognitive impairment. These effects are reversed by TGFß in the EVs from MSCs, which activates TGFß receptors, reducing microglia activation and NF-κB nuclear translocation in neurons by normalizing the Smad7-IkB pathway. This normalizes IL-1ß, AMPA and NMDA receptors membrane expression and, therefore, cognitive function. EVs from MSCs may be useful to improve cognitive function in patients with hyperammonemia and minimal HE.

Plasma Extracellular Vesicles Play a Role in Immune System Modulation in Minimal Hepatic Encephalopathy.

Minimal hepatic encephalopathy (MHE) is associated with changes in the immune system including an increased pro-inflammatory environment and altered differentiation of CD4+ T lymphocytes. The mechanisms remain unknown. Changes in extracellular vesicle (EV) cargo including proteins and miRNAs could play a main role as mediators of immune system changes associated with MHE. The aim was to assess whether plasma EVs from MHE patients played a role in inducing the pro-inflammatory environment and altered differentiation of CD4+ T lymphocyte subtypes in MHE patients. We characterized the miRNA and protein cargo of plasma EVs from 50 cirrhotic patients (27 without and 23 with MHE) and 24 controls. CD4+ T cells from the controls were cultured with plasma EVs from the three groups of study, and the cytokine release and differentiation to CD4+ T-cell subtypes were assessed. Plasma EVs from MHE patients had altered miRNA and protein contents, and were enriched in inflammatory factors compared to the controls and patients without MHE. EVs from MHE patients modulated the expression of pro-inflammatory IL-17, IL-21, and TNF-α and anti-inflammatory TGF-ß in cultured CD4+ T lymphocytes, and increased the proportion of Th follicular and Treg cells and the activation of Th17 cells. In conclusion, plasma EVs could play an important role in the induction of immune changes observed in MHE.

Implication of miR-155-5p and miR-143-3p in the Vascular Insulin Resistance and Instability of Human and Experimental Atherosclerotic Plaque.

(1) Background: Cardiovascular diseases (CVDs) are the main cause of death in developed countries, being atherosclerosis, a recurring process underlying their apparition. MicroRNAs (miRNAs) modulate the expression of their targets and have emerged as key players in CVDs; (2) Methods: 18 miRNAs were selected (Pubmed and GEO database) for their possible role in promoting atherosclerosis and were analysed by RT-qPCR in the aorta from apolipoprotein E-deficient (ApoE-/-) mice. Afterwards, the altered miRNAs in the aorta from 18 weeks-ApoE-/- mice were studied in human aortic and carotid samples; (3) Results: miR-155-5p was overexpressed and miR-143-3p was downregulated in mouse and human atherosclerotic lesions. In addition, a significant decrease in protein kinase B (AKT), target of miR-155-5p, and an increase in insulin-like growth factor type II receptor (IGF-IIR), target of miR-143-3p, were noted in aortic roots from ApoE-/- mice and in carotid plaques from patients with advanced carotid atherosclerosis (ACA). Finally, the overexpression of miR-155-5p reduced AKT levels and its phosphorylation in vascular smooth muscle cells, while miR-143-3p overexpression decreased IGF-IIR reducing apoptosis in vascular cells; (4) Conclusions: Our results suggest that miR-155-5p and miR-143-3p may be implicated in insulin resistance and plaque instability by the modulation of their targets AKT and IGF-IIR, contributing to the progression of atherosclerosis.

Using Geovisualization Tools to Examine Attitudes towards Alcohol Exposure in Urban Environments: A Pilot Study in Madrid, Spain.

Pervasiveness of alcohol products and their promotion in the urban landscape may normalize alcohol consumption. This study aims to utilize geovisualization-based methods to assess attitudes towards different levels of alcohol exposure in the urban environment. We selected a typical downtown location, Lavapiés Square in Madrid, Spain, to conduct our study. First, we designed and created realistic 3D models simulating three different urban scenes with varying degrees of exposure to alcohol in the environment. Second, we used a survey on 159 adults to explore the level of acceptance of, attitudes towards, and perceptions of alcohol exposure in each scene. Participants reported a higher level of comfort in the scene with null alcohol exposure compared with the other scenes (p < 0.001). Acceptance towards alcohol exposure decreased as the level of alcohol elements increased in the scenes (p < 0.01). Acceptance also decreased when children were present in the scenes (p < 0.01). This study demonstrated that geovisualization tools provide a useful and well-suited approach to analyze perceptions of the alcohol environment. The use of geovisualization can help understand attitudes and perceptions towards the alcohol environment and may offer a way to simulate different scenarios prior to development or retrofitting.

Hyperammonemia Alters the Function of AMPA and NMDA Receptors in Hippocampus: Extracellular cGMP Reverses Some of These Alterations.

Chronic hyperammonemia alters membrane expression of AMPA and NMDA receptors subunits in hippocampus leading to impaired memory and learning. Increasing extracellular cGMP normalizes these alterations. However, it has not been studied whether hyperammonemia alters the function of AMPA and NMDA receptors. The aims of this work were: (1) assess if hyperammonemia alters AMPA and NMDA receptors function; (2) analyze if extracellular cGMP reverses these alterations. A multielectrode array device was used to stimulate Schäffer collaterals and record postsynaptic currents in the CA1 region in hippocampal slices from control and hyperammonemic rats and analyze different features of the excitatory postsynaptic potentials. Hyperammonemia reduces the amplitude and delays appearance of AMPA EPSPs, whereas increases amplitude, hyperpolarization, depolarization and desensitization area of the NMDA EPSPs. These alterations in AMPA and NMDA function are accentuated as the stimulation intensity increases. Adding extracellular cGMP reverses the alteration in amplitude in both, AMPA and NMDA EPSPs. In control slices extracellular cGMP decreases the AMPA and NMDA EPSPs amplitude and delays the response of neurons and the return to the resting potential at all stimulation intensities. In conclusion, hyperammonemia decreases the AMPA response, whereas increases the NMDA response and extracellular cGMP reverses these alterations.

Intracellular and extracelluar cyclic GMP in the brain and the hippocampus.

Cyclic Guanosine-Monophosphate (cGMP) is implicated as second messenger in a plethora of pathways and its effects are executed mainly by cGMP-dependent protein kinases (PKG). It is involved in both peripheral (cardiovascular regulation, intestinal secretion, phototransduction, etc.) and brain (hippocampal synaptic plasticity, neuroinflammation, cognitive function, etc.) processes. Stimulation of hippocampal cGMP signaling have been proved to be beneficial in animal models of aging, Alzheimer's disease or hepatic encephalopathy, restoring different cognitive functions such as passive avoidance, object recognition or spatial memory. However, even when some inhibitors of cGMP-degrading enzymes (PDEs) are already used against peripheral pathologies, their utility as neurological treatments is still under clinical investigation. Additionally, it has been demonstrated a list of cGMP roles as not second but first messenger. The role of extracellular cGMP has been specially studied in hippocampal function and cognitive impairment in animal models and it has emerged as an important modulator of neuroinflammation-mediated cognitive alterations and hippocampal synaptic plasticity malfunction. Specifically, it has been demonstrated that extracellular cGMP decreases hippocampal IL-1ß levels restoring membrane expression of glutamate receptors in the hippocampus and cognitive function in hyperammonemic rats. The mechanisms implicated are still unclear and might involve complex interactions between hippocampal neurons, astrocytes and microglia. Membrane targets for extracellular cGMP are still poorly understood and must be addressed in future studies.

Disponibilidad y promoción de alcohol según la tipología de los locales y las condiciones socioeconómicas del área / Disponibilidad y promoción de alcohol según la tipología de los locales y las condiciones socioeconómicas del área / Availability and promotion of alcohol across different outlet typologies and under different area-level socioeconomic status / Availability and promotion of alcohol across different outlet typologies and under different area-level socioeconomic status

El objetivo fue caracterizar la disponibilidad y promoción de alcohol asociados a los locales de venta y consumo de alcohol en Madrid, así como explorar las diferencias en su distribución en función de la tipología del local y las características socioeconómicas del área. Se utilizó el instrumento OHCITIES para caracterizar locales situados en 42 secciones censales de Madrid durante 2016. Se registró la densidad de locales y el número de locales con amplios horarios de apertura (12 o más horas). Se registró cualquier tipo de promoción asociada al local visible desde el exterior. Se compararon los porcentajes de características de disponibilidad y promoción asociada a los locales de consumo y venta de alcohol utilizando el test de chi cuadrado y la prueba exacta de Fisher. Se estimó la densidad de disponibilidad y promoción por sección censal y se exploró su distribución en función de las características socioeconómicas del área mediante el test de Kruskal-Wallis. Se registraron 324 locales, 241 de consumo y 83 de venta. La mayoría tenía un horario amplio de apertura (73,77%) y algún elemento promocional (89,51%). Los locales de consumo tenían horarios más amplios de apertura y más elementos promocionales que los de venta (p <0,001). Se encontraron mayor densidad de locales, amplitud de horarios y elementos promocionales en áreas de nivel socioeconómico alto (todos p <0,001). La disponibilidad y promoción estuvieron asociadas con los locales de venta y consumo de alcohol en Madrid. Futuras políticas cuyo objetivo sea la prevención del consumo de alcohol deben tener en cuenta la influencia de los tipos de locales y las características socioeconómicas del área en la distribución de la disponibilidad y promoción de alcohol.(AU)

El objetivo fue caracterizar la disponibilidad y promoción de alcohol asociados a los locales de venta y consumo de alcohol en Madrid, así como explorar las diferencias en su distribución en función de la tipología del local y las características socioeconómicas del área. Se utilizó el instrumento OHCITIES para caracterizar locales situados en 42 secciones censales de Madrid durante 2016. Se registró la densidad de locales y el número de locales con amplios horarios de apertura (12 o más horas). Se registró cualquier tipo de promoción asociada al local visible desde el exterior. Se compararon los porcentajes de características de disponibilidad y promoción asociada a los locales de consumo y venta de alcohol utilizando el test de chi cuadrado y la prueba exacta de Fisher. Se estimó la densidad de disponibilidad y promoción por sección censal y se exploró su distribución en función de las características socioeconómicas del área mediante el test de Kruskal-Wallis. Se registraron 324 locales, 241 de consumo y 83 de venta. La mayoría tenía un horario amplio de apertura (73,77%) y algún elemento promocional (89,51%). Los locales de consumo tenían horarios más amplios de apertura y más elementos promocionales que los de venta (p <0,001). Se encontraron mayor densidad de locales, amplitud de horarios y elementos promocionales en áreas de nivel socioeconómico alto (todos p <0,001). La disponibilidad y promoción estuvieron asociadas con los locales de venta y consumo de alcohol en Madrid. Futuras políticas cuyo objetivo sea la prevención del consumo de alcohol deben tener en cuenta la influencia de los tipos de locales y las características socioeconómicas del área en la distribución de la disponibilidad y promoción de alcohol.(AU)

We aimed to characterize the availability and promotion of alcohol at alcohol outlets in Madrid and to compare them according to type of outlet and area-level socioeconomic status. We used the OHCITIES instrument to characterise the alcohol outlets in 42 census tracts of Madrid in 2016. We specified alcohol availability as the density of alcohol outlets and the number of alcohol outlets with extended opening hours (12 or more). We registered any type of promotion associated to alcohol outlets that could be perceived from outside the outlet. We calculated and compared proportions of availability and promotion by alcohol outlet (on- and off-premise) using chi-squared and Fisher Exact tests. We estimated the availability and promotion of alcohol densities per census tract according to area-level socioeconomic status. To assess statistical significance, we used Kruskal-Wallis tests. We recorded 324 alcohol outlets, 241 on-premise and 83 off-premise. Most of the outlets had extended opening hours (73.77%) and at least one sign promoting alcohol (89.51%). More on-premise outlets had extended opening hours and higher presence of alcohol promotion than off-premise (p <0.001). Higher density of alcohol outlets, extended opening hours and presence of alcohol promotion were found in higher socioeconomic areas (all p<0.001). These results were also observed for on-premise alcohol outlets. Alcohol availability and promotion were associated with alcohol outlets in Madrid. Future alcohol policies regulating the availability and promotion of alcohol should consider outlet types and area-level socioeconomic status.(AU)

We aimed to characterize the availability and promotion of alcohol at alcohol outlets in Madrid and to compare them according to type of outlet and area-level socioeconomic status. We used the OHCITIES instrument to characterise the alcohol outlets in 42 census tracts of Madrid in 2016. We specified alcohol availability as the density of alcohol outlets and the number of alcohol outlets with extended opening hours (12 or more). We registered any type of promotion associated to alcohol outlets that could be perceived from outside the outlet. We calculated and compared proportions of availability and promotion by alcohol outlet (on- and off-premise) using chi-squared and Fisher Exact tests. We estimated the availability and promotion of alcohol densities per census tract according to area-level socioeconomic status. To assess statistical significance, we used Kruskal-Wallis tests. We recorded 324 alcohol outlets, 241 on-premise and 83 off-premise. Most of the outlets had extended opening hours (73.77%) and at least one sign promoting alcohol (89.51%). More on-premise outlets had extended opening hours and higher presence of alcohol promotion than off-premise (p <0.001). Higher density of alcohol outlets, extended opening hours and presence of alcohol promotion were found in higher socioeconomic areas (all p<0.001). These results were also observed for on-premise alcohol outlets. Alcohol availability and promotion were associated with alcohol outlets in Madrid. Future alcohol policies regulating the availability and promotion of alcohol should consider outlet types and area-level socioeconomic status.(AU)

Availability and promotion of alcohol across different outlet typologies and under different area-level socioeconomic status. / Disponibilidad y promoción de alcohol según la tipología de los locales y las condiciones socioeconómicas del área.

We aimed to characterize the availability and promotion of alcohol at alcohol outlets in Madrid and to compare them according to type of outlet and area-level socioeconomic status. We used the OHCITIES instrument to characterise the alcohol outlets in 42 census tracts of Madrid in 2016. We specified alcohol availability as the density of alcohol outlets and the number of alcohol outlets with extended opening hours (12 or more). We registered any type of promotion associated to alcohol outlets that could be perceived from outside the outlet. We calculated and compared proportions of availability and promotion by alcohol outlet (on- and off-premise) using chi-squared and Fisher Exact tests. We estimated the availability and promotion of alcohol densities per census tract according to area-level socioeconomic status. To assess statistical significance, we used Kruskal-Wallis tests. We recorded 324 alcohol outlets, 241 on-premise and 83 off-premise. Most of the outlets had extended opening hours (73.77%) and at least one sign promoting alcohol (89.51%). More on-premise outlets had extended opening hours and higher presence of alcohol promotion than off-premise (p < 0.001). Higher density of alcohol outlets, extended opening hours and presence of alcohol promotion were found in higher socioeconomic areas (all p < 0.001). These results were also observed for on-premise alcohol outlets. Alcohol availability and promotion were associated with alcohol outlets in Madrid. Future alcohol policies regulating the availability and promotion of alcohol should consider outlet types and area-level socioeconomic status.

El objetivo fue caracterizar la disponibilidad y promoción de alcohol asociados a los locales de venta y consumo de alcohol en Madrid, así como explorar las diferencias en su distribución en función de la tipología del local y las características socioeconómicas del área. Se utilizó el instrumento OHCITIES para caracterizar locales situados en 42 secciones censales de Madrid durante 2016. Se registró la densidad de locales y el número de locales con amplios horarios de apertura (12 o más horas). Se registró cualquier tipo de promoción asociada al local visible desde el exterior. Se compararon los porcentajes de características de disponibilidad y promoción asociada a los locales de consumo y venta de alcohol utilizando el test de chi cuadrado y la prueba exacta de Fisher. Se estimó la densidad de disponibilidad y promoción por sección censal y se exploró su distribución en función de las características socioeconómicas del área mediante el test de Kruskal-Wallis. Se registraron 324 locales, 241 de consumo y 83 de venta. La mayoría tenía un horario amplio de apertura (73,77%) y algún elemento promocional (89,51%). Los locales de consumo tenían horarios más amplios de apertura y más elementos promocionales que los de venta (p < 0,001). Se encontraron mayor densidad de locales, amplitud de horarios y elementos promocionales en áreas de nivel socioeconómico alto (todos p < 0,001). La disponibilidad y promoción estuvieron asociadas con los locales de venta y consumo de alcohol en Madrid. Futuras políticas cuyo objetivo sea la prevención del consumo de alcohol deben tener en cuenta la influencia de los tipos de locales y las características socioeconómicas del área en la distribución de la disponibilidad y promoción de alcohol.

Concerted regulation of non-alcoholic fatty liver disease progression by microRNAs in apolipoprotein E-deficient mice.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is constantly increasing, and altered expression of microRNAs (miRNAs) fosters the development and progression of many pathologies, including NAFLD. Therefore, we explored the role of new miRNAs involved in the molecular mechanisms that trigger NAFLD progression and evaluated them as biomarkers for diagnosis. As a NAFLD model, we used apolipoprotein E-deficient mice administered a high-fat diet for 8 or 18 weeks. We demonstrated that insulin resistance and decreased lipogenesis and autophagy observed after 18 weeks on the diet are related to a concerted regulation carried out by miR-26b-5p, miR-34a-5p, miR-149-5p and miR-375-3p. We also propose circulating let-7d-5p and miR-146b-5p as potential biomarkers of early stages of NAFLD. Finally, we confirmed that circulating miR-34a-5p and miR-375-3p are elevated in the late stages of NAFLD and that miR-27b-3p and miR-122-5p are increased with disease progression. Our results reveal a synergistic regulation of key processes in NAFLD development and progression by miRNAs. Further investigation is needed to unravel the roles of these miRNAs for developing new strategies for NAFLD treatment. This article has an associated First Person interview with the joint first authors of the paper.

Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model.

BACKGROUND: Cardiovascular dysfunction is linked to insulin-resistant states. In this paper, we analyzed whether the severe hepatic insulin resistance of an inducible liver-specific insulin receptor knockout (iLIRKO) might generate vascular insulin resistance and dysfunction, and whether insulin receptor (IR) isoforms gene therapy might revert it. METHODS: We studied in vivo insulin signaling in aorta artery and heart from iLIRKO. Vascular reactivity and the mRNA levels of genes involved in vascular dysfunction were analyzed in thoracic aorta rings by qRT-PCR. Finally, iLIRKO mice were treated with hepatic-specific gene therapy to analyze vascular dysfunction improvement. RESULTS: Our results suggest that severe hepatic insulin resistance was expanded to cardiovascular tissues. This vascular insulin resistance observed in aorta artery from iLIRKO mice correlated with a reduction in both PI3K/AKT/eNOS and p42/44 MAPK pathways, and it might be implicated in their vascular alterations characterized by endothelial dysfunction, hypercontractility and eNOS/iNOS levels' imbalance. Finally, regarding long-term hepatic expression of IR isoforms, IRA was more efficient than IRB in the improvement of vascular dysfunction observed in iLIRKO mice. CONCLUSION: Severe hepatic insulin resistance is sufficient to produce cardiovascular insulin resistance and dysfunction. Long-term hepatic expression of IRA restored the vascular damage observed in iLIRKO mice.