Modulation of circulating levels of advanced glycation end products and its impact on intima-media thickness of both common carotid arteries: CORDIOPREV randomised controlled trial.

BACKGROUND: Increasing evidence supports the role of advanced glycation end products (AGEs) in atherosclerosis in both diabetic and non-diabetic patients, suggesting that therapeutic strategies targeting AGEs may offer potential benefits in this population. The Mediterranean diet is associated with improved biomarkers and anthropometric measurements related with atherosclerosis in addition to its ability to modulate AGE metabolism. Our aim was to determine whether the reduction in atherosclerosis progression (measured by changes in intima-media thickness of both common carotid arteries (IMT-CC)), observed after consumption of a Mediterranean diet compared to a low-fat diet, is associated with a modulation of circulating AGE levels in patients with coronary heart disease (CHD). METHODS: 1002 CHD patients were divided in: (1) Non-increased IMT-CC patients, whose IMT-CC was reduced or not changed after dietary intervention and (2) Increased IMT-CC patients, whose IMT-CC was increased after dietary intervention. Serum AGE levels (methylglyoxal-MG and Nε-Carboxymethyllysine-CML) and parameters related to AGE metabolism (AGER1 and GloxI mRNA and sRAGE levels) and reduced glutathione (GSH) levels were measured before and after 5-years of dietary intervention. RESULTS: The Mediterranean diet did not affect MG levels, whereas the low-fat diet significantly increased them compared to baseline (p = 0.029), leading to lower MG levels following the Mediterranean diet than the low-fat diet (p < 0.001). The Mediterranean diet, but not the low-fat diet, produced an upregulation of AGE metabolism, with increased AGER1 and GloxI gene expression as well as increased GSH and sRAGE levels in Non-increased IMT-CC patients (all p < 0.05). Although the Mediterranean diet increased MG levels in Increased IMT-CC patients, this increment was lower compared to the low-fat diet (all p < 0.05). CONCLUSIONS: Our results suggest that an improvement in modulation of AGE metabolism, which facilitates better management of circulating AGE levels, may be one of the mechanisms through which the Mediterranean diet, compared to a low-fat diet, reduces the progression of atherosclerosis in patients with CHD. Trial registration https://clinicaltrials.gov/ct2/show/NCT00924937 , Clinicaltrials.gov number, NCT00924937.

Recent treatment patterns and real-world survival following first-line anti-PD-L1 treatment for extensive-stage small cell lung cancer.

BACKGROUND: The landscape of small cell lung cancer (SCLC) has changed since the 2019 and 2020 approvals of anti-PD-L1 atezolizumab and durvalumab for first-line (1L) treatment in combination with chemotherapy. We studied treatment patterns and real-world overall survival (rwOS) following 1L-3L therapy. PATIENTS AND METHODS: A nationwide electronic health record (EHR)-derived de-identified database was used to describe treatment patterns, characteristics, and survival of patients with extensive-stage (ES)-SCLC by 1L anti-PD-L1 treatment. Patients with ES-SCLC who initiated ≥1 line of systemic therapy from 2013 to 2021, with potential follow-up through 2022, were included. RESULTS: Among 9952 patients with SCLC, there were 4308 patients with ES-SCLC treated during the study period who met eligibility criteria. Etoposide + platinum (EP) chemotherapy was most common in the 1L, with addition of anti-PD-L1 therapy to most regimens by 2019. Second-line regimens varied by platinum sensitivity status and shifted from topotecan to lurbinectedin over time. Median rwOS following 1L therapy was 8.3 months (95% CI, 7.9-8.8) in those treated with 1L anti-PD-L1 and 8.0 months (95% CI, 7.8-8.2) in those who were not. Following 2L and 3L, median rwOS was 5.6 (95% CI, 4.9-6.3) and 4.9 months (95% CI, 3.4-6.0), respectively, among 1L anti-PD-L1-treated, and 4.5 (95% CI, 4.2-4.9) and 4.0 months (95% CI, 3.7-4.5), respectively, among those who were not. CONCLUSION: Despite the introduction of frontline anti-PD-L1 therapy, survival remains dismal among patients with ES-SCLC treated in the real-world setting.

Quality of Life of Hematological Neoplasm Survivors After Hematopoietic Stem Cell Transplantation.

PURPOSE: This study aimed to assess changes in the quality of life (QoL) of patients with hematological neoplasms who underwent hematopoietic stem cell transplantation (HSCT), identify factors influencing these changes, and quantify the associated monetary value. METHODS: A total of 122 hematopoietic stem cell transplantation (HSCT) recipients participated in the study completing a recall survey with questions about 3 different stages: (1) pre-HSCT (baseline), (2) 6 months post-transplantation, and (3) between the first and fifth post-transplantation years. The study first estimated the incremental variation in QoL between phases and conducted regression analyses to identify factors linked to QoL changes. Second, it explored the transition probabilities of QoL between phases and their monetary value. RESULTS: Baseline QoL predominantly determined future QoL changes, with disease type, transplantation type, and other sociodemographic factors proving insignificant. Notably, patients with the lowest baseline QoL experienced greater QoL improvement post-HSCT compared to others. Specifically, 90% of patients elevated their QoL quartile within the first post-transplantation year, with over 20% reaching the highest quartile and an average QoL increase of 0.619. The incremental economic benefit for patients with poor baseline QoL, compared to those with high baseline QoL, was 56,880€. CONCLUSION: This study provides new, useful, and relevant information on the evolution of the QoL of these patients. Our findings support that HSCT significantly enhances QoL for survivors with initially low QoL, while those with high pre-HSCT QoL maintain their levels. Furthermore, other factors were not significant contributors to this relationship. The study introduced a novel method to measure the economic benefit of incremental QoL.

Oncologic and functional outcomes following robot assisted radical prostatectomy: 15-Year experience in a Latin American referral center.

BACKGROUND: Prostate cancer is the most common cancer in men with more than 52,000 cases diagnosed every year on average. With the introduction of robotic surgery, robotic assisted radical prostatectomy (RARP) has become a popular treatment option in recent years. Achieving oncological control, urinary continence and satisfactory erectile sexual function after RP is the main goal also known as "trifecta". All these outcomes are highly influenced by surgical experience and caseload. The main objective of this study is to analyze oncological and functional outcomes in RARP after 15 years of experience. METHODS: From 2008 until December 2023, 1790 RARP for localized prostate cancer were performed. A retrospective analysis was conducted based on prospectively collected data correlated with electronic medical records. RESULTS: Subgroup analyses were conducted in order to evaluate oncological and functional outcomes (n: 1400). Red blood cell transfusion and conversion to open surgery rate was 1.9 % and 0.1 %, respectively. Mean surgical time was 194 min. Mean follow-up time was 69.5 months, 23.8 % patients experienced biochemical recurrence and 1 % died, primarily due to disease progression. Estimated 10-year recurrence-free survival was 68.7 % (95 % CI 67.2-72.2) while estimated 10-year overall survival was 97.9 % (95 % CI 96.3-99.4). Overall urinary continence rate at 2 years was 86.9 % while satisfactory erectile function rate at 18 months was 56.8 %. CONCLUSIONS: Robotic-assisted radical prostatectomy has become a standard surgical technique in our urological practice for the management of clinically localized and locally advanced prostate tumors in selected cases. After 15 years since the inception of our robotic surgery program, we can conclude that our results are comparable to those published in the international literature, enabling patients to maintain satisfactory sexual function with a high continence rate within the first year of surgery.

Allosteric modulation of the CXCR4:CXCL12 axis by targeting receptor nanoclustering via the TMV-TMVI domain.

CXCR4 is a ubiquitously expressed chemokine receptor that regulates leukocyte trafficking and arrest in both homeostatic and pathological states. It also participates in organogenesis, HIV-1 infection, and tumor development. Despite the potential therapeutic benefit of CXCR4 antagonists, only one, plerixafor (AMD3100), which blocks the ligand-binding site, has reached the clinic. Recent advances in imaging and biophysical techniques have provided a richer understanding of the membrane organization and dynamics of this receptor. Activation of CXCR4 by CXCL12 reduces the number of CXCR4 monomers/dimers at the cell membrane and increases the formation of large nanoclusters, which are largely immobile and are required for correct cell orientation to chemoattractant gradients. Mechanistically, CXCR4 activation involves a structural motif defined by residues in TMV and TMVI. Using this structural motif as a template, we performed in silico molecular modeling followed by in vitro screening of a small compound library to identify negative allosteric modulators of CXCR4 that do not affect CXCL12 binding. We identified AGR1.137, a small molecule that abolishes CXCL12-mediated receptor nanoclustering and dynamics and blocks the ability of cells to sense CXCL12 gradients both in vitro and in vivo while preserving ligand binding and receptor internalization.

Sustained Clinical Benefit and Intracranial Activity of Tarlatamab in Previously Treated Small Cell Lung Cancer: DeLLphi-300 Trial Update.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3, has shown durable anticancer activity and manageable safety in previously treated small cell lung cancer (SCLC) in DeLLphi-300 phase I and DeLLphi-301 phase II trials. Here, we report extended follow-up of DeLLphi-300 (median follow-up, 12.1 months [range, 0.2-34.3]) in fully enrolled cohorts treated with tarlatamab ≥10 mg dose administered once every two weeks, once every three weeks, or once on day 1 and once on day 8 of a 21-day cycle (N = 152). Overall, the objective response rate (ORR) was 25.0%; the median duration of response (mDOR) was 11.2 months (95% CI, 6.6 to 22.3), and the median overall survival (mOS) was 17.5 months (95% CI, 11.4 to not estimable [NE]). Among 17 patients receiving 10 mg tarlatamab once every two weeks, the ORR was 35.3%, the mDOR was 14.9 months (95% CI, 3.0 to NE), the mOS was 20.3 months (95% CI, 5.1 to NE), and 29.4% had sustained disease control with time on treatment ≥52 weeks. No new safety signals were identified. In modified Response Assessment in Neuro-Oncology Brain Metastases analyses, CNS tumor shrinkage of ≥30% was observed in 62.5% of patients (10 of 16) who had a baseline CNS lesion of ≥10 mm, including in a subset of patients with tumor shrinkage long after previous brain radiotherapy. In DeLLphi-300 extended follow-up, tarlatamab demonstrated unprecedented survival and potential findings of intracranial activity in previously treated SCLC.

Single-cell genomics details the maturation block in BCP-ALL and identifies therapeutic vulnerabilities in DUX4-r cases.

ABSTRACT: B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood malignancy and is driven by multiple genetic alterations that cause maturation arrest and accumulation of abnormal progenitor B cells. Current treatment protocols with chemotherapy have led to favorable outcomes but are associated with significant toxicity and risk of side effects, highlighting the necessity for highly effective, less toxic, targeted drugs, even in subtypes with a favorable outcome. Here, we used multimodal single-cell sequencing to delineate the transcriptional, epigenetic, and immunophenotypic characteristics of 23 childhood BCP-ALLs belonging to the BCR::ABL1+, ETV6::RUNX1+, high hyperdiploid, and recently discovered DUX4-rearranged (DUX4-r) subtypes. Projection of the ALL cells along the normal hematopoietic differentiation axis revealed a diversity in the maturation pattern between the different BCP-ALL subtypes. Although the BCR::ABL1+, ETV6::RUNX1+, and high hyperdiploidy cells mainly showed similarities to normal pro-B cells, DUX4-r ALL cells also displayed transcriptional signatures resembling mature B cells. Focusing on the DUX4-r subtype, we found that the blast population displayed not only multilineage priming toward nonhematopoietic cells, myeloid, and T-cell lineages, but also an activation of phosphatidylinositol 3-kinase (PI3K)/AKT signaling that sensitized the cells to PI3K inhibition in vivo. Given the multilineage priming of DUX4-r blasts with aberrant expression of myeloid marker CD371 (CLL-1), we generated chimeric antigen receptor T cells, which effectively eliminated DUX4-r ALL cells in vivo. These results provide a detailed characterization of BCP-ALL at the single-cell level and reveal therapeutic vulnerabilities in the DUX4-r subtype, with implications for the understanding of ALL biology and new therapeutic strategies.

ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma.

Cancer cellular heterogeneity and therapy resistance arise substantially from metabolic and transcriptional adaptations, but how these are interconnected is poorly understood. Here, we show that, in melanoma, the cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) forms an enzymatic partnership with acetyl-coenzyme A (CoA) synthetase 2 (ACSS2) in the nucleus to couple high glucose metabolic flux with acetyl-histone H3 modification of neural crest (NC) lineage and glucose metabolism genes. Importantly, we show that acetaldehyde is a metabolite source for acetyl-histone H3 modification in an ALDH1A3-dependent manner, providing a physiologic function for this highly volatile and toxic metabolite. In a zebrafish melanoma residual disease model, an ALDH1-high subpopulation emerges following BRAF inhibitor treatment, and targeting these with an ALDH1 suicide inhibitor, nifuroxazide, delays or prevents BRAF inhibitor drug-resistant relapse. Our work reveals that the ALDH1A3-ACSS2 couple directly coordinates nuclear acetaldehyde-acetyl-CoA metabolism with specific chromatin-based gene regulation and represents a potential therapeutic vulnerability in melanoma.

Interdisciplinary innovative approach to an aggressive ossifying fibroma case: Integrating 3D surgery and customized reconstruction in maxillofacial and dental care.

Aggressive ossifying fibroma is a benign fibro-osseous disorder characterized by its aggressive behavior, which complicates its management. In this article, we present a case involving the recurrence of this condition in the maxillary region, with orbital and dental involvement, in a patient who had previously undergone surgery and reconstruction with a microvascularized free fibula flap. A multidisciplinary approach involving maxillofacial surgery and dentistry was employed to deliver a customized and entirely satisfactory solution for the patient. The use of 3D surgery was integral to our approach, encompassing pre-surgical digital planning and the transfer of this planning to the operating room via navigation software. Customized surgical cutting guides facilitated precise resection, while a personalized polyether ether ketone (PEEK) prosthesis was utilized for reconstruction of the malar and infraorbital region. Pre-prosthetic computer-aided design/computer-aided manufacturing (CAD/CAM) surgery, along with dental rehabilitation using transepithelial abutments and dental prostheses on a titanium framework, were employed for dental restoration. During the postoperative period, mobility in the reconstructed maxilla was observed due to the loss of support from the initial reconstruction plate. This was addressed by replacing the plate with a custom-made titanium plate, designed to accommodate the location of the transepithelial abutments and prevent disruption of the dental rehabilitation. This case demonstrates the potential of new technologies when applied within the collaborative framework of maxillofacial surgeons and dentists, enabling effective and definitive solutions in complex reconstruction cases. Key words:Aggressive ossifying fibroma; 3D surgery; customized reconstruction; complex dental reconstruction.

DAB2IP associates with hereditary angioedema: Insights into the role of VEGF signaling in HAE pathophysiology.

BACKGROUND: In the recent years, there was an important improvement in the understanding of the pathogenesis of hereditary angioedema (HAE). Notwithstanding, in a large portion of patients with unknown mutation (HAE-UNK) the genetic cause remains to be identified. OBJECTIVES: To identify new genetic targets associated with HAE, a large Argentine family with HAE-UNK spanning 3 generations was studied. METHODS: Whole exome sequencing was performed on affected family members to identify potential genetic variants associated with HAE-UNK. In silico analyses and experimental studies were applied to assess the role of the identified gene variant. RESULTS: A missense variant (p.D239N) in DAB2IP was identified. The variant occurred in the C2-domain, the region interacting with vascular endothelial growth factor receptor 2 (VEGFR2). It was found to be rare, and predicted to have a detrimental effect on the functionality of DAB2IP. Protein structure modeling predicted changes in the mutant p.D239N protein structure, impacting protein stability. The p.D239N variant affected the subcellular localization of VEGFR2. Cells transfected with the DAB2IP-239N transcript exhibited an intracellular distribution, and VEGFR2 remained associated with the cell membrane. The altered localization pattern indicated reduced colocalization of the mutant protein with VEGFR2, suggesting a diminished ability of VEGFR2 binding. CONCLUSIONS: The study identified a novel missense variant (p.D239N) in DAB2IP in a family with HAE-UNK and highlighted the role of dysregulated VEGF-mediated signaling in altered endothelial permeability. DAB2IP loss-of-function pathogenic variants lead to the impairment of the endothelial VEGF/VEGFR2 ligand system and represent a new pathophysiologic cause of HAE-UNK.

GPCR Function in Autophagy Control: A Systematic Approach of Chemical Intervention.

Autophagy facilitates the degradation of cellular content via the lysosome and is involved in cellular homeostasis and stress response pathways. As such, malfunction of autophagy is linked to a variety of diseases ranging from organ-specific illnesses like cardiomyopathy to systemic illnesses such as cancer or metabolic syndromes. Given the variety of autophagic functions within a cell and tissue, regulation of autophagy is complex and contains numerous positive and negative feedback loops. While our knowledge of mechanisms for cargo selectivity has significantly improved over the last decade, our understanding of signaling routes activating individual autophagy pathways remains rather sparse. In this resource study, we report on a well-characterized chemical library containing 77 GPCR-targeting ligands that was used to systematically analyze LC3B-based autophagy as well as ER-phagy flux upon compound treatment. Upon others, compounds TC-G 1004, BAY 60-6583, PSNCBAM-1, TC-G 1008, LPA2 Antagonist 1, ML-154, JTC-801 and ML-290 targeting adenosine receptor A2a (ADORA2A), adenosine receptor A2b (ADORA2B), cannabinoid receptor 1 (CNR1), G-protein coupled receptor 39 (GPR39), lysophosphatidic acid receptor 2 (LPAR2), neuropeptide S receptor 1 (NPSR1), opioid related nociceptin receptor 1 (OPRL1), and relaxin receptor 1 (RXFP1), respectively, were hit compounds for general autophagy flux. From these compounds, only JTC-801 markly increased ER-phagy flux. In addition, the global impact of these selected hit compounds were analyzed by TMT-based mass spectrometry and demonstrated the differential impact of targeting GPCRs on autophagy-associated proteins. This chemical screening exercise indicates to a significant cross-talk between GPCR signaling and regulation of autophagy pathways.

Natural history of SCLC patients treated in third-line and beyond: A retrospective real world study.

OBJECTIVES: To describe treatment patterns and estimate outcomes among real-world small cell lung cancer (SCLC) patients in the US who received three or more lines of therapy. MATERIALS AND METHODS: We conducted a retrospective analysis of adult patients with SCLC who received a front-line platinum-based regimen and two additional lines of therapy (ie., a cohort of at least three lines of therapy). De-identified patients were selected from a United States Flatiron Health oncology database of electronic health records. Treatment patterns were captured by line of therapy. Outcomes evaluated by line of therapy included real-world overall survival (rwOS), real-world progression free survival (rwPFS), real-world response rate (rwRR) and real-world duration of response (rwDOR). RESULTS: The analysis included 326 3L SCLC patients, of which 103 (32 %) received 4L treatment, and 38 % (39/103) of 4L treated received 5L of therapy. Among the 3L cohort, the average age was 67 years, 49 % were male, and nearly all had a history of smoking (96 %). In the 3L setting, the median rwOS was 5.3 months (95 % Confidence Interval (CI): 4.5, 6.0), median rwPFS was 2.5 months (95 % CI: 2.1, 2.7), rwRR was 19.3 % (95 % CI: 15.2, 24.0) and median DOR was 3.4 months (95 % CI: 2.8, 4.4). No differences were seen in outcomes between the overall cohort and a subgroup of patients treated with front-line platinum-based regimen with an anti-programmed cell death ligand 1 (PD-L1) agent (atezolizumab or durvalumab), in each respective line of therapy. CONCLUSION: Results from this large, real-world study of US patients with SCLC in the 3L setting and beyond highlight the poor treatment outcomes in advanced SCLC patients with existing therapies and underscore the dire need for new therapies for SCLC patients.

Glycogen synthesis prevents metabolic imbalance and disruption of photosynthetic electron transport from photosystem II during transition to photomixotrophy in Synechocystis sp. PCC 6803.

Some cyanobacteria can grow photoautotrophically or photomixotrophically by using simultaneously CO2 and glucose. The switch between these trophic modes and the role of glycogen, their main carbon storage macromolecule, was investigated. We analysed the effect of glucose addition on the physiology, metabolic and photosynthetic state of Synechocystis sp. PCC 6803 and mutants lacking phosphoglucomutase and ADP-glucose pyrophosphorylase, with limitations in glycogen synthesis. Glycogen acted as a metabolic buffer: glucose addition increased growth and glycogen reserves in the wild-type (WT), but arrested growth in the glycogen synthesis mutants. Already 30 min after glucose addition, metabolites from the Calvin-Benson-Bassham cycle and the oxidative pentose phosphate shunt increased threefold more in the glycogen synthesis mutants than the WT. These alterations substantially affected the photosynthetic performance of the glycogen synthesis mutants, as O2 evolution and CO2 uptake were both impaired. We conclude that glycogen synthesis is essential during transitions to photomixotrophy to avoid metabolic imbalance that induces inhibition of electron transfer from PSII and subsequently accumulation of reactive oxygen species, loss of PSII core proteins, and cell death. Our study lays foundations for optimising photomixotrophy-based biotechnologies through understanding the coordination of the crosstalk between photosynthetic electron transport and metabolism.

Tobacco policies and changes in the tendency of smoking cessation in cigarette users in Chile: a longitudinal cross-sectional study.

OBJECTIVE: To assess the impact of tobacco control regulations and policy implementation on smoking cessation tendencies in cigarette users born between 1982 and 1991 in Chile. DESIGN: Longitudinal cross-sectional study. SETTING: National level. PARTICIPANTS: Data from the National Survey of Drug Consumption (Service of Prevention and Rehabilitation for Drug and Alcohol Consumption). A pseudo-cohort of smokers born between 1982 and 1991 (N=17 905) was tracked from 2002 to 2016. PRIMARY AND SECONDARY OUTCOMES MEASURES: Primary outcome was the tendency to cease smoking conceptualised as the report of using cigarettes 1 month or more ago relative to using cigarettes in the last 30 days. The main exposure variable was the Tobacco Policy Index-tracking tobacco policy changes over time. Logistic regression, controlling for various factors, was applied. RESULTS: Models suggested a 14% increase in the smoking cessation tendency of individuals using cigarettes 1 month or more ago relative to those using cigarettes in the last 30 days (OR 1.14, CI 95% CI 1.10 to 1.19) for each point increment in the Tobacco Policy index. CONCLUSIONS: Our study contributes to documenting a positive impact of the implementation of interventions considered in the MPOWER strategy in the progression of smoking cessation tendencies in smokers born between 1982 and 1991 in Chile.

Biomarkers for response to TIL therapy: a comprehensive review.

Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) has demonstrated durable clinical responses in patients with metastatic melanoma, substantiated by recent positive results of the first phase III trial on TIL therapy. Being a demanding and logistically complex treatment, extensive preclinical and clinical effort is required to optimize patient selection by identifying predictive biomarkers of response. This review aims to comprehensively summarize the current evidence regarding the potential impact of tumor-related factors (such as mutational burden, neoantigen load, immune infiltration, status of oncogenic driver genes, and epigenetic modifications), patient characteristics (including disease burden and location, baseline cytokines and lactate dehydrogenase serum levels, human leucocyte antigen haplotype, or prior exposure to immune checkpoint inhibitors and other anticancer therapies), phenotypic features of the transferred T cells (mainly the total cell count, CD8:CD4 ratio, ex vivo culture time, expression of exhaustion markers, costimulatory signals, antitumor reactivity, and scope of target tumor-associated antigens), and other treatment-related factors (such as lymphodepleting chemotherapy and postinfusion administration of interleukin-2).

Uneven effects of twenty years of Chile's cannabis policy implementation in cannabis onset.

BACKGROUND: In Chile, Laws 19366 and 20000, implemented in 1995 and 2005 respectively, regulated and sanctioned cannabis' personal use, cultivation and trafficking. METHODS: We use thirteen biannual cross-sectional national surveys data from 1994 to 2018 to examine the effect of Laws 19366 and 20000-using the rate of individuals incarcerated per 100000 population due to drug-related crimes as proxy-on the age of onset of cannabis use over time. We estimate the effect of these policies using a mixed proportional hazards framework that models the transition to first cannabis use in 47,832 individuals aged 12-21. RESULTS: Overall, changes in these laws did not affect the transition to first cannabis use. However, increases in the rate of individuals incarcerated were associated with decreases on the age of onset of cannabis use in females and individuals living in affluent neighborhoods or in specific regions. CONCLUSION: We find no evidence of cannabis policy changes affecting the age of onset of cannabis use across all individuals aged 12-21. Policy effects associated with decreases in cannabis onset age in females and individuals from affluent neighborhoods or specific regions can be explained by using theoretical frames that recognize specific dynamics of cannabis supply and demand.

SEA 2024 Standards for Global Control of Vascular Risk. / Estándares de la Sociedad Española de Arteriosclerosis 2024 para el control global del riesgo vascular.

One of the objectives of the Spanish Society of Arteriosclerosis is to contribute to the knowledge, prevention and treatment of vascular diseases, which are the leading cause of death in Spain and entail a high degree of disability and health expenditure. Atherosclerosis is a multifactorial disease and its prevention requires a global approach that takes into account the associated risk factors. This document summarises the current evidence and includes recommendations for patients with established vascular disease or at high vascular risk: it reviews the symptoms and signs to evaluate, the laboratory and imaging procedures to request routinely or in special situations, and includes the estimation of vascular risk, diagnostic criteria for entities that are vascular risk factors, and general and specific recommendations for their treatment. Finally, it presents aspects that are not usually referenced in the literature, such as the organisation of a vascular risk consultation.

Heat-killed Mycobacterium tuberculosis induces trained immunity in vitro and in vivo administered systemically or intranasally.

Trained immunity (TI) represents a memory-like process of innate immune cells. TI can be initiated with various compounds such as fungal ß-glucan or the tuberculosis vaccine, Bacillus Calmette-Guérin. Nevertheless, considering the clinical applications of harnessing TI against infections and cancer, there is a growing need for new, simple, and easy-to-use TI inducers. Here, we demonstrate that heat-killed Mycobacterium tuberculosis (HKMtb) induces TI both in vitro and in vivo. In human monocytes, this effect represents a truly trained process, as HKMtb confers boosted inflammatory responses against various heterologous challenges, such as lipopolysaccharide (Toll-like receptor [TLR] 4 ligand) and R848 (TLR7/8 ligand). Mechanistically, HKMtb-induced TI relies on epigenetic mechanisms in a Syk/HIF-1α-dependent manner. In vivo, HKMtb induced TI when administered both systemically and intranasally, with the latter generating a more robust TI response. Summarizing, our research has demonstrated that HKMtb has the potential to act as a mucosal immunotherapy that can successfully induce trained responses.

Factores relacionados con la publicación de los trabajos de investigación presentados en los congresos científicos nacionales de estudiantes de Medicina de Perú entre los años 2017-2019 / Factors related to the publication of research papers presented at medical student national scientific conferences in Peru between 2017 and 2019

RESUMEN Objetivo: Describir las características de los trabajos presentados en los congresos de estudiantes de Medicina de la Sociedad Médico Estudiantil Peruana entre los años 2017 y 2019, así como los factores relacionados para su publicación. Materiales y métodos: Estudio de diseño observacional, transversal, bibliométrico y retrospectivo, de fuente secundaria en base a los libros de resúmenes de los trabajos de los congresos científicos entre los años 2017 y 2019. Los datos se analizaron mediante el software Stata, versión 13, y con estadística descriptiva. En el análisis multivariado se calcularon razones de prevalencias, con un intervalo de confianza al 95 % y p < 0,05 en los análisis crudos y ajustados. Resultados: De los 447 trabajos presentados, 170 (38,0 %) fueron investigaciones concluidas; 168 (37,6 %), protocolos de investigación, y 109 (24,4 %), casos clínicos. El 52,1 % (n = 233) de los autores procedían de una universidad de Lima; el 40,9 % (n = 183) eran de universidades públicas. En 376 de los trabajos (52,1 %), hubo un asesor entre los autores, de los cuales 332 (88,3 %) fueron médicos. La frecuencia de publicaciones fue 11,4 %. La prevalencia de publicación en formato de artículo original fue 131 % mayor (RPa: 2,31; IC 95 %: 1,22-4,37, p = 0,010) y 63 % menor (RPa: 0,37; IC 95 %: 0,17-0,81, p = 0,014) en los trabajos que fueron presentados en el año 2019 en comparación con el año 2017, lo cual fue estadísticamente significativo, con p < 0,05. Conclusiones: Uno de cada diez resúmenes de trabajos presentados en los congresos de la Sociedad Científico Médico Estudiantil Peruana (Socimep) fueron publicados, un número que sigue siendo bajo. Entre los factores asociados a la publicación se consideraron la presentación de un trabajo en formato de artículo original y del año 2019. Los resultados del presente estudio contribuirán a que las autoridades universitarias fortalezcan la investigación mediante estrategias y/o programas vinculados con la producción de índole científico estudiantil.

ABSTRACT Objective: To describe the characteristics of papers presented at medical student conferences of Sociedad Científica Médico Estudiantil Peruana (SOCIMEP Peruvian Medical Student Scientific Society) between 2017 and 2019, as well as the factors related to their publication. Materials and methods: An observational, cross-sectional, bibliometric, retrospective and secondary-source study based on the books of abstracts of papers presented at scientific conferences between 2017 and 2019. The data were analyzed with the Stata Statistical Software: Release 13 using descriptive statistics. In the multivariate analysis, prevalence ratios were calculated with a 95 % confidence interval and p < 0.05 in the crude and adjusted analyses. Results: From a total of 447 papers, 170 (38.0 %) were completed research studies, 168 (37.6 %) research protocols and 109 (24.4 %) case reports. In addition, 233 (52.1 %) authors came from a university in Lima and 183 (40.9 %) were from public universities. Moreover, 376 (52.1 %) papers had an advisor among the authors, 332 (88.3 %) of whom were physicians. The frequency of publications accounted for 11.4 %. The prevalence of original-article publications was 131 % higher (aPR: 2.31; 95 % CI: 1.22-4.37, p = 0.010) and 63 % lower (aPR: 0.37; 95 % CI: 0.17-0.81, p = 0.014) among papers presented in 2019 compared to 2017, thus being statistically significant, with p < 0.05. Conclusions: One out of 10 abstracts of papers presented at SOCIMEP conferences was published; however, this number is still low. Among the factors associated with the publication were presenting a research paper as an original article and in 2019. The results of this study will help the university leadership to strengthen research through strategies and/or programs linked to the student scientific production.

Reduction of circulating methylglyoxal levels by a Mediterranean diet is associated with preserved kidney function in patients with type 2 diabetes and coronary heart disease: From the CORDIOPREV randomized controlled trial.

AIM: Advanced glycation end products (AGEs) play a role in kidney disease in type 2 diabetes mellitus (T2DM). However, there have been no prior controlled clinical trials examining the effects of specific diets on AGE metabolism and their impact on kidney function. Our aim was to assess whether modulating AGE metabolism resulting in reduced AGEs levels, after consumption of two healthy diets, could delay kidney function decline in patients with T2DM and coronary heart disease (CHD). METHODS: T2DM patients (540 out of 1002 patients from the CORDIOPREV study), with estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73 m2, were classified based on their baseline kidney function: normal eGFR (≥ 90 ml/min/1.73 m2), mildly decreased eGFR (60- < 90 ml/min/1.73 m2) and moderately decreased eGFR (<60 ml/min/1.73 m2). Serum AGE levels, methylglyoxal (MG) and N-carboximethyllysine (CML), and gene expression related to AGE metabolism (AGER1, RAGE, and GloxI mRNA) were measured before and after 5-years of dietary intervention (a Mediterranean diet or a low-fat diet). RESULTS: Mediterranean diet produced a lower declined of eGFR compared to the low-fat diet only in patients with mildly decreased eGFR (P = 0.035). Moreover, Mediterranean diet was able to decrease MG levels and increase GloxI expression in normal and mildly decreased eGFR patients (all P < 0.05). One standard deviation increment of MG levels after dietary intervention resulted in a 6.8-fold (95 % CI 0.039;0.554) higher probability of eGFR decline. CONCLUSION: Our study showed that lowering circulating AGE levels, specifically MG, after following a Mediterranean diet, might be linked to the preservation of kidney function, evidenced by a decreased decline of eGFR in T2DM patients with CHD. Patients with mildly decreased eGFR could potentially benefit more from AGE reduction in maintaining kidney function.