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Introduction Dengue disease represents a large and growing global threat to public health, accounting for a significant burden to health systems of endemic countries. The World Health Organization’s (WHO) Strategic Advisory Group of Experts (SAGE) and the European Medicines Agency (EMA) currently recommend the use of TAK-003 dengue vaccine in high dengue burden and transmission settings for countries considering vaccination as part of their integrated management strategy for prevention and control of Dengue.Areas covered This paper describes the main conclusions of a workshop held by the Arbovirus Committee of the Latin American Society of Pediatric Infectious Diseases (SLIPE) in November 2023, to generate consensus recommendations on the introduction of this new vaccine in the region. Considerations were made regarding the molecular epidemiology of dengue infection in the Americas and the need for more precise phylogenetic classification and correlation with clinical outcome and disease severity.Expert opinion Introduction of dengue vaccine should be considered as an strategy for health entities in the region, with participation of social sectors, scientific societies, and ministries of health that could be able to create a successful vaccination program.

Background and objectives: Fibrosis contributes to 45% of deaths in industrialized nations and is characterized by an abnormal accumulation of extracellular matrix (ECM). There are no specific anti-fibrotic treatments for liver fibrosis, and previous unsuccessful attempts at drug development have focused on preventing ECM deposition. Because liver fibrosis is largely acknowledged to be reversible, regulating fibrosis resolution could offer novel therapeutical options. However, little is known about the mechanisms controlling ECM remodeling during resolution. Changes in proteolytic activity are essential for ECM homeostasis and macrophages are an important source of proteases. Herein, in this study we evaluate the role of macrophage-derived cathepsin D (CtsD) during liver fibrosis. Methods: CtsD expression and associated pathways were characterized in single-cell RNA sequencing and transcriptomic datasets in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD and hepatocyte-CtsD knock-out mice. Results: Analysis of single-cell RNA sequencing datasets demonstrated CtsD was expressed in macrophages and hepatocytes in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD (CtsDΔMyel) and hepatocyte-CtsD knock-out mice. CtsD deletion in macrophages, but not in hepatocytes, resulted in enhanced liver fibrosis. Both inflammatory and matrisome proteomic signatures were enriched in fibrotic CtsDΔMyel livers. Besides, CtsDΔMyel liver macrophages displayed functional, phenotypical and secretomic changes, which resulted in a degradomic phenotypical shift, responsible for the defective proteolytic processing of collagen I in vitro and impaired collagen remodeling during fibrosis resolution in vivo. Finally, CtsD-expressing mononuclear phagocytes of cirrhotic human livers were enriched in lysosomal and ECM degradative signaling pathways. Conclusions: Our work describes for the first-time CtsD-driven lysosomal activity as a central hub for restorative macrophage function during fibrosis resolution and opens new avenues to explore their degradome landscape to inform drug development.

Abstract Background The percentage of physicians identifying as Latina has not improved despite improvements in recruitment of Latina medical students, suggesting barriers to retention and career advancement. Discriminatory experiences and mental health inflictions throughout training may contribute to difficulties in recruitment, retainment, and advancement of Hispanic/Latinx trainees, a notably understudied population. Methods An anonymous, online survey was distributed to Latinas in the continental U.S. between June 22 to August 12, 2022. Eligibility criteria included: self-identifying as Hispanic/Latina, female/woman, and completing or have completed medical school, residency, or fellowship in the continental U.S. in the past 10 years. Recruitment was done via the Twitter account @LatinasInMed and outreach to Latino Medical Student Association chapters. Descriptive statistics summarized the self-reported experiences. Results The survey included 230 Hispanic/Latinx women, mostly medical students (46.9%). A majority (54.5%) reported negative ethnicity-based interactions from patients and/or patients’ families; 71.8%, from others in the medical field. High rates of depression (76.2%) and anxiety (92.6%) during training were reported by Latinas, especially medical students. Feelings of imposter syndrome and burnout were high at 90.7% and 87.4%, respectively. Conclusions This is the first study evaluating the unique experiences of Latinas in medicine, who reported discrimination and mental health struggles, specifically during medical school, at alarmingly high rates. Our findings could aid in creating the needed interventions to support Latinas in medical training to reduce the existing exodus of Latinas from medicine.

District energy systems (DES) offer an optimal solution for decarbonising the heating and cooling sector while attaining multiple additional benefits. The first step to analyse the potential of DES in both new and existing markets is through rapid assessments (RA). Currently, publicly available models lack rapid assessments of the technical-economic and environmental potential of DES. This RA model was developed within the framework of UNEP's District Energy in Cities Initiative to identify DES's potential spending low time and monetary resources. In this light, the study presents a model for conducting a rapid assessment applied to the case of Temuco, Chile. Results show that a total of 55 MW DH (district heating) capacity is required to cover the heating demand. A wood-chip boiler of 25 MW capacity and a gas boiler of 30 MW capacity are considered in the calculations. The total CAPEX of the project is around 25 billion CLP, with a NPV of 10.5 billion CLP and an IRR of 14%. The project is also estimated to achieve an annual reduction of 24,382 tons of PM10 and 23,692 tons of PM2.5. The model was validated against an independent study conducted by an international consulting company, and the results were found to be in close proximity with the study. Thus, the model can be an effective tool for performing rapid assessments of DES projects in the region and subjecting attractive projects to more detailed pre-feasibility analysis.

The goal of this work is to estimate the efficacy of interferon therapy in the inhibition of infection by the human immunodeficiency virus type 1 (HIV-1) in a cell culture. For this purpose, three viral dynamics models with the antiviral effect of interferons are presented; the dynamics of cell growth differ among the models, and a variant with Gompertz-type cell dynamics is proposed. A Bayesian statistics approach is used to estimate the cell dynamics parameters, viral dynamics and interferon efficacy. The models are fitted to sets of experimental data on cell growth, HIV-1 infection without interferon therapy and HIV-1 infection with interferon therapy, respectively. The Watanabe-Akaike information criterion (WAIC) is used to determine the model that best fits the experimental data. In addition to the estimated model parameters, the average lifespan of the infected cells and the basic reproductive number are calculated.

Abstract Background Recent lifestyle changes include increased consumption of highly processed foods (HPF), which has been associated with an increased risk of non-communicable diseases (NCDs). However, nutritional information relies on the estimation of HPF consumption from food-frequency questionnaires (FFQ) that are not explicitly developed for this purpose. We aimed to develop a short screening questionnaire of HPF consumption (sQ-HPF) that integrates criteria from the existing food classification systems. Methods Data from 4400 participants (48.1% female and 51.9% male, 64.9 ± 4.9 years) of the Spanish PREDIMED-Plus (“PREvention with MEDiterranean DIet”) trial were used for this analysis. Items from the FFQ were classified according to four main food processing-based classification systems (NOVA, IARC, IFIC and UNC). Participants were classified into tertiles of HPF consumption according to each system. Using binomial logistic regression, food groups associated with agreement in the highest tertile for at least two classification systems were chosen as items for the questionnaire. ROC analysis was used to determine cut-off points for the frequency of consumption of each item, from which a score was calculated. Internal consistency of the questionnaire was assessed through exploratory factor analysis (EFA) and Cronbach’s analysis, and agreement with the four classifications was assessed with weighted kappa coefficients. Results Regression analysis identified 14 food groups (items) associated with high HPF consumption for at least two classification systems. EFA showed that items were representative contributors of a single underlying factor, the “HPF dietary pattern” (factor loadings around 0.2). We constructed a questionnaire asking about the frequency of consumption of those items. The threshold frequency of consumption was selected using ROC analysis. Comparison of the four classification systems and the sQ-HPF showed a fair to high agreement. Significant changes in lifestyle characteristics were detected across tertiles of the sQ-HPF score. Longitudinal changes in HPF consumption were also detected by the sQ-HPF, concordantly with existing classification systems. Conclusions We developed a practical tool to measure HPF consumption, the sQ-HPF. This may be a valuable instrument to study its relationship with NCDs. Trial registration Retrospectively registered at the International Standard Randomized Controlled Trial Registry ( ISRCTN89898870 ) on July 24, 2014.

This study aimed to investigate the public health and economic benefit of using a quadrivalent influenza vaccine (QIV) instead of a trivalent influenza vaccine (TIV) in past seasons in Paraguay. The budget impact of switching from TIV to QIV in the Immunization Program was also evaluated. The adapted model includes two modules. The first compared retrospectively Health and Economic outcomes resulting from the use of QIV instead of TIV. The second forecast the spending and savings that would be associated with the switch from TIV to QIV. Our findings estimate that the switch from TIV to QIV during the seasons 2012 to 2017 could have prevented around 2,600 influenza cases, 67 hospitalizations and 10 deaths. An alternative scenario using standardized estimates of the burden of influenza showed that 234 influenza-related hospitalizations and 29 deaths could have been prevented. The estimated annual budget impact of a full switch from TIV to QIV was around USD1,6 million both from the payer and societal perspectives. Those results are mainly driven by vaccine prices and coverage rate. In sum, this manuscript describes how the use of QIV instead of TIV could have prevented influenza cases and subsequent complications that led to hospitalizations and deaths. This could have generated savings for the health system and society, offsetting part of the additional investment needed to switch from TIV to QIV.

Novel metal oxide nanoparticle (NP) contrast agents may offer safety and functionality advantages over conventional gadolinium-based contrast agents (GBCAs) for cancer diagnosis by magnetic resonance imaging. However, little is known about the behavior of metal oxide NPs, or of their effect, upon coming into contact with the innate immune system. As neutrophils are the body’s first line of defense, we sought to understand how manganese oxide and iron oxide NPs impact leukocyte functionality. Specifically, we evaluated whether contrast agents caused neutrophils to release web-like fibers of DNA known as neutrophil extracellular traps (NETs), which are known to enhance metastasis and thrombosis in cancer patients. Murine neutrophils were treated with GBCA, bare manganese oxide or iron oxide NPs, or poly(lactic-co-glycolic acid) (PLGA)-coated metal oxide NPs with different incorporated levels of poly(ethylene glycol) (PEG). Manganese oxide NPs elicited the highest NETosis rates and had enhanced neutrophil uptake properties compared to iron oxide NPs. Interestingly, NPs with low levels of PEGylation produced more NETs than those with higher PEGylation. Despite generating a low rate of NETosis, GBCA altered neutrophil cytokine expression more than NP treatments. This study is the first to investigate whether manganese oxide NPs and GBCAs modulate NETosis and reveals that contrast agents may have unintended off-target effects which warrant further investigation.

Manganese oxide (MnO) nanoparticles (NPs) can serve as robust pH-sensitive contrast agents for magnetic resonance imaging (MRI) due to Mn2+ release at low pH, which generates a ~30 fold change in T1 relaxivity. Strategies to control NP size, composition, and Mn2+ dissolution rates are essential to improve diagnostic performance of pH-responsive MnO NPs. We are the first to demonstrate that MnO NP size and composition can be tuned by the temperature ramping rate and aging time used during thermal decomposition of manganese(II) acetylacetonate. Two different temperature ramping rates (10°C/min and 20°C/min) were applied to reach 300°C and NPs were aged at that temperature for 5, 15, or 30 min. A faster ramping rate and shorter aging time produced the smallest NPs of ~23 nm. Shorter aging times created a mixture of MnO and Mn3O4 NPs, whereas longer aging times formed MnO. Our results indicate that a 20°C/min ramp rate with an aging time of 30 min was the ideal temperature condition to form the smallest pure MnO NPs of ~32 nm. However, Mn2+ dissolution rates at low pH were unaffected by synthesis conditions. Although Mn2+ production was high at pH 5 mimicking endosomes inside cells, minimal Mn2+ was released at pH 6.5 and 7.4, which mimic the tumor extracellular space and blood, respectively. To further elucidate the effects of NP composition and size on Mn2+ release and MRI contrast, the ideal MnO NP formulation (~32 nm) was compared with smaller MnO and Mn3O4 NPs. Small MnO NPs produced the highest amount of Mn2+ at acidic pH with maximum T1 MRI signal; Mn3O4 NPs generated the lowest MRI signal. MnO NPs encapsulated within poly(lactide-co-glycolide) (PLGA) retained significantly higher Mn2+ release and MRI signal compared to PLGA Mn3O4 NPs. Therefore, MnO instead of Mn3O4 should be targeted intracellularly to maximize MRI contrast.

Molecular approaches are powerful tools that are used for medical or environmental diagnoses. However, the main limitations of such a tools are that they extract low levels of DNA and they do not remove the inhibitors of polymerase chain reaction (PCR). Although the use of polycation to complex and purify DNA has been described in the literature, elution often requires a high ionic strength or pH levels not compatible with molecular analyses. In this paper, we described a new process that is based on the complexation of DNA with linear polylysine, followed by capturing the complex by a cation exchange resin. The originality of the process consisted of using mechanic force to elute DNA from the complex. The extraction method showed several advantages when compared to existing methods, such as being compatible with pH levels that range from 5 to 11, as well as high levels of DNA recovery and elimination of PCR inhibitors from complex samples. This method was successfully applied to different types of samples, such as environmental samples, beverage samples, and medical samples. Furthermore, it was proven to be a good solution for removing PCR inhibitors and assuring good DNA recovery yield.

This article provides an overview of the use of pseudowords—letter strings that resemble real words by adhering to phonotactic and orthotactic rules (e. g., fambo follows the rules of English phonology and orthography, but it does not have an actual meaning)—in written word processing research, with a focus on readers in alphabetic languages. We review how pseudowords have been used in research to isolate specific features of words to examine the cognitive mechanisms underlying various aspects of their processing, including orthographic, phonological decoding, lexical-semantic, and syntactic components, as well as to the way those empirical observations have shaped theories and models of word recognition. The overview also considers their broader applications, such as in studying non-alphabetic scripts, speech processing, and language disorders like dyslexia. By providing a focused synthesis of empirical findings, this article underscores the critical insights that research using pseudowords offers into the interconnected nature of cognitive mechanisms in language processing.

The elbow is one of the most commonly dislocated joints. Although simple dislocations of the elbow usually resolve with conservative management, certain patients can experience residual chronic instability. Posterolateral rotational instability accounts for approximately 80% of elbow chronic instability cases. We propose an all-arthroscopic reconstruction of the posterior, or ulnar, fascicle of the lateral ligament complex using an autograft or allograft, performed with a 5-mm-thick and 8-cm-long graft. The graft is first inserted distally into the supinator crest with an Arthrex 4.75-mm SwiveLock implant and, finally, at its origin in the epicondyle, also with a screw of the same characteristics. Arthroscopic techniques create fewer complications. This procedure allows the surgeon to address intra-articular elbow joint pathology with less chance of wound complications and the ability to use bone anchors if desired.

Due to the diversity of characteristics and the high number of World Heritage sites (49) inscribed by Spain, this country and its ICOMOS National Committee have a long experience in the application of the World Heritage Convention throughout these 50 years. The World Heritage Working Group of the Spanish National Committee of ICOMOS has therefore carried out an analysis of these sites, their history and evolution, typology, and state of conservation with the final goal of assessing their current heritage situation and the contribution of the Convention to the conservation of the Spanish natural and cultural heritage. We also aim to reflect on how Spain has contributed to the World Heritage Convention during these five decades and about the most important challenges that our country needs to confront in order to continue complying with the spirit of the Convention and the principles of its Operational Guidelines. To conduct this analysis, we first deal with the background of the ratification of the Convention in Spain, provide an overview of its application, and describe the evolution of the Spanish Tentative List. Second, we deepen on the Spanish nominations and the typologies of the Spanish properties inscribed on the World Heritage List. Thirdly, we focus on the preservation of the Spanish World Heritage sites basing on the State of Conservation Reports (SOCs) that affect them and the results of the first survey on these properties’ conservation, management and presentation carried out by the Heritage Observatory of ICOMOS Spain. This allows us to share some conclusions about the most positive effects of the Convention for the protection of Spanish cultural heritage and the most important challenges for its future development, many of which can be extended at least to the European context.

Background & Aims: : The accumulation of adipose tissue macrophages (ATMs) in obesity has been associated with hepatic injury. However, the contribution of ATMs to hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD) remains to be elucidated. Herein, we investigate the relationship between ATMs and liver fibrosis in patients with patients with NAFLD and evaluate the impact of modulation of ATMs over hepatic fibrosis in an experimental non-alcoholic steatohepatitis (NASH) model. Methods: Adipose tissue and liver biopsies from 42 patients with NAFLD with different fibrosis stages were collected. ATMs were characterised by immunohistochemistry and flow cytometry and the correlation between ATMs and liver fibrosis stages was assessed. Selective modulation of the ATM phenotype was achieved by i.p. administration of dextran coupled with dexamethasone in diet-induced obesity and NASH murine models. Chronic administration effects were evaluated by histology and gene expression analysis in adipose tissue and liver samples. In vitro crosstalk between human ATMs and hepatic stellate cells (HSCs) and liver spheroids was performed. Results: Patients with NAFLD presented an increased accumulation of pro-inflammatory ATMs that correlated with hepatic fibrosis. Long-term modulation of ATMs significantly reduced pro-inflammatory phenotype and ameliorated adipose tissue inflammation. Moreover, ATMs modulation was associated with an improvement in steatosis and hepatic inflammation and significantly reduced fibrosis progression in an experimental NASH model. In vitro, the reduction of the pro-inflammatory phenotype of human ATMs with dextran–dexamethasone treatment reduced the secretion of inflammatory chemokines and directly attenuated the pro-fibrogenic response in HSCs and liver spheroids. Conclusions: Pro-inflammatory ATMs increase in parallel with fibrosis degree in patients with NAFLD and their modulation in an experimental NASH model improves liver fibrosis, uncovering the potential of ATMs as a therapeutic target to mitigate liver fibrosis in NAFLD. Impact and implications: We report that human adipose tissue pro-inflammatory macrophages correlate with hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD). Furthermore, the modulation of adipose tissue macrophages (ATMs) by dextran-nanocarrier conjugated with dexamethasone shifts the pro-inflammatory phenotype of ATMs to an anti-inflammatory phenotype in an experimental murine model of non-alcoholic steatohepatitis. This shift ameliorates adipose tissue inflammation, hepatic inflammation, and fibrosis. Our results highlight the relevance of adipose tissue in NAFLD pathophysiology and unveil ATMs as a potential target for NAFLD.

The elbow is one of the most commonly dislocated joints. While conservative management is frequently performed for simple elbow dislocations, the importance of primary surgical treatment is still undetermined. However, promising results have been reached after surgical repair. We propose an arthroscopic surgical repair of the lateral ligament complex (LCL), performed with a horizontal suture and 2 Fibertak Knotless implants (Arthrex) placed on the LCL origin, one anterior and the other posterior. Operative treatment should be performed in patients with moderate and gross elbow laxity to avoid post-traumatic sequelae and decrease revision rates. Arthroscopic techniques create fewer complications. This procedure allows one to address intra-articular elbow joint pathology with less chance of wound complications and the ability to use bone anchors if desired.

La vacuna contra la COVID-19 ha sido objeto de una manifiesta desconfianza ligada al proceso de desarrollo de la propia vacuna, así como a la incertidumbre generada por el virus y la enfermedad. A pesar de existir numerosos factores que influyen en la reticencia a vacunarse, resulta de interés explorar la influencia de la raza en las actitudes de desconfianza y rechazo hacia la vacuna. En este artículo, se toma como caso de estudio la población negra en Estados Unidos por la preponderancia de la raza en ese país. Tras reconocer e identificar una serie de causas generales ligadas a la desconfianza en la vacuna contra la COVID-19, se profundiza en las causas específicas que aquejan a la población negra, la cual presentaba una mayor reticencia a vacunarse y se mantuvo como sector demográfico en los niveles más bajos en lo referente a las tasas de vacunación durante los primeros pasos de la campaña.

This paper outlines the contribution of the ICOMOS International Scientific Committee on Cultural Tourism (ICTC) to tourism management throughout the history of the UNESCO Convention Concerning the Protection of the World Natural and Cultural Heritage (1972) and traces the evolution of international standard-setting texts on tourism brought forward by ICOMOS. It presents the draft International Charter for Cultural Heritage Tourism - Reinforcing cultural heritage protection and community resilience through responsible and sustainable tourism management (2021). Its new principles are formulated to address challenges of our time, instigate change, improve practice, guide future cultural tourism development and support adaptive and responsive visitor management supporting a more resilient future.

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