COVID-19 and long-term impact on symptoms and Health-Related Quality of Life in Costa Rica: the RESPIRA cohort study.

BACKGROUND: Evidence continues to accumulate regarding the potential long-term health consequences of COVID-19 in the population. To distinguish between COVID-19-related symptoms and health limitations from those caused by other conditions, it is essential to compare cases with community controls using prospective data ensuring case-control status. The RESPIRA study addresses this need by investigating the lasting impact of COVID-19 on Health-related Quality of Life (HRQoL) and symptomatology in a population-based cohort in Costa Rica, thereby providing a robust framework for controlling HRQoL and symptoms. METHODS: The study comprised 641 PCR-confirmed, unvaccinated cases of COVID-19 and 947 matched population-based controls. Infection was confirmed using antibody tests on enrollment serum samples and symptoms were monitored monthly for 6 months post-enrolment. Administered at the 6-month visit (occurring between 6- and 2-months post-diagnosis for cases and 6 months after enrollment for controls), HRQoL and Self-Perceived Health Change were assessed using the SF-36, while brain fog, using three items from the Mental Health Inventory (MHI). Regression models were utilized to analyze SF-36, MHI scores, and Self-Perceived Health Change, adjusted for case/control status, severity (mild case, moderate case, hospitalized) and additional independent variables. Sensitivity analyses confirmed the robustness of the findings. RESULTS: Cases showed significantly higher prevalences of joint pain, chest tightness, and skin manifestations, that stabilized at higher frequencies from the fourth month post-diagnosis onwards (2.0%, 1.2%, and 0.8% respectively) compared to controls (0.9%, 0.4%, 0.2% respectively). Cases also exhibited significantly lower HRQoL than controls across all dimensions in the fully adjusted model, with a 12.4 percentage-point difference [95%CI: 9.4-14.6], in self-reported health compared to one year prior. Cases reported 8.0% [95%CI: 4.2, 11.5] more physical limitations, 7.3% [95%CI: 3.5, 10.5] increased lack of vitality, and 6.0% [95%CI: 2.4, 9.0] more brain fog compared to controls with similar characteristics. Undiagnosed cases detected with antibody tests among controls had HRQoL comparable to antibody negative controls. Differences were more pronounced in individuals with moderate or severe disease and among women. CONCLUSIONS: PCR-confirmed unvaccinated cases experienced prolonged HRQoL reductions 6 months to 2 years after diagnosis, this was particularly the case in severe cases and among women. Mildly symptomatic cases showed no significant long-term sequelae.

Role of Glycolytic and Glutamine Metabolism Reprogramming on the Proliferation, Invasion, and Apoptosis Resistance through Modulation of Signaling Pathways in Glioblastoma.

Glioma cells exhibit genetic and metabolic alterations that affect the deregulation of several cellular signal transduction pathways, including those related to glucose metabolism. Moreover, oncogenic signaling pathways induce the expression of metabolic genes, increasing the metabolic enzyme activities and thus the critical biosynthetic pathways to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates that are essential to accomplish the biosynthetic needs of glioma cells. In this review, we aim to explore how dysregulated metabolic enzymes and their metabolites from primary metabolism pathways in glioblastoma (GBM) such as glycolysis and glutaminolysis modulate anabolic and catabolic metabolic pathways as well as pro-oncogenic signaling and contribute to the formation, survival, growth, and malignancy of glioma cells. Also, we discuss promising therapeutic strategies by targeting the key players in metabolic regulation. Therefore, the knowledge of metabolic reprogramming is necessary to fully understand the biology of malignant gliomas to improve patient survival significantly.

Estimating vaccine effectiveness against SARS-CoV-2 infection, hospitalization and death from ecologic data in Costa Rica.

BACKGROUND: Clinical trials and individual-level observational data in Israel demonstrated approximately 95% effectiveness of mRNA-based vaccines against symptomatic SARS-CoV-2 infection. Individual-level data are not available in many countries, particularly low- and middle- income countries. Using a novel Poisson regression model, we analyzed ecologic data in Costa Rica to estimate vaccine effectiveness and assess the usefulness of this approach. METHODS: We used national data from December 1, 2020 to May 13, 2021 to ascertain incidence, hospitalizations and deaths within ecologic units defined by 14 age groups, gender, 105 geographic areas, and day of the epidemic. Within each unit we used the proportions of the population with one and with two vaccinations, primarily tozinameran. Using a non-standard Poisson regression model that included an ecologic-unit-specific rate factor to describe rates without vaccination and a factor that depended on vaccine effectiveness parameters and proportions vaccinated, we estimated vaccine effectiveness. RESULTS: In 3.621 million persons aged 20 or older, there were 125,031 incident cases, 7716 hospitalizations, and 1929 deaths following SARS-CoV-2 diagnosis; 73% of those aged ≥ 75 years received two doses. For one dose, estimated effectiveness was 59% (95% confidence interval 53% to 64%) for SARS-CoV-2 incidence, 76% (68% to 85%) for hospitalizations, and 63% (47% to 80%) for deaths. For two doses, the respective estimates of effectiveness were 93% (90% to 96%), 100% (97% to 100%), and 100% (97% to 100%). CONCLUSIONS: These effectiveness estimates agree well with findings from clinical trials and individual-level observational studies and indicate high effectiveness in the general population of Costa Rica. This novel statistical approach is promising for countries where ecologic, but not individual-level, data are available. The method could also be adapted to monitor vaccine effectiveness over calendar time.

[COVID-19 deaths: Distribution by age and universal medical coverage in 22 countriesMortes por COVID-19: distribuição por idade e universalidade da cobertura médica em 22 países]. / Defunciones por COVID-19: distribución por edad y universalidad de la cobertura médica en 22 países.

OBJECTIVE: Relate standardized age distribution of COVID-19 deaths in 22 countries in the Americas and Europe to different indicators of population characteristics and health systems. METHODS: Distributions of COVID-19 deaths by age group in 22 countries of the Americas and Europe were standardized based on the age pyramid of the world's population. Correlations were calculated between the standardized proportion of people aged <60 years among the deceased and each of six indicators. RESULTS: Standardization based on the world age pyramid revealed considerable differences in age distribution among countries; the proportion of people aged <60 years was higher in Latin America and the United States than in Canada or Western Europe. The standardized proportion of people aged <60 years among persons who died of COVID-19 is strongly correlated to the existence of universal quality medical coverage (r=-0.92, p<0.01). This relationship remained significant after being adjusted for the other indicators. CONCLUSION: We propose that weaknesses in medical coverage of the population may have created higher case-fatality in populations aged <60 years in Latin America and the United States.

OBJETIVO: Correlacionar a distribuição etária padronizada de mortes por COVID-19 em 22 países das Américas e da Europa com diversos indicadores das características das populações e dos sistemas de saúde. MÉTODOS: As distribuições das mortes por COVID-19 por faixa etária em 22 países das Américas e da Europa foram padronizadas pela pirâmide etária da população mundial. Foram calculadas correlações entre a proporção padronizada de pessoas com menos de 60 anos entre as pessoas que morreram e cada um dos seis indicadores. RESULTADOS: Foram evidenciadas diferenças importantes de distribuição etária entre os países estudados após a padronização pela pirâmide etária da população mundial, sendo maior a proporção de mortes de pessoas com menos de 60 anos na América Latina e nos Estados Unidos que no Canadá ou na Europa ocidental. A proporção padronizada de pessoas com menos de 60 anos entre as pessoas que morreram por COVID-19 está fortemente correlacionada com a universalidade de cobertura médica de qualidade (r=­0,92, p<0,01). Esta correlação se manteve significativa após o ajuste para outros indicadores analisados. CONCLUSÃO: O nosso estudo sugere que falhas na cobertura médica da população podem ter provocado maior letalidade nas pessoas com menos de 60 anos na América Latina e nos Estados Unidos.

Socioeconomic inequalities in cancer mortality: Is Costa Rica an exception to the rule?

Socioeconomic inequalities in cancer mortality have been described for a range of cancers sites worldwide, using diverse measures of socioeconomic position (SEP). These studies have shown a negative social gradient where lower SEP was associated with greater odds of having cancer, particularly in men. However, there is a lack of information regarding low and middle-income countries. The objective of our study was to analyze the relationship between the socioeconomic characteristics of patients' residential districts and mortality due to cancer in Costa Rica between 2011 and 2017. An ecological study at the level of the district of residence was conducted using the multilevel mixed-effects Poisson regression. All cancer-caused deaths between January 1, 2011 and December 31, 2017 were included (n = 32,117). Eleven cancer sites were analyzed independently. The 477 Costa Rican districts were divided by area (urban/mixed/rural) and wealth using census data. All-cancer combined a significant association between cancer mortality and wealth was found. Cancer mortality was lower in the poorest as compared to the richest districts (IRRQ4 = 0.79 [0.73-0.86]). The majority of cancer sites followed a similar pattern, showing a positive social gradient. These results contradict the international literature mostly conducted in high-income countries. These findings confirmed the importance of conducting studies in middle-income countries, since the socioeconomic and cultural contexts are different from those in high-income countries, which influence the social distribution of lifestyles and risk behaviors.

[Sociodemographic characteristics associated with the prevalence of tobacco use in Costa RicaCaracterísticas sociodemográficas associadas à prevalência do consumo de tabaco na Costa Rica]. / Características sociodemográficas asociadas a la prevalencia del consumo de tabaco en Costa Rica.

OBJECTIVE: To determine the associations between sociodemographic characteristics and the current prevalence of tobacco use in Costa Rica, based on the results of the Global Adult Tobacco Survey (GATS). METHODS: Cross-sectional observational epidemiological study, country-wide (n = 8607), that used the sociodemographic variables included in GATS 2015. A logistic regression model was designed to predict the impact of those variables on current tobacco use. The dependent variable is current tobacco use, considering the social determinants available in the survey: sex, educational level, area of residence, age, and household composition. RESULTS: The logistic regression model shows that being female (OR = 0.29; P < 0.01), being 65 years old and over (OR = 0.61; P = 0.02), living in a rural area (OR = 0.63; P < 0.01), and living with other people (OR = 0.68; P < 0.01), in particular with children 15 years old or under (OR = 0.55; P < 0.01), are protective factors against tobacco use. Tobacco use declines significantly with increased wealth, as measured by household items, in women but not in men. Completing secondary education is a protective factor in people 15-34 years old (OR = 0.47; P < 0.01) but not in people 35 and over . CONCLUSIONS: There is an association between the sociodemographic variables found in the GATS Costa Rica survey carried out in 2015 and current tobacco use. Interventions at the family and community levels could help consumers give up smoking.

OBJETIVO: Determinar as associações existentes entre as características sociodemográficas e a prevalência do consumo presente de tabaco na Costa Rica, segundo os resultados da Pesquisa Global sobre Tabagismo em Adultos (Global Adult Tobacco Survey - GATS). MÉTODOS: Trata-se de um estudo epidemiológico observacional transversal com representatividade nacional (n = 8.607) com o uso das variáveis sociodemográficas estudadas na GATS realizada em 2015. Usou-se um modelo de regressão logística para predizer a influência das variáveis estudadas no consumo presente de tabaco. A variável dependente foi o consumo presente de tabaco levando em consideração os determinantes sociais disponíveis na pesquisa: gênero, nível de escolaridade, área de residência, idade e composição do domicílio. RESULTADOS: Observou-se, no modelo de regressão logística, que ser do sexo feminino (OR 0,29; P < 0,01), ter 65 anos ou mais (OR 0,61; P = 0,02), residir na zona rural (OR 0,63; P < 0,01) e viver em um domicílio com outras pessoas (OR 0,68; P < 0,01), sobretudo com crianças menores de 15 anos (OR 0,55; P < 0,01), são fatores de proteção contra o consumo de tabaco. O consumo de tabaco diminui de forma significativa com o aumento da renda (medida de acordo com o número de serviços e utilidades domésticas) apenas entre as mulheres. Ter o ensino médio completo é um fator de proteção na faixa etária entre 15 e 34 anos (OR 0,47; P < 0,01), mas não entre as pessoas acima de 35 anos. CONCLUSÕES: Existe uma associação entre as variáveis sociodemográficas estudadas na GATS de 2015 e o consumo presente de tabaco na Costa Rica. Intervenções realizadas ao nível da família e da comunidade poderiam contribuir para a cessação do tabagismo.

Adverse childhood experiences and physiological wear-and-tear in midlife: Findings from the 1958 British birth cohort.

Allostatic load (AL) is a measure of overall physiological wear-and-tear over the life course, which could partially be the consequence of early life exposures. AL could allow a better understanding of the potential biological pathways playing a role in the construction of the social gradient in adult health. To explore the biological embedding hypothesis, we examined whether adverse childhood experiences (ACEs) are associated with elevated AL in midlife. We used imputed data on 3,782 women and 3,753 men of the National Child Development Study in Britain followed up seven times. ACEs were measured using prospective data collected at ages 7, 11, and 16. AL was operationalized using data from the biomedical survey collected at age 44 on 14 parameters representing four biological systems. We examined the role of adult health behaviors, body mass index (BMI), and socioeconomic status as potential mediators using a path analysis. ACEs were associated with higher AL for both men and women after adjustment for early life factors and childhood pathologies. The path analysis showed that the association between ACEs and AL was largely explained by early adult factors at age 23 and 33. For men, the total mediated effect was 59% (for two or more ACEs) via health behaviors, education level, and wealth. For women, the mediated effect represented 76% (for two or more ACEs) via smoking, BMI, education level, and wealth. Our results indicate that early psychosocial stress has an indirect lasting impact on physiological wear-and-tear via health behaviors, BMI, and socioeconomic factors in adulthood.

Autophagic and Apoptotic Pathways as Targets for Chemotherapy in Glioblastoma.

Glioblastoma multiforme is the most malignant and aggressive type of brain tumor, with a mean life expectancy of less than 15 months. This is due in part to the high resistance to apoptosis and moderate resistant to autophagic cell death in glioblastoma cells, and to the poor therapeutic response to conventional therapies. Autophagic cell death represents an alternative mechanism to overcome the resistance of glioblastoma to pro-apoptosis-related therapies. Nevertheless, apoptosis induction plays a major conceptual role in several experimental studies to develop novel therapies against brain tumors. In this review, we outline the different components of the apoptotic and autophagic pathways and explore the mechanisms of resistance to these cell death pathways in glioblastoma cells. Finally, we discuss drugs with clinical and preclinical use that interfere with the mechanisms of survival, proliferation, angiogenesis, migration, invasion, and cell death of malignant cells, favoring the induction of apoptosis and autophagy, or the inhibition of the latter leading to cell death, as well as their therapeutic potential in glioma, and examine new perspectives in this promising research field.

SEROPREVALENCE AND MOLECULAR CHARACTERIZATION OF FERLAVIRUS IN CAPTIVE VIPERS OF COSTA RICA.

Ferlaviruses (FV, previously referred to as ophidian paramyxoviruses, OPMV), are enveloped viruses with a negative-strand RNA genome, affecting snakes in captivity worldwide. Infection is characterized by respiratory and nervous clinical signs and carries high mortality rates, but no specific treatment or vaccine is currently available. Costa Rica has 16 species of vipers, found in captivity in collections essential for antivenom production, reintroduction, and public education. FV circulation in these populations was previously unknown, and the risk of introducing the viruses into naïve collections or free-ranging populations exists if the virus's presence is confirmed. The objective of this study was to determine seroprevalence and FV shedding in 150 samples from captive vipers in nine collections across Costa Rica. A hemagglutination inhibition (HI) assay was performed to determine the antibody titer against two Ferlavirus strains, Bush viper virus (BV) and Neotropical virus (NT), and reverse-transcriptase polymerase chain reaction (RT-PCR) and sequencing to determine virus secretion in cloacal swabs. Ferlavirus strains were replicated in Vero cells, and chicken anti-FV polyclonal antibodies were produced and used as a positive control serum for the HI. Results demonstrate that seroprevalence of anti-FV antibodies in viper serum was 26.6% (n = 40) for the BV strain and 30% (n = 45) for the NT strain in the population tested. Furthermore, molecular characterization of FV group A was possible by sequencing the virus recovered from three cloacal swabs, demonstrating circulation of FV in one collection. This study demonstrates for the first time serological evidence of FV exposure and infection in vipers in captivity in Costa Rica, and suggests cross reactivity between antibodies against both strains. Appropriate biosafety measures could prevent the spread of FV between and within collections of reptiles in the country.

Disentangling the respective roles of the early environment and parental BMI on BMI change across childhood: A counterfactual analysis using the Millennium Cohort Study.

This study has two objectives. First, to analyse the respective roles of parental BMI and the wider environment on children's BMI across childhood, using a counterfactual analysis. Second, to determine if the correlations between parents and offspring BMI are partly environmental. We used data on 4437 girls and 4337 boys born in 2000-2001 in the UK and included in the Millennium Cohort Study. Children's BMI was measured at ages 3years, 5years, 7years, and 11years. We described the environment using social class and behaviours within the family. At the age of 3, there was no link between the environment and children's BMI. In contrast, there was a clear link between the environment and BMI slopes between 3 and 11years of age. At the age of 11, we calculated that if all children had the most favourable environment, mean BMI would be reduced by 0.91kg/m(2) (95% CI: 0.57-1.26) for boys and by 1.65kg/m(2) (95% CI: 1.28-2.02) for girls. Associations between parents' and offspring BMI remained unchanged after adjustment for environmental variables. Conversely, the link between the environment and children's BMI is partly reduced after adjustment for parental BMI. This confirms that parental BMI is partly a broad proxy of the environment. We highlighted that if every child's environment was at its most favourable, the mean BMI would be significantly reduced. Thus, the recent rise is likely to be reversible.

Health inequalities in the geographic distribution of dental practitioners in Costa Rica: An ecological study.

OBJECTIVE: The uneven distribution of dental health services in a territory can cause an imbalance in accessibility, increasing health inequalities. This study aimed to describe the geographical distribution of dental health practitioners according to urbanicity and area-level socio-economic status in Costa Rica. METHODS: A National Dentist Survey was developed to identify employment status, number of working hours, address and list of the working clinics. Data was completed using information from the national College of Surgeons, including all Costa Rican dentists. The Minimal Geographic Units (MGU) allowed for aggregating the population's individual level socio-economic position. Local Potential Accessibility (LPA) calculated the density of full-time hour's equivalents around each MGU using floating sectors. Clinics were geocoded using Geographic Information Systems, creating 2853 clinical points. Distance between each MGU and the nearest accessible clinics considering full-time working hours equivalents was estimated. MGU were divided into six categories: 'No accessibility', 'Very low accessibility', 'Low accessibility', 'Good accessibility' 'High accessibility' and 'Very high accessibility'. RESULTS: Mean national LPA was 6.5 full-time equivalents per 10 000 inhabitants, 3.4% of the Costa Rican population had no access to dentist; 12.9% had very low accessibility, 22.7% had low accessibility, 35.0% had good accessibility, 16.2% had high accessibility, and 9.8% had very high accessibility. Overall, 39% of the population has a rather low accessibility. LPA was higher in urban districts compared to rural districts and in wealthiest districts compared to most disadvantaged districts. Within districts, after adjustment for district's characteristics, LPA was higher in urban MGU compared to rural MGU and in wealthiest MGU compared to most disadvantaged MGU. CONCLUSIONS: This study found that despite having a high number of dentists, their numbers are small in many areas, increasing inequalities in access to health care. The dentist's free establishment, where they can decide to provide private services within a community, creates zones with very high densities, in particular in the wealthiest urban areas, and others with very low densities, in particular the poorest rural areas. The lack of territorial planning has been one of the reasons that has encouraged an imbalance in the availability of dental human resources. To achieve effective universal health coverage, public institutions should focus their efforts on improving access to dental services in underserved areas.

Health inequalities in a middle-income country: a systematic review of the Costa Rican case.

Objective: This study systematically reviews evidence of socioeconomic health disparities in Costa Rica, a middle-income country, to elucidate the relationship between socioeconomic status and health outcomes. Methods: Published studies were identified through a systematic review of PubMed (English) and Scielo (Spanish) databases from December 2023 to January 2024, following PRISMA guidelines. Search terms included socioeconomic status, social determinants, social gradient in health, and health inequalities. Results: Of 236 identified references, 55 met the inclusion criteria. Findings were categorized into health inequalities in mortality (among the general population, infants, and older adults), life expectancy, cause-specific mortality, and health determinants or risk factors mediating the association between the social environment and health. The studies indicate higher mortality among the most disadvantaged groups, including deaths from respiratory diseases, violence, and infections. Higher socioeconomic status was associated with lower mortality rates in the 1990s, indicating a positive social gradient in health (RII = 1.3, CI [1.1-1.5]). Disparities were less pronounced among older adults. Urban areas exhibited concentrated wealth and increased risky behaviors, while rural areas, despite greater socioeconomic deprivation, showed a lower prevalence of risky behaviors. Regarding smoking, people living in rural areas smoked significantly less than those in urban areas (7% vs. 10%). Despite the relatively equitable distribution of public primary healthcare, disparities persisted in the timely diagnosis and treatment of chronic diseases. Cancer survival rates post-diagnosis were positively correlated with the wealth of districts (1.23 [1.12-1.35] for all cancers combined). Conclusion: The study highlights the existence of social health inequalities in Costa Rica. However, despite being one of the most unequal OECD countries, Costa Rica shows relatively modest social gradients in health compared to other middle and high-income nations. This phenomenon can be attributed to distinctive social patterns in health behaviors and the equalizing influence of the universal healthcare system.

Social gradient and rural-urban disparities in cancer mortality in Costa Rica.

INTRODUCTION: Data on social inequalities in cancer mortality are sparse, especially in low- and middle-income countries. We aimed to analyze the socioeconomic inequalities in cancer mortality in Costa Rica between 2010 and 2018. METHODS: We linked 9-years of data from the National Electoral Rolls, National Birth Index and National Death Index to classify deaths due to cancer and socioeconomic characteristics of the district of residence, as measured by levels of urbanicity and wealth. We analyzed the fifteen most frequent cancer sites in Costa Rica among the 2.7 million inhabitants aged 20 years and older. We used a parametric survival model based on a Gompertz distribution. RESULTS: Compared to urban areas, mixed and rural area residents had lower mortality from pancreas, lung, breast, prostate, kidney, and bladder cancers, and higher mortality from stomach cancer. Mortality from stomach, lung and cervical cancer was higher, and mortality from colorectal cancer, non-Hodgkin lymphoma and leukemia was lower in the most disadvantaged districts, compared to the wealthiest ones. CONCLUSION: We observed marked disparities in cancer mortality in Costa Rica in particular from infection- and lifestyle- related cancers. There are important opportunities to reduce disparities in cancer mortality by targeting cancer prevention, early detection and opportune treatment, mainly in urban and disadvantaged districts.

Metabolic dysregulation of tricarboxylic acid cycle and oxidative phosphorylation in glioblastoma.

Glioblastoma multiforme (GBM) exhibits genetic alterations that induce the deregulation of oncogenic pathways, thus promoting metabolic adaptation. The modulation of metabolic enzyme activities is necessary to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates essential for fulfilling the biosynthetic needs of glioma cells. Moreover, the TCA cycle produces intermediates that play important roles in the metabolism of glucose, fatty acids, or non-essential amino acids, and act as signaling molecules associated with the activation of oncogenic pathways, transcriptional changes, and epigenetic modifications. In this review, we aim to explore how dysregulated metabolic enzymes from the TCA cycle and oxidative phosphorylation, along with their metabolites, modulate both catabolic and anabolic metabolic pathways, as well as pro-oncogenic signaling pathways, transcriptional changes, and epigenetic modifications in GBM cells, contributing to the formation, survival, growth, and invasion of glioma cells. Additionally, we discuss promising therapeutic strategies targeting key players in metabolic regulation. Therefore, understanding metabolic reprogramming is necessary to fully comprehend the biology of malignant gliomas and significantly improve patient survival.

Metabolic Roles of HIF1, c-Myc, and p53 in Glioma Cells.

The metabolic reprogramming that promotes tumorigenesis in glioblastoma is induced by dynamic alterations in the hypoxic tumor microenvironment, as well as in transcriptional and signaling networks, which result in changes in global genetic expression. The signaling pathways PI3K/AKT/mTOR and RAS/RAF/MEK/ERK stimulate cell metabolism, either directly or indirectly, by modulating the transcriptional factors p53, HIF1, and c-Myc. The overexpression of HIF1 and c-Myc, master regulators of cellular metabolism, is a key contributor to the synthesis of bioenergetic molecules that mediate glioma cell transformation, proliferation, survival, migration, and invasion by modifying the transcription levels of key gene groups involved in metabolism. Meanwhile, the tumor-suppressing protein p53, which negatively regulates HIF1 and c-Myc, is often lost in glioblastoma. Alterations in this triad of transcriptional factors induce a metabolic shift in glioma cells that allows them to adapt and survive changes such as mutations, hypoxia, acidosis, the presence of reactive oxygen species, and nutrient deprivation, by modulating the activity and expression of signaling molecules, enzymes, metabolites, transporters, and regulators involved in glycolysis and glutamine metabolism, the pentose phosphate cycle, the tricarboxylic acid cycle, and oxidative phosphorylation, as well as the synthesis and degradation of fatty acids and nucleic acids. This review summarizes our current knowledge on the role of HIF1, c-Myc, and p53 in the genic regulatory network for metabolism in glioma cells, as well as potential therapeutic inhibitors of these factors.

Health inequalities in cause-specific mortality in Costa Rica: a population-based cohort study.

OBJECTIVE: To analyze health inequalities in cause-specific mortality in Costa Rica from 2010 to 2018, observing the main causes for inequality in the country. METHODS: The National Electoral Rolls were used to follow-up all Costa Rican adults aged 20 years or older from 2010 to 2018 (n = 2,739,733) in an ecological study. A parametric survival model based on the Gompertz distribution was performed and the event death was classified according to the ICD-10. RESULTS: After adjustment for urbanicity, the poorest districts had a higher mortality than the wealthier districts for most causes of death except neoplasms, mental and behavioral disorders, and diseases of the nervous system. Urban districts showed significantly higher mortality than mixed and rural districts after adjustment for wealth for most causes except mental and behavioral disorders, diseases of the nervous system, and diseases of the respiratory system. Differences according to wealth were more frequent in women than men, whereas differences according to urbanicity were more frequent in men than in women. CONCLUSIONS: The study's findings were consistent, but not fully similar, to the international literature.

Excess mortality from COVID 19 in Costa Rica: a registry based study using Poisson regression.

Background: Official death toll related to COVID-19 has been considerably underestimated in reports from some Latin American countries. This study aimed to analyze the mortality associated with the COVID-19 pandemic in Costa Rica between March 2020 and December 2021. Methods: A registry based study based on 2017-2021 data from the National Institute of Statistics and Census was designed (N = 128,106). Excess deaths were defined by the WHO as "the difference in the total number of deaths in a crisis compared to those expected under normal conditions"; and were estimated using a Poisson regression, and mortality and years of potential life lost (YPLL) rates were calculated. Findings: The COVID-19 pandemic represented 15% of the deaths in Costa Rica between March 2020 and December 2021. The mortality rate related to COVID-19 was 83 per 100,000 person-years. Between March and July 2020 (low-incidence period), observed number of deaths was 9%-lower than expected, whereas it was 15% and 24% higher than expected between July 2020 and March 2021 (high incidence period - no vaccination), and between March 2021 and December 2021 (high incidence period - progressive vaccination) respectively. Between July 2020 and December 2021, excess deaths observed and COVID-19 deaths reported were comparable (7461 and 7620 respectively). Nevertheless, there were more deaths than expected for conditions that predispose to COVID-19 deaths. YPLL and mortality rates increased with age, but significant excess deaths were observed in all age-groups older than 30-39 years. No large differences were noted by districts' socioeconomic characteristics although excess death rate was lower in rural compared to urban areas. Interpretation: Reporting of deaths was only slightly underestimated. In the pre-vaccination period, mortality rate and YPLL rates increased with age, being highest in people aged 60 years or older and justifying the decision to initially prioritize vaccination of older individuals. Funding: The study was supported by the University of Costa Rica and the Agencia Costarricense de Investigaciones Biomédicas - Fundación Inciensa.

Cohort profile: evaluation of immune response and household transmission of SARS-CoV-2 in Costa Rica: the RESPIRA study.

PURPOSE: The RESPIRA cohort aims to describe the nature, magnitude, time course and efficacy of the immune response to SARS-CoV-2 infection and vaccination, population prevalence, and household transmission of COVID-19. PARTICIPANTS: From November 2020, we selected age-stratified random samples of COVID-19 cases from Costa Rica confirmed by PCR. For each case, two population-based controls, matched on age, sex and census tract were recruited, supplemented with hospitalised cases and household contacts. Participants were interviewed and blood and saliva collected for antibodies and PCR tests. Participants will be followed for 2 years to assess antibody response and infection incidence. FINDINGS TO DATE: Recruitment included 3860 individuals: 1150 COVID-19 cases, 1999 population controls and 719 household contacts from 304 index cases. The age and regional distribution of cases was as planned, including four age strata, 30% rural and 70% urban. The control cohort had similar sex, age and regional distribution as the cases according to the study design. Among the 1999 controls recruited, 6.8% reported at enrolment having had COVID-19 and an additional 12.5% had antibodies against SARS-CoV-2. Compliance with visits and specimens has been close to 70% during the first 18 months of follow-up. During the study, national vaccination was implemented and nearly 90% of our cohort participants were vaccinated during follow-up. FUTURE PLANS: RESPIRA will enable multiple analyses, including population prevalence of infection, clinical, behavioural, immunological and genetic risk factors for SARS-CoV-2 acquisition and severity, and determinants of household transmission. We are conducting retrospective and prospective assessment of antibody levels, their determinants and their protective efficacy after infection and vaccination, the impact of long-COVID and a series of ancillary studies. Follow-up continues with bimonthly saliva collection for PCR testing and biannual blood collection for immune response analyses. Follow-up will be completed in early 2024. TRIAL REGISTRATION NUMBER: NCT04537338.

Transsulfuration pathway: a targeting neuromodulator in Parkinson's disease.

The transsulfuration pathway (TSP) is a metabolic pathway involving sulfur transfer from homocysteine to cysteine. Transsulfuration pathway leads to many sulfur metabolites, principally glutathione, H2S, taurine, and cysteine. Key enzymes of the TSP, such as cystathionine ß-synthase and cystathionine γ-lyase, are essential regulators at multiple levels in this pathway. TSP metabolites are implicated in many physiological processes in the central nervous system and other tissues. TSP is important in controlling sulfur balance and optimal cellular functions such as glutathione synthesis. Alterations in the TSP and related pathways (transmethylation and remethylation) are altered in several neurodegenerative diseases, including Parkinson's disease, suggesting their participation in the pathophysiology and progression of these diseases. In Parkinson's disease many cellular processes are comprised mainly those that regulate redox homeostasis, inflammation, reticulum endoplasmic stress, mitochondrial function, oxidative stress, and sulfur content metabolites of TSP are involved in these damage processes. Current research on the transsulfuration pathway in Parkinson's disease has primarily focused on the synthesis and function of certain metabolites, particularly glutathione. However, our understanding of the regulation of other metabolites of the transsulfuration pathway, as well as their relationships with other metabolites, and their synthesis regulation in Parkinson´s disease remain limited. Thus, this paper highlights the importance of studying the molecular dynamics in different metabolites and enzymes that affect the transsulfuration in Parkinson's disease.

Copper compound induces autophagy and apoptosis of glioma cells by reactive oxygen species and JNK activation.

BACKGROUND: Glioblastoma multiforme (GBM) is the most aggressive of the primary brain tumors, with a grim prognosis despite intensive treatment. In the past decades, progress in research has not significantly increased overall survival rate. METHODS: The in vitro antineoplastic effect and mechanism of action of Casiopeina III-ia (Cas III-ia), a copper compound, on rat malignant glioma C6 cells was investigated. RESULTS: Cas III-ia significantly inhibited cell proliferation, inducing autophagy and apoptosis, which correlated with the formation of autophagic vacuoles, overexpression of LC3, Beclin 1, Atg 7, Bax and Bid proteins. A decrease was detected in the mitochondrial membrane potential and in the activity of caspase 3 and 8, together with the generation of intracellular reactive oxygen species (ROS) and increased activity of c-jun NH(2)-terminal kinase (JNK). The presence of 3-methyladenine (as selective autophagy inhibitor) increased the antineoplastic effect of Cas III-ia, while Z-VAD-FMK only showed partial protection from the antineoplastic effect induced by Cas III-ia, and ROS antioxidants (N-acetylcysteine) decreased apoptosis, autophagy and JNK activity. Moreover, the JNK -specific inhibitor SP600125 prevented Cas III-ia-induced cell death. CONCLUSIONS: Our data suggest that Cas III-ia induces cell death by autophagy and apoptosis, in part due to the activation of ROS -dependent JNK signaling. These findings support further studies of Cas III-ia as candidate for treatment of human malignant glioma.