Age and Comorbidities as Risk Factors for Severe COVID-19 in Mexico, before, during and after Massive Vaccination.

During 2020-2023, Mexico had a large COVID-19 emergency with >331,000 adult deaths and one of the highest excess mortalities worldwide. Age at COVID-19 death has been lower in Mexico than in high-income countries, presumably because of the young demographics and high prevalence of chronic metabolic diseases in young and middle-aged adults. SARS-CoV-2 vaccination covered 85% of adults with at least one dose and 50% with booster(s) up to April 2022. No new vaccination efforts or updated boosters were introduced until October 2023; thus, we explored the public health impact of massive SARS-CoV-2 vaccination against ancestral strains and asked whether their real-world protection has persisted through time. We compared three periods with respect to vaccine roll-outs: before, during and after vaccine introduction in a national retrospective cohort of >7.5 million COVID-19 cases. The main findings were that after vaccination, COVID-19 mortality decreased, age at COVID-19 death increased by 5-10 years, both in populations with and without comorbidities; obesity stopped being a significant risk factor for COVID-19 death and protection against severe disease persisted for a year after boosters, including at ages 60-79 and 80+. Middle-aged adults had the highest protection from vaccines/hybrid immunity and they more than halved their proportions in COVID-19 deaths.

Donated Blood Screening for HIV, HCV and HBV by ID-NAT and the Residual Risk of Iatrogenic Transmission in a Tertiary Care Hospital Blood Bank in Puebla, Mexico.

Hepatitis C virus (HCV), human immunodeficiency virus (HIV) and hepatitis B virus (HBV) can be transmitted by blood transfusion. Most transmission occurs during the acute viremic phase (AVP), before antibody development. To reduce transmission risk, individual donor nucleic acid testing (ID-NAT) is used. In Puebla, Mexico, serological tests and ID-NAT have been applied to screen blood donors and detect individuals in AVP. In the present study, 106,125 blood donors' data in two periods (2012-2015 and 2017-2019) were analyzed. The residual risk (RR) values were calculated considering ID-NAT results. The RR for HIV was 14 in 1 million donations or 1 in 71,428, the RR for HVC was 6.8 in 1 million donations or 1 in 147,058 and, for HBV, it was 156 in 1 million donations, or 1 in 6410. Previously, it was predicted that the transmission RR of these viruses would be reduced in Mexico through better screening with NAT. The use of ID-NAT has, indeed, increased the safety of blood reserves for HIV and HCV. However, more research is needed to determine why the residual risk of HBV did not decrease as much over the study period. ID-NAT is an important complementary tool for blood donor screening that should be implemented.

The Role of the Estrogen-Related Receptor Alpha (ERRa) in Hypoxia and Its Implications for Cancer Metabolism.

Under low oxygen conditions (hypoxia), cells activate survival mechanisms including metabolic changes and angiogenesis, which are regulated by HIF-1. The estrogen-related receptor alpha (ERRα) is a transcription factor with important roles in the regulation of cellular metabolism that is overexpressed in hypoxia, suggesting that it plays a role in cell survival in this condition. This review enumerates and analyses the recent evidence that points to the role of ERRα as a regulator of hypoxic genes, both in cooperation with HIF-1 and through HIF-1- independent mechanisms, in invertebrate and vertebrate models and in physiological and pathological scenarios. ERRα's functions during hypoxia include two mechanisms: (1) direct ERRα/HIF-1 interaction, which enhances HIF-1's transcriptional activity; and (2) transcriptional activation by ERRα of genes that are classical HIF-1 targets, such as VEGF or glycolytic enzymes. ERRα is thus gaining recognition for its prominent role in the hypoxia response, both in the presence and absence of HIF-1. In some models, ERRα prepares cells for hypoxia, with important clinical/therapeutic implications.

Chronic Comorbidities in Middle Aged Patients Contribute to Ineffective Emergency Hematopoiesis in Covid-19 Fatal Outcomes.

BACKGROUND AND AIMS: Mexico is among the countries with the highest estimated excess mortality rates due to the COVID-19 pandemic, with more than half of reported deaths occurring in adults younger than 65 years old. Although this behavior is presumably influenced by the young demographics and the high prevalence of metabolic diseases, the underlying mechanisms have not been determined. METHODS: The age-stratified case fatality rate (CFR) was estimated in a prospective cohort with 245 hospitalized COVID-19 cases, followed through time, for the period October 2020-September 2021. Cellular and inflammatory parameters were exhaustively investigated in blood samples by laboratory test, multiparametric flow cytometry and multiplex immunoassays. RESULTS: The CFR was 35.51%, with 55.2% of deaths recorded in middle-aged adults. On admission, hematological cell differentiation, physiological stress and inflammation parameters, showed distinctive profiles of potential prognostic value in patients under 65 at 7 days follow-up. Pre-existing metabolic conditions were identified as risk factors of poor outcomes. Chronic kidney disease (CKD), as single comorbidity or in combination with diabetes, had the highest risk for COVID-19 fatality. Of note, fatal outcomes in middle-aged patients were marked from admission by an inflammatory landscape and emergency myeloid hematopoiesis at the expense of functional lymphoid innate cells for antiviral immunosurveillance, including NK and dendritic cell subsets. CONCLUSIONS: Comorbidities increased the development of imbalanced myeloid phenotype, rendering middle-aged individuals unable to effectively control SARS-CoV-2. A predictive signature of high-risk outcomes at day 7 of disease evolution as a tool for their early stratification in vulnerable populations is proposed.

Decrease in COVID-19 adverse outcomes in adults during the Delta and Omicron SARS-CoV-2 waves, after vaccination in Mexico.

Mexico, one of the countries severely affected by COVID-19, accumulated more than 5. 1 all-cause excess deaths/1,000 inhabitants and 2.5 COVID-19 confirmed deaths/1,000 inhabitants, in 2 years. In this scenario of high SARS-CoV-2 circulation, we analyzed the effectiveness of the country's vaccination strategy that used 7 different vaccines from around the world, and focused on vaccinating the oldest population first. We analyzed the national dataset published by Mexican health authorities, as a retrospective cohort, separating cases, hospitalizations, deaths and excess deaths by wave and age group. We explored if the vaccination strategy was effective to limit severe COVID-19 during the active outbreaks caused by Delta and Omicron variants. Vaccination of the eldest third of the population reduced COVID-19 hospitalizations, deaths and excess deaths by 46-55% in the third wave driven by Delta SARS-CoV-2. These adverse outcomes dropped 74-85% by the fourth wave driven by Omicron, when all adults had access to vaccines. Vaccine access for the pregnant resulted in 85-90% decrease in COVID-19 fatalities in pregnant individuals and 80% decrease in infants 0 years old by the Omicron wave. In contrast, in the rest of the pediatric population that did not access vaccination before the period analyzed, COVID-19 hospitalizations increased >40% during the Delta and Omicron waves. Our analysis suggests that the vaccination strategy in Mexico has been successful to limit population mortality and decrease severe COVID-19, but children in Mexico still need access to SARS-CoV-2 vaccines to limit severe COVID-19, in particular those 1-4 years old.

Senescence in Primary Rat Astrocytes Induces Loss of the Mitochondrial Membrane Potential and Alters Mitochondrial Dynamics in Cortical Neurons.

The decline in brain function during aging is one of the most critical health problems nowadays. Although senescent astrocytes have been found in old-age brains and neurodegenerative diseases, their impact on the function of other cerebral cell types is unknown. The aim of this study was to evaluate the effect of senescent astrocytes on the mitochondrial function of a neuron. In order to evaluate neuronal susceptibility to a long and constant senescence-associated secretory phenotype (SASP) exposure, we developed a model by using cellular cocultures in transwell plates. Rat primary cortical astrocytes were seeded in transwell inserts and induced to premature senescence with hydrogen peroxide [stress-induced premature senescence (SIPS)]. Independently, primary rat cortical neurons were seeded at the bottom of transwells. After neuronal 6 days in vitro (DIV), the inserts with SIPS-astrocytes were placed in the chamber and cocultured with neurons for 6 more days. The neuronal viability, the redox state [reduced glutathione/oxidized glutathione (GSH/GSSG)], the mitochondrial morphology, and the proteins and membrane potential were determined. Our results showed that the neuronal mitochondria functionality was altered after being cocultured with senescent astrocytes. In vivo, we found that old animals had diminished mitochondrial oxidative phosphorylation (OXPHOS) proteins, redox state, and senescence markers as compared to young rats, suggesting effects of the senescent astrocytes similar to the ones we observed in vitro. Overall, these results indicate that the microenvironment generated by senescent astrocytes can affect neuronal mitochondria and physiology.

Effectiveness, tolerability and safety of Direct Acting Antivirals in Mexican individuals with Hepatitis C virus genotype-1 and previous pegylated interferon and ribavirin therapy.

BACKGROUND: Direct Acting Antivirals (DAAs) represent a large improvement in the treatment of chronic hepatitis C, resulting in <90% sustained virological response (SVR). There are no reports on the real-world DAA response for Mexico and few reports exist for Latin America. The aim of the study was to report SVR, and immediate benefits with the DAA treatments sofosbuvir, ledispavir, with/without ribavirin (SOF/LDV ± RBV) and ombitasvir, paritaprevir, ritonavir, dasabuvir with/without RBV (OBV/PTV/r/DSV ± RBV) in patients with viral genotype 1a or 1b, and who did not respond to previous peginterferon/ribavirin (PegIFNα2a+RBV) therapy. METHODS: A descriptive, ambispective, longitudinal study was conducted. A cohort of 261 adult patients received PegIFNα2a+RBV therapy before 2014; 167 (64%) did not respond, 83 of these were subsequently treated with SOF/LDV ± RBV or OBV/PTV/r/DSV ± RBV. Child-Pugh-Score (CPS), Fibrosis-4 (FIB-4), and AST to Platelet Ratio Index (APRI) were evaluated before and after treatment. RESULTS: SVR with PegIFNα2a+RBV was 36%, and 97.5% with DAAs. CPS, FIB-4 and APRI improved significantly after DAA treatment, mainly because of liver transaminase reduction. CONCLUSIONS: DAA treatment showed excellent SVR rates in Mexican patients who had not responded to PegIFNα2a+RBV therapy. Improvement in CPS, FIB-4 and APRI without improvement in fibrosis was observed in cirrhotic and non-cirrhotic patients, as well as considerable reduction in liver transaminases, which suggests a reduction in hepatic necroinflammation.

Serum Th17 and TNF-α distinguish between patients with occult hepatitis B infection, chronic hepatitis B infection and healthy individuals.

Chronic hepatitis B (CHB) is classified into five phases based on virus-host interactions: immune tolerance, immune clearance, inactive carrier state, reactive phase and occult hepatitis B infection (OBI). OBI is an uncommon asymptomatic phase of CHB that can be reactivated when the immune system is compromised, occasionally giving rise to severe liver disease. Host immune factors play essential roles in all phases of the CHB infection. Cytokines may alter infection course, influencing the propensity for and the progression of CHB and thus warrant study. Three clinical groups were studied: 48 healthy individuals (HI), 28 patients with persistent positive anti-HBc serological markers and negative HBsAg over time, who were diagnosed as OBI and 12 patients with active CHB. OBI patients were defined by three independent detections of the hepatitis B virus genome through nested PCR and real-time PCR. Quantitative measurement of 20 Th1, Th2 and Th17 human cytokines was performed in the sera of HI, OBI and CHB patients. Levels of IFN-γ, TNF-ß, IL-28A, IL-4, IL-5, IL-13, IL-1ß, IL-6, IL-21, IL-22, IL-23, GM-CSF and MIP-3α were similar between groups. IL-2, IL-12p70, IL-10, IL-17F and TGF-ß1 were similar in HI and OBI, but higher in CHB. TNF-α and the IL-17A:IL-17F ratio were significantly different between the three groups. TNF-α was progressively higher in HI, OBI and CHB (P = 0.004), while the IL-17A:IL-17F ratio was 1.1 in HI, 3.4 in OBI and 0.4 in CHB. Detection and levels of these pro-inflammatory cytokines in OBI patients suggest that they are undergoing a silent hepatic inflammatory process.

SARS-CoV-2: basic concepts, origin and treatment advances.

The first cases of COVID-19, caused by the virus called SARS-CoV-2, were recorded in Wuhan, China, in December 2019; however, its transmission ability caused for the infection to be practically present throughout the world six months later. The origin of the virus appears to be zoonotic; it has been proposed that it comes from a bat and that it may have had an intermediate host that led to its introduction in the human population. SARS-CoV-2 is an enveloped virus, with a positive single-stranded RNA genome, and it binds to the angiotensin-converting enzyme, present in susceptible cells, to infect the human respiratory system. Although other coronaviruses have been previously known, they have not had the same impact, and, therefore, research on pharmacological treatments is not sufficiently developed to face the current challenge. Almost since the beginning of the epidemic, several molecules have been proposed for the treatment of infection; however, there is not yet a drug available with sufficient effectiveness for treatment. This review describes SARS-CoV-2 main characteristics, its replicative cycle, its possible origin and some advances in the development of antiviral treatments.

Los primeros casos de COVID-19, causada por el virus denominado SARS-CoV-2, se registraron en Wuhan, China, en diciembre de 2019; sin embargo, su capacidad de transmisión ocasionó que seis meses después la infección prácticamente estuviera presente en todo el mundo. El origen del virus parece ser zoonótico; se propone que proviene del murciélago y podría haber tenido un hospedero intermediario que llevó a su introducción en la población humana. SARS-CoV-2 es un virus envuelto, con genoma de ARN de cadena sencilla en sentido positivo y se ancla a la enzima convertidora de angiotensina, presente en las células susceptibles para infectar el sistema respiratorio de los humanos. Aunque previamente se han conocido otros coronavirus, no han tenido el mismo impacto, por lo que la investigación en tratamientos farmacológicos no tiene el desarrollo suficiente para afrontar el reto actual. Casi desde el comienzo de la epidemia se han propuesto moléculas para el tratamiento de la infección, sin embargo, aún no se cuenta con un fármaco con suficiente efectividad terapéutica. En esta revisión se describen las características principales de SARS-CoV-2, su ciclo replicativo, su posible origen y algunos avances en el desarrollo de tratamientos antivirales.

SARS-CoV-2: generalidades, origen y avances en el tratamiento / SARS-CoV-2: basic concepts, origin and treatment advances

Resumen Los primeros casos de COVID-19, causada por el virus denominado SARS-CoV-2, se registraron en Wuhan, China, en diciembre de 2019; sin embargo, su capacidad de transmisión ocasionó que seis meses después la infección prácticamente estuviera presente en todo el mundo. El origen del virus parece ser zoonótico; se propone que proviene del murciélago y podría haber tenido un hospedero intermediario que llevó a su introducción en la población humana. SARS-CoV-2 es un virus envuelto, con genoma de ARN de cadena sencilla en sentido positivo y se ancla a la enzima convertidora de angiotensina, presente en las células susceptibles para infectar el sistema respiratorio de los humanos. Aunque previamente se han conocido otros coronavirus, no han tenido el mismo impacto, por lo que la investigación en tratamientos farmacológicos no tiene el desarrollo suficiente para afrontar el reto actual. Casi desde el comienzo de la epidemia se han propuesto moléculas para el tratamiento de la infección, sin embargo, aún no se cuenta con un fármaco con suficiente efectividad terapéutica. En esta revisión se describen las características principales de SARS-CoV-2, su ciclo replicativo, su posible origen y algunos avances en el desarrollo de tratamientos antivirales.

Abstract The first cases of COVID-19, caused by the virus called SARS-CoV-2, were recorded in Wuhan, China, in December 2019; however, its transmission ability caused for the infection to be practically present throughout the world six months later. The origin of the virus appears to be zoonotic; it has been proposed that it comes from a bat and that it may have had an intermediate host that led to its introduction in the human population. SARS-CoV-2 is an enveloped virus, with a positive single-stranded RNA genome, and it binds to the angiotensin-converting enzyme, present in susceptible cells, to infect the human respiratory system. Although other coronaviruses have been previously known, they have not had the same impact, and, therefore, research on pharmacological treatments is not sufficiently developed to face the current challenge. Almost since the beginning of the epidemic, several molecules have been proposed for the treatment of infection; however, there is not yet a drug available with sufficient effectiveness for treatment. This review describes SARS-CoV-2 main characteristics, its replicative cycle, its possible origin and some advances in the development of antiviral treatments.