Statistical explanation of the protective effect of four COVID-19 vaccine doses in the general population.

Objectives: To assess the effectiveness of four doses of the vaccine against SARS-CoV-2 in the general population and the impact of this on the severity of the disease by age group. Methods: By using data from the health authority public data base, we build statistical models using R and the GAMLSS library to explain the behavior of new SARS-CoV-2 infections, active COVID-19 cases, ICU bed requirement total and by age group, and deaths at the national level. Results: The four doses of vaccine and at least the interaction between the first and second doses were important explanatory factors for the protective effect against COVID-19. The R2 for new cases per day was 0.5644 and for occupied ICU beds the R2 is 0.9487. For occupied ICU beds for >70 years R2 is 0.9195 and with the interaction between 4 doses as the main factor. Conclusions: Although the increase in the number of vaccine doses did not adequately explain the decrease in the number of COVID-19 cases, it explained the decrease in ICU admissions and deaths nationwide and by age group.

Differential Severe Acute Respiratory Syndrome Coronavirus 2-Specific Humoral Response in Inactivated Virus-Vaccinated, Convalescent, and Breakthrough-Infected Subjects.

BACKGROUND: We sought to identify potential antigens for discerning between humoral responses elicited after vaccination with CoronaVac (a severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] inactivated vaccine), natural infection, or breakthrough infection. METHODS: Serum samples obtained from volunteers immunized with CoronaVac (2 and 3 doses), breakthrough case patients, and from convalescent individuals were analyzed to determine the immunoglobulin (Ig) G responses against 3 structural and 8 nonstructural SARS-CoV-2 antigens. RESULTS: Immunization with CoronaVac induced higher levels of antibodies against the viral membrane (M) protein compared with convalescent subjects both after primary vaccination and after a booster dose. Individuals receiving a booster dose displayed equivalent levels of IgG antibodies against the nucleocapsid (N) protein, similar to convalescent subjects. Breakthrough case patients produced the highest antibody levels against the N and M proteins. Antibodies against nonstructural viral proteins were present in >50% of the convalescent subjects. CONCLUSIONS: Vaccinated individuals elicited a different humoral response compared to convalescent subjects. The analysis of particular SARS-CoV-2 antigens could be used as biomarkers for determining infection in subjects previously vaccinated with CoronaVac.

Gut microbiota short-chain fatty acids and their impact on the host thyroid function and diseases.

Thyroid disorders are clinically characterized by alterations of L-3,5,3',5'-tetraiodothyronine (T4), L-3,5,3'-triiodothyronine (T3), and/or thyroid-stimulating hormone (TSH) levels in the blood. The most frequent thyroid disorders are hypothyroidism, hyperthyroidism, and hypothyroxinemia. These conditions affect cell differentiation, function, and metabolism. It has been reported that 40% of the world's population suffers from some type of thyroid disorder and that several factors increase susceptibility to these diseases. Among them are iodine intake, environmental contamination, smoking, certain drugs, and genetic factors. Recently, the intestinal microbiota, composed of more than trillions of microbes, has emerged as a critical player in human health, and dysbiosis has been linked to thyroid diseases. The intestinal microbiota can affect host physiology by producing metabolites derived from dietary fiber, such as short-chain fatty acids (SCFAs). SCFAs have local actions in the intestine and can affect the central nervous system and immune system. Modulation of SCFAs-producing bacteria has also been connected to metabolic diseases, such as obesity and diabetes. In this review, we discuss how alterations in the production of SCFAs due to dysbiosis in patients could be related to thyroid disorders. The studies reviewed here may be of significant interest to endocrinology researchers and medical practitioners.

Humoral and cellular response induced by a second booster of an inactivated SARS-CoV-2 vaccine in adults.

BACKGROUND: The Omicron variant has challenged the control of the COVID-19 pandemic due to its immuno-evasive properties. The administration of a booster dose of a SARS-CoV-2 vaccine showed positive effects in the immunogenicity against SARS-CoV-2, effect that is even enhanced after the administration of a second booster. METHODS: During a phase-3 clinical trial, we evaluated the effect of a second booster of CoronaVac®, an inactivated vaccine administered 6 months after the first booster, in the neutralization of SARS-CoV-2 (n = 87). In parallel, cellular immunity (n = 45) was analyzed in stimulated peripheral mononuclear cells by flow cytometry and ELISPOT. FINDINGS: Although a 2.5-fold increase in neutralization of the ancestral SARS-CoV-2 was observed after the second booster when compared with prior its administration (Geometric mean units p < 0.0001; Geometric mean titer p = 0.0002), a poor neutralization against the Omicron variant was detected. Additionally, the activation of specific CD4+ T lymphocytes remained stable after the second booster and, importantly, equivalent activation of CD4+ T lymphocytes against the Omicron variant and the ancestral SARS-CoV-2 were found. INTERPRETATION: Although the neutralizing response against the Omicron variant after the second booster of CoronaVac® was slightly increased, these levels are far from those observed against the ancestral SARS-CoV-2 and could most likely fail to neutralize the virus. In contrast, a robust CD4+T cell response may confer protection against the Omicron variant. FUNDING: The Ministry of Health, Government of Chile, the Confederation of Production and Commerce, Chile and SINOVAC Biotech.NIHNIAID. The Millennium Institute on Immunology and Immunotherapy.

Inactivated Vaccine-Induced SARS-CoV-2 Variant-Specific Immunity in Children.

Multiple vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been evaluated in clinical trials. However, trials addressing the immune response in the pediatric population are scarce. The inactivated vaccine CoronaVac has been shown to be safe and immunogenic in a phase 1/2 clinical trial in a pediatric cohort in China. Here, we report interim safety and immunogenicity results of a phase 3 clinical trial for CoronaVac in healthy children and adolescents in Chile. Participants 3 to 17 years old received two doses of CoronaVac in a 4-week interval until 31 December 2021. Local and systemic adverse reactions were registered for volunteers who received one or two doses of CoronaVac. Whole-blood samples were collected from a subgroup of 148 participants for humoral and cellular immunity analyses. The main adverse reaction reported after the first and second doses was pain at the injection site. Four weeks after the second dose, an increase in neutralizing antibody titer was observed in subjects relative to their baseline visit. Similar results were found for activation of specific CD4+ T cells. Neutralizing antibodies were identified against the Delta and Omicron variants. However, these titers were lower than those for the D614G strain. Importantly, comparable CD4+ T cell responses were detected against these variants of concern. Therefore, CoronaVac is safe and immunogenic in subjects 3 to 17 years old, inducing neutralizing antibody secretion and activating CD4+ T cells against SARS-CoV-2 and its variants. (This study has been registered at ClinicalTrials.gov under no. NCT04992260.) IMPORTANCE This work evaluated the immune response induced by two doses of CoronaVac separated by 4 weeks in healthy children and adolescents in Chile. To date, few studies have described the effects of CoronaVac in the pediatric population. Therefore, it is essential to generate knowledge regarding the protection of vaccines in this population. Along these lines, we reported the anti-S humoral response and cellular immune response to several SARS-CoV-2 proteins that have been published and recently studied. Here, we show that a vaccination schedule consisting of two doses separated by 4 weeks induces the secretion of neutralizing antibodies against SARS-CoV-2. Furthermore, CoronaVac induces the activation of CD4+ T cells upon stimulation with peptides from the proteome of SARS-CoV-2. These results indicate that, even though the neutralizing antibody response induced by vaccination decreases against the Delta and Omicron variants, the cellular response against these variants is comparable to the response against the ancestral strain D614G, even being significantly higher against Omicron.

Contribution of Two-Dose Vaccination Toward the Reduction of COVID-19 Cases, ICU Hospitalizations and Deaths in Chile Assessed Through Explanatory Generalized Additive Models for Location, Scale, and Shape.

Objectives: To assess the impact of the initial two-dose-schedule mass vaccination campaign in Chile toward reducing adverse epidemiological outcomes due to SARS-CoV-2 infection. Methods: Publicly available epidemiological data ranging from 3 February 2021 to 30 September 2021 were used to construct GAMLSS models that explain the beneficial effect of up to two doses of vaccination on the following COVID-19-related outcomes: new cases per day, daily active cases, daily occupied ICU beds and daily deaths. Results: Administered first and second vaccine doses, and the statistical interaction between the two, are strong, statistically significant predictors for COVID-19-related new cases per day (R2 = 0.847), daily active cases (R2 = 0.903), ICU hospitalizations (R2 = 0.767), and deaths (R2 = 0.827). Conclusion: Our models stress the importance of completing vaccination schedules to reduce the adverse outcomes during the pandemic. Future work will continue to assess the influence of vaccines, including booster doses, as the pandemic progresses, and new variants emerge. Policy Implications: This work highlights the importance of attaining full (two-dose) vaccination status and reinforces the notion that a second dose provides increased non-additive protection. The trends we observed may also support the inclusion of booster doses in vaccination plans. These insights could contribute to guiding other countries in their vaccination campaigns.

Contribution of Gut Microbiota to Immune Tolerance in Infants.

The prevalence of food allergy has increased in recent years, especially among the pediatric population. Differences in the gut microbiota composition between children with FA and healthy children have brought this topic into the spotlight as a possible explanation for the increase in FA. The gut microbiota characteristics are acquired through environmental interactions starting early in life, such as type of delivery during birth and breastfeeding. The microbiota features may be shaped by a plethora of immunomodulatory mechanisms, including a predominant role of Tregs and the transcription factor FOXP3. Additionally, a pivotal role has been given to vitamin A and butyrate, the main anti-inflammatory metabolite. These observations have led to the study and development of therapies oriented to modifying the microbiota and metabolite profiles, such as the use of pre- and probiotics and the determination of their capacity to induce tolerance to allergens that are relevant to FA. To date, evidence supporting these approaches in humans is scarce and inconclusive. Larger cohorts and dose-titration studies are mandatory to evaluate whether the observed changes in gut microbiota composition reflect medical recovery and increased tolerance in pediatric patients with FA. In this article, we discuss the establishment of the microbiota, the immunological mechanisms that regulate the microbiota of children with food allergies, and the evidence in research focused on its regulation as a means to achieve tolerance to food allergens.

Adherence to a gluten-free diet and quality of life in Chilean celiac patients.

INTRODUCTION: a gluten-free diet (GFD) is the treatment for celiac disease (CD), with adherence oscillating between 42 % and 91 %. The purpose of this study was to assess adherence to GFD and its relation to quality of life in Chilean celiac patients. METHODS: three surveys were performed on-line: sociodemographic-health status, adherence to GFD and quality of life. RESULTS: forty-eight per cent of respondents reported an excellent adherence to GFD and 49 % a good quality of life. CONCLUSIONS: adherence to GFD is low among Chilean celiac patients.

Sobrepeso y obesidad en la enfermedad celiaca activa: posibles mecanismos fisiopatológicos / Overweight and obesity in active celiac disease: possible pathophysiological mechanisms

RESUMEN La enfermedad celiaca (EC) es una enteropatía crónica del intestino delgado, mediado por una respuesta inmune, gatillada por la exposición al gluten en individuos genéticamente susceptibles. La presentación clínica de la EC es variada y conduce a mala absorción. El estado nutricional en el momento del diagnóstico de la EC depende del tiempo en que la enfermedad ha estado activa, la extensión de la inflamación intestinal, grado de mala absorción e ingesta alimentaria. Sin embargo, en los últimos años se ha observado un cambio epidemiológico del estado nutricional en los pacientes celiacos al momento del diagnóstico. La presente revisión tuvo por objetivo realizar un análisis descriptivo de la presencia de obesidad en pacientes celiacos y de los posibles mecanismos fisiopatológicos que la explicarían.

ABSTRACT Celiac disease (CD) is a chronic enteropathy of the small intestinal, mediated by an immune response triggered by exposure to dietary gluten in genetically predisposed individuals. The clinical presentation of CD is varied and leads to malabsorption. Nutritional status at the time of diagnosis of CD depends on the time in which the disease has been active, the extent of intestinal inflammation, degree of malabsorption, and dietary intake. However, in recent years an epidemiological change of nutritional status has been observed in celiac patients at the time of diagnosis. The objective of this review was to perform a descriptive analysis of the presence of obesity in celiac patients and the possible physiopathological mechanisms that would explain it.

Excess weight and gastrointestinal symptoms in Chilean celiac patients at the time of diagnosis.

INTRODUCTION: celiac disease is an immune condition that results in histologic changes in the small bowel and produces both digestive and extra-digestive symptoms. Intestinal damage results in malabsorption and impaired weight or impaired optimal weight gain. However, these patients may be overweight or obese in spite of histologic damage. The aim of this study was to determine the prevalence of excess weight in newly diagnosed (adult) celiac patients. METHODS: this was a retrospective observational study of patients recently diagnosed with celiac disease according to the standard Marsh classification. Nutritional status was assessed based on body mass index (BMI), as categorized by the World Health Organization (WHO). Clinical presentation was classified as typical or atypical. Potential differences in gastrointestinal symptoms according to nutritional status were also assessed. RESULTS: a total of 135 medical records of adult celiac patients (women = 123; men = 12) were reviewed. The average weight and BMI were 61.1 kg and 23.7 kg/m2, respectively. The proportion of typical clinical presentations was 59.2% and of atypical presentations 40.8%. A total of 71.8% of patients had a BMI indicating low or normal weight and 28.1% had a BMI indicative of being overweight or obese. No differences with regard to the presence of gastrointestinal symptoms were found according to nutritional status. CONCLUSIONS: further studies are needed to jointly assess energy intake and intestinal absorption in these patients, in order to explain the high rate of excess weight.

Caracterización de la enfermedad celiaca en niños atendidos en hospitales públicos chilenos / Characterization of celiac disease in chilean public hospitals

Resumen: Introducción: La prevalencia global de enfermedad celíaca (EC) es ~1% de la población. En Chile, la Encuesta Nacional de Salud 2009-2010 mostró una prevalencia serológica en mayores de 15 años de 0,76% (IgA-TTG2), que en Concepción correspondió a 0,6%. Objetivo: Determinar las caracte rísticas clínicas, de búsqueda, diagnóstico, tratamiento y seguimiento de la EC en los dos hospitales públicos de Concepción con servicio de Gastroenterología. Pacientes y Método: Estudio descriptivo, se recogieron datos de las fichas electrónicas (código CIE10) y clínicas de menores de 18 años estu diados por EC entre 2010 - 2016 provenientes de dos hospitales públicos de la ciudad de Concepción, Chile. Se identificaron los casos cuyo protocolo diagnóstico cumplía con los criterios ESPGHAN 2012 (confirmación con biopsia intestinal), 207 de 216 pacientes identificados cumplían los criterios de inclusión. El estado nutricional se clasificó según grupo etario (menores de 5 años OMS 2006; en los niños entre 5 y 18 años OMS 2007). Se calculó el Z-score (Z), a través del software WHO Anthro (en menores de 5 años) y WHO Anthro Plus (entre 5-18 años). Los anticuerpos antiendomisio se evaluaron mediante inmuno fluorescencia en cortes de esófago de mono; los anticuerpos antitrans- glutaminasa IgA e IgG a través ELISA; e IgA en sangre mediante ELISA. Resultados: Se confirmó EC por biopsias duodenales en 33,8%. IgA-TTG estuvo registrada en 70% e IgG-TTG en 52,9%, aunque solo dos pacientes tenían deficiencia de IgA. Los motivos de consulta preponderantes fueron gas trointestinales (80%) y/o derivación por un endocrinólogo (45,7%). La principal presentación clínica fue gastrointestinal, con diarrea (71,4%). El 17,1% presentaba Síndrome de Down (SD), 11,4% talla baja y 5,7% diabetes mellitus 1. Al diagnóstico, la relación obesidad: desnutrición (Z-score IMC) fue 2:1 y 6,8% de los pacientes eran obesos. Al año post-diagnóstico, en 26 pacientes celíacos sin SD la frecuencia de estado nutricional eutrófico disminuyó de 65,4% a 42,3%, aumentando el sobrepeso de 23,1 a 34,6% y la obesidad de 0 a 7,7%. Conclusiones: En Concepción, la especialidad de endo crinología efectúa una significativa y exitosa búsqueda activa, siendo responsable de 47,3% de los diagnósticos. La alta proporción de pacientes con sobrepeso/obesidad concuerda con el fenómeno descrito actualmente en Chile y otros países.

Abstract: Introduction: The worldwide prevalence of celiac disease (CD) is ~1% of the population. In Chile, the National Health Survey 2009-2010 showed a serological prevalence in individuals older than 15 years of 0.76% (IgA-tTG2), which corresponded in Concepción to 0.6%. Objective: Determine cli nical characteristics, search, diagnosis, treatment and follow-up of CD in the two public hospitals in Concepción that have a Gastroenterology Department. Patients and Method: Descriptive study. Data were collected from electronic medical records (CIE10 code) and medical records of patients youn ger than 18 years of age, assessed for CD during 2010 - 2016 from two public hospitals in the city of Concepción, Chile. Cases whose diagnostic protocol met the ESPGHAN 2012 criteria (confirmation with intestinal biopsy), 207 out of 216 identified patients met the inclusion criteria. The nutritional status was classified according to age group (in children under five years old by WHO 2006 and in children between five and 18 years old by WHO 2007). The Z-score (Z) was calculated using the WHO Anthro software (in children under five years old) and WHO Anthro Plus software (in those between five and 18 years old). Antiendomysial antibodies were assessed by immunofluorescence test in cuts of the esophagus of mono, IgA and IgG anti-transglutaminase antibodies via ELISA, as well as serum IgA. Results: CD was confirmed by duodenal biopsies in 33.8% of the patients. IgA-tTG was identified in 70% and IgG-tTG in 52.9%, although only two patients had IgA deficiency. The main reasons for consultation were gastrointestinal (80%) and/or referral by an endocrinologist (45.7%). The main clinical presentation was gastrointestinal, with diarrhea (71.4%). 17.1% of the patients had Down syndrome (DS), 11.4% short stature, and 5.7% had type 1 diabetes mellitus. At diagnosis, the obesitymalnutrition ratio (Z-score BMI) was 2:1 and 6.8% of the patients were obese. One year after diagnosis, in 26 patients without DS, the frequency of eutrophic patients decreased from 65.4% to 42.3%, increasing overweight from 23.1% to 34.6% and obesity from 0 to 7.7%. Conclusions: In Con cepción, endocrinologists conduct a significant and successful active search of CD, being responsible for 47.3% of the diagnoses. The high proportion of overweight/obese patients is consistent with the phenomenon currently described in Chile and other countries.

[Characterization of celiac disease in chilean public hospitals]. / Caracterización de la enfermedad celiaca en niños atendidos en hospitales públicos chilenos.

INTRODUCTION: The worldwide prevalence of celiac disease (CD) is ~1% of the population. In Chile, the National Health Survey 2009-2010 showed a serological prevalence in individuals older than 15 years of 0.76% (IgA-tTG2), which corresponded in Concepción to 0.6%. OBJECTIVE: Determine cli nical characteristics, search, diagnosis, treatment and follow-up of CD in the two public hospitals in Concepción that have a Gastroenterology Department. PATIENTS AND METHOD: Descriptive study. Data were collected from electronic medical records (CIE10 code) and medical records of patients youn ger than 18 years of age, assessed for CD during 2010 - 2016 from two public hospitals in the city of Concepción, Chile. Cases whose diagnostic protocol met the ESPGHAN 2012 criteria (confirmation with intestinal biopsy), 207 out of 216 identified patients met the inclusion criteria. The nutritional status was classified according to age group (in children under five years old by WHO 2006 and in children between five and 18 years old by WHO 2007). The Z-score (Z) was calculated using the WHO Anthro software (in children under five years old) and WHO Anthro Plus software (in those between five and 18 years old). Antiendomysial antibodies were assessed by immunofluorescence test in cuts of the esophagus of mono, IgA and IgG anti-transglutaminase antibodies via ELISA, as well as serum IgA. RESULTS: CD was confirmed by duodenal biopsies in 33.8% of the patients. IgA-tTG was identified in 70% and IgG-tTG in 52.9%, although only two patients had IgA deficiency. The main reasons for consultation were gastrointestinal (80%) and/or referral by an endocrinologist (45.7%). The main clinical presentation was gastrointestinal, with diarrhea (71.4%). 17.1% of the patients had Down syndrome (DS), 11.4% short stature, and 5.7% had type 1 diabetes mellitus. At diagnosis, the obesitymalnutrition ratio (Z-score BMI) was 2:1 and 6.8% of the patients were obese. One year after diagnosis, in 26 patients without DS, the frequency of eutrophic patients decreased from 65.4% to 42.3%, increasing overweight from 23.1% to 34.6% and obesity from 0 to 7.7%. CONCLUSIONS: In Con cepción, endocrinologists conduct a significant and successful active search of CD, being responsible for 47.3% of the diagnoses. The high proportion of overweight/obese patients is consistent with the phenomenon currently described in Chile and other countries.

Gibberellin oxidase activities in Bradyrhizobium japonicum bacteroids.

Bradyrhizobium japonicum bacteroids isolated from root nodules of soybean (Glycine max.) plants converted the gibberellin (GA) precursor [(14)C1]GA12 into several products identified by combined gas chromatography-mass spectrometry as [(14)C1]GA24, [(14)C1]GA9, [(14)C1]GA15, GA9 17-nor-16-one and unidentified products. The oxidation of GA12, catalyzed by the GA 20-oxidase, was present in symbiotic bacteroids from plants around flowering, but not in bacteroids from plants at either an early vegetative stage or at late growth stages. Expression of cps and ks genes, involved in ent-kaurene biosynthesis, was also demonstrated in bacteroids from soybean plants around flowering. Earlier precursors of the GA pathway, ent-[(14)C1]kaurenoic acid or [(14)C4]GA12-aldehyde, were efficiently utilized by B. japonicum bacteroids to give labelled GA9 plus intermediates partially oxidized at C-20, as well as GA9 17-nor-16-one and an unidentified product. No 3ß or 13-hydroxylated [(14)C]GAs were detected in any of the incubations. Moreover the C19-GAs [(14)C1]GA4 or [(14)C1]GA20 were recovered unconverted upon incubation with the bacteroids which supports the absence of GA 3ß-hydroxylase activity in B. japonicum. The bacterial 20-oxidase utilized the 13-hydroxylated substrates [(14)C1]GA53, [(14)C1]GA44 or [(14)C1]GA19, although with less efficiency than [(14)C1]GA12 to give [(14)C1]GA20 as final product, while the 3ß-hydroxylated substrate [(14)C1]GA14 was converted to [(14)C1]GA4 to a very small extent. Endogenous GA9 and GA24 were identified by GC-MS in methanolic nodule extracts. These results suggest that B. japonicum bacteroids would synthesize GA9 under the symbiotic conditions present in soybean root nodules.