Phthalate exposure and subclinical carotid atherosclerosis: A systematic review and meta-analysis.

Phthalates may be associated with an increased risk of cardiometabolic diseases by interfering with glucose and lipid metabolism and by promoting adipogenesis. This study aimed to perform a systematic review and meta-analysis of the association between phthalate exposure and subclinical carotid atherosclerosis, using surrogate markers such as carotid intima-media thickness (IMT) and carotid plaques. The literature search was performed using four databases (Web of Science, Medline, PubMed, and Scopus), and this systematic review includes all available observational studies until July 6th, 2023. The Joanna Briggs Institute critical appraisal tool was used to assess the risk of bias. Meta-analyses were performed, and random effects models were used. Six high-quality cross-sectional studies and 2570 participants aged 12 to 70 were included. Six phthalate metabolites showed significant associations with subclinical carotid atherosclerosis. Exposure to MBzP, ΣDEHP, and MnBP was associated with increased carotid IMT. Exposure to MEP was associated with a higher prevalence of carotid plaques, and MiBP was associated with a lower prevalence. Mixed results were observed for MMP in older adults. The meta-analyses showed a high degree of heterogeneity, and the results are based on single studies. This study accurately describes the evidence of this association to date, suggesting that phthalates are associated with increased carotid IMT and a higher prevalence of carotid plaques. Further research is needed to elucidate this association, as phthalates are still used in the manufacture of everyday products, humans continue to be exposed to them, and atherosclerosis is a public health concern.

How Dedicated Ribosomes Translate a Leaderless mRNA.

In bacteriophage λ lysogens, the λcI repressor is encoded by the leaderless transcript (lmRNA) initiated at the λpRM promoter. Translation is enhanced in rpsB mutants deficient in ribosomal protein uS2. Although translation initiation of lmRNA is conserved in bacteria, archaea, and eukaryotes, structural insight of a lmRNA translation initiation complex is missing. Here, we use cryo-EM to solve the structures of the uS2-deficient 70S ribosome of host E. coli mutant rpsB11 and the wild-type 70S complex with λcI lmRNA and fMet-tRNAfMet. Importantly, the uS2-deficient 70S ribosome also lacks protein bS21. The anti-Shine-Dalgarno (aSD) region is structurally supported by bS21, so that the absence of the latter causes the aSD to divert from the normal mRNA exit pathway, easing the exit of lmRNA. A π-stacking interaction between the monitor base A1493 and A(+4) of lmRNA potentially acts as a recognition signal. Coulomb charge flow, along with peristalsis-like dynamics within the mRNA entrance channel due to the increased 30S head rotation caused by the absence of uS2, are likely to facilitate the propagation of lmRNA through the ribosome. These findings lay the groundwork for future research on the mechanism of translation and the co-evolution of lmRNA and mRNA that includes the emergence of a defined ribosome-binding site of the transcript.

Structural insight into translation initiation of the λcl leaderless mRNA.

In bacteriophage λ lysogens, the λcI repressor is encoded by the leaderless transcript (lmRNA) initiated at the λpRM promoter. Translation is enhanced in rpsB mutants deficient in ribosomal protein uS2. Although translation initiation of lmRNA is conserved in bacteria, archaea, and eukaryotes, structural insight of a lmRNA translation initiation complex is missing. Here, we use cryo-EM to solve the structures of the uS2-deficient 70S ribosome of host E. coli mutant rpsB11 and the wild-type 70S complex with λcI lmRNA and fmet-tRNAfMet. Importantly, the uS2-deficient 70S ribosome also lacks protein bS21. The anti-Shine-Dalgarno (aSD) region is structurally supported by bS21, so that the absence of the latter causes the aSD to divert from the normal mRNA exit pathway, easing the exit of lmRNA. A π-stacking interaction between the monitor base A1493 and A(+4) of lmRNA potentially acts as a recognition signal. Coulomb charge flow, along with peristalsis-like dynamics within the mRNA entry channel due to the increased 30S head rotation caused by the absence of uS2, are likely to facilitate the propagation of lmRNA through the ribosome. These findings lay the groundwork for future research on the mechanism of translation and the co-evolution of lmRNA and mRNA that includes the emergence of a defined ribosome-binding site of the transcript.

Acetate acts as a metabolic immunomodulator by bolstering T-cell effector function and potentiating antitumor immunity in breast cancer.

Acetate metabolism is an important metabolic pathway in many cancers and is controlled by acetyl-CoA synthetase 2 (ACSS2), an enzyme that catalyzes the conversion of acetate to acetyl-CoA. While the metabolic role of ACSS2 in cancer is well described, the consequences of blocking tumor acetate metabolism on the tumor microenvironment and antitumor immunity are unknown. We demonstrate that blocking ACSS2, switches cancer cells from acetate consumers to producers of acetate thereby freeing acetate for tumor-infiltrating lymphocytes to use as a fuel source. We show that acetate supplementation metabolically bolsters T-cell effector functions and proliferation. Targeting ACSS2 with CRISPR-Cas9 guides or a small-molecule inhibitor promotes an antitumor immune response and enhances the efficacy of chemotherapy in preclinical breast cancer models. We propose a paradigm for targeting acetate metabolism in cancer in which inhibition of ACSS2 dually acts to impair tumor cell metabolism and potentiate antitumor immunity.

Comparative Analysis of Clinical Practice Guidelines for the Pharmacological Treatment of Type 2 Diabetes Mellitus in Latin America.

PURPOSE OF REVIEW: Type 2 diabetes mellitus (T2DM) is one of the leading causes of death and disability in the world. The majority of diabetes deaths (> 80%) occur in low- and middle-income countries, which are predominant in Latin America. Therefore, the purpose of this article is to compare the clinical practice guideline (CPG) for the pharmacological management of T2DM in Latin America (LA) with international reference guidelines. RECENT FINDINGS: Several LA countries have recently developed CPGs. However, the quality of these guidelines is unknown according to the AGREE II tool and taking as reference three CPGs of international impact: American Diabetes Association (ADA), European Diabetes Association (EASD), and Latin American Diabetes Association (ALAD). Ten CPGs were selected for analysis. The ADA scored > 80% on the AGREE II domains and was selected as the main comparator. Eighty percent of LA CPGs were developed before 2018. Only one was not recommended (all domains < 60%). The CPGs in LA have good quality but are outdated. They have significant gaps compared to the reference. There is a need for improvement, as proposing updates every three years to maintain the best available clinical evidence in all guidelines.

[Voluntary interruption of pregnancy and sexual and reproductive health in migrant women in BarranquillaInterrupção voluntária da gravidez e saúde sexual e reprodutiva em mulheres migrantes em Barranquilla]. / Interrupción voluntaria del embarazo y salud sexual y reproductiva en mujeres migrantes en Barranquilla.

Objective: Identify knowledge about and barriers to effective access to voluntary interruption of pregnancy (VIP), and to sexual and reproductive health (SRH) services in general, among women from Venezuela (Venezuelan migrants and Colombian returnees). Methods: Qualitative study of 20 semi-structured interviews with women from Venezuela who are residents of Barranquilla and who carry out leadership activities in communities or who participate in or benefit from those activities. The interviews included opinions and experiences related to access to VIP, and to SRH in general, as well as suggestions for improving access for migrant women. The relationship between access to these services and the migration process was explored, as well as the role of social organizations. Results: A lack of information on SRH-related rights was identified as the main access barrier to VIP. Other identified barriers were: attitude towards VIP, excessive steps involved in accessing medical care, difficulties in admission to the social security system, lack of training and care in SRH, and xenophobia in hospitals. The interviewees said they did not understand the legal framework in Colombia and did not know the channels for safe abortion care. Conclusions: Despite the efforts of institutions and international cooperation, Venezuelan migrant women in Barranquilla are in a situation of vulnerability due to their lack of access to sexual and reproductive health, including voluntary interruption of pregnancy. Implementing strategies for comprehensive care for migrants will improve current health conditions and the effective enjoyment of SRH-related rights.

Objetivo: Identificar os conhecimentos e as barreiras para o acesso efetivo das mulheres provenientes da Venezuela (migrantes venezuelanas e retornadas colombianas) à interrupção voluntária da gravidez (IVG) e aos serviços de saúde sexual e reprodutiva (SSR) em geral. Métodos: Estudo qualitativo de 20 entrevistas semiestruturadas com mulheres provenientes da Venezuela, residentes em Barranquilla, que atuam na liderança comunitária ou que participam (ou se beneficiam) das atividades. As entrevistas compreenderam as dimensões de opiniões e experiências relacionadas ao acesso à IVG e aos serviços de SSR em geral, e sugestões para melhorar o acesso das mulheres migrantes. Explorou-se a relação do acesso a esses serviços com o processo migratório e o papel das organizações sociais. Resultados: Identificou-se a falta de informações sobre direitos em SSR como a principal barreira para o acesso à IVG. Outras barreiras identificadas foram: atitude em relação à IVG, excesso de burocracia para obter atenção médica, dificuldades para inclusão no sistema de seguridade social, falta de capacitação e atenção em SSR e xenofobia nos hospitais. As entrevistadas declararam desconhecer o enquadramento jurídico na Colômbia e os trâmites para obter atenção ao aborto seguro. Conclusões: Apesar dos esforços institucionais e de cooperação internacional, as mulheres migrantes venezuelanas em Barranquilla estão em situação de vulnerabilidade por falta de acesso aos serviços de SSR, incluindo a IVG. A implementação de estratégias para atenção integral a migrantes possibilitará a melhoria das condições atuais de saúde e a efetiva fruição dos direitos em SSR.

Longitudinal health survey of women from Venezuela in Colombia (ELSA-VENCOL): First report.

BACKGROUND: Colombia is currently the world's main recipient country for Venezuelan migrants, and women represent a high proportion of them. This article presents the first report of a cohort of Venezuelan migrant women entering Colombia through Cúcuta and its metropolitan area. The study aimed to describe the health status and access to healthcare services among Venezuelan migrant women in Colombia with irregular migration status, and to analyze changes in those conditions at a one-month follow-up. METHODS: We carried out a longitudinal cohort study of Venezuelan migrant women, 18 to 45 years, who entered Colombia with an irregular migration status. Study participants were recruited in Cúcuta and its metropolitan area. At baseline, we administered a structured questionnaire including sociodemographic characteristics, migration history, health history, access to health services, sexual and reproductive health, practice of early detection of cervical cancer and breast cancer, food insecurity, and depressive symptoms. The women were again contacted by phone one month later, between March and July 2021, and a second questionnaire was applied. RESULTS: A total of 2,298 women were included in the baseline measurement and 56.4% could be contacted again at the one-month follow-up. At the baseline, 23.0% of the participants reported a self-perceived health problem or condition in the past month and 29.5% in the past 6 months, and 14.5% evaluated their health as fair or poor. A significant increase was found in the percentage of women who reported a self-perceived health problem during the past month (from 23.1% to 31.4%; p<0.01); as well as in the share who reported moderate, severe, or extreme difficulty working or performing daily chores (from 5.5% to 11.0%; p = 0.03) and who rated their health as fair (from 13.0% to 31.2%; p<0.01). Meanwhile, the percentage of women with depressive symptoms decreased from 80.5% to 71.2% (p<0.01). CONCLUSION: This report presents initial information on the health status of Venezuelan migrant women in Colombia, and is a starting point for further longer longitudinal follow-ups to assess changes over time in health conditions.

Interrupción voluntaria del embarazo y salud sexual y reproductiva en mujeres migrantes en Barranquilla

[RESUMEN]. Objetivo. Identificar el conocimiento y las barreras para acceder efectivamente a la interrupción voluntaria del embarazo (IVE), y en general a los servicios sexuales y reproductivos (SSR), entre mujeres provenientes de Venezuela (migrantes venezolanas y colombianas retornadas). Métodos. Estudio cualitativo de 20 entrevistas semiestructuradas en mujeres provenientes de Venezuela, resi- dentes en Barranquilla que ejecutan acciones de liderazgo en comunidades o que participan (o se benefician) de las actividades. Las entrevistas comprendieron dimensiones sobre opiniones y experiencias relacionadas con el acceso a IVE, y en general a SSR, y sugerencias para mejorar el acceso para las mujeres migrantes. Se exploró la relación del acceso a estos servicios con el proceso migratorio y el papel de las organizaciones sociales. Resultados. Se identificó la falta de información sobre derechos en SSR como principal barrera para acceso a la IVE. Otras barreras identificadas fueron: actitud hacia la IVE, exceso de trámites para atención médica, dificultades para la inclusión al sistema de seguridad social, falta de capacitación y atención en SSR y xeno- fobia en hospitales. Las entrevistadas manifestaron desconocer el marco legal en Colombia y las rutas para la atención de un aborto seguro. Conclusiones. Pese a los esfuerzos institucionales y de cooperación internacional, las mujeres migrantes venezolanas en Barranquilla se encuentran en una situación de vulnerabilidad debido a la falta de acceso a los SSR incluida la IVE. Implementar estrategias para atención integral a migrantes, permitirá mejorar condi- ciones de salud actual y el goce efectivo de los derechos en SSR.

[ABSTRACT]. Objective. Identify knowledge about and barriers to effective access to voluntary interruption of pregnancy (VIP), and to sexual and reproductive health (SRH) services in general, among women from Venezuela (Vene- zuelan migrants and Colombian returnees). Methods. Qualitative study of 20 semi-structured interviews with women from Venezuela who are residents of Barranquilla and who carry out leadership activities in communities or who participate in or benefit from those activities. The interviews included opinions and experiences related to access to VIP, and to SRH in general, as well as suggestions for improving access for migrant women. The relationship between access to these services and the migration process was explored, as well as the role of social organizations. Results. A lack of information on SRH-related rights was identified as the main access barrier to VIP. Other identified barriers were: attitude towards VIP, excessive steps involved in accessing medical care, difficulties in admission to the social security system, lack of training and care in SRH, and xenophobia in hospitals. The interviewees said they did not understand the legal framework in Colombia and did not know the channels for safe abortion care. Conclusions. Despite the efforts of institutions and international cooperation, Venezuelan migrant women in Barranquilla are in a situation of vulnerability due to their lack of access to sexual and reproductive health, including voluntary interruption of pregnancy. Implementing strategies for comprehensive care for migrants will improve current health conditions and the effective enjoyment of SRH-related rights.

[RESUMO]. Objetivo. Identificar os conhecimentos e as barreiras para o acesso efetivo das mulheres provenientes da Venezuela (migrantes venezuelanas e retornadas colombianas) à interrupção voluntária da gravidez (IVG) e aos serviços de saúde sexual e reprodutiva (SSR) em geral. Métodos. Estudo qualitativo de 20 entrevistas semiestruturadas com mulheres provenientes da Venezuela, residentes em Barranquilla, que atuam na liderança comunitária ou que participam (ou se beneficiam) das atividades. As entrevistas compreenderam as dimensões de opiniões e experiências relacionadas ao acesso à IVG e aos serviços de SSR em geral, e sugestões para melhorar o acesso das mulheres migrantes. Explo- rou-se a relação do acesso a esses serviços com o processo migratório e o papel das organizações sociais. Resultados. Identificou-se a falta de informações sobre direitos em SSR como a principal barreira para o acesso à IVG. Outras barreiras identificadas foram: atitude em relação à IVG, excesso de burocracia para obter atenção médica, dificuldades para inclusão no sistema de seguridade social, falta de capacitação e atenção em SSR e xenofobia nos hospitais. As entrevistadas declararam desconhecer o enquadramento jurí- dico na Colômbia e os trâmites para obter atenção ao aborto seguro. Conclusões. Apesar dos esforços institucionais e de cooperação internacional, as mulheres migrantes vene- zuelanas em Barranquilla estão em situação de vulnerabilidade por falta de acesso aos serviços de SSR, incluindo a IVG. A implementação de estratégias para atenção integral a migrantes possibilitará a melhoria das condições atuais de saúde e a efetiva fruição dos direitos em SSR.

High levels of cardiovascular biomarkers in fatal Chikungunya virus infection.

Chikungunya virus (CHIKV) infection is an emerging arboviral disease that has spread geographically to many previously unaffected areas. Although severe cases of acute CHIKV infection have been documented, little is known about its pathogenesis. We aimed to determine the levels of cardiovascular biomarkers in fatal and non-fatal patients with acute CHIKV infection. This study included fatal and non-fatal patients with CHIKV reported to National System for Public Health Surveillance and laboratory-confirmed by the Colombian National Institute of Health. Each fatal patient was matched to 2 non-fatal patients for age (± 10 years). Blood samples were processed for cardiovascular biomarkers by multiplex immunoassays. Twenty-five cases of fatal CHIKV infection and 50 patients of non-fatal CHIKV infection were included. Nearly 20% of the population were under 10 years old and 52% were over 60. The median serum levels of endocan-1 (p = 0.000), creatine kinase MB isoenzyme (p = 0.000), oncostatin (p = 0.000), fatty-acid-binding protein 3 (p = 0.000) and fatty-acid-binding protein 4 (p = 0.000) were significantly higher in fatal CHIKV infection cases than in non-fatal patients. Troponin I tended to be higher in fatal CHIKV infection cases than in non-fatal CHIKV infection patients (p = 0.063). Among fatal patients, no significant differences were found in serum levels of cardiovascular biomarkers among younger (< 50 years-old) and older (≥ 50 years-old) patients. We found high serum levels of cardiovascular biomarkers in fatal CHIKV infection. These results promote the fact that endothelial and cardiac damage can occurs and may be significant factors related organ failure and death in these patients.

Acné en la adolescencia: como reconocerlo y abordarlo / Acne in adolescents: how to recognize it and treat it / Acne na adolescencia: como reconhecer-lo e tratá-lo

El acné una de las enfermedades dermatológicas crónicas más frecuentes, siendo la adolescencia donde se observa su mayor incidencia y prevalencia. Constituye un motivo de consulta frecuente y a pesar de que su abordaje inicial es de resorte del pediatra, dependiendo de la evolución y los tipos de acné requieren la derivación y tratamiento con dermatólogo. Es una enfermedad cutánea, de carácter inflamatorio y que involucra la unidad pilosebácea. Su etiología es multifactorial y el diagnóstico es clínico al constatar las lesiones típicas. Teniendo en cuenta la importancia de la imagen corporal en esta etapa de la vida y el impacto de esta en la calidad de vida de los adolescentes, es imprescindible el reconocimiento precoz y tratamiento inicial por parte del pediatra. Existen posibilidades terapéuticas cada vez más novedosas, exigiendo a los profesionales de salud estar actualizados. Esta revisión pretende mostrar una puesta al día de la temática y ofrecer información actualizada sobre los tratamientos disponibles a nivel local.

Acne is one of the most common chronic dermatological diseases and it is primarily observed in adolescents. It is one of the causes of frequent consultation, and despite the fact that Its initial detection and approach is that of the pediatrician, depending on the evolution and the types of acne, referral and treatment by a dermatologist will be required. It is a skin disease, inflammatory in nature and involving the pilosebaceous unit. It has a multifactorial etiology and it requires clinical diagnosis when typical lesions are found. Considering importance of adolescents' image at this stage and the impact on their quality of life, early detection and treatment by the pediatrician are essential. There are increasing new therapeutic possibilities, which require health professionals to be updated. This review aims at showing an update of the subject and at providing updated information regarding the available treatments locally.

A acne é uma das doenças dermatológicas crônicas mais comuns, sendo a adolescência onde observase sua maior incidência e prevalência. Constitui motivo de consulta frequente e apesar de sua abordagem inicial é a do pediatra, dependendo da evolução e dos tipos de acne que necessitam de tratamento e encaminhamento feito por um dermatologista. É uma doença cutânea, de natureza inflamatória e que envolve a unidade pilossebácea. Sua etiologia é multifatorial e o diagnóstico é clínico quando são encontradas lesões típicas. Tendo em conta a importância da imagem corporal nesta fase da vida e o impacto dela na qualidade de vida dos adolescentes, o reconhecimento inicial pelo pediatra e o tratamento precoces são essenciais. Existem cada vez mais novas possibilidades terapêuticas, exigindo que os profissionais de saúde estejam atualizados. Este papertem como objetivo mostrar uma atualização do assunto e fornecer informação atualizada sobre os tratamentos disponíveis a nível local.

Interrupción voluntaria del embarazo y salud sexual y reproductiva en mujeres migrantes en Barranquilla / Voluntary interruption of pregnancy and sexual and reproductive health in migrant women in Barranquilla / Interrupção voluntária da gravidez e saúde sexual e reprodutiva em mulheres migrantes em Barranquilla

RESUMEN Objetivo. Identificar el conocimiento y las barreras para acceder efectivamente a la interrupción voluntaria del embarazo (IVE), y en general a los servicios sexuales y reproductivos (SSR), entre mujeres provenientes de Venezuela (migrantes venezolanas y colombianas retornadas). Métodos. Estudio cualitativo de 20 entrevistas semiestructuradas en mujeres provenientes de Venezuela, residentes en Barranquilla que ejecutan acciones de liderazgo en comunidades o que participan (o se benefician) de las actividades. Las entrevistas comprendieron dimensiones sobre opiniones y experiencias relacionadas con el acceso a IVE, y en general a SSR, y sugerencias para mejorar el acceso para las mujeres migrantes. Se exploró la relación del acceso a estos servicios con el proceso migratorio y el papel de las organizaciones sociales. Resultados. Se identificó la falta de información sobre derechos en SSR como principal barrera para acceso a la IVE. Otras barreras identificadas fueron: actitud hacia la IVE, exceso de trámites para atención médica, dificultades para la inclusión al sistema de seguridad social, falta de capacitación y atención en SSR y xenofobia en hospitales. Las entrevistadas manifestaron desconocer el marco legal en Colombia y las rutas para la atención de un aborto seguro. Conclusiones. Pese a los esfuerzos institucionales y de cooperación internacional, las mujeres migrantes venezolanas en Barranquilla se encuentran en una situación de vulnerabilidad debido a la falta de acceso a los SSR incluida la IVE. Implementar estrategias para atención integral a migrantes, permitirá mejorar condiciones de salud actual y el goce efectivo de los derechos en SSR.

ABSTRACT Objective. Identify knowledge about and barriers to effective access to voluntary interruption of pregnancy (VIP), and to sexual and reproductive health (SRH) services in general, among women from Venezuela (Venezuelan migrants and Colombian returnees). Methods. Qualitative study of 20 semi-structured interviews with women from Venezuela who are residents of Barranquilla and who carry out leadership activities in communities or who participate in or benefit from those activities. The interviews included opinions and experiences related to access to VIP, and to SRH in general, as well as suggestions for improving access for migrant women. The relationship between access to these services and the migration process was explored, as well as the role of social organizations. Results. A lack of information on SRH-related rights was identified as the main access barrier to VIP. Other identified barriers were: attitude towards VIP, excessive steps involved in accessing medical care, difficulties in admission to the social security system, lack of training and care in SRH, and xenophobia in hospitals. The interviewees said they did not understand the legal framework in Colombia and did not know the channels for safe abortion care. Conclusions. Despite the efforts of institutions and international cooperation, Venezuelan migrant women in Barranquilla are in a situation of vulnerability due to their lack of access to sexual and reproductive health, including voluntary interruption of pregnancy. Implementing strategies for comprehensive care for migrants will improve current health conditions and the effective enjoyment of SRH-related rights.

RESUMO Objetivo. Identificar os conhecimentos e as barreiras para o acesso efetivo das mulheres provenientes da Venezuela (migrantes venezuelanas e retornadas colombianas) à interrupção voluntária da gravidez (IVG) e aos serviços de saúde sexual e reprodutiva (SSR) em geral. Métodos. Estudo qualitativo de 20 entrevistas semiestruturadas com mulheres provenientes da Venezuela, residentes em Barranquilla, que atuam na liderança comunitária ou que participam (ou se beneficiam) das atividades. As entrevistas compreenderam as dimensões de opiniões e experiências relacionadas ao acesso à IVG e aos serviços de SSR em geral, e sugestões para melhorar o acesso das mulheres migrantes. Explorou-se a relação do acesso a esses serviços com o processo migratório e o papel das organizações sociais. Resultados. Identificou-se a falta de informações sobre direitos em SSR como a principal barreira para o acesso à IVG. Outras barreiras identificadas foram: atitude em relação à IVG, excesso de burocracia para obter atenção médica, dificuldades para inclusão no sistema de seguridade social, falta de capacitação e atenção em SSR e xenofobia nos hospitais. As entrevistadas declararam desconhecer o enquadramento jurídico na Colômbia e os trâmites para obter atenção ao aborto seguro. Conclusões. Apesar dos esforços institucionais e de cooperação internacional, as mulheres migrantes venezuelanas em Barranquilla estão em situação de vulnerabilidade por falta de acesso aos serviços de SSR, incluindo a IVG. A implementação de estratégias para atenção integral a migrantes possibilitará a melhoria das condições atuais de saúde e a efetiva fruição dos direitos em SSR.

Recovery of Conformational Continuum From Single-Particle Cryo-EM Images: Optimization of ManifoldEM Informed by Ground Truth.

This work is based on the manifold-embedding approach to study biological molecules exhibiting continuous conformational changes. Previous work established a method-now termed ManifoldEM-capable of reconstructing 3D movies and accompanying free-energy landscapes from single-particle cryo-EM images of macromolecules exercising multiple conformational degrees of freedom. While ManifoldEM has proven its viability in several experimental studies, critical limitations and uncertainties have been found throughout its extended development and use. Guided by insights from studies with cryo-EM ground-truth data, simulated from atomic structures undergoing conformational changes, we have built a novel framework, ESPER, able to retrieve the free-energy landscape and respective 3D Coulomb potential maps for all states simulated. As shown by a direct comparison of ground truth vs. recovered maps, and analysis of experimental data from the 80S ribosome and ryanodine receptor, ESPER offers substantial improvements relative to the previous work.

Effectiveness and safety of available preventive tuberculosis treatment regimens for children and adolescents: protocol for a systematic review and network meta-analysis.

INTRODUCTION: Approximately 5%-10% of individuals with untreated latent tuberculosis infection (LTBI) will progress to active tuberculosis (TB). Children are at a higher risk for progression to TB disease than adults. Isoniazid prophylaxis treatment period is long and can cause liver damage. Alternatives to isoniazid, such as rifamycin containing regimens, should be considered for prophylaxis. Previous systematic reviews, with different study designs and data combining results on children and adults, have evaluated the comparative efficacy and harms of LTBI treatment regimens. We aim to determine the effectiveness and safety of all the different regimens available for the treatment of LTBI for children and adolescents less than 18 years of age, contacts of drug-susceptible TB, without HIV infection. METHODS AND ANALYSIS: MEDLINE, Embase and Cochrane Central Register of Controlled Trials will be systematically searched for randomised controlled trials without any language or publication date restriction. Screening and extraction will be performed in duplicate. Risk of bias will be performed in duplicate with Cochrane Risk of Bias tool V.2. Pairwise meta-analysis of direct comparisons and network meta-analyses (NMAs) will be performed. Heterogeneity will be assessed using I2 and Cochrane thresholds. Direct and indirect estimates in an NMA will be combined if justifiable. Subgroups analyses will be performed in different mean age and study year groups. Sensitivity analysis based on the risk of bias will be conducted. Publication bias will be investigated using funnel plots and Egger's regression test. Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria will assess certainty of the evidence for the direct comparisons. GRADE approach for NMA will assess the quality of the evidence from the indirect and NMA. ETHICS AND DISSEMINATION: Ethical approval is not required as no primary data are collected. This systematic review will be disseminated in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42021271512.

Uncovering translation roadblocks during the development of a synthetic tRNA.

Ribosomes are remarkable in their malleability to accept diverse aminoacyl-tRNA substrates from both the same organism and other organisms or domains of life. This is a critical feature of the ribosome that allows the use of orthogonal translation systems for genetic code expansion. Optimization of these orthogonal translation systems generally involves focusing on the compatibility of the tRNA, aminoacyl-tRNA synthetase, and a non-canonical amino acid with each other. As we expand the diversity of tRNAs used to include non-canonical structures, the question arises as to the tRNA suitability on the ribosome. Specifically, we investigated the ribosomal translation of allo-tRNAUTu1, a uniquely shaped (9/3) tRNA exploited for site-specific selenocysteine insertion, using single-molecule fluorescence. With this technique we identified ribosomal disassembly occurring from translocation of allo-tRNAUTu1 from the A to the P site. Using cryo-EM to capture the tRNA on the ribosome, we pinpointed a distinct tertiary interaction preventing fluid translocation. Through a single nucleotide mutation, we disrupted this tertiary interaction and relieved the translation roadblock. With the continued diversification of genetic code expansion, our work highlights a targeted approach to optimize translation by distinct tRNAs as they move through the ribosome.

Continued expansion of the genetic code has required the use of synthetic tRNAs for decoding. Some of these synthetic tRNAs have unique structural features that are not observed in canonical tRNAs. Here, the authors applied single-molecule, biochemical and structural methods to determine whether these distinct features were deleterious for efficient protein translation on the ribosome. With a focus on selenocysteine insertion, the authors explored an allo-tRNA with a 9/3 acceptor domain. They observed a translational roadblock that occurred in A to P site tRNA translocation. This block was mediated by a tertiary interaction across the tRNA core, directing the variable arm position into an unfavorable conformation. A single-nucleotide mutation disrupted this interaction, providing flexibility in the variable arm and promoting efficient protein production.

Hiperplasia sebácea ectópica en mucosa oral de neonatos: reporte de tres casos / Ectopic sebaceous gland hyperplasia in neonates oral mucosa: 3 case studies / Hiperplasia sebácea ectópica na mucosa oral de recém-nascidos: relato de 3 casos

La hiperplasia de glándulas sebáceas es un hallazgo benigno y transitorio, común en el período neonatal. Secundariamente al estímulo hormonal androgénico se produce un hipercrecimiento de las glándulas, con mayor frecuencia en nariz y mejillas, donde existen en mayor densidad. La hiperplasia de glándulas en una localización ectópica, llamada gránulos de Fordyce (GF), es excepcional en el período neonatal. Se han reportado en aproximadamente 1% de los recién nacidos, y con frecuencia se localizan en la mucosa oral. Los GF se describen como lesiones papulares de aspecto vesiculoso blanco amarillentas de 1-3 mm2, que podrían confundir al neonatólogo o al pediatra con entidades infecciosas, dando lugar a pruebas invasivas y tratamientos innecesarios. Se describen tres casos clínicos de neonatos con diagnóstico de hiperplasia sebácea ectópica localizada en mucosa oral, con el objetivo de revisar la etiología, las características clínicas, los diagnósticos diferenciales y la evolución de esta entidad benigna. Conclusiones: la hiperplasia sebácea ectópica en mucosa oral de neonatos es un hallazgo benigno autolimitado que se presenta con baja frecuencia. El reconocimiento clínico de esta entidad es importante para evitar diagnósticos incorrectos y tratamientos innecesarios.

Sebaceous gland hyperplasia is a common transient and benign finding in neonates. After androgenic hormonal stimulation, there is a gland overgrowth mainly in the nose and cheeks where there is a greater density of glands. Ectopic sebaceous gland hyperplasia, called Fordyce's Granules (FG), is exceptional in neonates and it is reported in approximately 1% of newborns and frequently located in the oral mucosa. FGs are described as 1-3mm2 yellowish-white papular and vesicular lesions. Neonatologists or pediatricians may confuse these clinical features with infectious diseases, leading to invasive tests and unnecessary treatment. We describe three clinical cases of neonates with diagnosis of ectopic sebaceous gland hyperplasia located in the oral mucosa, with the aim of reviewing the etiology, clinical characteristics, differential diagnoses and evolution of this benign entity. Conclusions: ectopic sebaceous gland hyperplasia of the lips is a self-limited benign finding occurring infrequently in newborns. The clinical recognition of this entity is important to avoid inaccurate diagnoses or unnecessary treatment.

A hiperplasia das glândulas sebáceas é um achado benigno e transitório comum nos neonatos. Secundário ao estímulo hormonal androgênico, há um hipercrescimento das glândulas com mais frequência no nariz e nas bochechas onde há uma maior densidade das glândulas. A hiperplasia das glândulas num local ectópico, chamado Fordyce Granules (FG), é excepcional no período neonatal, e ela é relatada em aproximadamente 1% dos recém-nascidos e muitas vezes está localizada na mucosa oral. Os FGs são descritos como lesões vesiculares brancas amareladas de 1-3mm2, o que poderia confundir o neonatologista ou pediatra com entidades infecciosas, levando a testes invasivos e tratamentos desnecessários. Descrevemos três relatos clínicos de recém-nascidos com diagnóstico de hiperplasia sebácea ectópica localizada na mucosa oral, com o objetivo de rever a etiologia, características clínicas, diagnósticos diferenciais e evolução desta entidade benigna. Conclusões: hiperplasia sebácea ectópica na mucosa oral de recém-nascidos é um achado benigno autolimitante que ocorre com baixa frequência. O reconhecimento clínico desta entidade é importante para evitar diagnósticos incorretos e tratamentos desnecessários.

Seroprevalence of anti-SARS-CoV-2 antibodies in Colombia, 2020: A population-based study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to cause very high morbidity and mortality throughout Latin American countries. However, few population-based seroprevalence surveys have been conducted to quantify attack rates and characterize drivers of transmission. METHODS: We conducted a population-based cross-sectional study to assess the seroprevalence of antibodies against SARS-CoV-2 in ten cities in Colombia between September and December 2020. The study involved multi-stage cluster sampling at each city. Participants provided a serum sample and answered a demographic and risk factor questionnaire. Prior infection by SARS-CoV-2 was ascertained using the "SARS-CoV-2 Total (COV2T) Advia Centaur - Siemens" chemiluminescence assay. FINDINGS: A total of 17863 participants from 7320 households participated in the study. Seroprevalence varied substantially between cities, ranging from 26% (95%CI 23-29 %) in Medellín to 68% (95%CI 62-74 %) in Guapi. There were no differences in seroprevalence by sex, but seropositivity was higher in certain ethnic groups. There was substantial heterogeneity in seroprevalence within cities, driven to a large extent by a strong association between socioeconomic stratum and seropositivity. INTERPRETATION: Colombia has been one of the Latin American countries most affected by the COVID-19 pandemic. This study documented very high attack rates in several Colombian cities by the end of 2020 and identified key drivers of heterogeneities including ethnicity and socioeconomic stratum. Few studies of seroprevalence of SARS-CoV-2 have been conducted in Latin America, and therefore this study contributes to the fundamental understanding of the pandemic in the region. FUNDING: The study was sponsored by, Ministerio de Ciencia y Tecnología e Innovación -CT361/2020, Ministerio de Salud y Protección Social, Fundación Universitaria del Norte, Imperial College of London, Universidad Nacional de Colombia (Sede Medellín), Universidad de Córdoba, California University, Unidad Nacional de Gestión del Riesgo, Centro de Atención y Diagnóstico de Enfermedades Infecciosas -CDI-, Centro Internacional de Entrenamiento e Investigaciones Médicas -CIDEIM-, Departamento Administrativo Nacional de Estadística - DANE, Fondo Nacional de Turismo -FONTUR-, Secretarías de Salud Departamentales, Distritales y Municipales and Instituto Nacional de Salud.

International alliance and AGREE-ment of 71 clinical practice guidelines on the management of critical care patients with COVID-19: a living systematic review.

OBJECTIVE: We aimed to systematically identify and critically assess the clinical practice guidelines (CPGs) for the management of critically ill patients with COVID-19 with the AGREE II instrument. STUDY DESIGN AND SETTING: We searched Medline, CINAHL, EMBASE, CNKI, CBM, WanFang, and grey literature from November 2019 - November 2020. We did not apply language restrictions. One reviewer independently screened the retrieved titles and abstracts, and a second reviewer confirmed the decisions. Full texts were assessed independently and in duplicate. Disagreements were resolved by consensus. We included any guideline that provided recommendations on the management of critically ill patients with COVID-19. Data extraction was performed independently and in duplicate by two reviewers. We descriptively summarized CPGs characteristics. We assessed the quality with the AGREE II instrument and we summarized relevant therapeutic interventions. RESULTS: We retrieved 3,907 records and 71 CPGs were included. Means (Standard Deviations) of the scores for the 6 domains of the AGREE II instrument were 65%(SD19.56%), 39%(SD19.64%), 27%(SD19.48%), 70%(SD15.74%), 26%(SD18.49%), 42%(SD34.91) for the scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, editorial independence domains, respectively. Most of the CPGs showed a low overall quality (less than 40%). CONCLUSION: Future CPGs for COVID-19 need to rely, for their development, on standard evidence-based methods and tools.

Ferritin levels in children with juvenile idiopathic arthritis of systemic onset and children with other causes of fever of unknown origin: A multicenter study of diagnostic tests / Niveles de ferritina en artritis idiopática juvenil de inicio sistémico comparada con otras fiebres de origen desconocido: estudio multicéntrico de pruebas diagnósticas

Introduction: There are no sensitive or specific tests available to diagnose systemic juvenile idiopathic arthritis (sJIA). Objective: To assess the utility as diagnostic tests of total ferritin (TF) levels greater than 5 times the normal value (TF>5N) and the decreased percentage (less than or equal to 20% of TF) of glycosylated ferritin (GF≤20%) for the diagnosis of sJIA in patients with fever of unknown origin evaluated by pediatric rheumatology. Materials and methods: We conducted an observational, cross-sectional study of diagnostic tests in children under 16 years of age hospitalized between 2010 and 2014. The reference diagnostic standard was the fulfillment of the classification criteria or confirmed diagnosis at follow-up. We determined the measures of utility of the tests. Results: We included 40 patients with fever of unknown origin, 11 with sJIA, and 29 with other diagnoses. The median TF was higher in sAIJ (3992 ng/ml) versus other causes of fever of unknown origin (155 ng/ml) (p=0.0027), as well as TF>5N (90.91% versus 51.72%) (p=0.023). The percentage of GF≤20% was higher in patients with other causes of fever of unknown origin (96.5%) compared to sJIA (81.8%) (p=0.178). TF>5N had a sensitivity of 91%, specificity of 48%, positive likelihood ratio (LR) of 1.76, and negative LR of 0.19 demonstrating greater utility for the diagnosis of sJIA than the combination of FT> 5N with GFR <20%, with a sensitivity of 81.8%, specificity of 48.3%, positive LR of 1.58, and negative LR of 0.38. Conclusion: In patients with FUO evaluated by pediatric rheumatology, TF> 5N proved useful as a screening test for the diagnosis of sJIA.

Introducción. No se dispone de pruebas sensibles ni específicas para diagnosticar la artritis idiopática juvenil sistémica. Objetivo. Evaluar la utilidad diagnóstica de niveles de ferritina total cinco veces por encima del valor normal (ferritina total>5N) y el porcentaje disminuido (menor de o igual a 20 % de la ferritina total) de la ferritina glucosilada (ferritina glucosilada<20 %) para el diagnóstico de artritis idiopática juvenil sistémica en pacientes con fiebre de origen desconocido evaluados por reumatología pediátrica. Materiales y métodos. Se hizo un estudio observacional de pruebas diagnósticas de corte transversal en menores de 16 años hospitalizados entre el 2010 y el 2014. El patrón diagnóstico de referencia fue el cumplimiento de los criterios de clasificación o diagnóstico confirmado en el seguimiento. Se determinaron las medidas de utilidad de las pruebas. Resultados. Se incluyeron 40 pacientes con fiebre de origen desconocido: 11 con artritis idiopática juvenil sistémica y 29 con otros diagnósticos. La mediana de la ferritina total fue mayor en la artritis idiopática juvenil sistémica (3.992 ng/ml) comparada con otras causas de fiebre de origen desconocido (155 ng/ml) (p=0,0027), así como la ferritina total>5N (90,91 % Vs. 51,72 %) (p=0,023). El porcentaje de ferritina glucosilada≤20 % fue de 96,5 % en otras fiebres de origen desconocido en comparación con la artritis idiopática juvenil sistémica (81,8 %) (p=0,178). La ferritina total>5N tuvo una sensibilidad del 91 %, una especificidad del 48 %; un cociente de probabilidades (Likelihood Ratio, LR) positivo de 1,76 y uno negativo de 0,19, demostrando mayor utilidad para el diagnóstico que la combinación de la ferritina total>5N y ferritina glucosilada≤20 %, cuya sensibilidad fue del 81,8 %, la especificidad del 48,3 %, un cociente de probabilidades LR positivo de 1,58 y un LR negativo de 0,38. Conclusión. En pacientes con fiebre de origen desconocido evaluados por reumatología pediátrica, la ferritina total>5N demostró ser útil como prueba de tamización para el diagnóstico de artritis idiopática juvenil sistémica.