Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

Genomic insights into the comorbidity between type 2 diabetes and schizophrenia.

Multimorbidity represents an increasingly important public health challenge with far-reaching implications for health management and policy. Mental health and metabolic diseases have a well-established epidemiological association. In this study, we investigate the genetic intersection between type 2 diabetes and schizophrenia. We use Mendelian randomization to examine potential causal relationships between the two conditions and related endophenotypes. We report no compelling evidence that type 2 diabetes genetic liability potentially causally influences schizophrenia risk and vice versa. Our findings show that increased body mass index (BMI) has a protective effect against schizophrenia, in contrast to the well-known risk-increasing effect of BMI on type 2 diabetes risk. We identify evidence of colocalization of association signals for these two conditions at 11 genomic loci, six of which have opposing directions of effect for type 2 diabetes and schizophrenia. To elucidate these colocalizing signals, we integrate multi-omics data from bulk and single-cell gene expression studies, along with functional information. We identify putative effector genes and find that they are enriched for homeostasis and lipid-related pathways. We also highlight drug repurposing opportunities including N-methyl-D-aspartate (NMDA) receptor antagonists. Our findings provide insights into shared biological mechanisms for type 2 diabetes and schizophrenia, highlighting common factors that influence the risk of the two conditions in opposite directions and shedding light on the complex nature of this comorbidity.

Advancing equity in human genomics through tissue-specific multi-ancestry molecular data.

There is a pressing need to generate molecular data from diverse tissues across global populations. These currently missing data are necessary to resolve genome-wide association study loci, identify effector genes, and move the translational genomics needle beyond European-ancestry individuals and the minority of diseases for which blood is the relevant tissue.

Genomic insights into the comorbidity between type 2 diabetes and schizophrenia.

Multimorbidity represents an increasingly important public health challenge with far-reaching implications for health management and policy. Mental health and metabolic diseases have a well-established epidemiological association. In this study, we investigate the genetic intersection between type 2 diabetes and schizophrenia. We use Mendelian randomization to examine potential causal relationships between the two conditions and related endophenotypes. We report no compelling evidence that type 2 diabetes genetic liability potentially causally influences schizophrenia risk and vice versa. Our findings show that increased body mass index (BMI) has a protective effect against schizophrenia, in contrast to the well-known risk-increasing effect of BMI on type 2 diabetes risk. We identify evidence of colocalization of association signals for these two conditions at 11 genomic loci, six of which have opposing directions of effect for type 2 diabetes and schizophrenia. To elucidate these colocalizing signals, we integrate multi-omics data from bulk and single-cell gene expression studies, along with functional information. We identify high-confidence effector genes and find that they are enriched for homeostasis and lipid-related pathways. We also highlight drug repurposing opportunities including N-methyl-D-aspartate (NMDA) receptor antagonists. Our findings provide insights into shared biological mechanisms for type 2 diabetes and schizophrenia, highlighting common factors that influence the risk of the two conditions in opposite directions and shedding light on the complex nature of this comorbidity.

Genetic underpinning of the comorbidity between type 2 diabetes and osteoarthritis.

Multimorbidity is a rising public health challenge with important implications for health management and policy. The most common multimorbidity pattern is the combination of cardiometabolic and osteoarticular diseases. Here, we study the genetic underpinning of the comorbidity between type 2 diabetes and osteoarthritis. We find genome-wide genetic correlation between the two diseases and robust evidence for association-signal colocalization at 18 genomic regions. We integrate multi-omics and functional information to resolve the colocalizing signals and identify high-confidence effector genes, including FTO and IRX3, which provide proof-of-concept insights into the epidemiologic link between obesity and both diseases. We find enrichment for lipid metabolism and skeletal formation pathways for signals underpinning the knee and hip osteoarthritis comorbidities with type 2 diabetes, respectively. Causal inference analysis identifies complex effects of tissue-specific gene expression on comorbidity outcomes. Our findings provide insights into the biological basis for the type 2 diabetes-osteoarthritis disease co-occurrence.

Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10-8) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.

Microbiological analysis of tongue dorsum coating in patients hospitalized in ICU / Análise microbiológica da saburra em dorso lingual de pacientes internados em UTI

ABSTRACT Objective: ssess quantitatively and qualitatively tongue coating microbiota in ICU patients. Methods: Analytical observational study, convenience sample comprising 65 patients was included for medical report analysis and collection of general data, tongue coating assessment through visual inspection and microbiological sample collection for further laboratory analysis. The collection was performed by a single examiner using a sterile swab introduced and rubbing the posterior portion of the tongue close to the oropharynx. Results: Most patients (60%) belonged to the female sex, at mean age of 74.2 years. The main reasons for hospitalization were lung issues (26.2%) - prevailing associated comorbidities were diabetes (43.1%) and high blood pressure (66.2%). The mean length of stay in the ICU was one day. All patients presented tongue dorsum coating. There were Candida albicans (37%), Streptococcus parasanguinis (26.1%) and Streptococcus mitis (32.6%) in 1/3 of lingual extension. Streptococcus mitis (p=0,0265) was the most prevalent species. Conclusion: There was no significance between the amount of coating and number of observed species, although all assessed patients had presented coating. The most prevalent microorganisms were Candida albicans, Streptococcus parasanguinis and Streptococcus mitis.

RESUMO Objetivo: Avaliar quantitativa e qualitativamente a microbiota da saburra lingual em pacientes internados em UTI. Métodos: Estudo observacional analítico, amostra de conveniência composta por 65 pacientes para análise de laudo médico e coleta de dados gerais, avaliação da saburra lingual por inspeção visual e coleta de amostra microbiológica para posterior análise laboratorial. A coleta foi realizada por um único examinador por meio de swab estéril introduzida e fricção na porção posterior de língua próxima à orofaringe. Resultados: A maioria dos pacientes (60%) pertencia ao sexo feminino, com média de idade de 74,2 anos. Os principais motivos de internação foram problemas pulmonares (26,2%) - as comorbidades associadas predominantes foram diabetes (43,1%) e hipertensão arterial (66,2%). O tempo de internação médio na UTI foi de um dia. Todos os pacientes apresentavam saburra do dorso da língua. Havia Candida albicans (37%), Streptococcus parasanguinis (26,1%) e Streptococcus mitis (32,6%) em 1/3 da extensão lingual. Streptococcus mitis (p=0,0265) foi a espécie mais prevalente. Conclusões: Não houve significância entre a quantidade de recobrimento e o número de espécies observadas, embora todos os pacientes avaliados tenham apresentado recobrimento. Os microrganismos mais prevalentes foram Candida albicans, Streptococcus parasanguinis e Streptococcus mitis.

Is Mandatory Vaccination for COVID-19 Constitutional under Brazilian Law?

Mandatory vaccination for COVID-19 has been the object of heated debate in Brazil. This article discusses the legality and constitutionality of such a policy. First, it analyzes the laws, regulations, and Supreme Court decisions that provide for the possibility of mandatory COVID-19 vaccination. Subsequently, it analyzes the constitutionality of a mandatory vaccination policy through the proportionality method to address the conflict between, on one side, the right to individual autonomy, which includes the right to refuse a medical intervention, and, on the other, health policies that interfere with individual autonomy to protect the rights to life and health. The application of this method allows for the identification of key questions that need to be answered to determine the constitutionality of a mandatory vaccination program. These questions cannot be answered a priori and in the abstract because they depend on the concrete circumstances of the pandemic, on the characteristics of the vaccine(s) against COVID-19, and on how a mandatory vaccination policy might be designed and implemented by authorities.

Toxicologia e profissionais de saúde: uso abusivo e dependência / Toxicology and health professionals: drug abuse and dependence

Na década de 1990, foi demonstrada alta prevalência no uso abusivo de opioides pelos anestesiologistas. Desde então, houve aumento nas pesquisas desse tipo de comportamento entre os profissionais da área de saúde. No entanto, observa-se aumento da prevalência da dependência de drogas entre esses profissionais, devido a várias situações como: estresse, extensas jornadas de trabalho e o fácil acesso aos medicamentos. Outros fatores envolvidos estão relacionados a aspectos bioquímicos, genéticos e psiquiátricos. Objetivo: discutir a real prevalência, a etiologia e as estratégias de controle no abuso de propofol, opioides e cetamina entre os profissionais da saúde, especialmente entre as especialidades médicas. Métodos: revisão de artigos científicos disponíveis nos bancos de dados do Pubmed e Scielo. Resultados: entre os profissionais de saúde, a prevalência da dependência química de propofol, opioides (principalmente fentanil e sufentanil) e cetamina é mais alta entre os anestesiologistas, médicos socorristas e psiquiatras. Foi encontrada considerável associação entre a dependência química desses profissionais e outras psicopatogenias, como transtornos de personalidade e depressão. Esses transtornos podem até mesmo influenciar a escolha da droga utilizada. Conclusão: apesar do aumento do número de dependentes químicos em propofol, opioides e cetamina entre os profissionais da saúde, existem poucas estratégias de controle para impedir o acesso a esses medicamentos para uso próprio. Além disso, há poucas informações sobre a segurança do profissional em relação ao retorno ao ambiente de trabalho após o período de reabilitação.

A high prevalence of opioid abuse was found among anesthesiologists in the 1990s. Ever since, an increased number of studies have focused on health professionals? behaviors. However, the prevalence of drug abuse has increased among these professionals as a result of: stress, long work hours, and easy access to the drugs. Other factors involved are of biochemical, genetic and psychiatric nature. Objective: To discuss the actual prevalence, etiology and control strategies related to propofol, opioid and ketamine abuse among health professionals, particularly specialist physicians. Methods: Review of academic articles available on Pubmed and Scielo databases. Results: The prevalence of chemical dependence on propofol, opioids (specially fentanyl and sufentanil) and ketamine is higher among the anesthesiologists, paramedics, and psychiatrists. A meaningful correlation was found between these professionals? chemical dependence and other psychopathologies, including personality disorder, and depression. Such disorders may.