Integration of stool microbiota, proteome and amino acid profiles to discriminate patients with adenomas and colorectal cancer

BACKGROUND: Screening for colorectal cancer (CRC) reduces its mortality but has limited sensitivity and specificity. Aims We aimed to explore potential biomarker panels for CRC and adenoma detection and to gain insight into the interaction between gut microbiota and human metabolism in the presence of these lesions. METHODS: This multicenter case-control cohort was performed between February 2016 and November 2019. Consecutive patients ≥18 years with a scheduled colonoscopy were asked to participate and divided into three age, gender, body-mass index and smoking status-matched subgroups: CRC (n = 12), adenomas (n = 21) and controls (n = 20). Participants collected fecal samples prior to bowel preparation on which proteome (LC-MS/MS), microbiota (16S rRNA profiling) and amino acid (HPLC) composition were assessed. Best predictive markers were combined to create diagnostic biomarker panels. Pearson correlation-based analysis on selected markers was performed to create networks of all platforms. RESULTS: Combining omics platforms provided new panels which outperformed hemoglobin in this cohort, currently used for screening (AUC 0.98, 0.95 and 0.87 for CRC vs controls, adenoma vs controls and CRC vs adenoma, respectively). Integration of data sets revealed markers associated with increased blood excretion, stress- and inflammatory responses and pointed toward downregulation of epithelial integrity. CONCLUSIONS: Integrating fecal microbiota, proteome and amino acids platforms provides for new biomarker panels that may improve noninvasive screening for adenomas and CRC, and may subsequently lead to lower incidence and mortality of colon cancer

Type 1 Human Immunodeficiency Virus (HIV-1) Incidence, Adherence, and Drug Resistance in Individuals Taking Daily Emtricitabine/Tenofovir Disoproxil Fumarate for HIV-1 Pre-exposure Prophylaxis: Pooled Analysis From 72 Global Studies

BACKGROUND: Oral pre-exposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (F/TDF) has high efficacy against HIV-1 acquisition. Seventy-two prospective studies of daily oral F/TDF PrEP were conducted to evaluate HIV-1 incidence, drug resistance, adherence, and bone and renal safety in diverse settings. METHODS: HIV-1 incidence was calculated from incident HIV-1 diagnoses after PrEP initiation and within 60 days of discontinuation. Tenofovir concentration in dried blood spots (DBS), drug resistance, and bone/renal safety indicators were evaluated in a subset of studies. RESULTS: Among 17,274 participants, there were 101 cases with new HIV-1 diagnosis (0.77 per 100 person-years; 95% CI 0.63-0.94). In 78 cases with resistance data, 18 (23%) had M184I or V, one (1.3%) had K65R, and three (3.8%) had both mutations. In 54 cases with tenofovir concentration data from DBS, 45 (83.3%), 2 (3.7%), 6 (11.1%), and 1 (1.9%) had average adherence of <2, 2-3, 4-6, and ≥7 doses/week, respectively, and the corresponding incidence was 3.9 (95% CI 2.9-5.3), 0.24 (0.060-0.95), 0.27 (0.12-0.60), and 0.054 (0.008-0.38) per 100 person-years. Adherence was low in younger participants, Hispanic/Latinx and Black participants, cisgender women, and transgender women. Bone and renal adverse event incidence rates were 0.69 and 11.8 per 100 person-years, respectively, consistent with previous reports. CONCLUSIONS: Leveraging the largest pooled analysis of global PrEP studies to date, we demonstrate that F/TDF is safe and highly effective, even with less than daily dosing, in diverse clinical settings, geographies, populations, and routes of HIV-1 exposure

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

52 Genetic Loci Influencing Myocardial Mass.

BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets

An agent-based model of sign language persistence informed by real-world data

As evidence from sign languages is increasingly used to investigate the process of language emergence and evolution, it is important to understand the conditions that allow for sign languages to persist. We build on a mathematical model of sign language persistence (i.e. protection from loss) which takes into account the genetic transmission of deafness, the cultural transmission of sign language and marital patterns (Aoki Feldman, 1991). We use agent-based modeling techniques and draw inspiration from the wealth of genetic and cultural data on the sign language Kata Kolok to move towards a less abstract model of sign language persistence. In a set of experiments we explorehow sign language persistence is affected by language transmission types, the distribution of deafalleles, population size and marital patterns. We highlight the value of using agent-based modeling for this type of research, which allows for the incorporation of real-world data into model development

Shared Context Facilitates Lexical Variation in Sign Language Emergence

It has been suggested that social structure affects the degree of lexical variation in sign language emergence. Evidence from signing communities supports this, with smaller, more insular communities typically displaying a higher degree of lexical variation compared to larger, more dispersed and diverse communities. Though several factors have been proposed to affect the degree of variation, here we focus on how shared context, facilitating the use of iconic signs, facilitates the retention of lexical variation in language emergence. As interlocutors with the same background have similar salient features for real world concepts, shared context allows for the successful communication of iconic mappings between form and culturally salient features (i.e., the meaning specific to an individual based on their cultural context). Because in this case the culturally salient features can be retrieved from the form, there is less pressure to converge on a single form for a concept. We operationalize the relationship between lexical variation and iconic affordances using an agent-based model, studying how shared context and also population size affects the degree of lexical variation in a population of agents. Our model provides support for the relationship between shared context, population size and lexical variation, though several extensions would help improve the explanatory power of this model

The effect of cultural transmission on shared sign language persistence

In this paper, we revisit a mathematical model of sign language persistence by Aoki and Feldman (Theor Popul Biol 39(3):358–372, 1991), which investigates the evolution of genes causing deafness, affected by an assortative mating parameter, and the cultural transmission of sign language. To assess their model, we reimplement it as an agent-based simulation to be able to easily represent structured relationships in a finite population. We study the persistence of shared sign languages, a categorization of sign languages, which are typically shared by deaf and hearing members of a small community with a high incidence of hereditary deafness (Nyst, 2012. Shared sign languages. Sign language: An international handbook, pp. 552–574). We observe how shared sign language persistence is affected by hearing signers, marriage patterns, and various modes of sign language transmission: vertical, horizontal, oblique, and grandparental transmission. In contrast to Aoki and Feldman’s (Theor Popul Biol 9(3):358–372, 1991) finding that modes of transmission other than vertical are negligible, in the agent-based model we find that adding modes of transmission helps to ensure shared sign language persistence. A better understanding of sign language persistence has relevance for processes of cultural evolution, (sign language) linguistics, and language endangerment

An agent-based model of sign language persistence informed by real-world data

As evidence from sign languages is increasingly used to investigate the process of language emergence and evolution, it is important to understand the conditions that allow for sign languages to persist. We build on a mathematical model of sign language persistence (i.e. protection from loss) which takes into account the genetic transmission of deafness, the cultural transmission of sign language and marital patterns (Aoki Feldman, 1991). We use agent-based modeling techniques and draw inspiration from the wealth of genetic and cultural data on the sign language Kata Kolok to move towards a less abstract model of sign language persistence. In a set of experiments we explorehow sign language persistence is affected by language transmission types, the distribution of deafalleles, population size and marital patterns. We highlight the value of using agent-based modeling for this type of research, which allows for the incorporation of real-world data into model development