Advancing the Microbiome Research Community

The human microbiome has become a recognized factor in promoting and maintaining health. We outline opportunities in interdisciplinary research, analytical rigor, standardization, and policy development for this relatively new and rapidly developing field. Advances in these aspects of the research community may in turn advance our understanding of human microbiome biology. It is now widely recognized that disturbances in our normal microbial populations may be linked to acute infections such as Clostridium difficile and to chronic diseases such as heart disease, cancer, obesity, and autoimmune disorders (Clemente et al., 2012). This has prompted substantial interest in the microbiome from both basic and clinical perspectives. Although our genome is relatively static throughout life, each of our microbial communities changes profoundly from infancy through adulthood, continuing to adapt through ongoing exposures to diet, drugs and environment. Understanding the microbiome and its dynamic nature may be critical for diagnostics and, eventually, interventions based on the microbiome itself. However, several important challenges limit the ability of researchers to enter the microbiome field and/or conduct research most effectively

Melanoma in a patient with DNMT3A overgrowth syndrome

Alterations in epigenetic regulators are increasingly recognized as early events in tumorigenesis; thus, patients with acquired or inherited variants in epigenetic regulators may be at increased risk for developing multiple types of cancer. DNMT3A overgrowth syndrome (DOS), caused by germline pathogenic variants in the DNA methyltransferase gen

Persistent molecular disease in adult patients with AML evaluated with whole-exome and targeted error-corrected DNA sequencing

PURPOSE: Persistent molecular disease (PMD) after induction chemotherapy predicts relapse in AML. In this study, we used whole-exome sequencing (WES) and targeted error-corrected sequencing to assess the frequency and mutational patterns of PMD in 30 patients with AML. MATERIALS AND METHODS: The study cohort included 30 patients with adult AML younger than 65 years who were uniformly treated with standard induction chemotherapy. Tumor/normal WES was performed for all patients at presentation. PMD analysis was evaluated in bone marrow samples obtained during clinicopathologic remission using repeat WES and analysis of patient-specific mutations and error-corrected sequencing of 40 recurrently mutated AML genes (MyeloSeq). RESULTS: WES for patient-specific mutations detected PMD in 63% of patients (19/30) using a minimum variant allele fraction (VAF) of 2.5%. In comparison, MyeloSeq identified persistent mutations above 0.1% VAF in 77% of patients (23/30). PMD was usually present at relatively high levels (\u3e2.5% VAFs), such that WES and MyeloSeq agreed for 73% of patients despite differences in detection limits. Mutations in CONCLUSION: PMD and clonal hematopoiesis are both common in patients with AML in first remission. These findings demonstrate the importance of baseline testing for accurate interpretation of mutation-based tumor monitoring assays for patients with AML and highlight the need for clinical trials to determine whether these complex mutation patterns correlate with clinical outcomes in AML

Add Health Wave IV Documentation: Measures of Inflammation and Immune Function

During Wave IV, Add Health collected biological specimens from a large, nationally representative sample of young adults. Given the size of the Wave IV sample, its geographic distribution, and in-home setting of the respondent interviews, biological specimen collection involved practical, relatively non-invasive, cost-efficient and innovative methods. These methods included collection of capillary whole blood via finger prick by trained and certified field interviewers, its in situ desiccation, then shipment, assay and archival of dried blood spots. The collection of capillary whole blood followed the collection of cardiovascular and anthropometric measures (Entzel et al, 2009) and saliva (Smolen et al, 2012). It preceded the collection of data on respondent use of prescription and select over-the-counter medications (Tabor et al, 2010). Further details on the design of Add Health Waves I-IV, are available elsewhere (Harris, 2011). Included in the Add Health Wave IV data are two measures of inflammation and immune function based on assay of the dried blood spots: • High Sensitivity C-Reactive Protein (hsCRP, mg/L) and • Epstein Barr Viral Capsid Antigen IgG (EBV, AU/ml) To facilitate analysis and interpretation of hsCRP and EBV, the restricted-use Add Health Wave IV data also include two data quality flags and 11constructed measures: • CRP_FLAG • EBV_FLAG • Classification of hsCRP (Pearson et al, 2003) • Count of Common Subclinical Symptoms (Vaidya et al, 2006) • Count of Common Infectious or Inflammatory Diseases • NSAID/Salicylate Medication Use in the Past 24 Hours • NSAID/Salicylate Medication Use in the Past 4 Weeks • Cox-2 Inhibitor Medication Use in the Past 4 Weeks • Inhaled Corticosteroid Medication Use in the Past 4 Weeks • Corticotropin/Glucocorticoid Medication Use in the Past 4 Weeks • Anti-rheumatic/Anti-psoriatic Medication Use in the Past 4 Weeks • Immunosuppressive Medication Use in the Past 4 Weeks • Anti-inflammatory Medication Use. This document summarizes the rationale, equipment, protocol, assay, internal quality control, data cleaning, external quality control, and classification procedures for each measure listed above. Measures of glucose homeostasis and candidate genes are documented elsewhere 3 (Whitsel et al, 2012; Smolen et al, 2012). Documentation of lipids will be provided in a separate report

Central America urgently needs to reduce the growing adaptation gap to climate change

Central America is highly impacted by current extreme events associated with climate variability and the adverse effects of climate change, showing high vulnerability compounded by its historical context and socioeconomic structure. In light of the important findings published by the WGII of the IPCC AR6 in 2022 on the adverse effects of climate change on the Central American region, there is still a clear need to improve data availability and to increase the number of studies on projections of changes in the climate, risks, impacts, vulnerability, and adaptation from the region to inform decision-makers and practitioners. The region has seen an increase in the number of adaptation projects implemented; however, there is limited information about their success or failure, and there are few case studies and reviews of lessons learned, highlighting an important gap in the implementation of effective adaptation measures. This article presents a current review of the literature on climatology, hydrology, impacts and vulnerability, mitigation and adaptation responses, action plans, and potential losses and damages in the region. It also proposes actionable recommendations based on the main gaps found and presents a case study of the Central American Dry Corridor, one of the climate change and underdevelopment hotspots of the region. We finish with a discussion highlighting the importance of considering system transitions perspectives and the need to plan and implement more transformational adaptation approaches to reduce further losses and damages and to further address adaptation gaps in Central America

Genomic landscape of TP53-mutated myeloid malignancies

TP53-mutated myeloid malignancies are associated with complex cytogenetics and extensive structural variants, which complicates detailed genomic analysis by conventional clinical techniques. We performed whole-genome sequencing (WGS) of 42 acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS) cases with paired normal tissue to better characterize the genomic landscape of TP53-mutated AML/MDS. WGS accurately determines TP53 allele status, a key prognostic factor, resulting in the reclassification of 12% of cases from monoallelic to multihit. Although aneuploidy and chromothripsis are shared with most TP53-mutated cancers, the specific chromosome abnormalities are distinct to each cancer type, suggesting a dependence on the tissue of origin. ETV6 expression is reduced in nearly all cases of TP53-mutated AML/MDS, either through gene deletion or presumed epigenetic silencing. Within the AML cohort, mutations of NF1 are highly enriched, with deletions of 1 copy of NF1 present in 45% of cases and biallelic mutations in 17%. Telomere content is increased in TP53-mutated AMLs compared with other AML subtypes, and abnormal telomeric sequences were detected in the interstitial regions of chromosomes. These data highlight the unique features of TP53-mutated myeloid malignancies, including the high frequency of chromothripsis and structural variation, the frequent involvement of unique genes (including NF1 and ETV6) as cooperating events, and evidence for altered telomere maintenance

Add Health Wave IV Documentation: Measures of Glucose Homeostasis

During Wave IV, Add Health collected biological specimens from a large, nationally representative sample of young adults. Given the size of the Wave IV sample, its geographic distribution, and in-home setting of the respondent interviews, biological specimen collection involved practical, relatively non-invasive, cost-efficient and innovative methods. These methods included collection of capillary whole blood via finger prick by trained and certified field interviewers, its in situ desiccation, then shipment, assay and archival of dried blood spots. The collection of capillary whole blood followed the collection of cardiovascular and anthropometric measures (Entzel et al., 2009) and saliva (in preparation). It preceded the collection of data on respondent use of prescription and select over-the-counter medications (Tabor et al., 2010). Further details on the design of Add Health Waves I-IV, are available elsewhere (Harris, 2011). Included in the Add Health Wave IV data are two measures of glucose homeostasis based on assay of the dried blood spots: • Glucose (mg/dl) and • Hemoglobin A1c (HbA1c, %). To facilitate analysis and interpretation of HbA1c, the restricted-use Add Health Wave IV data also include a trichotomous flag distinguishing the original (0) from two types (1,2) of inter-converted assay results (see Section 4.2.3.3): • Convert (0,1,2) Moreover, the restricted-use Add Health Wave IV data include six constructed measures: • Fasting duration (h) • Classification of fasting glucose (ADA, 2011) • Classification of non-fasting glucose (ADA, 2011) • Classification of HbA1c (ADA, 2011) • Anti-diabetic medication use • Joint classification of glucose, HbA1c, self-reported history of diabetes, and anti-diabetic medication use. This document summarizes the rationale, equipment, protocol, assay, internal quality control, data cleaning, external quality control, and classification procedures for each measure listed above. Documentation of other (metabolic; inflammatory; immune; genetic) measures based on assay of the dried blood spots and genotyping of DNA extracted from salivary buccal cells will be provided in separate reports