Patterns of Anti-Osteoporosis Medication Use among Women at High Risk of Fracture : Findings from the Global Longitudinal Study of Osteoporosis in Women (GLOW)

To assess patterns of anti-osteoporosis medication (AOM) use over 3 years among women at high risk of major fracture. The GLOW registry follows a cohort of more than 40,000 women aged ≥55 from 615 primary care practices in 10 countries. Self-administered surveys (baseline, 12, 24, and 36 months) collected data on patient characteristics, perception of fracture risk, and AOM use. FRAX scores were calculated from the baseline surveys and women classified as high risk if their FRAX 10-year probability of major fracture was ≥20%. A total of 5774 women were classified as at high risk and had complete data over 3 years. At baseline, 2271 (39%) reported receiving AOM, 739 (13%) reported prior but not current use, and 2764 (48%) said they had never used AOM. Over 3 years, 85% of baseline non-users continued as non-users and 15% initiated AOM; among baseline users, 49% continued the same medication class, 29% stopped AOM, and 12% switched. Women who stopped AOM were less likely to self-report osteoporosis (HR 0.56, 95% CI 0.42-0.75) than women who continued AOM. Compared with non-users who did not begin treatment, women initiating AOM were more likely to report a diagnosis of osteoporosis (HR 11.3, 95% CI 8.2-15.5) or osteopenia (HR 4.1, 95% CI 2.9-5.7) and be very concerned about osteoporosis (HR 1.9, 95% CI 1.3-2.8). Less than 40% of women at high risk of fracture reported taking AOM. Women who stopped AOM were less likely to believe they have osteoporosis. Women who initiated treatment appeared motivated primarily by a diagnosis of osteoporosis or osteopenia and concern about the condition

Patterns of anti-osteoporosis medication use among women at high risk of fracture: findings from the Global Longitudinal Study of Osteoporosis in Women (GLOW)

OBJECTIVE: To assess patterns of anti-osteoporosis medication (AOM) use over 3 years among women at high risk of major fracture. METHODS: The GLOW registry follows a cohort of more than 40,000 women aged \u3e /= 55 from 615 primary care practices in 10 countries. Self-administered surveys (baseline, 12, 24, and 36 months) collected data on patient characteristics, perception of fracture risk, and AOM use. FRAX scores were calculated from the baseline surveys and women classified as high risk if their FRAX 10-year probability of major fracture was \u3e /= 20%. RESULTS: A total of 5774 women were classified as at high risk and had complete data over 3 years. At baseline, 2271 (39%) reported receiving AOM, 739 (13%) reported prior but not current use, and 2764 (48%) said they had never used AOM. Over 3 years, 85% of baseline non-users continued as non-users and 15% initiated AOM; among baseline users, 49% continued the same medication class, 29% stopped AOM, and 12% switched. Women who stopped AOM were less likely to self-report osteoporosis (HR 0.56, 95% CI 0.42-0.75) than women who continued AOM. Compared with non-users who did not begin treatment, women initiating AOM were more likely to report a diagnosis of osteoporosis (HR 11.3, 95% CI 8.2-15.5) or osteopenia (HR 4.1, 95% CI 2.9-5.7) and be very concerned about osteoporosis (HR 1.9, 95% CI 1.3-2.8). CONCLUSIONS: Less than 40% of women at high risk of fracture reported taking AOM. Women who stopped AOM were less likely to believe they have osteoporosis. Women who initiated treatment appeared motivated primarily by a diagnosis of osteoporosis or osteopenia and concern about the condition

Automated and Accurate Estimation of Gene Family Abundance from Shotgun Metagenomes

Shotgun metagenomic DNA sequencing is a widely applicable tool for characterizing the functions that are encoded by microbial communities. Several bioinformatic tools can be used to functionally annotate metagenomes, allowing researchers to draw inferences about the functional potential of the community and to identify putative functional biomarkers. However, little is known about how decisions made during annotation affect the reliability of the results. Here, we use statistical simulations to rigorously assess how to optimize annotation accuracy and speed, given parameters of the input data like read length and library size. We identify best practices in metagenome annotation and use them to guide the development of the Shotgun Metagenome Annotation Pipeline (ShotMAP). ShotMAP is an analytically flexible, end-to-end annotation pipeline that can be implemented either on a local computer or a cloud compute cluster. We use ShotMAP to assess how different annotation databases impact the interpretation of how marine metagenome and metatranscriptome functional capacity changes across seasons. We also apply ShotMAP to data obtained from a clinical microbiome investigation of inflammatory bowel disease. This analysis finds that gut microbiota collected from Crohn’s disease patients are functionally distinct from gut microbiota collected from either ulcerative colitis patients or healthy controls, with differential abundance of metabolic pathways related to host-microbiome interactions that may serve as putative biomarkers of diseaseData Availability Statement: The Gilbert et al. L4 metagenomes and metatranscriptomes are available from the MG-RAST database (project number 109,  http://metagenomics.anl.gov/metagenomics.cgi?page=MetagenomeProject&project=109), the Qin et al. MetaHIT inflammatory bowel disease metagenomes are available in the EBI (accession ERA000116), and the Nielsen et al. MGS inflammatory bowel disease metagenomes are available in the EBI (accession ERP002061)

When, where and how osteoporosis-associated fractures occur: An analysis from the global longitudinal study of osteoporosis in women (GLOW)

Objective: To examine when, where and how fractures occur in postmenopausal women. Methods: We analyzed data from the Global Longitudinal Study of Osteoporosis in Women (GLOW), including women aged ≥55 years from the United States of America, Canada, Australia and seven European countries. Women completed questionnaires including fracture data at baseline and years 1, 2 and 3. Results: Among 60,393 postmenopausal women, 4122 incident fractures were reported (86% non-hip, non-vertebral [NHNV], 8% presumably clinical vertebral and 6% hip). Hip fractures were more likely to occur in spring, with little seasonal variation for NHNV or spine fractures. Hip fractures occurred equally inside or outside the home, whereas 65% of NHNV fractures occurred outside and 61% of vertebral fractures occurred inside the home. Falls preceded 68-86% of NHNV and 68-83% of hip fractures among women aged ≤64 to ≥85 years, increasing with age. About 45% of vertebral fractures were associated with falls in all age groups except those ≥85 years, when only 24% occurred after falling. Conclusion: In this multi-national cohort, fractures occurred throughout the year, with only hip fracture having a seasonal variation, with a higher proportion in spring. Hip fractures occurred equally within and outside the home, spine fractures more often in the home, and NHNV fractures outside the home. Falls were a proximate cause of most hip and NHNV fractures. Postmenopausal women at risk for fracture need counseling about reducing potentially modifiable fracture risk factors, particularly falls both inside and outside the home and during all seasons of the year. © 2013 Costa et al

Crystal structure of human XLF/Cernunnos reveals unexpected differences from XRCC4 with implications for NHEJ

The recently characterised 299-residue human XLF/Cernunnos protein plays a crucial role in DNA repair by non-homologous end joining (NHEJ) and interacts with the XRCC4–DNA Ligase IV complex. Here, we report the crystal structure of the XLF (1–233) homodimer at 2.3 Å resolution, confirming the predicted structural similarity to XRCC4. The XLF coiled-coil, however, is shorter than that of XRCC4 and undergoes an unexpected reverse in direction giving rise to a short distorted four helical bundle and a C-terminal helical structure wedged between the coiled-coil and head domain. The existence of a dimer as the major species is confirmed by size-exclusion chromatography, analytical ultracentrifugation, small-angle X-ray scattering and other biophysical methods. We show that the XLF structure is not easily compatible with a proposed XRCC4:XLF heterodimer. However, we demonstrate interactions between dimers of XLF and XRCC4 by surface plasmon resonance and analyse these in terms of surface properties, amino-acid conservation and mutations in immunodeficient patients. Our data are most consistent with head-to-head interactions in a 2:2:1 XRCC4:XLF:Ligase IV complex

Nuclear versus mitochondrial DNA: evidence for hybridization in colobine monkeys

<p>Abstract</p> <p>Background</p> <p>Colobine monkeys constitute a diverse group of primates with major radiations in Africa and Asia. However, phylogenetic relationships among genera are under debate, and recent molecular studies with incomplete taxon-sampling revealed discordant gene trees. To solve the evolutionary history of colobine genera and to determine causes for possible gene tree incongruences, we combined presence/absence analysis of mobile elements with autosomal, X chromosomal, Y chromosomal and mitochondrial sequence data from all recognized colobine genera.</p> <p>Results</p> <p>Gene tree topologies and divergence age estimates derived from different markers were similar, but differed in placing <it>Piliocolobus/Procolobus </it>and langur genera among colobines. Although insufficient data, homoplasy and incomplete lineage sorting might all have contributed to the discordance among gene trees, hybridization is favored as the main cause of the observed discordance. We propose that African colobines are paraphyletic, but might later have experienced female introgression from <it>Piliocolobus</it>/<it>Procolobus </it>into <it>Colobus</it>. In the late Miocene, colobines invaded Eurasia and diversified into several lineages. Among Asian colobines, <it>Semnopithecus </it>diverged first, indicating langur paraphyly. However, unidirectional gene flow from <it>Semnopithecus </it>into <it>Trachypithecus </it>via male introgression followed by nuclear swamping might have occurred until the earliest Pleistocene.</p> <p>Conclusions</p> <p>Overall, our study provides the most comprehensive view on colobine evolution to date and emphasizes that analyses of various molecular markers, such as mobile elements and sequence data from multiple loci, are crucial to better understand evolutionary relationships and to trace hybridization events. Our results also suggest that sex-specific dispersal patterns, promoted by a respective social organization of the species involved, can result in different hybridization scenarios.</p

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Automated and Accurate Estimation of Gene Family Abundance from Shotgun Metagenomes

<div><p>Shotgun metagenomic DNA sequencing is a widely applicable tool for characterizing the functions that are encoded by microbial communities. Several bioinformatic tools can be used to functionally annotate metagenomes, allowing researchers to draw inferences about the functional potential of the community and to identify putative functional biomarkers. However, little is known about how decisions made during annotation affect the reliability of the results. Here, we use statistical simulations to rigorously assess how to optimize annotation accuracy and speed, given parameters of the input data like read length and library size. We identify best practices in metagenome annotation and use them to guide the development of the Shotgun Metagenome Annotation Pipeline (ShotMAP). ShotMAP is an analytically flexible, end-to-end annotation pipeline that can be implemented either on a local computer or a cloud compute cluster. We use ShotMAP to assess how different annotation databases impact the interpretation of how marine metagenome and metatranscriptome functional capacity changes across seasons. We also apply ShotMAP to data obtained from a clinical microbiome investigation of inflammatory bowel disease. This analysis finds that gut microbiota collected from Crohn’s disease patients are functionally distinct from gut microbiota collected from either ulcerative colitis patients or healthy controls, with differential abundance of metabolic pathways related to host-microbiome interactions that may serve as putative biomarkers of disease.</p></div