The Genetics of Atypical Femur Fractures—a Systematic Review

Purpose of Review: Atypical femur fractures (AFFs) are rare subtrochanteric or diaphyseal fractures regarded as side effects of bisphosphonates (BPs), possibly with a genetic background. Here, we summarize the most recent knowledge about genetics of AFFs. Recent Findings: AFF has been reported in 57 patients with seven different monogenic bone disorders including hypophosphatasia and osteogenesis imperfecta; 56.1% had never used BPs, while 17.5% were diagnosed with the disorder only after the AFF. Gene mutation finding in familial and sporadic cases identified possible AFF-related variants in the GGPS1 and ATRAID genes respectively. Functional follow-up studies of mutant proteins showed possible roles in AFF. A recent small genome-wide association study on 51 AFF cases did not identify significant hits associated with AFF. Summary: Recent findings have strengthened the hypothesis that AFFs have underlying genetic components but more studies are needed in AFF families and larger cohorts of sporadic cases to confirm previous results and/or find novel gene variants involved in the pathogenesis of AFFs

Evaluation of Treatment Thresholds for Unconjugated Hyperbilirubinemia in Preterm Infants:Effects on Serum Bilirubin and on Hearing Loss?

Background: Severe unconjugated hyperbilirubinemia may cause deafness. In the Netherlands, 25% lower total serum bilirubin (TSB) treatment thresholds were recently implemented for preterm infants.Objective: To determine the rate of hearing loss in jaundiced preterms treated at high or at low TSB thresholds.Design/Methods: In this retrospective study conducted at two neonatal intensive care units in the Netherlands, we included preterms (gestational age 35 dB).Results: There were 479 patients in the high and 144 in the low threshold group. Both groups had similar gestational ages (29.5 weeks) and birth weights (1300 g). Mean and mean peak TSB levels were significantly lower after the implementation of the novel thresholds: 152 +/- 43 mu mol/L and 212 +/- 52 mu mol/L versus 131 +/- 37 mu mol/L and 188 +/- 46 mu mol/L for the high versus low thresholds, respectively (PConclusions: Implementation of lower treatment thresholds resulted in reduced mean and peak TSB levels. The incidence of hearing impairment in preterms with a gestational age</p

Genetic Risk Factors for Atypical Femoral Fractures (AFFs): A Systematic Review

Atypical femoral fractures (AFFs) are uncommon and have been associated particularly with long-term antiresorptive therapy, including bisphosphonates. Although the pathogenesis of AFFs is unknown, their identification in bisphosphonate-naïve individuals and in monogenetic bone disorders has led to the hypothesis that genetic factors predispose to AFF. Our aim was to review and summarize the evidence for genetic factors in individuals with AFF. We conducted structured literature searches and hand-searching of conference abstracts/reference lists for key words relating to AFF and identified 2566 citations. Two individuals independently reviewed citations for (i) cases of AFF in monogenetic bone diseases and (ii) genetic studies in individuals with AFF. AFFs were reported in 23 individuals with the following 7 monogenetic bone disorders (gene): osteogenesis imperfecta (COL1A1/COL1A2), pycnodysostosis (CTSK), hypophosphatasia (ALPL), X-linked osteoporosis (PLS3), osteopetrosis, X-linked hypophosphatemia (PHEX), and osteoporosis pseudoglioma syndrome (LRP5). In 8 cases (35%), the monogenetic bone disorder was uncovered after the AFF occurred. Cases of bisphosphonate-naïve AFF were reported in pycnodysostosis, hypophosphatasia, osteopetrosis, X-linked hypophosphatemia, and osteoporosis pseudoglioma syndrome. A pilot study in 13 AFF patients and 268 controls identified a greater number of rare variants in AFF cases using exon array analysis. A whole-exome sequencing study in 3 sisters with AFFs showed, among 37 shared genetic variants, a p.Asp188Tyr mutation in the GGPS1 gene in the mevalonate pathway, critical to osteoclast function, which is also inhibited by bisphosphonates. Two studies completed targeted ALPL gene sequencing, an ALPL heterozygous mutation was found in 1 case of a cohort of 11 AFFs, whereas the second study comprising 10 AFF cases did not find mutations in ALPL. Targeted sequencing of ALPL, COL1A1, COL1A2, and SOX9 genes in 5 cases of AFF identified a variant in COL1A2 in 1 case. These findings suggest a genetic susceptibility for AFFs.

Hotspots of land use change in Europe

Die Zweitveröffentlichung der Publikation wurde durch Studierende des Projektseminars "Open Access Publizieren an der HU" im Sommersemester 2017 betreut. Nachgenutzt gemäß den CC-Bestimmungen des Lizenzgebers bzw. einer im Dokument selbst enthaltenen CC-Lizenz.Assessing changes in the extent and management intensity of land use is crucial to understanding land-system dynamics and their environmental and social outcomes. Yet, changes in the spatial patterns of land management intensity, and thus how they might relate to changes in the extent of land uses, remains unclear for many world regions.Wecompiled and analyzed high-resolution, spatiallyexplicit land-use change indicators capturing changes in both the extent and management intensity of cropland, grazing land, forests, and urban areas for all of Europe for the period 1990–2006. Based on these indicators, we identified hotspots of change and explored the spatial concordance of area versus intensity changes.Wefound a clear East–West divide with regard to agriculture, with stronger cropland declines and lower management intensity in the East compared to the West. Yet, these patterns were not uniform and diverging patterns of intensification in areas highly suitable for farming, and disintensification and cropland contraction in more marginal areas emerged. Despite the moderate overall rates of change, many regions in Europe fell into at least one land-use change hotspot during 1990–2006, often related to a spatial reorganization of land use (i.e., co-occurring area decline and intensification or co-occurring area increase and disintensification). Our analyses highlighted the diverse spatial patterns and heterogeneity of land-use changes in Europe, and the importance of jointly considering changes in the extent and management intensity of land use, as well as feedbacks among land-use sectors. Given this spatial differentiation of land-use change, and thus its environmental impacts, spatially-explicit assessments of land-use dynamics are important for context-specific, regionalized land-use policy making.Peer Reviewe

Atom cooling and trapping by disorder

We demonstrate the possibility of three-dimensional cooling of neutral atoms by illuminating them with two counterpropagating laser beams of mutually orthogonal linear polarization, where one of the lasers is a speckle field, i.e. a highly disordered but stationary coherent light field. This configuration gives rise to atom cooling in the transverse plane via a Sisyphus cooling mechanism similar to the one known in standard two-dimensional optical lattices formed by several plane laser waves. However, striking differences occur in the spatial diffusion coefficients as well as in local properties of the trapped atoms.Comment: 11 figures (postscript

Prevalence of Monogenic Bone Disorders in a Dutch Cohort of Atypical Femur Fracture Patients

Atypical femur fractures (AFFs), considered rare associations of bisphosphonates, have also been reported in patients with monogenic bone disorders without bisphosphonate use. The exact association between AFFs and monogenic bone disorders remains unknown. Our aim was to determine the prevalence of monogenic bone disorders in a Dutch AFF cohort. AFF patients were recruited from two specialist bone centers in the Netherlands. Medical records of the AFF patients were reviewed for clinical features of monogenic bone disorders. Genetic variants identified by whole-exome sequencing in 37 candidate genes involved in monogenic bone disorders were classified based on the American College of Medical Genetics and Genomics (ACMG) classification guidelines. Copy number variations overlapping the candidate genes were also evaluated using DNA array genotyping data. The cohort comprises 60 AFF patients (including a pair of siblings), with 95% having received bisphosphonates. Fifteen AFF patients (25%) had clinical features of monogenic bone disorders. Eight of them (54%), including the pair of siblings, had a (likely) pathogenic variant in either PLS3, COL1A2, LRP5, or ALPL. One patient carried a likely pathogenic variant in TCIRG1 among patients not suspected of monogenic bone disorders (2%). In total, nine patients in this AFF cohort (15%) had a (likely) pathogenic variant. In one patient, we identified a 12.7 Mb deletion in chromosome 6, encompassing TENT5A. The findings indicate a strong relationship between AFFs and monogenic bone disorders, particularly osteogenesis imperfecta and hypophosphatasia, but mainly in individuals with symptoms of these disorders. The high yield of (likely) pathogenic variants in AFF patients with a clinical suspicion of these disorders stresses the importance of careful clinical evaluation of AFF patients. Although the relevance of bisphosphonate use in this relationship is currently unclear, clinicians should consider these findings in medical management of these patients.</p

Mapping wood production in European forests

Wood production is an important forest use, impacting a range of other ecosystem services. However, information on the spatial patterns in wood production is limited and often available only for larger administrative units. In this study, we developed high-resolution wood production maps for European forests. We collected wood production statistics for 29 European countries from 2000 to 2010, as well as comprehensive sets of biophysical and socioeconomic location factors. We used regression analyses to produce maps indicating the harvest likelihood on a 1 × 1 km2 grid. These likelihood maps were validated using national forest inventory plot data. We then disaggregated wood production statistics from larger administrative units to the grid level using the harvest likelihood as weights. We verified the resulting wood production maps by correlating predicted and observed wood production at the level of smaller administrative units not used for generating the wood production maps. We conclude that (i) productivity, tree species composition and terrain ruggedness are the most important location factors that determine the spatial patterns of wood production at the pan-European scale and that (ii) incorporating these location factors substantially improves the results of disaggregating wood production statistics compared to a disaggregation based on forest cover only. Our wood production maps give insight into forest ecosystem service provisioning and can be used to improve the assessment of potentials and costs of woody biomass supply

Low-Cost High-Throughput Genotyping for Diagnosing Familial Hypercholesterolemia

BACKGROUND: Familial hypercholesterolemia (FH) is a common but underdiagnosed genetic disorder characterized by high low-density lipoprotein cholesterol levels and premature cardiovascular disease. Current sequencing methods to diagnose FH are expensive and time-consuming. In this study, we evaluated the accuracy of a low-cost, high-throughput genotyping array for diagnosing FH. METHODS: An Illumina Global Screening Array was customized to include probes for 636 variants, previously classified as FH-causing variants. First, its theoretical coverage was assessed in all FH variant carriers diagnosed through next-generation sequencing between 2016 and 2022 in the Netherlands (n=1772). Next, the performance of the array was validated in another sample of FH variant carriers previously identified in the Dutch FH cascade screening program (n=1268). RESULTS: The theoretical coverage of the array for FH-causing variants was 91.3%. Validation of the array was assessed in a sample of 1268 carriers of whom 1015 carried a variant in LDLR, 250 in APOB, and 3 in PCSK9. The overall sensitivity was 94.7% and increased to 98.2% after excluding participants with variants not included in the array design. Copy number variation analysis yielded a 89.4% sensitivity. In 18 carriers, the array identified a total of 19 additional FH-causing variants. Subsequent DNA analysis confirmed 5 of the additionally identified variants, yielding a false-positive result in 16 subjects (1.3%).CONCLUSIONS: The FH genotyping array is a promising tool for genetically diagnosing FH at low costs and has the potential to greatly increase accessibility to genetic testing for FH. Continuous customization of the array will further improve its performance.</p

Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression

Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2x)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted