Search

The number of spring staging brent geese on the salt marshes of the Dutch island of Schiermonnikoog increased from about 1500 individuals in the late 1960s to >4000 in the late 1970s. Since then, numbers on Schiermonnikoog have levelled off, while the world population continued to increase. Although the extent of salt-marsh area on the island has dramatically increased over the past 20 yr, the number of brent geese on Schiermonnikoog was rather constant in this period. We hypothesise that the number of geese did not increase because of successional changes in the vegetation. On the basis of 24 yr of counts, we show that geese had to give up older parts of the marsh. Over time, tall growing species like the shrub Atriplex portulacoides have invaded, making the marsh unsuitable for goose grazing. Newly developed marsh, however, was readily exploited by the geese. The area of older salt marsh lost due to succession was almost exactly compensated for by the development of new feeding grounds. Geese which persistently utilised the older marsh were faced with a high proportion of non-preferred species, although they still managed to assemble a diet largely composed of preferred plant species. In the older marsh, a significant reduction in the time spent foraging was also observed. We conclude that brent geese are largely excluded as vegetation succession progresses. Numbers on the island as a whole, however, are sustained due to the dynamic nature of the island. If development of new salt marshes were to be prevented, geese would be forced to abandon the salt marsh. [ABSTRACT FROM AUTHOR]

Accurate detection of somatic structural variation (SV) in cancer genomes remains a challenging problem. This is in part due to the lack of high-quality, gold-standard datasets that enable the benchmarking of experimental approaches and bioinformatic analysis pipelines. Here, we performed somatic SV analysis of the paired melanoma and normal lymphoblastoid COLO829 cell lines using four different sequencing technologies. Based on the evidence from multiple technologies combined with extensive experimental validation, we compiled a comprehensive set of carefully curated and validated somatic SVs, comprising all SV types. We demonstrate the utility of this resource by determining the SV detection performance as a function of tumor purity and sequence depth, highlighting the importance of assessing these parameters in cancer genomics projects. The truth somatic SV dataset as well as the underlying raw multi-platform sequencing data are freely available and are an important resource for community somatic benchmarking efforts., Competing Interests: A.M.W. is an employee and shareholder of Pacific Biosciences. W.P.K. is an employee and shareholder of Cyclomics B.V., (© 2022 The Author(s).)

Health psychology is at the forefront of developing and disseminating evidence, theories, and methods that have improved the understanding of health behaviour change. However, current dissemination approaches may be insufficient for promoting broader application and impact of this evidence to benefit the health of patients and the public. Nevertheless, behaviour change theory/methods typically directed towards health behaviours are now used in implementation science to understand and support behaviour change in individuals at different health system levels whose own behaviour impacts delivering evidence-based health behaviour change interventions. Despite contributing to implementation science, health psychology is perhaps doing less to draw from it. A redoubled focus on implementation science in health psychology could provide novel prospects for enhancing the impact of health behaviour change evidence. We report a Health Psychology Review -specific review-of-reviews of trials of health behaviour change interventions published from inception to April 2020. We identified 34 reviews and assessed whether implementation readiness of behaviour change interventions was discussed. We then narratively review how implementation science has integrated theory/methods from health psychology and related discipline. Finally, we demonstrate how greater synergy between implementation science and health psychology could promote greater follow-through on advances made in the science of health behaviour change.

Background: Fusion genes are typically identified by RNA sequencing (RNA-seq) without elucidating the causal genomic breakpoints. However, non-poly(A)-enriched RNA-seq contains large proportions of intronic reads that also span genomic breakpoints., Results: We have developed an algorithm, Dr. Disco, that searches for fusion transcripts by taking an entire reference genome into account as search space. This includes exons but also introns, intergenic regions, and sequences that do not meet splice junction motifs. Using 1,275 RNA-seq samples, we investigated to what extent genomic breakpoints can be extracted from RNA-seq data and their implications regarding poly(A)-enriched and ribosomal RNA-minus RNA-seq data. Comparison with whole-genome sequencing data revealed that most genomic breakpoints are not, or minimally, transcribed while, in contrast, the genomic breakpoints of all 32 TMPRSS2-ERG-positive tumours were present at RNA level. We also revealed tumours in which the ERG breakpoint was located before ERG, which co-existed with additional deletions and messenger RNA that incorporated intergenic cryptic exons. In breast cancer we identified rearrangement hot spots near CCND1 and in glioma near CDK4 and MDM2 and could directly associate this with increased expression. Furthermore, in all datasets we find fusions to intergenic regions, often spanning multiple cryptic exons that potentially encode neo-antigens. Thus, fusion transcripts other than classical gene-to-gene fusions are prominently present and can be identified using RNA-seq., Conclusion: By using the full potential of non-poly(A)-enriched RNA-seq data, sophisticated analysis can reliably identify expressed genomic breakpoints and their transcriptional effects., (© The Author(s) 2021. Published by Oxford University Press GigaScience.)

Whole genome sequencing (WGS) using fresh-frozen tissue and matched blood samples from cancer patients may become the most complete genetic tumor test. With the increasing availability of small biopsies and the need to screen more number of biomarkers, the use of a single all-inclusive test is preferable over multiple consecutive assays. To meet high-quality diagnostics standards, we optimized and clinically validated WGS sample and data processing procedures, resulting in a technical success rate of 95.6% for fresh-frozen samples with sufficient (≥20%) tumor content. Independent validation of identified biomarkers against commonly used diagnostic assays showed a high sensitivity (recall; 98.5%) and precision (positive predictive value; 97.8%) for detection of somatic single-nucleotide variants and insertions and deletions (across 22 genes), and high concordance for detection of gene amplification (97.0%; EGFR and MET) as well as somatic complete loss (100%; CDKN2A/p16). Gene fusion analysis showed a concordance of 91.3% between DNA-based WGS and an orthogonal RNA-based gene fusion assay. Microsatellite (in)stability assessment showed a sensitivity of 100% with a precision of 94%, and virus detection (human papillomavirus), an accuracy of 100% compared with standard testing. In conclusion, whole genome sequencing has a >95% sensitivity and precision compared with routinely used DNA techniques in diagnostics, and all relevant mutation types can be detected reliably in a single assay., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: The ultimate impact of a health innovation depends not only on its effectiveness but also on its reach in the population and the extent to which it is implemented with high levels of completeness and fidelity. Implementation science has emerged as the potential solution to the failure to translate evidence from research into effective practice and policy evident in many fields. Implementation scientists have developed many frameworks, theories and models, which describe implementation determinants, processes, or outcomes; yet, there is little guidance about how these can inform the development or selection of implementation strategies (methods or techniques used to improve adoption, implementation, sustainment, and scale-up of interventions) (1, 2). To move the implementation science field forward and to provide a practical tool to apply the knowledge in this field, we describe a systematic process for planning or selecting implementation strategies: Implementation Mapping. Methods: Implementation Mapping is based on Intervention Mapping (a six-step protocol that guides the design of multi-level health promotion interventions and implementation strategies) and expands on Intervention Mapping step 5. It includes insights from both the implementation science field and Intervention Mapping. Implementation Mapping involves five tasks: (1) conduct an implementation needs assessment and identify program adopters and implementers; (2) state adoption and implementation outcomes and performance objectives, identify determinants, and create matrices of change objectives; (3) choose theoretical methods (mechanisms of change) and select or design implementation strategies; (4) produce implementation protocols and materials; and (5) evaluate implementation outcomes. The tasks are iterative with the planner circling back to previous steps throughout this process to ensure all adopters and implementers, outcomes, determinants, and objectives are addressed. Discussion: Implementation Mapping provides a systematic process for developing strategies to improve the adoption, implementation, and maintenance of evidence-based interventions in real-world settings.

Sexual harassment-unwanted sexual comments, advances, or behaviors-and sexual violence are still prevalent worldwide, leading to a variety of physical, cognitive, and emotional problems among those being harassed. In particular, youth in care are at risk of becoming perpetrators (and victims) of sexual harassment. However, in general, there are very few interventions targeting this at-risk group, and no such programs exist in the Netherlands. To this end, a group intervention program-Make a Move-targeting determinants of sexual harassment was developed. This program was implemented and evaluated among boys ( N = 177) in Dutch residential youth care (20 institutions). A pre-test, post-test, and 6-month follow-up design including an intervention and a waiting list control group with randomized assignment of institutions (cluster randomized trial) was used to measure the effects of the intervention on determinants of sexual harassment. Multilevel (mixed) regression analysis with Bonferroni correction for multiple testing (α = .005) showed no significant effects of Make a Move on determinants of sexual harassment ( ps > .03, Cohen's ds < .44). Results are discussed in light of a three-way explanatory model focusing on intervention content, evaluation, and implementation as potential explanations for not finding any measurable intervention effects.

Schools are a common setting for adolescents to receive health education, but implementation of these programs with high levels of completeness and fidelity is not self-evident. Programs that are only partially implemented (completeness) or not implemented as instructed (fidelity) are unlikely to be effective. Therefore, it is important to identify which determinants affect completeness and fidelity of program implementation. As part of the launch of Long Live Love+ (LLL+), an online school-based sexuality education program for adolescents aged 15-17, we performed a process evaluation among teachers and students to measure the levels of completeness and fidelity, identify factors influencing teachers' implementation, and to evaluate the students' response. Sixteen Biology teachers from nine secondary schools throughout the Netherlands who implemented LLL+ were interviewed and 60 students participated in 13 focus group discussions. Results showed that teachers' completeness ranged between 22-100% (M = 75%). Fidelity was high, but many teachers added elements. Teachers and students enjoyed LLL+, particularly the diversity in the exercises and its interactive character. The most important factors that influenced implementation were time and organizational constraints, lack of awareness on the impact of completeness and fidelity, and student response. These factors should be taken into account when developing school-based prevention programs., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Development of cancer is driven by somatic alterations, including numerical and structural chromosomal aberrations. Currently, several computational methods are available and are widely applied to detect numerical copy number aberrations (CNAs) of chromosomal segments in tumor genomes. However, there is lack of computational methods that systematically detect structural chromosomal aberrations by virtue of the genomic location of CNA-associated chromosomal breaks and identify genes that appear non-randomly affected by chromosomal breakpoints across (large) series of tumor samples. 'GeneBreak' is developed to systematically identify genes recurrently affected by the genomic location of chromosomal CNA-associated breaks by a genome-wide approach, which can be applied to DNA copy number data obtained by array-Comparative Genomic Hybridization (CGH) or by (low-pass) whole genome sequencing (WGS). First, 'GeneBreak' collects the genomic locations of chromosomal CNA-associated breaks that were previously pinpointed by the segmentation algorithm that was applied to obtain CNA profiles. Next, a tailored annotation approach for breakpoint-to-gene mapping is implemented. Finally, dedicated cohort-based statistics is incorporated with correction for covariates that influence the probability to be a breakpoint gene. In addition, multiple testing correction is integrated to reveal recurrent breakpoint events. This easy-to-use algorithm, 'GeneBreak', is implemented in R ( www.cran.r-project.org ) and is available from Bioconductor ( www.bioconductor.org/packages/release/bioc/html/GeneBreak.html )., Competing Interests: Competing interests: No competing interests were disclosed.

The structural maintenance of chromosomes (SMC) family of proteins supports mitotic proliferation, meiosis, and DNA repair to control genomic stability. Impairments in chromosome maintenance are linked to rare chromosome breakage disorders. Here, we have identified a chromosome breakage syndrome associated with severe lung disease in early childhood. Four children from two unrelated kindreds died of severe pulmonary disease during infancy following viral pneumonia with evidence of combined T and B cell immunodeficiency. Whole exome sequencing revealed biallelic missense mutations in the NSMCE3 (also known as NDNL2) gene, which encodes a subunit of the SMC5/6 complex that is essential for DNA damage response and chromosome segregation. The NSMCE3 mutations disrupted interactions within the SMC5/6 complex, leading to destabilization of the complex. Patient cells showed chromosome rearrangements, micronuclei, sensitivity to replication stress and DNA damage, and defective homologous recombination. This work associates missense mutations in NSMCE3 with an autosomal recessive chromosome breakage syndrome that leads to defective T and B cell function and acute respiratory distress syndrome in early childhood.

Background: Targeted Next Generation Sequencing (NGS) offers a way to implement testing of multiple genetic aberrations in diagnostic pathology practice, which is necessary for personalized cancer treatment. However, no standards regarding input material have been defined. This study therefore aimed to determine the effect of the type of input material (e.g. formalin fixed paraffin embedded (FFPE) versus fresh frozen (FF) tissue) on NGS derived results. Moreover, this study aimed to explore a standardized analysis pipeline to support consistent clinical decision-making., Method: We used the Ion Torrent PGM sequencing platform in combination with the Ion AmpliSeq Cancer Hotspot Panel v2 to sequence frequently mutated regions in 50 cancer related genes, and validated the NGS detected variants in 250 FFPE samples using standard diagnostic assays. Next, 386 tumour samples were sequenced to explore the effect of input material on variant detection variables. For variant calling, Ion Torrent analysis software was supplemented with additional variant annotation and filtering., Results: Both FFPE and FF tissue could be sequenced reliably with a sensitivity of 99.1%. Validation showed a 98.5% concordance between NGS and conventional sequencing techniques, where NGS provided both the advantage of low input DNA concentration and the detection of low-frequency variants. The reliability of mutation analysis could be further improved with manual inspection of sequence data., Conclusion: Targeted NGS can be reliably implemented in cancer diagnostics using both FFPE and FF tissue when using appropriate analysis settings, even with low input DNA.

Background/aim: Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms. The exact genetic alterations underlying the pathophysiology of PEComas are largely unknown, although it has been shown that activation of the Mammalian target of rapamycin (mTOR) signaling pathway plays a pivotal role. Herein we describe the successful treatment of a patient with metastatic PEComa with the mTOR inhibitor everolimus and a comprehensive analysis to identify mechanisms for response., Materials and Methods: Immunohistochemistry, array comparative genomic hybridization (aCGH) and genetic analyses were performed., Results: Immunohistochemistry confirmed constitutive activation of mTOR. aCGH revealed a hyperdiploid karyotype affecting large regions of the genome. Next-generation sequencing did not reveal any tumor-specific mutations in mTOR-related genes., Conclusion: Our results show the complexity of determining causal genetic alterations that can predict responsiveness to mTOR inhibition, even for a tumor with a complete remission to this specific treatment., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Objective: Recently, de novo SCN8A missense mutations have been identified as a rare dominant cause of epileptic encephalopathies (EIEE13). Functional studies on the first described case demonstrated gain-of-function effects of the mutation. We describe a novel de novo mutation of SCN8A in a patient with epileptic encephalopathy, and functional characterization of the mutant protein., Design: Whole exome sequencing was used to discover the variant. We generated a mutant cDNA, transfected HEK293 cells, and performed Western blotting to assess protein stability. To study channel functional properties, patch-clamp experiments were carried out in transfected neuronal ND7/23 cells., Results: The proband exhibited seizure onset at 6 months of age, diffuse brain atrophy, and more profound developmental impairment than the original case. The mutation p.Arg233Gly in the voltage sensing transmembrane segment D1S4 was present in the proband and absent in both parents. This mutation results in a temperature-sensitive reduction in protein expression as well as reduced sodium current amplitude and density and a relative increased response to a slow ramp stimulus, though this did not result in an absolute increased current at physiological temperatures., Conclusion: The new de novo SCN8A mutation is clearly deleterious, resulting in an unstable protein with reduced channel activity. This differs from the gain-of-function attributes of the first SCN8A mutation in epileptic encephalopathy, pointing to heterogeneity of mechanisms. Since Nav1.6 is expressed in both excitatory and inhibitory neurons, a differential effect of a loss-of-function of Nav1.6 Arg223Gly on inhibitory interneurons may underlie the epilepsy phenotype in this patient., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Primary immunodeficiency (PID) disorders are a heterogeneous group of inherited disorders caused by a variety of monogenetic immune defects. Thus far, mutations in more than 170 different genes causing PIDs have been described. A clear genotype-phenotype correlation is often not available, which makes a genetic diagnosis in patients with PIDs complex and laborious., Objective: We sought to develop a robust, time-effective, and cost-effective diagnostic method to facilitate a genetic diagnosis in any of 170 known PID-related genes by using next-generation sequencing (NGS)., Methods: We used both targeted array-based and in-solution enrichment combined with a SOLiD sequencing platform and a bioinformatic pipeline developed in house to analyze genetic changes in the DNA of 41 patients with PIDs with known mutations and 26 patients with undiagnosed PIDs., Results: This novel NGS-based method accurately detected point mutations (sensitivity and specificity >99% in covered regions) and exonic deletions (100% sensitivity and specificity). For the 170 genes of interest, the DNA coverage was greater than 20× in 90% to 95%. Nine PID-related genes proved not eligible for evaluation by using this NGS-based method because of inadequate coverage. The NGS method allowed us to make a genetic diagnosis in 4 of 26 patients who lacked a genetic diagnosis despite routine functional and genetic testing. Three of these patients proved to have an atypical presentation of previously described PIDs., Conclusion: This novel NGS tool facilitates accurate simultaneous detection of mutations in 161 of 170 known PID-related genes. In addition, these analyses will generate more insight into genotype-phenotype correlations for the different PID disorders., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Ablepharon macrostomia syndrome (AMS; OMIM 200110) is an extremely rare congenital malformation syndrome. It overlaps clinically with Fraser syndrome (FS; OMIM 219000), which is known to be caused by mutations in either FRAS1, FREM2, or GRIP1, encoding components of a protein complex that plays a role in epidermal-dermal interactions during morphogenetic processes. We explored the hypothesis that AMS might be either allelic to FS or caused by mutations in other genes encoding known FRAS1 interacting partners. No mutation in either of these genes was found in a cohort of 11 patients with AMS from 10 unrelated families. These findings demonstrate that AMS is genetically distinct from FS. It is proposed that it constitutes a separate entity within the group of FRAS-FREM complex disorders., (© 2013 Wiley Periodicals, Inc.)

Background: We present a large Dutch family with seven males affected by a novel syndrome of X-linked intellectual disability, hypogonadism, gynaecomastia, truncal obesity, short stature and recognisable craniofacial manifestations resembling but not identical to Wilson-Turner syndrome. Seven female relatives show a much milder expression of the phenotype., Methods and Results: We performed X chromosome exome (X-exome) sequencing in five individuals from this family and identified a novel intronic variant in the histone deacetylase 8 gene (HDAC8), c.164+5G>A, which disturbs the normal splicing of exon 2 resulting in exon skipping, and introduces a premature stop at the beginning of the histone deacetylase catalytic domain. The identified variant completely segregates in this family and was absent in 96 Dutch controls and available databases. Affected female carriers showed a notably skewed X-inactivation pattern in lymphocytes in which the mutated X-chromosome was completely inactivated., Conclusions: HDAC8 is a member of the protein family of histone deacetylases that play a major role in epigenetic gene silencing during development. HDAC8 specifically controls the patterning of the skull with the mouse HDAC8 knock-out showing craniofacial deformities of the skull. The present family provides the first evidence for involvement of HDAC8 in a syndromic form of intellectual disability.

Cantú syndrome is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. By using family-based exome sequencing, we identified a de novo mutation in ABCC9. Subsequently, we discovered novel dominant missense mutations in ABCC9 in 14 of the 16 individuals with Cantú syndrome examined. The ABCC9 protein is part of an ATP-dependent potassium (K(ATP)) channel that couples the metabolic state of a cell with its electrical activity. All mutations altered amino acids in or close to the transmembrane domains of ABCC9. Using electrophysiological measurements, we show that mutations in ABCC9 reduce the ATP-mediated potassium channel inhibition, resulting in channel opening. Moreover, similarities between the phenotype of individuals with Cantú syndrome and side effects from the K(ATP) channel agonist minoxidil indicate that the mutations in ABCC9 result in channel opening. Given the availability of ABCC9 antagonists, our findings may have direct implications for the treatment of individuals with Cantú syndrome.

Background: Structural rearrangements form a major class of somatic variation in cancer genomes. Local chromosome shattering, termed chromothripsis, is a mechanism proposed to be the cause of clustered chromosomal rearrangements and was recently described to occur in a small percentage of tumors. The significance of these clusters for tumor development or metastatic spread is largely unclear., Results: We used genome-wide long mate-pair sequencing and SNP array profiling to reveal that chromothripsis is a widespread phenomenon in primary colorectal cancer and metastases. We find large and small chromothripsis events in nearly every colorectal tumor sample and show that several breakpoints of chromothripsis clusters and isolated rearrangements affect cancer genes, including NOTCH2, EXO1 and MLL3. We complemented the structural variation studies by sequencing the coding regions of a cancer exome in all colorectal tumor samples and found somatic mutations in 24 genes, including APC, KRAS, SMAD4 and PIK3CA. A pairwise comparison of somatic variations in primary and metastatic samples indicated that many chromothripsis clusters, isolated rearrangements and point mutations are exclusively present in either the primary tumor or the metastasis and may affect cancer genes in a lesion-specific manner., Conclusions: We conclude that chromothripsis is a prevalent mechanism driving structural rearrangements in colorectal cancer and show that a complex interplay between point mutations, simple copy number changes and chromothripsis events drive colorectal tumor development and metastasis.