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Background Inclusion body myositis (IBM) is the most common acquired myopathy in adults over the age of 50 years, characterised by inflammatory and degenerative features that lead to progressive muscle weakness and physical disability for lack of effective therapies. The complex interplay between inflammatory and degenerative processes, occurring seemingly simultaneously, presents a challenge to systematically dissect disease pathology and discover novel therapeutic targets. Methods To identify proteomic IBM disease signatures and upstream regulators of disease processes in an unbiased manner, we performed high‐resolution iTRAQ‐labelled mass spectrometry on whole muscle lysates of 28 IBM patients and 28 control individuals. Validation experiments were carried out by conducting immunohistochemical (IHC) stainings on KDM5A and myogenin using control and IBM patient muscle tissue sections. Human myoblasts were used to study involvement of KDM5A, a selected candidate‐upstream regulator, in IBM pathomechanisms in vitro. Results A total of 627 significantly differentially expressed proteins were found in IBM patients compared to control individuals. The proteomics dataset strongly reflected inflammatory signatures, dysregulations in cellular energy metabolism and altered myogenesis in IBM muscle. Identification of upstream regulators of IBM pathology yielded KDM5A as the top activated and RB1 as the top inhibited upstream regulator. KDM5A, a histone demethylase involved in transcription regulation and (myogenic) differentiation, interacts with RB1 and interconnects core IBM disease signatures in patient muscle tissue. IHC stainings on muscle tissue showed increased presence of myogenin‐positive myonuclei (p < 0.0001). KDM5A levels were increased in these myogenin‐positive myonuclei in IBM patient muscle tissue compared to healthy controls (p < 0.0001). In vitro differentiation of myoblasts showed gradual KDM5A downregulation throughout myogenic differentiation, confirming presence in immature myoblasts and low levels in more mature myotubes. Proof‐of‐concept pharmacological inhibition of KDM5A with ryuvidine showed a significant effect on amyloid precursor protein (APP) abundance (p = 0.0003) and aggregation (p = 0.0132) in a conditional IBM‐mimicking inflammatory model. Conclusions This unbiased proteomics study reflects known core features of IBM pathomechanisms while simultaneously providing novel insights into the proteomic landscape of IBM, most notably dysregulation of metabolic pathways and failure of myogenesis. The identification and exploration of KDM5A as a potential upstream driver of disease pathology could interconnect failure of myogenic differentiation with (known) disease processes in IBM and provides a target for future study and therapy.

Inflammatory bowel disease (IBD) patients are at increased risk of developing colorectal cancer. However, histologically, it is challenging to distinguish between IBD-associated dysplasia from sporadic adenomas. We have molecularly characterized these precursor lesions and show that IBD-associated dysplasia lesions are genomically much more unstable.AbstractBackgroundPatients with longstanding inflammatory bowel disease (IBD; ie, ulcerative colitis and Crohn’s disease) have an increased risk of colorectal cancer (CRC). Due to ongoing inflammation, IBD-associated dysplastic lesions can develop. These lesions have an increased risk to progress to cancer compared with sporadic adenomas, which are also found in these patients. Differentiating between these 2 types of dysplasia remains challenging, both clinically and histologically, while treatment strategies may differ. Therefore, the aim of this study was to investigate molecular alterations associated with colorectal dysplasia to cancer progression in IBD and evaluate to what extent these alterations differ from sporadic adenomas.MethodsDNA copy number aberrations and mutation analyses of 48 genes were performed by next-generation sequencing in 43 IBD-associated dysplastic lesions, 30 of which were dysplastic and 13 of which were cancers. Results were compared with existing DNA copy number and mutation data from 118 sporadic adenomas and 24 sporadic cancers.ResultsInflammatory bowel disease–associated dysplastic lesions harbor patterns of DNA copy number aberrations comparable to carcinomas, which are rare in sporadic adenomas. TP53 mutation was the most frequent mutation observed in IBD-associated dysplastic lesions and in cancers. FBXW7 was mutated significantly more often in IBD-associated dysplastic lesions than in sporadic adenomas.ConclusionsInflammatory bowel disease–associated dysplastic lesions show more DNA copy number aberrations than sporadic adenomas. TP53 and FBXW7 mutations appear to be involved in the development of IBD-associated dysplastic lesions and cancer. These findings indicate that IBD-associated dysplastic lesions are more genomically unstable, possibly reflecting a faster progression toward cancer.

Nature-based solutions (NBSs) offer an opportunity to address environmental and societal challenges worldwide while simultaneously providing benefits for human well-being as well as biodiversity. Despite a growing demand and evidence base for NBSs in coastal systems, the scaling of their implementation and mainstreaming of their principles in policy and practice are constrained by multiple barriers, such as misinterpretations of concepts, effectiveness, or locked-in preferences or conventions of traditional solutions. To address these constraints, an international consortium of coastal authorities and experts in the North Sea Region collaborates to validate, document, and share learnings of NBSs to establish a framework for mainstreaming NBSs for flood and coastal erosion risk management around the North Sea. Co-creation processes of workshops, field visits, and expert knowledge sessions contributed to a theoretical framework and baseline assessments of exemplary sandy and muddy case study sites in the region, amongst others, iteratively providing and showcasing building blocks for the mainstreaming framework. This article takes stock halfway of the project’s activities, learnings, and status of the called-for common language.

Background Guideline adherence in physical therapy is far from optimal, which has consequences for the effectiveness and efficiency of physical therapy care. Programmes to enhance guideline adherence have, so far, been relatively ineffective. We systematically developed a theory-based Quality Improvement in Physical Therapy (QUIP) programme aimed at the individual performance level (practicing physiotherapists; PTs) and the practice organization level (practice quality manager; PQM). The aim of the study was to pilot test the multilevel QUIP programme’s effectiveness and the fidelity, acceptability and feasibility of its implementation. Methods A one-group, pre-test, post-test pilot study (N = 8 practices; N = 32 PTs, 8 of whom were also PQMs) done between September and December 2009. Guideline adherence was measured using clinical vignettes that addressed 12 quality indicators reflecting the guidelines’ main recommendations. Determinants of adherence were measured using quantitative methods (questionnaires). Delivery of the programme and management changes were assessed using qualitative methods (observations, group interviews, and document analyses). Changes in adherence and determinants were tested in the paired samples T-tests and expressed in effect sizes (Cohen’s d). Results Overall adherence did not change (3.1%; p = .138). Adherence to three quality indicators improved (8%, 24%, 43%; .000 ≤ p ≤ .023). Adherence to one quality indicator decreased (−15.7%; p = .004). Scores on various determinants of individual performance improved and favourable changes at practice organizational level were observed. Improvements were associated with the programme’s multilevel approach, collective goal setting, and the application of self-regulation; unfavourable findings with programme deficits. The one-group pre-test post-test design limits the internal validity of the study, the self-selected sample its external validity. Conclusions The QUIP programme has the potential to change physical therapy practice but needs considerable revision to induce the ongoing quality improvement process that is required to optimize overall guideline adherence. To assess its value, the programme needs to be tested in a randomized controlled trial.

Background Systematic planning could improve the generally moderate effectiveness of interventions to enhance adherence to clinical practice guidelines. The aim of our study was to demonstrate how the process of Intervention Mapping was used to develop an intervention to address the lack of adherence to the national CPG for low back pain by Dutch physical therapists. Methods We systematically developed a program to improve adherence to the Dutch physical therapy guidelines for low back pain. Based on multi-method formative research, we formulated program and change objectives. Selected theory-based methods of change and practical applications were combined into an intervention program. Implementation and evaluation plans were developed. Results Formative research revealed influential determinants for physical therapists and practice quality managers. Self-regulation was appropriate because both the physical therapists and the practice managers needed to monitor current practice and make and implement plans for change. The program stimulated interaction between practice levels by emphasizing collective goal setting. It combined practical applications, such as knowledge transfer and discussion-and-feedback, based on theory-based methods, such as consciousness raising and active learning. The implementation plan incorporated the wider environment. The evaluation plan included an effect and process evaluation. Conclusions Intervention Mapping is a useful framework for formative data in program planning in the field of clinical guideline implementation. However, a decision aid to select determinants of guideline adherence identified in the formative research to analyse the problem may increase the efficiency of the application of the Intervention Mapping process.

The aim of this study was to test whether the associations between adolescent-parent attachment and externalizing problem behavior of adolescents were mediated by adolescent cognitive distortions, self-esteem, parental monitoring and association with deviant peers. A total of 102 adolescents (71 % male; aged 12-19 years) at risk for developing delinquent behaviors reported on attachment, parental monitoring, aggressive and delinquent behavior and peers. Mediation effects were tested by using structural equation modeling. Different pathways were found depending on the type of externalizing behavior. The association between attachment and direct and indirect aggressive behavior was mediated by cognitive distortions. The relation between attachment and delinquency was mediated by deviant peers and parental monitoring. We argue that clinical practice should focus on the attachment relationship between adolescent and parents in order to positively affect risk and protective factors for adolescents' aggressive and delinquent behavior.