Data-driven support to decision-making in molecular tumour boards for lymphoma: A design science approach.

Background: The increasing amount of molecular data and knowledge about genomic alterations from next-generation sequencing processes together allow for a greater understanding of individual patients, thereby advancing precision medicine. Molecular tumour boards feature multidisciplinary teams of clinical experts who meet to discuss complex individual cancer cases. Preparing the meetings is a manual and time-consuming process. Purpose: To design a clinical decision support system to improve the multimodal data interpretation in molecular tumour board meetings for lymphoma patients at Karolinska University Hospital, Stockholm, Sweden. We investigated user needs and system requirements, explored the employment of artificial intelligence, and evaluated the proposed design with primary stakeholders. Methods: Design science methodology was used to form and evaluate the proposed artefact. Requirements elicitation was done through a scoping review followed by five semi-structured interviews. We used UML Use Case diagrams to model user interaction and UML Activity diagrams to inform the proposed flow of control in the system. Additionally, we modelled the current and future workflow for MTB meetings and its proposed machine learning pipeline. Interactive sessions with end-users validated the initial requirements based on a fictive patient scenario which helped further refine the system. Results: The analysis showed that an interactive secure Web-based information system supporting the preparation of the meeting, multidisciplinary discussions, and clinical decision-making could address the identified requirements. Integrating artificial intelligence via continual learning and multimodal data fusion were identified as crucial elements that could provide accurate diagnosis and treatment recommendations. Impact: Our work is of methodological importance in that using artificial intelligence for molecular tumour boards is novel. We provide a consolidated proof-of-concept system that could support the end-to-end clinical decision-making process and positively and immediately impact patients. Conclusion: Augmenting a digital decision support system for molecular tumour boards with retrospective patient material is promising. This generates realistic and constructive material for human learning, and also digital data for continual learning by data-driven artificial intelligence approaches. The latter makes the future system adaptable to human bias, improving adequacy and decision quality over time and over tasks, while building and maintaining a digital log.

Effects of Dance Movement Therapy and Dance on Health-Related Psychological Outcomes. A Meta-Analysis Update.

Background: Dance is an embodied activity and, when applied therapeutically, can have several specific and unspecific health benefits. In this meta-analysis, we evaluated the effectiveness of dance movement therapy(DMT) and dance interventions for psychological health outcomes. Research in this area grew considerably from 1.3 detected studies/year in 1996-2012 to 6.8 detected studies/year in 2012-2018. Method: We synthesized 41 controlled intervention studies (N = 2,374; from 01/2012 to 03/2018), 21 from DMT, and 20 from dance, investigating the outcome clusters of quality of life, clinical outcomes (with sub-analyses of depression and anxiety), interpersonal skills, cognitive skills, and (psycho-)motor skills. We included recent randomized controlled trials (RCTs) in areas such as depression, anxiety, schizophrenia, autism, elderly patients, oncology, neurology, chronic heart failure, and cardiovascular disease, including follow-up data in eight studies. Results: Analyses yielded a medium overall effect (d = 0.60), with high heterogeneity of results (I 2 = 72.62%). Sorted by outcome clusters, the effects were medium to large (d = 0.53 to d = 0.85). All effects, except the one for (psycho-)motor skills, showed high inconsistency of results. Sensitivity analyses revealed that type of intervention (DMT or dance) was a significant moderator of results. In the DMT cluster, the overall medium effect was small, significant, and homogeneous/consistent (d = 0.30, p < 0.001, I 2 = 3.47). In the dance intervention cluster, the overall medium effect was large, significant, yet heterogeneous/non-consistent (d = 0.81, p < 0.001, I 2 = 77.96). Results suggest that DMT decreases depression and anxiety and increases quality of life and interpersonal and cognitive skills, whereas dance interventions increase (psycho-)motor skills. Larger effect sizes resulted from observational measures, possibly indicating bias. Follow-up data showed that on 22 weeks after the intervention, most effects remained stable or slightly increased. Discussion: Consistent effects of DMT coincide with findings from former meta-analyses. Most dance intervention studies came from preventive contexts and most DMT studies came from institutional healthcare contexts with more severely impaired clinical patients, where we found smaller effects, yet with higher clinical relevance. Methodological shortcomings of many included studies and heterogeneity of outcome measures limit results. Initial findings on long-term effects are promising.

User Requirements for an Electronic Medical Records System for Oncology in Developing Countries: A Case Study of Uganda.

Cancer is a major public health challenge in developing countries but the healthcare systems are not well prepared to deal with the epidemic. Health information technologies such as electronic medical records (EMRs) have the potential to improve cancer care yet their adoption remains low, in part due to EMR systems not meeting user requirements. This study aimed at analyzing the user requirements for an EMR for a cancer hospital in Uganda. A user-centered approach was taken, through focus group discussion and interviews with target end users to analyze workflow, challenges and wishes. Findings highlight the uniqueness of oncology in low-resource settings and the requirements including support for oncology-specific documentation, reuse of data for research and reporting, assistance with care coordination, computerized clinical decision support, and the need to meet the constraints in terms of technological infrastructure, stretched healthcare workforce and flexibility to allow variations and exceptions.

Living with Lung Cancer--Patients' Experiences as Input to eHealth Service Design.

The objective of the study is to describe the lung cancer care process as experienced by patients, as well as to perform a qualitative analysis of problems they encounter throughout the patient journey. A user-centered design approach was used and data collected through two focus group meetings with patients. We present the results in the form of a patient journey model, descriptions of problems related to the journey as expressed by patients and proposed eHealth services discussed by patients in the focus groups. The results indicate that not only is the patient journey fragmented and different for each patient going through it depending upon their specific type of lung cancer and treatment options, but their experiences are also highly individual and dependent on their personal needs and interpretations of the process. Designing eHealth to improve the patient journey will therefore require flexibility and adaptability to the individual's needs.

Experiences as input to eHealth design - a hip surgery patient journey case.

The objective of the study is to describe the planned hip-surgery care process as experienced by patients and healthcare professionals, as well as a qualitative analysis of problems. Data was collected through 3 focus group meetings with patients and healthcare professionals. We present the results in form of a patient journey model, examples of problems as expressed by patients and examples of proposed eHealth services by both patients and care professionals. The results indicate that although the patient journey is similar for most patients, their experiences are highly individual and designing eHealth to improve the patient journey will require flexibility and adaptability to the individual's needs.

[Potential analysis for research on Advanced Practice Nursing (APN) for persons with dementia living in long-term care facilities]. / Potenzialanalyse zu "Advanced Practice Nursing (APN)" für Bewohner mit dementiellen Erkrankungen in deutschen Einrichtungen der stationären Langzeitpflege.

HEALTH PROBLEM: The nursing Minimum Data Set 3.0 (MDS 3.0) and other nursing quality indices summarise relevant health and nursing outcomes for long-term care that are recommended as quality measures. These are measures like "Percent of High-Risk Residents with Pressure Ulcers", "Percent of Low-Risk Residents Who Lose Control of Their Bowels or Bladder", "Percent of Residents Experiencing One or More Falls with Major Injury", "Percent of Residents Who Lose Too Much Weight" etc. Analyses of healthcare data in Germany showed a substantial higher risk for negative outcomes in the long-term care setting in persons with dementia compared to persons without dementia. There already exist evidence-based guidelines and recommendations for most of the quality measures and underlying health problems (e.g., the German "Expertenstandards in der Pflege"). Implementation and translation of evidence have not been systematically researched yet, and there is uncertainty about structures and processes that support implementation and eventually lead to improved nursing outcomes in people with dementia in long-term care. CORPUS OF EVIDENCE: Studies showed a potential benefit of master-level geriatric advanced practice nurses (GAPNs) concerning the implementation of evidence-based guidelines. This corresponds to the expectation that academic nursing staff positively influences research utilisation in practice. A systematic review identified four controlled trials that evaluated the effectiveness of GAPN on select quality measures. Both the internal and external validity of the trials require a thorough investigation into the intervention before translation and effectiveness research in Germany can be recommended. IMPLICATION FOR RESEARCH: In accordance with national and international recommendations on the development and clinical evaluation of complex interventions, we recommend a multistage model. Such a model comprises the conceptualisation and adaptation of the original intervention. In this way, the original concept of a GAPN has to be translated into the context of the German healthcare system. Furthermore, feasibility of the intervention in general has to be investigated. This includes acceptance of GAPNs in practice and the necessary prerequisites, especially concerning a comprehensive commitment of one APN to more than one long-term care facility.

Cis-regulatory underpinnings of human GLI3 expression in embryonic craniofacial structures and internal organs.

The zinc finger transcription factor Gli3 is an important mediator of Sonic hedgehog (Shh) signaling. During early embryonic development Gli3 participates in patterning and growth of the central nervous system, face, skeleton, limb, tooth and gut. Precise regulation of the temporal and spatial expression of Gli3 is crucial for the proper specification of these structures in mammals and other vertebrates. Previously we reported a set of human intronic cis-regulators controlling almost the entire known repertoire of endogenous Gli3 expression in mouse neural tube and limbs. However, the genetic underpinning of GLI3 expression in other embryonic domains such as craniofacial structures and internal organs remain elusive. Here we demonstrate in a transgenic mice assay the potential of a subset of human/fish conserved non-coding sequences (CNEs) residing within GLI3 intronic intervals to induce reporter gene expression at known regions of endogenous Gli3 transcription in embryonic domains other than central nervous system (CNS) and limbs. Highly specific reporter expression was observed in craniofacial structures, eye, gut, and genitourinary system. Moreover, the comparison of expression patterns directed by these intronic cis-acting regulatory elements in mouse and zebrafish embryos suggests that in accordance with sequence conservation, the target site specificity of a subset of these elements remains preserved among these two lineages. Taken together with our recent investigations, it is proposed here that during vertebrate evolution the Gli3 expression control acquired multiple, independently acting, intronic enhancers for spatiotemporal patterning of CNS, limbs, craniofacial structures and internal organs.

Human intronic enhancers control distinct sub-domains of Gli3 expression during mouse CNS and limb development.

BACKGROUND: The zinc-finger transcription factor GLI3 is an important mediator of Sonic hedgehog signaling and crucial for patterning of many aspects of the vertebrate body plan. In vertebrates, the mechanism of SHH signal transduction and its action on target genes by means of activating or repressing forms of GLI3 have been studied most extensively during limb development and the specification of the central nervous system. From these studies it has emerged, that Gli3 expression must be subject to a tight spatiotemporal regulation. However, the genetic mechanisms and the cis-acting elements controlling the expression of Gli3 remained largely unknown. RESULTS: Here, we demonstrate in chicken and mouse transgenic embryos that human GLI3-intronic conserved non-coding sequence elements (CNEs) autonomously control individual aspects of Gli3 expression. Their combined action shows many aspects of a Gli3-specific pattern of transcriptional activity. In the mouse limb bud, different CNEs enhance Gli3-specific expression in evolutionary ancient stylopod and zeugopod versus modern skeletal structures of the autopod. Limb bud specificity is also found in chicken but had not been detected in zebrafish embryos. Three of these elements govern central nervous system specific gene expression during mouse embryogenesis, each targeting a subset of endogenous Gli3 transcription sites. Even though fish, birds, and mammals share an ancient repertoire of gene regulatory elements within Gli3, the functions of individual enhancers from this catalog have diverged significantly. During evolution, ancient broad-range regulatory elements within Gli3 attained higher specificity, critical for patterning of more specialized structures, by abolishing the potential for redundant expression control. CONCLUSION: These results not only demonstrate the high level of complexity in the genetic mechanisms controlling Gli3 expression, but also reveal the evolutionary significance of cis-acting regulatory networks of early developmental regulators in vertebrates.

Novel mutation and the first prenatal screening of cathepsin D deficiency (CLN10).

The neuronal ceroid lipofuscinoses (NCLs) are autosomal recessively inherited disorders collectively considered to be one among the most common pediatric neurodegenerative lysosomal storage diseases. Four main clinical subtypes have been described based on the age at presentation: infantile, late infantile, juvenile and adult types. In addition, rare congenital cases of NCL have been reported in the literature. Previously, a homozygous mutation in the cathepsin D gene has been shown to cause congenital NCL in a patient of Pakistani origin. We report a case of a 39-week estimated gestational age female infant with severe microcephaly and hypertonia, whereas MRI showed generalized hypoplasia of the cerebral and cerebellar hemispheres. The infant died on day two after birth. Postmortem examination revealed a small, firm brain with extensive neuronal loss and gliosis. Remaining neurons, astrocytes and macrophages contained PAS-positive storage material with granular ultrastructure and immunoreactivity against sphingolipid activator protein D. A diagnosis of congenital NCL was rendered with a novel mutation, c.299C > T (p.Ser100Phe) in exon 3 of the cathepsin D gene. In the patient fibroblasts, cathepsin D activity was marginal, but the protein appeared stable and normally processed. This was confirmed in overexpression studies. Importantly, by identification of the mutation in the family, we were able to confirm the first prenatal diagnosis excluding cathepsin D deficiency in the younger sibling of the patient.

A new redox-dependent mechanism of MMP-1 activity control comprising reduced low-molecular-weight thiols and oxidizing radicals.

Matrix metalloproteinases (MMPs), a family of zinc-dependent proteinases, participate in remodeling and degradation of the extracellular matrix proteins. The activity of MMPs is thought to be predominately posttranslationally regulated via proteolytic activation of precursor zymogens or via their naturally occurring endogenous inhibitors. Here, using recombinant MMP-1, we investigated new redox-dependent mechanisms of proteinase activity regulation by low-molecular-weight thiols. We find that glutathione (GSH), cysteine, homocysteine, and N-acetylcysteine at physiological concentrations competitively reduce MMP-1 activity up to 75% with an efficiency of cysteine > or = GSH > homocysteine > N-acetylcysteine. In contrast, S-derivatized thiols completely lack this inhibitory activity. Interestingly, the competitive GSH-mediated inhibition of MMP-1-activity can be fully reversed abrogated by oxidizing radicals like (*)NO(2) or Trolox radicals, here generated by UVA irradiation of nitrite or Trolox, two relevant agents in human skin physiology. This redox-dependent reactivation of the inactive GSH-MMP-1-complex comprises GSH oxidation and is significantly inhibited in the presence of ascorbic acid, an effective (*)NO(2) and Trolox radical scavenger. We here offer a new concept of redox-sensitive control of MMP-1 activity based on the inhibitory effect of reduced thiols and reactivation by a mechanism comprising derivatization or oxidation of the MMP-1-bound inhibitory-acting thiol.

Development of a composite degradable/nondegradable tissue-engineered vascular graft.

The present study aimed to determine the feasibility of constructing a reinforced autologous vascular graft by combining the advantages of fibrin gel as an autologous cell carrier material with the inherent mechanical strength of an integrated mesh structure. It was hypothesized that the mesh and dynamic culture conditions could be combined to generate mechanically stable and implantable vascular grafts within a shorter cultivation period than traditional methods. A two-step moulding technique was developed to integrate a polyvinylidene fluoride (PVDF) mesh (pore size: 1-2 mm) in the wall of a fibrin-based vascular graft (I.D. 5 mm) seeded with carotid myofibroblasts. The graft was cultured under increasing physiological flow conditions for 2 weeks. Histology, burst strength, and suture retention strength were evaluated. Cell growth and tissue development was excellent within the fibrin gel matrix surrounding the PVDF fibers, and tissue structure demonstrated remarkable similarity to native tissue. The grafts were successfully subjected to physiological flow rates and pressure gradients from the outset, and mechanical properties were enhanced by the mesh structure. Mean suture retention strength of the graft tissue was 6.3 N and the burst strength was 236 mm Hg. Using the vascular composite graft technique, the production of tissue engineered, small-caliber vascular grafts with good mechanical properties within a conditioning period of 14 days is feasible.

The in vitro development of autologous fibrin-based tissue-engineered heart valves through optimised dynamic conditioning.

Our group has previously demonstrated the synthesis of a completely autologous fibrin-based heart valve structure using the principles of tissue engineering. The present approach aims to guide more mature tissue development in fibrin-based valves based on in vitro conditioning in a custom-designed bioreactor system. Moulded fibrin-based tissue-engineered heart valves seeded with ovine carotid artery-derived cells were subjected to 12 days of mechanical conditioning in a bioreactor system. The bioreactor pulse rate was increased from 5 to 10 b.p.m. after 6 days, while a pressure difference of 20 mmH(2)O was maintained over the valve leaflets. Control valves were cultured under stirred conditions in a beaker. Cell phenotype and extracellular matrix (ECM) composition were analysed in all samples and compared to native ovine aortic valve tissue using routine histological and immunohistochemical techniques. Conditioned valve leaflets showed reduced tissue shrinkage compared to stirred controls. Limited ECM synthesis was evident in stirred controls, while the majority of cells were detached from the fibrin scaffold. Dynamic conditioning increased cell attachment/alignment and expression of alpha-smooth muscle actin, while enhancing the deposition of ECM proteins, including types I and III collagen, fibronectin, laminin and chondroitin sulphate. There was no evidence for elastin synthesis in either stirred controls or conditioned samples. The present study demonstrates that the application of low-pressure conditions and increasing pulsatile flow not only enhances seeded cell attachment and alignment within fibrin-based heart valves, but dramatically changes the manner in which these cells generate ECM proteins and remodel the valve matrix. Optimised dynamic conditioning, therefore, might accelerate the maturation of surgically feasible and implantable autologous fibrin-based tissue-engineered heart valves.

Gene expression in synovial membrane cells after intraarticular delivery of plasmid-linked superparamagnetic iron oxide particles--a preliminary study in sheep.

This study evaluated in vivo gene delivery and subsequent gene expression within cells of the synovium in the presence of static and pulsating magnetic field application following intraarticular injection of superparamagnetic iron oxide nanoparticles linked to plasmids containing reporter genes encoding for fluorescent proteins. Plasmids encoding genes for either green fluorescent protein or red fluorescent protein were bound to superparamagnetic nanoparticles coated with polyethyleneimine. Larger (200-250 nm) and smaller (50 nm) nanoparticles were compared to evaluate the effects of size on transfection efficiency as well as any associated intraarticular reaction. Comparisons between groups were evaluated at 24, 72, and 120 h time periods. Inflammatory response was mild to moderate for all injected particles, but was present in the majority of synovial membrane samples evaluated. Larger particles tended to be associated with more inflammation than smaller ones. Nevertheless, intraarticular application of both experimental and control nanoparticles were well tolerated clinically. Gene expression as determined by observation of either green or red intracellular fluorescence was difficult to assess by both epifluorescent light, and confocal microscopy. An insufficient concentration of nanoparticles in relation to joint volume likely resulted in a limited number of samples with positive evidence of iron staining and with suspected positive evidence of cells expressing fluorescent proteins. Our results indicate that intraarticular administration of functionalized superparamagnetic iron oxide nanoparticles resulted in a mild to moderate synovitis and there was in conclusive evidence of gene expression. Further research is warranted to determine the best and most effective reporter assay for assessment of the in vivo gene delivery into the joints. In addition, the best suited concentration and size of nanoparticles, which will optimize gene delivery and expression, while minimizing intraarticular inflammation, needs to be determined.

Differential expression of desmosomal plakophilins in various types of carcinomas: correlation with cell type and differentiation.

Plakophilins (PKPs) are a set of 3 constitutive armadillo repeat proteins of the desmosomal plaque, termed PKP 1, PKP 2, and PKP 3, which have been shown to be functionally relevant for desmosomal adhesion. We have performed a systematic immunohistochemical study of the 3 PKPs in oral and pharyngeal squamous cell carcinomas (SqCCs; n = 40); colorectal, pancreatic, and prostate adenocarcinomas (n = 31), and hepatocellular carcinomas (HCCs; n = 8). In SqCCs, PKP 1 and PKP 3 revealed common desmosome-type immunostaining, their expression level being inversely correlated with the degree of malignancy. Instead, staining for PKP 2 was limited. In contrast, all adenocarcinomas contained PKP 2 and-often abundantly-PKP 3 in desmosome-typical pattern, whereas PKP 1 was expressed only in prostate tumors. The presence of PKP 3 in adenocarcinomas was confirmed by immunoblotting. In HCCs, only PKP 2 was detected. Under certain staining conditions, focal nuclear immunoreactivity for PKP 1 was observed in some SqCCs and HCCs. Our results, which are inconsistent with previously published data to some extent, indicate a principal preservation of the cell type and differentiation-related expression patterns of PKPs in normal epithelia. For PKP 1, a suppressor function of malignant behavior seems conceivable, whereas the putative functional significance of its occurrence in tumor cell nuclei requires further studies.

Modification of collagen matrices for enhancing angiogenesis.

The vascularization of engineered tissues in many cases does not keep up with the ingrowth of cells. Nutrient and oxygen supply are not sufficient, which ultimately leads to the death of the invading cells. The enhancement of the angiogenic capabilities of engineered tissues therefore represents a major challenge in the field of tissue engineering. The immobilization of angiogenic growth factors may be useful for enhancing angiogenesis. The most potent angiogenic growth factor specific to endothelial cells, vascular endothelial growth factor (VEGF), occurs in several splice variants. The variant with 165 amino acids both has a high angiogenic activity and a high affinity for heparin. We therefore incorporated heparin molecules into collagen matrices by covalently cross-linking them to amino functions on the collagen. Physical binding of VEGF to the heparin may then prevent a rapid clearance from the implant, while the release rate may become coupled to the degradation of the collagen matrix. The modified matrices were characterized by determination of the extent of the heparin immobilization, the in vitro degradation rate by collagenase. For testing the angiogenic properties, non-modified and heparinized collagen specimens were--either loaded with VEGF or non-loaded--subcutaneously implanted on the back of rats. Specimens were explanted after varying periods of implantation, the dry weights and the hemoglobin contents, as well as immunostained histological sections were evaluated: heparinized collagen matrices loaded with VEGF are vascularized to a substantially higher extent as compared to non-modified matrices.