Complex Organization Research Articles

Barriers to and Facilitators of Key Stakeholders Influencing Successful Digital Implementation of Remote Monitoring Solutions: Mixed Methods Analysis.

Implementation of remote monitoring solutions and digital alerting tools in health care has historically been challenging, despite the impetus provided by the COVID-19 pandemic. To date, a health systems-based approach to systematically describe barriers and facilitators across multiple domains has not been undertaken. We aimed to undertake a comprehensive mixed methods analysis of barriers and facilitators for successful implementation of remote monitoring and digital alerting tools in complex health organizations. A mixed methods approach using a modified Technology Acceptance Model questionnaire and semistructured interviews mapped to the validated fit among humans, organizations, and technology (HOT-fit) framework was undertaken. Likert frequency responses and deductive thematic analyses were performed. A total of 11 participants responded to the questionnaire and 18 participants to the interviews. Key barriers and facilitators could be mapped onto 6 dimensions, which incorporated aspects of digitization: system use (human), user satisfaction (human), environment (organization), structure (organization), information and service quality (technology), and system quality (technology). The recommendations proposed can enhance the potential for future remote sensing solutions to be more successfully integrated in health care practice, resulting in more successful use of "virtual wards." ClinicalTrials.gov NCT05321004; https://www.clinicaltrials.gov/study/NCT05321004.

Network science: Ising states of matter.

Network science provides very powerful tools for extracting information from interacting data. Although recently the unsupervised detection of phases of matter using machine learning has raised significant interest, the full prediction power of network science has not yet been systematically explored in this context. Here we fill this gap by providing an in-depth statistical, combinatorial, geometrical, and topological characterization of 2D Ising snapshot networks (IsingNets) extracted from Monte Carlo simulations of the 2D Ising model at different temperatures, going across the phase transition. Our analysis reveals the complex organization properties of IsingNets in both the ferromagnetic and paramagnetic phases and demonstrates the significant deviations of the IsingNets with respect to randomized null models. In particular percolation properties of the IsingNets reflect the existence of the symmetry between configurations with opposite magnetization below the critical temperature and the very compact nature of the two emerging giant clusters revealed by our persistent homology analysis of the IsingNets. Moreover, the IsingNets display a very broad degree distribution and significant degree-degree correlations and weight-degree correlations demonstrating that they encode relevant information present in the configuration space of the 2D Ising model. The geometrical organization of the critical IsingNets is reflected in their spectral properties deviating from the one of the null model. This work reveals the important insights that network science can bring to the characterization of phases of matter. The set of tools described hereby can be applied as well to numerical and experimental data.

Optimization of management of economic companies of the agroindustrial complex with state share of ownership

On the basis of the current composition and structure of agroindustrial complex organizations of the Republic of Belarus, the dynamics of change of the state’s share in the authorized capital of agricultural, as well as industrial and service economic societies has been revealed; the peculiarities of normative-legal regulation of management of economic societies of agroindustrial complex with the state share of ownership have been studied; the scheme of the organizational mechanism of their management and the directions of improving the assessment of the performance of the state representatives in the management structure have been proposed.

Viable System Model (VSM): A New Approach to Accounting Information System Development Model

This article discusses the potential for using the Viable System Model (VSM) as a new approach in developing accounting information systems. This article takes the form of a systematic literature review. The analysis was carried out using a comparative approach between the System Development Life Cycle (SDLC-Model) and the Viable System Model (VSM) in general and specifically in the field of accounting and accounting information systems. The SDLC is primarily focused on the development and management of software or systems, while the VSM is concerned with the broader understanding and management of complex organizations. Both concepts have their unique applications and are important in their respective domains. The results of the study show that the VSM has a more holistic approach in developing accounting information systems. The research results also show that VSM is more suitable for developing accounting information systems in organizations that are complex, flexible, and adaptive to the speed of change in the company’s ongoing organizational business environment. The VSM provides a framework for understanding how organizations and systems can adapt to changing environments and maintain viability. It is particularly useful for complex organizations that need to respond to dynamic conditions. Keywords: accounting information system development, viable system model, system development life cycle

Abstract PO2-25-03: Deciphering the immune molecular signature associated with pembrolizumab efficacy in the neoadjuvant setting of Triple-Negative Breast Cancer patients: a single-centre experience

Abstract Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancers and is characterized by a high rate of recurrence, despite the improvement of the therapeutic approaches in recent years. Neoadjuvant chemotherapy (NACT) is the standard treatment for early-stage TNBC. Achieving a pathological complete response (pCR) is considered an essential prognostic factor for long-term outcomes. However, the percentage of pCR patients after NACT is limited to 30-40%, thus requiring the implementation of novel therapeutic strategies. Recently, by applying a morphology-guided spatial transcriptomic approach on Tru-Cut biopsies, we showed that intratumoral infiltrating lymphocytes (iTILs) and stromal Natural Killer (NK) cells are major determinants of chemotherapy efficacy in TNBC. These data highlight a complex three-dimensional organization of the tumor landscape and underline how spatiality and molecular activation of immune cells are essential to enhance the efficacy of neoadjuvant NACT in TNBC. The fact that immune cells are important players in this setting is corroborated by the clinical success shown by the KEYNOTE-522 study. This trial paved the way for the use of immunotherapy in neoadjuvant settings, obtaining a significant improvement in the patient’s overall response compared to standard NACT. Still, the implementation of chemotherapy with immunotherapy in the TNBC neoadjuvant treatment implicates several compelling questions, including how to further increase the percentage of patients with a complete response, overcoming resistance mechanisms, and how to improve the personalization of treatment, evaluating which patients can benefit from a therapy de-scalation or another combined therapeutic strategy. In this prospective cohort study, we decided to define the relevance of different immune populations in affecting pembrolizumab efficacy in the neoadjuvant treatment of TNBC patients. We treated 40 patients with an early-TNBC diagnosis with the KEYNOTE-522 regimen that consists of four cycles of an intravenous infusion of pembrolizumab plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab plus epirubicin and cyclophosphamide. Only patients with evident side effects to immunotherapy administration were a priori excluded. Currently, 18 patients ended the neoadjuvant schedule and underwent surgical excision. Our data indicate that 15 patients displayed a pCR at the end of the therapy, whereas 3 patients displayed only partial response. To further clarify the immune dynamics that lead to a complete response to pembrolizumab in these patients, we collected peripheral blood before and after neoadjuvant treatment to isolate peripheral blood mononucleated cells (PBMCs). We applied a single-cell transcriptome analysis to shape any variations in circulating immune cells occurring during neoadjuvant treatment and associated with patient response. In addition, we collected residual tumors at surgery from partial responders and derived three-dimensional organoids that recapitulate the characteristics of the original patient tumor. These ex vivo organoid-based platforms are applied to clarify the molecular mechanisms driving neoadjuvant resistance. To this aim, we are performing co-cultures with autologous immune cells to identify novel combined therapeutic strategies to rescue pembrolizumab efficacy in these models. Overall, our study is defining the immune-related molecular mechanisms driving pembrolizumab and chemotherapy response in the neoadjuvant treatment of TNBC patients. Our findings can improve our understanding of which immune populations are determinant players in anti-TNBC immune response and can be proposed as novel biomarkers of pembrolizumab efficacy during the neoadjuvant treatment. Citation Format: Elisa Gasparini, Gloria Manzotti, Moira Ragazzi, Benedetta Donati, Federica Torricelli, Elisa Salviato, Alessandra Bisagni, Eleonora Zanetti, Alessandra Bologna, Saverio Coiro, Rita Vacondio, Guglielmo Ferrari, Giancarlo Bisagni, Carmine Pinto, Alessia Ciarrocchi, Francesca Reggiani. Deciphering the immune molecular signature associated with pembrolizumab efficacy in the neoadjuvant setting of Triple-Negative Breast Cancer patients: a single-centre experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-25-03.

AI-based analysis and linking of technical and organisational data using graph models as a basis for decision-making in systems engineering

AbstractThe increased complexity of development projects surpass the capabilities of existing methods. While Model Based Systems Engineering pursues technically holistic approaches to realize complex products, aspects of organization as well as risk management, are still considered separately. The identification and management of risks are crucial in order to take suitable measures to minimize adverse effects on the project or the organization. To counter this, a new graph-based method and tool using AI, tailored to the needs of complex development projects and organizations is introduced here.

Biallelic Variants of MRPS36 Cause a New Form of Leigh Syndrome.

The MRPS36 gene encodes a recently identified component of the 2-oxoglutarate dehydrogenase complex (OGDHC), a key enzyme of the Krebs cycle catalyzing the oxidative decarboxylation of 2-oxoglutarate to succinyl-CoA. Defective OGDHC activity causes a clinically variable metabolic disorder characterized by global developmental delay, severe neurological impairment, liver failure, and early-onset lactic acidosis. We investigated the molecular cause underlying Leigh syndrome with bilateral striatal necrosis in two siblings through exome sequencing. Functional studies included measurement of the OGDHC enzymatic activity and MRPS36 mRNA levels in fibroblasts, assessment of protein stability in transfected cells, and structural analysis. A literature review was performed to define the etiological and phenotypic spectrum of OGDHC deficiency. In the two affected brothers, exome sequencing identified a homozygous nonsense variant (c.283G>T, p.Glu95*) of MRPS36. The variant did not affect transcript processing and stability, nor protein levels, but resulted in a shorter protein lacking nine residues that contribute to the structural and functional organization of the OGDHC complex. OGDHC enzymatic activity was significantly reduced. The review of previously reported cases of OGDHC deficiency supports the association of this enzymatic defect with Leigh phenotypic spectrum and early-onset movement disorder. Slightly elevated plasma levels of glutamate and glutamine were observed in our and literature patients with OGDHC defect. Our findings point to MRPS36 as a new disease gene implicated in Leigh syndrome. The slight elevation of plasma levels of glutamate and glutamine observed in patients with OGDHC deficiency represents a candidate metabolic signature of this neurometabolic disorder. © 2024 International Parkinson and Movement Disorder Society.

Swedish crisis preparedness planners' understanding and sense‐making of preparedness work in a public organisation: Implications for future development

AbstractThe sometimes rapid development of (new) threats and extraordinary events calls for a robust, flexible, and well‐equipped civil crisis preparedness system to respond and limit the damage of crisis events. To achieve this, Swedish municipalities and regions are required by law to regularly perform and report risk and vulnerability analysis ‘bottom up’ to governmental agencies. When performed in large and complex public organisations, crisis preparedness planning activities require negotiation, coordination, and cooperation among large numbers of people. Crisis preparedness planners facilitate and produce this proactive crisis preparedness work. However, research has revealed that preparedness planners face organisational and practical challenges when performing their work.This study aims at increasing the knowledge of crisis preparedness planners' understandings and sense‐making of their work in one Swedish region when fulfilling the requirements set by the Swedish national regulations. The objectives of this paper are to present findings on (1) how the preparedness planners understand and make sense of their crisis preparedness work; (2) which major enablers and barriers that affect their work; and, based on the results, (3) forward possibilities for improvement.Semi‐structured interviews were conducted with the 10 crisis preparedness planners. A narrative stepwise analysis approach was applied. The analysis results revealed challenges in the crisis preparedness work due to uncommitted managers, unclear goalsetting, and the planners' sometimes limited skills in crisis preparedness work. It also report on managers' autonomy and varying focus on crisis preparedness, planners' unclear individual work space, and many different and sometimes strong voices about the work performance and content. This raises the question whose interest that in practice sets the agenda for crisis preparedness planning in the organisation.The study demonstrates needs for increased organisational sense‐making on the concept of crisis preparedness and how it should be performed, and for conceptual and technical skills to perform the preparedness work. To increase sense‐making and strengthen generic subjectivity on crisis preparedness work, further discussions are needed about enablers and barriers in preparedness work and an increased joint focus on possible internal and external threats. There are also needs for increased manager‐coworker‐planner cooperation when developing the preparedness work, and strategic changes in the organisational development involving goalsetting for crisis preparedness ‘top‐down’ as well as ‘bottom‐up’.

Exploring the Role of Complexity in Health Care Technology Bottom-Up Innovations: Multiple-Case Study Using the Nonadoption, Abandonment, Scale-Up, Spread, and Sustainability Complexity Assessment Tool.

New digital technology presents new challenges to health care on multiple levels. There are calls for further research that considers the complex factors related to digital innovations in complex health care settings to bridge the gap when moving from linear, logistic research to embracing and testing the concept of complexity. The nonadoption, abandonment, scale-up, spread, and sustainability (NASSS) framework was developed to help study complexity in digital innovations. This study aims to investigate the role of complexity in the development and deployment of innovations by retrospectively assessing challenges to 4 digital health care innovations initiated from the bottom up. A multicase retrospective, deductive, and explorative analysis using the NASSS complexity assessment tool LONG was conducted. In total, 4 bottom-up innovations developed in Region Västra Götaland in Sweden were explored and compared to identify unique and shared complexity-related challenges. The analysis resulted in joint insights and individual learning. Overall, the complexity was mostly found outside the actual innovation; more specifically, it related to the organization's readiness to integrate new innovations, how to manage and maintain innovations, and how to finance them. The NASSS framework sheds light on various perspectives that can either facilitate or hinder the adoption, scale-up, and spread of technological innovations. In the domain of condition or diagnosis, a well-informed understanding of the complexity related to the condition or illness (diabetes, cancer, bipolar disorders, and schizophrenia disorders) is of great importance for the innovation. The value proposition needs to be clearly described early to enable an understanding of costs and outcomes. The questions in the NASSS complexity assessment tool LONG were sometimes difficult to comprehend, not only from a language perspective but also due to a lack of understanding of the surrounding organization's system and its setting. Even when bottom-up innovations arise within the same support organization, the complexity can vary based on the developmental phase and the unique characteristics of each project. Identifying, defining, and understanding complexity may not solve the issues but substantially improves the prospects for successful deployment. Successful innovation within complex organizations necessitates an adaptive leadership and structures to surmount cultural resistance and organizational impediments. A rigid, linear, and stepwise approach risks disregarding interconnected variables and dependencies, leading to suboptimal outcomes. Success lies in embracing the complexity with its uncertainty, nurturing creativity, and adopting a nonlinear methodology that accommodates the iterative nature of innovation processes within complex organizations.

The oil and gas complex efficiency: An ecosystem-based approach

Subject. The article considers approaches to improving efficiency. Objectives. The purpose is to determine the possibility to increase efficiency in shaping the prospects for the development of modern Russian organizations of the oil and gas complex from the standpoint of the ecosystem approach. Methods. The study draws on methods of content analysis, synthesis, and verbal modeling. Results. The paper shows that organizations of the country's oil and gas complex can create ecosystems. It established that the ecosystem functioning ensures an increase in the efficiency of interaction and mutual development of its participants, customers, and external environment as a whole. The novelty of the obtained results consists in the justification of the ecosystem approach, which is based on a combination of categories, like cooperation, coevolution, competition, and strategic management. Conclusions. The findings prove the feasibility of implementing a synergistic effect as a model that ensures the development of modern Russian oil and gas complex organizations based on an ecosystem approach, in the process of finding solutions to increase the efficiency of core activities of all ecosystem participants, including suppliers and consumers of goods and services.

Short fiber bundle filtering and test-retest reproducibility of the Superficial White Matter.

In recent years, there has been a growing interest in studying the Superficial White Matter (SWM). The SWM consists of short association fibers connecting near giry of the cortex, with a complex organization due to their close relationship with the cortical folding patterns. Therefore, their segmentation from dMRI tractography datasets requires dedicated methodologies to identify the main fiber bundle shape and deal with spurious fibers. This paper presents an enhanced short fiber bundle segmentation based on a SWM bundle atlas and the filtering of noisy fibers. The method was tuned and evaluated over HCP test-retest probabilistic tractography datasets (44 subjects). We propose four fiber bundle filters to remove spurious fibers. Furthermore, we include the identification of the main fiber fascicle to obtain well-defined fiber bundles. First, we identified four main bundle shapes in the SWM atlas, and performed a filter tuning in a subset of 28 subjects. The filter based on the Convex Hull provided the highest similarity between corresponding test-retest fiber bundles. Subsequently, we applied the best filter in the 16 remaining subjects for all atlas bundles, showing that filtered fiber bundles significantly improve test-retest reproducibility indices when removing between ten and twenty percent of the fibers. Additionally, we applied the bundle segmentation with and without filtering to the ABIDE-II database. The fiber bundle filtering allowed us to obtain a higher number of bundles with significant differences in fractional anisotropy, mean diffusivity, and radial diffusivity of Autism Spectrum Disorder patients relative to controls.

Between & Betwixt: Considerations of Cross-Organizational Readiness in University/Public School Partnership

University partnerships with public schools are an innovative opportunity to marry research and practice. One such endeavor was the Heinz Fellows Program at the Center for Urban Education in the School of Education at the University of Pittsburgh. The Heinz Fellows Program existed at the intersection of community engagement, public school praxis, and university collaboration, with a pursuit of equity and justice. Yet, despite four years of programming, significant investment from philanthropy, and deep commitment from the university and public-school partners, much of the services and activities were not sustained beyond the conclusion of the program. What has remained, though, are salient lessons about the preparatory work each organization must engage in prior to collaboration. A public school is an inherently complex organization, while a university is also complex, but in substantially different ways. Thus, to bridge the chasm, both organizations must participate in self-reflection about their readiness, resources, and right constituents to implement, evaluate, and sustain the collaboration. The article offers a robust framework to consider cross-organizational collaborative readiness and to guide future university/public school partnerships into sustainability.

Organization and Role of Bacterial SMC, MukBEF, MksBEF, Wadjet, and RecN Complexes

Organization and Role of Bacterial SMC, MukBEF, MksBEF, Wadjet, and RecN Complexes

A Stepwise Multivariate Granger Causality Method for Constructing Hierarchical Directed Brain Functional Network.

The directed brain functional network construction gives us the new insights into the relationships between brain regions from the causality point of view. The Granger causality analysis is one of the powerful methods to model the directed network. The complex brain network is also hierarchically constructed, which is particularly suited to facilitate segregated functions and the global integration of the segregated functions. Therefore, it is of great interest to explore new approach to model the hierarchical architecture of the directed network. In the present study, we proposed a new approach, namely, stepwise multivariate Granger causality (SMGC), considering both the directed and hierarchical features of brain functional network to explore the stepwise causal relationship in the network. The simulation study demonstrated that the diverse and complex hierarchical organization could be embedded in the apparently simple directed network. The proposed SMGC method could capture the multiple hierarchy of the directed network. When applying to the real functional magnetic resonance imaging (fMRI) datasets, the core triple resting-state networks in human brain showed within-network directed connections in the first-level directed network and rich and diverse between-network pathways in the second-level hierarchical network. The default mode network (DMN) had a prominent role in the resting-state acting as both the causal source and the important relay station. Further exploratory research on the adaption of directed hierarchical network in athletes suggested the enhanced bidirectional communication between the DMN and the central executive network (CEN) and the enhanced directed connections from the salience network (SN) to the CEN in the athlete group. The SMGC approach is capable of capturing the hierarchical architecture of the brain directed functional network, which refreshes the new stepwise causal relationship in the directed network. This might shed light on the potential application for exploring the altered hierarchical organization of brain directed network in neuropsychiatric disorders.

Peculiarities of urban planning organization of underground research complexes

The relevance of the construction and operation of underground research facilities specializing in the fields of astrophysics, particle physics, geophysics and biology has developed significantly over the past 30 years. Underground research facilities are able to provide the necessary conditions for conducting experimental studies of physical phenomena that go beyond the Standard Model of Physics. Among the publications devoted to the theoretical foundations of the development of underground urbanism, it is worth noting the works of E. Reynolds, R. Sterling, W. Breuer, and G. Haiko. The main aspects of the architectural and planning and volumetric-spatial structure of underground buildings and structures are outlined in the works of H. Admiral, A. Cornaro, J. Besner. The exploitation of underground space in the conditions of sustainable development of modern cities is studied in the works of L. von der Tann and S. Ritter, Fang-Le Peng, Yong-Kang Xiao. Ukrainian scientists have made a significant contribution to the theoretical issues of underground urbanism: S.V. Ryndyuk, M.A. Maksymenko. Prospects for the integrated development of underground space in Ukraine are highlighted in the works of T.O. Nishchyk. Scientific works of G.I. Gayko are devoted to the priority tasks of development of underground urbanism in Ukraine, assessment of risks of underground construction, historical development of underground space in Ukraine. The historical development of underground buildings and structures is also studied in the works of V. Biletskyi, L. Korkushko, A. Pleshkanovska. The overview of the planning structure of modern underground research complexes is presented in the articles by A. Ianni, A. Bettini, E. Coccia. The article presents a number of prerequisites that influence the choice of a site for the design of underground research complexes in Ukraine. Their brief description is presented. Based on a preliminary analysis of the world experience in designing this type of facilities, important criteria that should be used when choosing a design site are identified. A complete set of functional zones of the master plan of the above-ground territory of the underground research complex is defined. A number of basic recommendations have been formulated that should guide the designer in the development of the master plan.

Ranking of asset maintenance process KPIs using Fermatean fuzzy Delphi and Fermatean fuzzy ELECTRE method

The paper aims to present a hybrid model for measuring the performance of business processes in complex organizations based on the subjective decision-making of expert teams. The subject of the research is finding ways to measure, analyze and improve the key performance indicators (KPIs) process. Obtaining the values of KPIs, which reflect the real state of the process, creates a basis for their ranking, i.e. insight into KPIs that are extremely important for the process as well as KPIs that are of lesser importance, but as such are not excluded from consideration because they are necessary for the beginning, realization and completion of the process. The model was compiled through five phases and was tested through a case study in a real business organization, which deals with the maintenance of complex combat systems. The obtained results helped the management to take certain measures in order to improve the performance of the maintenance process. In the model, it is proposed to form two expert teams, which make assessments based on experience and express them in linguistic terms according to a predefined scale. Modeling of linguistic expressions is realized using intuitive fuzzy sets of a higher order, more precisely Fermatean fuzzy sets (FFS). Selecting KPIs, decomposing the process into sub-processes and assessing the relative importance of sub-processes is carried out by one team of experts, while another team carries out the assessment of KPIs at the level of each sub-process. Determining the relative importance of sub-processes is realized using the Delphi method extended to FFS while reaching a consensus. The measurement of process performance, i.e. the value of KPIs, is realized using Multi-Criteria Group Decision-Making (MCGDM), such as the ELECTRE method extended with FFS. The sensitivity analysis of the developed model is realized by uncertainty modeling with q-rung orthopair fuzzy sets.

Еволюція поглядів на функціональну анатомію міхурово-сечовідного сегмента та етіопатогенетичні особливості міхурово-сечовідного рефлюксу в дітей

Bladder-ureteral reflux is a pathological condition in which there is a periodic and/or permanent retrograde flow of urine from the bladder into the urinary tract due to a malfunction of the anti-reflux mechanism of the vesicoureteral segment. The aim - to study etio-pathological mechanisms of vesicoureteral reflux in children to improve diagnostic and therapeutic tactics. Every year in Ukraine, 3,600-3,700 children with congenital defects of the urinary tract are diagnosed, with 1/3 of the defects occurring in their upper parts. According to statistics, there are 40-50 cases of congenital diseases of the urinary system per 1000 newborns. There are reports that the frequency of vesicoureteral reflux in the general pediatric population exceeds 2%. According to modern data, vesicoureteral reflux accounts for 0.1% to 1.0% of all pathology in the general pediatric population, accounting for 10% of all diseases of the urinary system in hospitalized children. Bladder-ureter is the initial link in the chain of pathological reflux in the urinary tract. The leading importance of the mechanism of the vesicoureteral reflux belongs to the study functional anatomy of the urinary tract as a whole. Bladder-ureteral reflux is most often detected during urination against the background of increased intravesical pressure, but it can occur during any of the stages of the urination cycle. Nephrosclerosis with vesicoureteral reflux is formed in 30-60% of cases, which leads to the development of the terminal stage of chronic renal failure in 25-60% of patients due to a decrease in the functional renal reserve, as an indicator of the compensatory capabilities of the kidneys. Conclusions. Review of literature dataregarding the structure and functional anatomy of the vesicoureteral segment convincingly testifies to the complexity and multi-level organization of its antireflux mechanism. Therefore, any further research in this direction will undoubtedly contribute to a deeper understanding of the normal functioning of this complex anatomical part of the human urinary system, which will allow the development and implementation of the latest physiological treatment methods in the practice of pediatric surgeons. No conflict of interests was declared by the authors.

Putting Outcomes into Practice: The Implementation of a Framework of Outcome Measures within a Child and Family Service

Abstract Of utmost concern for effective child protection and child and family services is evidence-based practice. There is an onus of accountability on providers of therapeutic services to establish the merit and cost efficiency of their work. Developing standardised evidence-based outcome measures for children and families, towards which the service provider can strive, is assuredly required as a yardstick against which progress can be measured and modified. Yet, outcome measures will only work in conducive organisational conditions. Specifically, to operationalise a suite of outcome measures into a complex organisation, from administrative policy to grassroots practice, requires understanding of barriers and facilitators of implementation. Through funded research, we investigate these factors within the implementation of a new outcomes framework in a European child and family service. Following a literature review exercise, qualitative research findings from two focus groups targeted, respectively, at the managerial and front line practitioner level, illuminate complex conditions and underlying mechanisms, as well as attitudinal, resource and knowledge factors upon which implementation is predicated. We conclude with recommendations around establishing sustainable conditions and arrangements in organisations, to ensure outcome measures act as effective instruments, rather than costly and dispensable paper exercises.

Transcriptionally active chromatin loops contain both ‘active’ and ‘inactive’ histone modifications that exhibit exclusivity at the level of nucleosome clusters

Chromatin state is thought to impart regulatory function to the underlying DNA sequence. This can be established through histone modifications and chromatin organisation, but exactly how these factors relate to one another to regulate gene expression is unclear. In this study, we have used super-resolution microscopy to image the Y loops of Drosophila melanogaster primary spermatocytes, which are enormous transcriptionally active chromatin fibres, each representing single transcription units that are individually resolvable in the nuclear interior. We previously found that the Y loops consist of regular clusters of nucleosomes, with an estimated median of 54 nucleosomes per cluster with wide variation.In this study, we report that the histone modifications H3K4me3, H3K27me3, and H3K36me3 are also clustered along the Y loops, with H3K4me3 more associated with diffuse chromatin compared to H3K27me3. These histone modifications form domains that can be stretches of Y loop chromatin micrometres long, or can be in short alternating domains. The different histone modifications are associated with different sizes of chromatin clusters and unique morphologies. Strikingly, a single chromatin cluster almost always only contains only one type of the histone modifications that were labelled, suggesting exclusivity, and therefore regulation at the level of individual chromatin clusters. The active mark H3K36me3 is more associated with actively elongating RNA polymerase II than H3K27me3, with polymerase often appearing on what are assumed to be looping regions on the periphery of chromatin clusters.These results provide a foundation for understanding the relationship between chromatin state, chromatin organisation, and transcription regulation – with potential implications for pause-release dynamics, splicing complex organisation and chromatin dynamics during polymerase progression along a gene.

Abstract 6848: Analysis of the bone microenvironment cells by single cell transcriptomics reveals altered features in multiple myeloma patients compared to pre-malignant monoclonal gammopathies

Abstract Multiple myeloma (MM) is a malignant plasma cell dyscrasia that can be preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). How the bone microenvironment (BME) changes and contributes to tumoral progression in MM remains unresolved. Published data on BME are mainly produced in vitro and few data are on MGUS/SMM patients. Up to date, no single-cell RNA sequencing database of the BME cells has been described in MM. The aim of this project was to characterize for the first time at single cell level, the BME in patients with newly diagnosed MM (MMD) and MGUS/SMM to identify alterations involved in tumoral progression. From 15 bone biopsies of MMD, MGUS and SMM patients, we depleted CD235a+, CD45+, CD31+, and CD138+ cells to enrich the rare BME non-hemopoietic cells. The CD45-CD31-CD235a-CD138- cells were analyzed by scRNAseq. Data were generated on Chromium 10X Genomics. Cellranger and Seurat pipeline in R software has been used. Cell identities were assigned by manual curation. The trajectory analysis has been made by Monocle3. Decouple R and FindMarkers were used to compare pathways, and differential gene expression (DGE) of the samples throughout the different conditions. A total of 35723 cells were profiled. We identified 13 BME cell type clusters: 7 mesenchymal stromal cells (MSCs) clusters (proliferating MSC, MSC DDK-OPG-, MSC DKK+, MSC RUNX2-, MSC OPG+, MSC Osteogenic, Perivascular MSC) and 6 osteoblasts (OBs) clusters (OB precursor, OB precursor LEPR+, OB BGLAP+, OB SPP1+, OB NFkB+, OB late). Psdeudotime analyses highlighted a complex trajectory of differentiation from more immature cell clusters (proliferating MSC) to late OB cluster, confirming the ability of the dataset to snapshot the in vivo complexity of BME and we highlighted an alteration of the MSCs clusters trajectories starting in SMM samples till a disruption in MM. Pathway analyses, in MMD compared to MGUS/SMM, revealed an upregulation of VEGF and PI3K activity in proliferating MSC, perivascular MSC and OB clusters. TRAIL pathway activity, known to suppress MM cell proliferation, was upregulated in MSC osteogenic and OB BGLAP+ in MGUS. Finally, DGE analyses revealed the modulation of different genes, many not yet described in MM. MGUS MSCs clusters showed an upregulation of FBLN1, SERPNF1 and MMD MSCs clusters dramatically downregulated WISP2 and upregulated SRGN, involved in MM cell proliferation. Interestingly, in SMM samples, we reported an upregulation of genes involved both in the promotion of osteoblastogenesis (SCARA3, SPON2) and inhibition (GREM1), likely underling the attempt to contrast the establishment of altered BME, characteristic of MM. Our approach is able to dissect the complex organization of the BME and to highlight at single cells level the alterations of the BME in patients with MM compared to MGUS and SMM. Citation Format: Paola Storti, Tommaso Torelli, Cristina Manferdini, Denise Toscani, Alessandro Guidi, Rosanna Vescovini, Nicolas Thomas Iannozzi, Benedetta Dalla Palma, Matteo Scita, Federica Librale, Stefania Ricci, Vincenzo Raimondi, Oxana Lungu, Giannalisa Todaro, Gabriella Sammarelli, Emanuela Aleo, Gina Lisignoli, Luca Agnelli, Nicola Giuliani. Analysis of the bone microenvironment cells by single cell transcriptomics reveals altered features in multiple myeloma patients compared to pre-malignant monoclonal gammopathies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6848.