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Abstract Background Gene expression profile analysis on mammalian cell lines and animal models after exposure to botulinum neurotoxin (BoNT) has been investigated in several studies in recent years. Microarray analysis provides a powerful tool for identifying critical signaling pathways involved in the biological and inflammatory responses to BoNT and helps determine the mechanism of the function of botulinum toxins. One of the pivotal clinical characteristics of BoNT is its prolonged on-site effects. The role of BoNT on the blockage of neurotransmitter acetylcholine release in the neuromuscular junction has been well established. However, the effects of the treatment time of BoNT on the human cellular model and its potential mechanism remain to be defined. Methods This study aimed to use gene microarray technology to compare the two physiological critical time points of BoNT type A (BoNT/A) treatment of human neuroblastoma cells and to advance our understanding of the profound biological influences that toxin molecules play in the neuronal cellular system. SH-SY5Y neuroblastoma cells were treated with BoNT/A for 4 and 48 h, which represent the time needed for the entrance of toxin into the cells and the time necessary for the initial appearance of the on-site effects after BoNT application, respectively. Results A comparison of the two time points identified 122 functional groups that are significantly changed. The top five groups are alternative splicing, phosphoprotein, nucleus, cytoplasm, and acetylation. Furthermore, after 48 h, there were 744 genes significantly up-regulated, and 624 genes significantly down-regulated (p‹ 0.01). These genes fell into the following neurological and biological annotation groups: Nervous system development, proteinaceous extracellular matrix, signaling pathways regulating pluripotency of stem cells, cellular function and signal transduction, and apoptosis. We have also noticed that the up-regulated groups contained neuronal cell development, nervous system development, and metabolic processes. In contrast, the down-regulated groups contained many chromosomes and cell cycle categories. Conclusions The effects of BoNT/A on neuronal cells extend beyond blocking the neurotransmitter release, and that BoNT/A is a multifunctional molecule that can evoke profound cellular responses which warrant a more in-depth understanding of the mechanism of the toxin’s effects after administration.

Abstract Background Skin-to-skin contact (SSC) practice improves newborn survival and child development through preventing hypothermia in newborns, improving early initiation of breastfeeding practice, and strengthening mother-child bonding. Despite having numerous benefits, it is one of the least practiced interventions in low and middle-income countries (1 to 74%). In Bangladesh, the prevalence of SSC was 26% in 2014. In this study, we aimed to estimate the prevalence of SSC in the study districts and identify factors that facilitate or inhibit SSC practice so that context-specific recommendations can be made to advance the use of this intervention. Methods We used baseline household survey data of USAID’s MaMoni MNCSP project conducted in 10 districts of Bangladesh in 2019. Our analysis included 13,695 recently delivered women (RDW) with a live birth outcome. Our primary outcome was the mother’s reported practice of SSC. We examined various antepartum, intrapartum, newborn, and sociodemographic factors associated with SSC using a multivariable generalized linear model. Our findings were reported using adjusted Prevalence Risk Ratios (aPRRs) and 95% Confidence Intervals (CIs). Results Overall, 28% of RDW reported practicing SSC across the 10 surveyed districts. Our multivariable analysis showed that public facility delivery (aPRR 2.01; 95%CI: 1.80, 2.26), private facility delivery (aPRR 1.23; 95%CI: 1.06, 1.42) and ≥ 4 antenatal care (ANC) visits at least one from a medically trained provider (MTP) (aPRR 1.17; 95%CI: 1.03, 1.26) had a significant positive association with SSC practice. Caesarean section (aPRR 0.64; 95%CI: 0.56, 0.73) had a significant negative association with SSC practice compared to vaginal births. We also found a significant positive association of SSC practice with mothers’ who perceived the birth size of their baby to be small, mothers with a higher education level (≥10 years), and mothers from households in the highest wealth quintile. Conclusions The prevalence of SSC is very low in the surveyed districts of Bangladesh. Considering the factors associated with SSC, relevant stakeholders need to increase their efforts on improving ANC and facility delivery coverages as well as improving SSC practice in the facilities especially after caesarean deliveries. Countries with a high burden of home deliveries, also need to emphasize community-based interventions and increasing coverage of skilled birth attendance for improving this life-saving intervention.

Abstract Background Disease management programs, especially those based on the Chronic Care Model (CCM), are increasingly common in the Netherlands. While disease management programs have been well-researched quantitatively and economically, less qualitative research has been done. The overall aim of the study is to explore how disease management programs are implemented within primary care settings in the Netherlands; this paper focuses on the early development and implementation stages of five disease management programs in the primary care setting, based on interviews with project leadership teams. Methods Eleven semi-structured interviews were conducted at the five selected sites with sixteen professionals interviewed; all project directors and managers were interviewed. The interviews focused on each project’s chosen chronic illness (diabetes, eating disorders, COPD, multi-morbidity, CVRM) and project plan, barriers to development and implementation, the project leaders’ action and reactions, as well as their roles and responsibilities, and disease management strategies. Analysis was inductive and interpretive, based on the content of the interviews. After analysis, the results of this research on disease management programs and the Chronic Care Model are viewed from a traveling technology framework. Results This analysis uncovered four themes that can be mapped to disease management and the Chronic Care Model: (1) changing the health care system, (2) patient-centered care, (3) technological systems and barriers, and (4) integrating projects into the larger system. Project leaders discussed the paths, both direct and indirect, for transforming the health care system to one that addresses chronic illness. Patient-centered care was highlighted as needed and a paradigm shift for many. Challenges with technological systems were pervasive. Project leaders managed the expenses of a traveling technology, including the social, financial, and administration involved. Conclusions At the sites, project leaders served as travel guides, assisting and overseeing the programs as they traveled from the global plans to local actions. Project leaders, while hypothetically in control of the programs, in fact shared control of the traveling of the programs with patients, clinicians, and outside consultants. From this work, we can learn what roadblocks and expenses occur while a technology travels, from a project leader’s point of view.

Abstract Background In health care, many organizations are working on quality improvement and/or innovation of their care practices. Although the effectiveness of improvement processes has been studied extensively, little attention has been given to sustainability of the changed work practices after implementation. The objective of this study is to develop a theoretical framework and measurement instrument for sustainability. To this end sustainability is conceptualized with two dimensions: routinization and institutionalization. Methods The exploratory methodological design consisted of three phases: a) framework development; b) instrument development; and c) field testing in former improvement teams in a quality improvement program for health care (N teams = 63, N individual = 112). Data were collected not until at least one year had passed after implementation. Underlying constructs and their interrelations were explored using Structural Equation Modeling and Principal Component Analyses. Internal consistency was computed with Cronbach's alpha coefficient. A long and a short version of the instrument are proposed. Results The χ2- difference test of the -2 Log Likelihood estimates demonstrated that the hierarchical two factor model with routinization and institutionalization as separate constructs showed a better fit than the one factor model (p < .01). Secondly, construct validity of the instrument was strong as indicated by the high factor loadings of the items. Finally, the internal consistency of the subscales was good. Conclusions The theoretical framework offers a valuable starting point for the analysis of sustainability on the level of actual changed work practices. Even though the two dimensions routinization and institutionalization are related, they are clearly distinguishable and each has distinct value in the discussion of sustainability. Finally, the subscales conformed to psychometric properties defined in literature. The instrument can be used in the evaluation of improvement projects.

Abstract Background although there is a wealth of information available about quality improvement tools and techniques in healthcare there is little understanding about overcoming the challenges of day-to-day implementation in complex organisations like hospitals. The 'Quality and Safety in Europe by Research' (QUASER) study will investigate how hospitals implement, spread and sustain quality improvement, including the difficulties they face and how they overcome them. The overall aim of the study is to explore relationships between the organisational and cultural characteristics of hospitals and how these impact on the quality of health care; the findings will be designed to help policy makers, payers and hospital managers understand the factors and processes that enable hospitals in Europe to achieve-and sustain-high quality services for their patients. Methods/design in-depth multi-level (macro, meso and micro-system) analysis of healthcare quality policies and practices in 5 European countries, including longitudinal case studies in a purposive sample of 10 hospitals. The project design has three major features: • a working definition of quality comprising three components: clinical effectiveness, patient safety and patient experience • a conceptualisation of quality as a human, social, technical and organisational accomplishment • an emphasis on translational research that is evidence-based and seeks to provide strategic and practical guidance for hospital practitioners and health care policy makers in the European Union. Throughout the study we will adopt a mixed methods approach, including qualitative (in-depth, narrative-based, ethnographic case studies using interviews, and direct non-participant observation of organisational processes) and quantitative research (secondary analysis of safety and quality data, for example: adverse incident reporting; patient complaints and claims). Discussion the protocol is based on the premise that future research, policy and practice need to address the sociology of improvement in equal measure to the science and technique of improvement, or at least expand the discipline of improvement to include these critical organisational and cultural processes. We define the 'organisational and cultural characteristics associated with better quality of care' in a broad sense that encompasses all the features of a hospital that might be hypothesised to impact upon clinical effectiveness, patient safety and/or patient experience.

Abstract Background Disease management programmes (DMPs) have been developed to improve effectiveness and economic efficiency within chronic care delivery by combining patient-related, professional-directed, and organisational interventions. The benefits of DMPs within different settings, patient groups, and versions remain unclear. In this article we propose a protocol to evaluate a range of current DMPs by capturing them in a single conceptual framework, employing comparable structure, process, and outcome measures, and combining qualitative and quantitative research methods. Methods To assess DMP effectiveness a practical clinical trial will be conducted. Twenty-two disease management experiments will be studied in various Dutch regions consisting of a variety of collaborations between organisations and/or professionals. Patient cohorts include those with cardiovascular diseases, chronic obstructive pulmonary disease, diabetes, stroke, depression, psychotic diseases, and eating disorders. Our methodological approach combines qualitative and quantitative research methods to enable a comprehensive evaluation of complex programmes. Process indicators will be collected from health care providers' data registries and measured via physician and staff questionnaires. Patient questionnaires include health care experiences, health care utilisation, and quality of life. Qualitative data will be gathered by means of interviews and document analysis for an in depth description of project interventions and the contexts in which DMPs are embedded, and an ethnographic process evaluation in five DMPs. Such a design will provide insight into ongoing DMPs and demonstrate which elements of the intervention are potentially (cost)-effective for which patient populations. It will also enable sound comparison of the results of the different programmes. Discussion The study will lead to a better understanding of (1) the mechanisms of disease management, (2) the feasibility, and cost-effectiveness of a disease management approach to improving health care, and (3) the factors that determine success and failure of DMPs. Our study results will be relevant to decision makers and managers who confront the challenge of implementing and integrating DMPs into the health care system. Moreover, it will contribute to the search for methods to evaluate complex healthcare interventions.

Abstract Background Quality improvement collaboratives are often labeled as black boxes because effect studies usually do not describe exactly how the results were obtained. In this article we propose a way of opening such a black box, by taking up a dynamic perspective based on Actor-Network Theory. We thereby analyze how the problematisation process and the measurement practices are constructed. Findings from this analysis may have consequences for future evaluation studies of collaboratives. Methods In an ethnographic design we probed two projects within a larger quality improvement collaborative on long term mental health care and care for the intellectually disabled. Ethnographic observations were made at nine national conferences. Furthermore we conducted six case studies involving participating teams. Additionally, we interviewed the two program leaders of the overall projects. Results In one project the problematisation seemed to undergo a shift of focus away from the one suggested by the project leaders. In the other we observed multiple roles of the measurement instrument used. The instrument did not only measure effects of the improvement actions but also changed these actions and affected the actors involved. Conclusions Effectiveness statistics ideally should be complemented with an analysis of the construction of the collaborative and the improvement practices. Effect studies of collaboratives could benefit from a mixed methods research design that combines quantitative and qualitative methods.

Abstract Background A quality improvement collaborative (QIC) in the Dutch long-term care sector (nursing homes, assisted living facilities, home care) used evidence-based prevention methods to reduce the incidence and prevalence of pressure ulcers (PUs). The collaborative consisted of a core team of experts and 25 organizational project teams. Our aim was to determine its cost-effectiveness from a healthcare perspective. Methods We used a non-controlled pre-post design to establish the change in incidence and prevalence of PUs in 88 patients over the course of a year. Staff indexed data and prevention methods (activities, materials). Quality of life (Qol) weights were assigned to the PU states. We assessed the costs of activities and materials in the project. A Markov model was built based on effectiveness and cost data, complemented with a probabilistic sensitivity analysis. To illustrate the results of longer term, three scenarios were created in which change in incidence and prevalence measures were (1) not sustained, (2) partially sustained, and (3) completely sustained. Results Incidence of PUs decreased from 15% to 4.5% for the 88 patients. Prevalence decreased from 38.6% to 22.7%. Average Quality of Life (Qol) of patients increased by 0.02 Quality Adjusted Life Years (QALY)s in two years; healthcare costs increased by €2000 per patient; the Incremental Cost-effectiveness Ratio (ICER) was between 78,500 and 131,000 depending on whether the changes in incidence and prevalence of PU were sustained. Conclusions During the QIC PU incidence and prevalence significantly declined. When compared to standard PU care, the QIC was probably more costly and more effective in the short run, but its long-term cost-effectiveness is questionable. The QIC can only be cost-effective if the changes in incidence and prevalence of PU are sustained.

Abstract Background Collaborative approaches in quality improvement have been promoted since the introduction of the Breakthrough method. The effectiveness of this method is inconclusive and further independent evaluation of the method has been called for. For any evaluation to succeed, data collection on interventions performed within the collaborative and outcomes of those interventions is crucial. Getting enough data from Quality Improvement Collaboratives (QICs) for evaluation purposes, however, has proved to be difficult. This paper provides a retrospective analysis on the process of data management in a Dutch Quality Improvement Collaborative. From this analysis general failure and success factors are identified. Discussion This paper discusses complications and dilemma's observed in the set-up of data management for QICs. An overview is presented of signals that were picked up by the data management team. These signals were used to improve the strategies for data management during the program and have, as far as possible, been translated into practical solutions that have been successfully implemented. The recommendations coming from this study are: From our experience it is clear that quality improvement programs deviate from experimental research in many ways. It is not only impossible, but also undesirable to control processes and standardize data streams. QIC's need to be clear of data protocols that do not allow for change. It is therefore minimally important that when quantitative results are gathered, these results are accompanied by qualitative results that can be used to correctly interpret them. Monitoring and data acquisition interfere with routine. This makes a database collecting data in a QIC an intervention in itself. It is very important to be aware of this in reporting the results. Using existing databases when possible can overcome some of these problems but is often not possible given the change objective of QICs. Introducing a standardized spreadsheet to the teams is a very practical and helpful tool in collecting standardized data within a QIC. It is vital that the spreadsheets are handed out before baseline measurements start.

Abstract Background Information systems can play a key role in care innovations including task redesign and shared care. Many demonstration projects have presented evidence of clinical and cost effectiveness and high levels of patient satisfaction. Yet these same projects often fail to become part of everyday clinical routines. The aim of the paper is to gain insight into a common paradox that a technology can meet the criteria for success set out at the start of the project yet fail to become part of everyday clinical routines. Methods We evaluated a telecare service set up to reduce the workload of ophthalmologists. In this project, optometrists in 10 optical shops made digital images to detect patients with glaucoma which were further assessed by trained technicians in the hospital. Over a period of three years, we conducted interviews with the project team and the users about the workability of the system and its integration in practice. Beside the interviews, we analyzed record data to measure the quality of the images. We compared the qualitative accounts with these measurements. Results According to our measurements, the quality of the images was at least satisfactory in 90% of the cases, i.e. the images could be used to screen the patients – reducing the workload of the ophthalmologist considerably. However, both the ophthalmologist and the optometrists became increasingly dissatisfied respectively with the perceived quality of the pictures and the perceived workload. Through a detailed analysis of how the professionals discussed the quality of the pictures, we re-constructed how the notion of quality of the images and being a good professional were constructed and linked. The IT system transformed into a quality system and, at the same time, transformed the notions of being a good professional. While a continuous dialogue about the quality of the pictures became an emblem for the quality of care, this dialogue was hindered by the system and the way the care process was structured. Conclusion To conceptualize what telemedicine does in interdisciplinary work practices, a fine-tuned analysis is needed to assess how IT systems re-shape the social relations between professional groups. Such transformations should not be exclusively attributed to the technology itself or to the professionals working with it. Instead we need to assess these technologies through an empirically grounded study of the sociotechnical functioning of telemedicine.

Abstract Background This article seeks to identify the role of databases in health policy. Access to information and communication technologies has changed traditional relationships between the state and professionals, creating new systems of surveillance and control. As a result, databases may have a profound effect on controlling clinical practice. Methods We conducted three case studies to reconstruct the development and use of databases as policy instruments. Each database was intended to be employed to control the use of one particular pharmaceutical in the Netherlands (growth hormone, antiretroviral drugs for HIV and Taxol, respectively). We studied the archives of the Dutch Health Insurance Board, conducted in-depth interviews with key informants and organized two focus groups, all focused on the use of databases both in policy circles and in clinical practice. Results Our results demonstrate that policy makers hardly used the databases, neither for cost control nor for quality assurance. Further analysis revealed that these databases facilitated self-regulation and quality assurance by (national) bodies of professionals, resulting in restrictive prescription behavior amongst physicians. Conclusion The databases fulfill control functions that were formerly located within the policy realm. The databases facilitate collaboration between policy makers and physicians, since they enable quality assurance by professionals. Delegating regulatory authority downwards into a network of physicians who control the use of pharmaceuticals seems to be a good alternative for centralized control on the basis of monitoring data.

Abstract Background Tailor-made approaches enable the uptake of interventions as they are seen as a way to overcome the incompatibility of general interventions with local knowledge about the organisation of routine medical practice and the relationship between the patients and the professionals in practice. Our case is the Quattro project which is a prevention programme for cardiovascular diseases in high-risk patients in primary health care centres in deprived neighbourhoods. This programme was implemented as a pragmatic trial and foresaw the importance of local knowledge in primary health care and internal, or locally made, guidelines. The aim of this paper is to show how this prevention programme, which could be tailored to routine care, was implemented in primary care. Methods An ethnographic design was used for this study. We observed and interviewed the researchers and the practice nurses. All the research documents, observations and transcribed interviews were analysed thematically. Results Our ethnographic process evaluation showed that the opportunity of tailoring intervention procedures to routine care in a pragmatic trial setting did not result in a well-organised and well-implemented prevention programme. In fact, the lack of standard protocols hindered the implementation of the intervention. Although it was not the purpose of this trial, a guideline was developed. Despite the fact that the developed guideline functioned as a tool, it did not result in the intervention being organised accordingly. However, the guideline did make tailoring the intervention possible. It provided the professionals with the key or the instructions needed to achieve organisational change and transform the existing interprofessional relations. Conclusion As tailor-made approaches are developed to enable the uptake of interventions in routine practice, they are facilitated by the brokering of tools such as guidelines. In our study, guidelines facilitated organisational change and enabled the transformation of existing interprofessional relations, and thus made tailoring possible. The attractive flexibility of pragmatic trial design in taking account of local practice variations may often be overestimated.

Abstract Background The aim of this paper is to show how researchers balance between scientific rigour and localisation in conducting pragmatic trial research. Our case is the Quattro Study, a pragmatic trial on the effectiveness of multidisciplinary patient care teams used in primary health care centres in deprived neighbourhoods of two major cities in the Netherlands for intensified secondary prevention of cardiovascular diseases. Methods For this study an ethnographic design was used. We observed and interviewed the researchers and the practice nurses. All gathered research documents, transcribed observations and interviews were analysed thematically. Results Conducting a pragmatic trial is a continuous balancing act between meeting methodological demands and implementing a complex intervention in routine primary health care. As an effect, the research design had to be adjusted pragmatically several times and the intervention that was meant to be tailor-made became a rather stringent procedure. Conclusion A pragmatic trial research is a dynamic process that, in order to be able to assess the validity and reliability of any effects of interventions must also have a continuous process of methodological and practical reflection. Ethnographic analysis, as we show, is therefore of complementary value.