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We develop a quantitative single cell-based mathematical model for multi-cellular tumor spheroids (MCTS) of SK-MES-1 cells, a non-small cell lung cancer (NSCLC) cell line, growing under various nutrient conditions: we confront the simulations performed with this model with data on the growth kinetics and spatial labeling patterns for cell proliferation, extracellular matrix (ECM), cell distribution and cell death. We start with a simple model capturing part of the experimental observations. We then show, by performing a sensitivity analysis at each development stage of the model that its complexity needs to be stepwise increased to account for further experimental growth conditions. We thus ultimately arrive at a model that mimics the MCTS growth under multiple conditions to a great extent. Interestingly, the final model, is a minimal model capable of explaining all data simultaneously in the sense, that the number of mechanisms it contains is sufficient to explain the data and missing out any of its mechanisms did not permit fit between all data and the model within physiological parameter ranges. Nevertheless, compared to earlier models it is quite complex i.e., it includes a wide range of mechanisms discussed in biological literature. In this model, the cells lacking oxygen switch from aerobe to anaerobe glycolysis and produce lactate. Too high concentrations of lactate or too low concentrations of ATP promote cell death. Only if the extracellular matrix density overcomes a certain threshold, cells are able to enter the cell cycle. Dying cells produce a diffusive growth inhibitor. Missing out the spatial information would not permit to infer the mechanisms at work. Our findings suggest that this iterative data integration together with intermediate model sensitivity analysis at each model development stage, provide a promising strategy to infer predictive yet minimal (in the above sense) quantitative models of tumor growth, as prospectively of other tissue organization processes. Importantly, calibrating the model with two nutriment-rich growth conditions, the outcome for two nutriment-poor growth conditions could be predicted. As the final model is however quite complex, incorporating many mechanisms, space, time, and stochastic processes, parameter identification is a challenge. This calls for more efficient strategies of imaging and image analysis, as well as of parameter identification in stochastic agent-based simulations.

We develop a quantitative single cell-based mathematical model for multi-cellular tumor spheroids (MCTS) of SK-MES-1 cells, a non-small cell lung cancer (NSCLC) cell line, growing under various nutrient conditions: we confront the simulations performed with this model with data on the growth kinetics and spatial labeling patterns for cell proliferation, extracellular matrix (ECM), cell distribution and cell death. We start with a simple model capturing part of the experimental observations. We then show, by performing a sensitivity analysis at each development stage of the model that its complexity needs to be stepwise increased to account for further experimental growth conditions. We thus ultimately arrive at a model that mimics the MCTS growth under multiple conditions to a great extent. Interestingly, the final model, is a minimal model capable of explaining all data simultaneously in the sense, that the number of mechanisms it contains is sufficient to explain the data and missing out any of its mechanisms did not permit fit between all data and the model within physiological parameter ranges. Nevertheless, compared to earlier models it is quite complex i.e., it includes a wide range of mechanisms discussed in biological literature. In this model, the cells lacking oxygen switch from aerobe to anaerobe glycolysis and produce lactate. Too high concentrations of lactate or too low concentrations of ATP promote cell death. Only if the extracellular matrix density overcomes a certain threshold, cells are able to enter the cell cycle. Dying cells produce a diffusive growth inhibitor. Missing out the spatial information would not permit to infer the mechanisms at work. Our findings suggest that this iterative data integration together with intermediate model sensitivity analysis at each model development stage, provide a promising strategy to infer predictive yet minimal (in the above sense) quantitative models of tumor growth, as prospectively of other tissue organization processes. Importantly, calibrating the model with two nutriment-rich growth conditions, the outcome for two nutriment-poor growth conditions could be predicted. As the final model is however quite complex, incorporating many mechanisms, space, time, and stochastic processes, parameter identification is a challenge. This calls for more efficient strategies of imaging and image analysis, as well as of parameter identification in stochastic agent-based simulations.

Background The first wave of the COVID-19 pandemic reached Germany between March and May 2020. In order to contain the spread of the virus and particularly protect vulnerable people, the government imposed a lockdown in March 2020. In addition to infection control measures, such as hygiene and social distancing requirements, a general ban on access to nursing homes for relatives and external service providers was issued. Methods To investigate the challenges and consequences of the enacted infection prevention measures and specific strategies for nursing homes in Germany, a multicentre cross-sectional qualitative interview study with nursing home managers and ward managers was conducted. Recorded audio data were transcribed, analysed using thematic framework analysis and reflected in peer debriefings. Results Seventy-eight interviews with 40 nursing home managers and 38 ward managers from 43 German nursing homes were conducted. At organisational level, the following six themes were identified: Appointing a multi-professional crisis task force, reorganizing the use of building and spatial structures, continuous adaption and implementation of hygiene plans, adapting staff deployment to dynamically changing demands, managing additional communicative demands and relying on and resorting to informal networks. To deal with the pandemic challenges also six themes can be described for the direct care level: Changed routines, taking over non-nursing tasks, increased medical responsibility, increased documentation demands, promoting social participation and increased communication demands. Also various negative consequences were identified (four themes): Psychological stress, negative emotional consequences, permanent feeling of responsibility and increased potential for conflicts. Positive emotional consequences were also reported (two themes): resources for the challenges and positive emotional consequences for home managers and staff. Conclusions The results of the described challenges, strategies and consequences allow recommendations as basis for possible approaches and successful adaptation processes in nursing home care in the future. In particular, there is a need for local networks to act in a coordinated way and a need for quantitative and qualitative support for nurses, such as staff support as well as advanced nursing practice, to cope with the challenges of the pandemic.

Background A system of dementia-specific case conferences (WELCOME-IdA) was evaluated using a stepped-wedge design in six nursing homes (NHs) to enable nursing staff to analyse properly the behavioural and psychological symptoms (BPSD) of residents with dementia. A process evaluation of the context, the recruitment and target populations reached (residents and nursing staff) and the delivery of the intervention and implementation strategy was carried out to explore the lack of effectiveness of WELCOME-IdA on the residents’ prevalence of BPSD. Methods This study was part of a larger process evaluation using a mixed-methods design. Standardised questionnaires, semi-structured interviews, attendance lists, standardised protocols and written self-reports were used to collect the data. The quantitative data were analysed by calculating descriptive statistics. The qualitative interviews were analysed using deductive content analysis and the self-reports were analysed using a documentary analysis. Results None of the NHs had prior experience with dementia-specific case conferences on a specific concept related to BPSD. The number of residents for whom a dementia-specific case conference was held was lower than expected. The number of nursing staff reached was high, although as defined in the study protocol, core nursing teams continuously participating in all components of the intervention were not established throughout the study. An analysis of the delivery of the intervention showed a reduction in the frequency of dementia-specific case conferences and deviations in the process structure and role structure of WELCOME-IdA. The strategy used to facilitate the implementation of WELCOME-IdA was mostly followed. An analysis of the recruitment of residents indicated that the variation in which residents were included in the study sample was high and that the intended sample size required to achieve a power >80% was not reached. Conclusion An analysis of the process evaluation data indicated that there were inaccuracies in the implementation of WELCOME-IdA and there were methodological limitations within the design of the effectiveness trial, both of which could explain the lack of effectiveness of WELCOME-IdA. To optimise the process structure of WELCOME-IdA, an assessment of BPSD and a pre-selection of possible domains for the behavioural analysis could be conducted prior to a dementia-specific case conference. Trial registration ISRCTN20203855 . Registered on 10 July 2013.

In this contribution, a preliminary analysis of the first part of the experiment S2012 conducted at the ISAC-II facility of Canada’s particle accelerator center TRIUMF in Vancouver will be presented. The experiment aims to study highly clustered structures of nuclei created in multi-nucleon transfer reactions of 9Li radioactive beam on natural boron target (11B and 10B). The main objective of the experiment is to study exotic structures created in neutron-rich 16C nucleus in the range of higher excitation energies. The analysis presented here probes the existence of exotic cluster configurations and the quality of detected results using the invariant mass techniques.

Background The implementation of clearly structured dementia-specific case conferences could be an important tool to enable nursing staff to properly analyse and manage challenging behaviour in nursing home residents with dementia. A process evaluation of the responses of nursing homes to the implementation of WELCOME-IdA ( Wittener model of case conferences for people with dementia – the Innovative dementia-oriented Assessment tool) was carried out to gain insight into which key elements of the intervention were adopted by the nursing homes and which elements were adapted. Methods This study was part of a larger process evaluation using a qualitative design. Thirty-four semi-structured telephone interviews and 15 focus group interviews were conducted in four nursing homes. The interviews were analysed using deductive content analysis, although inductive categories have been developed. Results Nursing home staff adopted the roles of moderator, case reporter, keeper of the minutes and reflection partner in WELCOME-IdA, but the selection of the staff members who filled these roles differed across nursing homes. The recommended group size of 5–8 participants per case conference was sometimes adopted. The key element of having core nursing teams who participated continuously in all case conferences was not adopted at all. Instead, there was a high level of rotation among staff members. The pre-defined process structure of WELCOME-IdA was adapted in such a way that the assessment of the residents’ behaviour and the selection of the relevant domain for the behaviour analysis were conducted in advance of the case conference. The evaluation of the interventions was also organized differently. Conclusion The scope of the response implies that WELCOME-IdA requires further adaptation to the requirements of nursing processes in nursing homes. The results provide important information on the selection of role keepers and offer insights into a) how knowledge of the structured training was circulated and transformed into self-organized case conferences and b) how knowledge was circulated throughout the entire processing of one case. Thus, these results can be used to optimize intervention and implementation. Overall, the intervention should allow more possibilities for tailored adaptation than it currently does.

Many decisions in drug development and medical practice are based on measuring blood concentrations of endogenous and exogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Also, most drugs with few notable exceptions exert their effects not within the bloodstream, but in defined target tissues into which drugs have to distribute from the central compartment. Assessing tissue drug chemistry has, thus, for long been viewed as a more rational way to provide clinically meaningful data rather than gaining information from blood samples. More specifically, it is often the extracellular (interstitial) tissue space that is most closely related to the site of action (biophase) of the drug. Currently microdialysis (microD) is the only tool available that explicitly provides data on the extracellular space. Although microD as a preclinical and clinical tool has been available for two decades, there is still uncertainty about the use of microD in drug research and development, both from a methodological and a regulatory point of view. In an attempt to reduce this uncertainty and to provide an overview of the principles and applications of microD in preclinical and clinical settings, an AAPS-FDA workshop took place in November 2005 in Nashville, TN, USA. Stakeholders from academia, industry and regulatory agencies presented their views on microD as a tool in drug research and development.

Background Case conferences for people with dementia and challenging behaviors (e.g., apathy) are recommended as useful tools that enable staff in nursing homes to understand the behavior of people with this type of disease. Understanding peoples’ behaviors is the basis for the initiation of targeted interventions to improve the quality of care for people with dementia. Furthermore, case conferences demonstrate positive effects on burnout, dementia-specific burden, and vocational action competence of the staff. The two likely approaches for conducting case conferences include the following: A) using a structured assessment instrument, which guides the staff in understanding the residents’ behaviors and B) using a narrative approach in which the staff must identify the reasons for the residents’ behaviors in an unstructured manner. Case conferences are a complex intervention, and evaluating their multiple effects is challenging. The aim of this study protocol was to describe a likely solution for evaluating this type of complex intervention using a special cluster randomized trial. Methods In this stepped-wedged cluster randomized trial, the two interventions will be sequentially implemented every three months in a group of 12 nursing homes (clusters) with a minimum of 360 residents over 19 months (7 months of intervention for each cluster and follow-up). The primary outcome is the reduction of challenging behavior (measured with the neuropsychiatric inventory-nursing home version [NPI-NH]). Secondary outcomes are residents’ quality of life, prescription of psychotropic medications, staff burnout, dementia-related stress, and vocational action competence. The effectiveness of the study will be accompanied by a process evaluation. The primary data will be analyzed using a Bayesian mixed effect model; the secondary data will be analyzed using descriptive statistics and mixed effects models. Discussion The implementation and effect measurement of complex interventions such as case conferences within a cluster randomized trial are challenging (e.g., complex and intensive training, delayed treatment effect). In this study protocol, the methodological advantages and disadvantages of using the stepped wedge design to answer the research questions are discussed. Trial registration http://www.controlled-trials.com/ISRCTN20203855 ; registered 10 July 2013.

Background Challenging behaviors exhibited by individuals with dementia might result from an unmet need that they cannot communicate directly due to cognitive restrictions. A dementia-specific case conference represents a promising means of analyzing and exploring these unmet needs. The ongoing FallDem study is a stepped-wedged, cluster-randomized trial evaluating the effects of two different types of dementia-specific case conferences on the challenging behaviors of nursing home residents. This study protocol describes the process evaluation that is conducted, along with the FallDem study. The goal of the process evaluation is to explain potential discrepancies between expected and observed outcomes, and to provide insights into implementation processes and recruitment strategies, as well as the contexts and contextual factors that promote or inhibit the implementation of dementia-specific case conferences. Methods/Design The process evaluation will use a mixed-method design comprising longitudinal elements, in which quantitative and qualitative data will be gathered. Qualitative data will be analyzed using content analysis, documentary analysis and a documentary method. Quantitative data (standardized questionnaires) will be analyzed using descriptive statistics. Both types of data will complement one another and provide a more comprehensive picture of the different objects under investigation. Discussion The process evaluation will allow for a comprehensive understanding of the changing processes and mechanisms underlying the ‘black box’ of the complex intervention of the FallDem study. These findings will provide practical knowledge regarding issues related to the implementation of dementia-specific case conferences in nursing homes. Trial registration Current Controlled Trials identifier: ISRCTN20203855 , registered on 10th July 2013.

A system of dementia-specific case conferences (WELCOME-IdA) was evaluated using a stepped-wedge design in six nursing homes (NHs) to enable nursing staff to analyse properly the behavioural and psychological symptoms (BPSD) of residents with dementia. A process evaluation of the context, the recruitment and target populations reached (residents and nursing staff) and the delivery of the intervention and implementation strategy was carried out to explore the lack of effectiveness of WELCOME-IdA on the residents' prevalence of BPSD. This study was part of a larger process evaluation using a mixed-methods design. Standardised questionnaires, semi-structured interviews, attendance lists, standardised protocols and written self-reports were used to collect the data. The quantitative data were analysed by calculating descriptive statistics. The qualitative interviews were analysed using deductive content analysis and the self-reports were analysed using a documentary analysis. None of the NHs had prior experience with dementia-specific case conferences on a specific concept related to BPSD. The number of residents for whom a dementia-specific case conference was held was lower than expected. The number of nursing staff reached was high, although as defined in the study protocol, core nursing teams continuously participating in all components of the intervention were not established throughout the study. An analysis of the delivery of the intervention showed a reduction in the frequency of dementia-specific case conferences and deviations in the process structure and role structure of WELCOME-IdA. The strategy used to facilitate the implementation of WELCOME-IdA was mostly followed. An analysis of the recruitment of residents indicated that the variation in which residents were included in the study sample was high and that the intended sample size required to achieve a power >80% was not reached. An analysis of the process evaluation data indicated that there were inaccuracies in the implementation of WELCOME-IdA and there were methodological limitations within the design of the effectiveness trial, both of which could explain the lack of effectiveness of WELCOME-IdA. To optimise the process structure of WELCOME-IdA, an assessment of BPSD and a pre-selection of possible domains for the behavioural analysis could be conducted prior to a dementia-specific case conference.