Estimating the opportunity costs of bed-days.

Opportunity costs of bed-days are fundamental to understanding the value of healthcare systems. They greatly influence burden of disease estimations and economic evaluations involving stays in healthcare facilities. However, different estimation techniques employ assumptions that differ crucially in whether to consider the value of the second-best alternative use forgone, of any available alternative use, or the value of the actually chosen alternative. Informed by economic theory, this paper provides a taxonomic framework of methodologies for estimating the opportunity costs of resources. This taxonomy is then applied to bed-days by classifying existing approaches accordingly. We highlight differences in valuation between approaches and the perspective adopted, and we use our framework to appraise the assumptions and biases underlying the standard approaches that have been widely adopted mostly unquestioned in the past, such as the conventional use of reference costs and administrative accounting data. Drawing on these findings, we present a novel approach for estimating the opportunity costs of bed-days in terms of health forgone for the second-best patient, but expressed monetarily. This alternative approach effectively re-connects to the concept of choice and explicitly considers net benefits. It is broadly applicable across settings and for other resources besides bed-days

26. Spotlight: Expert*innen auf dem Gebiet der SynBio : Eine Recherche unter Anwendung des ExpertExplorers

In the ‘Fifth Gene Technology Report’, renowned experts provide an overview of current developments and their applications in the dynamically evolving research field of gene and biotechnologies. They examine, among other topics, genetic diagnostics, somatic gene therapy, the development of vaccines, stem cell and organoid research, green gene technology, synthetic biology, gene drives, genome editing, epigenetics and single cell analysis. In addition to reporting on the current state of affairs in this field, the authors also discuss society’s perception of gene technologies and ethical and legal issues relating to them, such as genome edit-ing, cerebral organoids and big data in personalised medicine. Moreover, the interdisciplinary task force ‘Gentechnologiebericht’ (Gene Technology Report) offers recommendations on action that could be taken in relation to the key issues. With contributions by Karla Alex, Sina Bartfeld, Meik Bittkowski, Inge Broer, Lorina Buhr, Stephan Clemens, Wolfgang Van den Daele, Hans-Georg Dederer, Tobias J. Erb, Nina Gasparoni, Heiner Fangerau, Boris Fehse, Jürgen Hampel, Louise Herde, Ferdinand Hucho, Ali Jawaid, Aida Khachatryan, Sarah Kohler, Alma Kolleck, Martin Korte, Cordula Kropp, Alfons Labisch, Markus Lehmkuhl, Melanie Leidecker-Sandmann, Annette Leßmöllmann, Isabelle M. Mansuy, Lilian Marx-Stölting, Andreas Merk, Yannick Milhahn, Fruzsina Molnár-Gábor, Stefan Mundlos, Staffan Müller-Wille, Angela Osterheider, Anja Pichl, Barbara Prainsack, Jens Reich, Marlen Reinschke, Ortwin Renn, Hans-Jörg Rheinberger, Arnold Sauter, Hannah Schickl, Silke Schicktanz, Volker Stollorz, Constanze Störk-Biber, Jochen Taupitz, Jörn Walter, Eva C. Winkler, Martin Zenke and Michael M. Zwick

Estimating the Hospital Burden of Norovirus-Associated Gastroenteritis in England and Its Opportunity Costs for Nonadmitted Patients.

Background: Norovirus places a substantial burden on healthcare systems, arising from infected patients, disease outbreaks, beds kept unoccupied for infection control, and staff absences due to infection. In settings with high rates of bed occupancy, opportunity costs arise from patients who cannot be admitted due to beds being unavailable. With several treatments and vaccines against norovirus in development, quantifying the expected economic burden is timely. Methods: The number of inpatients with norovirus-associated gastroenteritis in England was modeled using infectious and noninfectious gastrointestinal Hospital Episode Statistics codes and laboratory reports of gastrointestinal pathogens collected at Public Health England. The excess length of stay from norovirus was estimated with a multistate model and local outbreak data. Unoccupied bed-days and staff absences were estimated from national outbreak surveillance. The burden was valued conventionally using accounting expenditures and wages, which we contrasted to the opportunity costs from forgone patients using a novel methodology. Results: Between July 2013 and June 2016, 17.7% (95% confidence interval [CI], 15.6%‒21.6%) of primary and 23.8% (95% CI, 20.6%‒29.9%) of secondary gastrointestinal diagnoses were norovirus attributable. Annually, the estimated median 290000 (interquartile range, 282000‒297000) occupied and unoccupied bed-days used for norovirus displaced 57800 patients. Conventional costs for the National Health Service reached £107.6 million; the economic burden approximated to £297.7 million and a loss of 6300 quality-adjusted life-years annually. Conclusions: In England, norovirus is now the second-largest contributor of the gastrointestinal hospital burden. With the projected impact being greater than previously estimated, improved capture of relevant opportunity costs seems imperative for diseases such as norovirus

The Role of Clonal Evolution on Progression, Blood Parameters, and Response to Therapy in Multiple Myeloma

IntroductionA variety of biomarkers are considered for diagnosis (e.g., β2-microgobulin, albumin, or LDH) and prognosis [e.g., cytogenetic aberrations detected by fluorescence in situ hybridization (FISH)] of multiple myeloma (MM). More recently, clonal evolution has been established as key. Little is known on the clinical implications of clonal evolution.MethodsWe performed in-depth analyses of 25 patients with newly diagnosed MM with respect to detailed clinical information analyzing blood samples collected at several time points during follow-up (median follow-up: 3.26 years since first diagnosis). We split our cohort into two subgroups: with and without new FISH clones developing in the course of disease.ResultsEach subgroup showed a characteristic chromosomal profile. Forty-three percent of patients had evidence of appearing new clones. The patients with new clones showed an increased number of translocations affecting chromosomes 14 (78% vs. 33%; p = 0.0805) and 11, and alterations in chromosome 4 (amplifications and translocations). New clones, on the contrary, were characterized by alterations affecting chromosome 17. Subsequent to the development of the new clone, 6 out of 9 patients experienced disease progression compared to 3 out of 12 for patients without new clones. Duration of the therapy applied for the longest time was significantly shorter within the group of patients developing new clones (median: 273 vs. 406.5 days; p = 0.0465).DiscussionWe demonstrated that the development of new clones, carrying large-scale alterations, was associated with inferior disease course and shorter response to therapy, possibly affecting progression-free survival and overall survival as well. Further studies evaluating larger cohorts are necessary for the validation of our results

Building in Quatar - Field excursion of the Faculty of Civil Engineering of the HTWG Konstanz

Die große Exkursion 2010 der Fakultät Bauingenieurwesen führte in das Emirat Qatar am persischen Golf. Qatar verfügt über 15% der weltweiten Reserven anErdgas und investiert u.a. in Infrastruktur- und Bau¬maßnahmen. Deutsche Firmen sind an diesem Aufbau beteiligt. Bei der Exkursion wurden verschiedene Hoch- und Tiefbaustellen, „Mega-Projekte“ deutscher Unternehmen, aber auch eines arabischen Baukonzerns besucht. Auch das Ausstellungszentrum der Deutschen Bahn stand auf dem Programm. Der Bericht gibt die Eindrücke beim Besuch der Projekte wie auch die Reiseerlebnisse wieder.The student excursion of the University of Applied Sciences, Konstanz, Germany, lead to the Emirat of Qatar at the Persian Gulf. The country possesses 15% of the reserves of natural gas and is investing in building and infrastructures measures. German companies are part of this development. During the excursion different structural sites of “mega-projects” of German and Arabic Companies as well as the exposition Center of the “Deutsche Bahn” have been visited

ETMR-05: Single-cell transcriptomics of ETMR reveals developmental cellular programs and tumor-pericyte communications in the microenvironment [Abstract]

BACKGROUND: Embryonal tumors with multilayered rosettes (ETMR) are pediatric brain tumors bearing a grim prognosis, despite intensive multimodal therapeutic approaches. Insights into cellular heterogeneity and cellular communication of tumor cells with cells of the tumor microenvironment (TME), by applying single-cell (sc) techniques, potentially identify mechanisms of therapy resistance and target-directed treatment approaches. MATERIAL AND METHODS: To explore ETMR cell diversity, we used single-cell RNA sequencing (scRNA-seq) in human (n=2) and murine ETMR (transgenic mode; n=4) samples, spatial transcriptomics, 2D and 3D cultures (including co-cultures with TME cells), multiplex immunohistochemistry and drug screens. RESULTS: ETMR microenvironment is composed of tumor and non-tumor cell types. The ETMR malignant compartment harbour cells representing distinct transcriptional metaprograms, (NSC-like, NProg-like and Neuroblast-like), mirroring embryonic neurogenic cell states and fuelled by neurogenic pathways (WNT, SHH, Hippo). The ETMR TME is composed of oligodendrocyte and neuronal progenitor cells, neuroblasts, microglia, and pericytes. Tumor-specific ligand-receptor interaction analysis showed enrichment of intercellular communication between NProg-like ETMR cells and pericytes (PC). Functional network analyses reveal ETMR-PC interactions related to stem-cell signalling and extracellular matrix (ECM) organization, involving factors of the WNT, BMP, and CxCl12 networks. Results from ETMR-PC co-culture and spatial transcriptomics pointed to a pivotal role of pericytes in keeping ETMR in a germinal neurogenic state, enriched in stem-cell signalling. Drug screening considering cellular heterogeneity and cellular communication suggested novel therapeutic approaches. CONCLUSION: ETMR demonstrated diversity in the microenvironment, with enrichment of cell-cell communications with pericytes, supporting stem-cell signalling and interfering in the organization of the tumor extracellular matrix. Targeting ETMR-PC interactions might bring new opportunities for target-directed therapy

Clinical relevance of molecular characteristics in Burkitt lymphoma differs according to age

While survival has improved for Burkitt lymphoma patients, potential differences in outcome between pediatric and adult patients remain unclear. In both age groups, survival remains poor at relapse. Therefore, we conducted a comparative study in a large pediatric cohort, including 191 cases and 97 samples from adults. While TP53 and CCND3 mutation frequencies are not age related, samples from pediatric patients showed a higher frequency of mutations in ID3, DDX3X, ARID1A and SMARCA4, while several genes such as BCL2 and YY1AP1 are almost exclusively mutated in adult patients. An unbiased analysis reveals a transition of the mutational profile between 25 and 40 years of age. Survival analysis in the pediatric cohort confirms that TP53 mutations are significantly associated with higher incidence of relapse (25 ± 4% versus 6 ± 2%, p-value 0.0002). This identifies a promising molecular marker for relapse incidence in pediatric BL which will be used in future clinical trials

Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia.

BACKGROUND: Genetic mutations underlying familial Alzheimer\u27s disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression of mutated transgenes have yielded key insights in mechanisms of disease, those models are subject to artifacts, including random genetic integration of the transgene, ectopic expression and non-physiological protein levels. The genetic engineering of novel mouse models using knock-in approaches addresses some of those limitations. With mounting evidence of the role played by microglia in AD, high-dimensional approaches to phenotype microglia in those models are critical to refine our understanding of the immune response in the brain. METHODS: We engineered a novel App knock-in mouse model (App RESULTS: Leveraging multi-omics approaches, we discovered profound alteration of diverse lipids and metabolites as well as an exacerbated disease-associated transcriptomic response in microglia with high intracellular Aβ content. The App DISCUSSION: Our findings demonstrate that fibrillar Aβ in microglia is associated with lipid dyshomeostasis consistent with lysosomal dysfunction and foam cell phenotypes as well as profound immuno-metabolic perturbations, opening new avenues to further investigate metabolic pathways at play in microglia responding to AD-relevant pathogenesis. The in-depth characterization of pathological hallmarks of AD in this novel and open-access mouse model should serve as a resource for the scientific community to investigate disease-relevant biology

Assessing Computational Methods of Cis-Regulatory Module Prediction

Computational methods attempting to identify instances of cis-regulatory modules (CRMs) in the genome face a challenging problem of searching for potentially interacting transcription factor binding sites while knowledge of the specific interactions involved remains limited. Without a comprehensive comparison of their performance, the reliability and accuracy of these tools remains unclear. Faced with a large number of different tools that address this problem, we summarized and categorized them based on search strategy and input data requirements. Twelve representative methods were chosen and applied to predict CRMs from the Drosophila CRM database REDfly, and across the human ENCODE regions. Our results show that the optimal choice of method varies depending on species and composition of the sequences in question. When discriminating CRMs from non-coding regions, those methods considering evolutionary conservation have a stronger predictive power than methods designed to be run on a single genome. Different CRM representations and search strategies rely on different CRM properties, and different methods can complement one another. For example, some favour homotypical clusters of binding sites, while others perform best on short CRMs. Furthermore, most methods appear to be sensitive to the composition and structure of the genome to which they are applied. We analyze the principal features that distinguish the methods that performed well, identify weaknesses leading to poor performance, and provide a guide for users. We also propose key considerations for the development and evaluation of future CRM-prediction methods