Treatment Patterns and Adherence to Guidelines for Uncomplicated Urinary Tract Infection in Germany: A Retrospective Cohort Study.

INTRODUCTION: Understanding antibiotic prescribing for uncomplicated urinary tract infection (uUTI) could help to optimize management. However, data on uUTI treatment patterns in the European Union are scarce. We used real-world data to evaluate adherence to antibiotic prescribing guidelines for femalepatients with uUTI in Germany. METHODS: This retrospective cohort study used anonymized German statutory health insurance claims data from the Wissenschaftliches Institut für Gesundheitsökonomie und Gesundheitssystemforschung from January 2013 to December 2019. Patients were female, aged ≥ 12 years, with an index uUTI diagnosis. Patient characteristics and treating physician specialties were examined overall and in sub-cohorts for recommended/non-recommended treatment (based on initial therapy adherence to German uUTI treatment guidelines) and optimal/sub-optimal outcome (based on a prescription of different antibiotics or a urinary tract infection-related episode). RESULTS: Overall, 144,645 uUTI cases in 124,971 patients were analyzed; 51,230 (35.4%) and 93,415 (64.6%) cases were assigned to the recommended/non-recommended treatment sub-cohorts, respectively. Clinically meaningful differences in age and comorbidities were observed between these sub-cohorts. Most cases had an optimal outcome (n = 122,823; 84.9%); of these, a higher proportion received antibiotics that were recommended but not as first-choice versus first-choice therapies as their initial treatment (58.6% vs. 35.3%). In the sub-optimal outcome cohort, 49.1% received antibiotics that were recommended but not as first-choice and 41.1% received first-choice therapies as their initial treatment. Most uUTIs were treated by general practitioners (GPs; 82.3%), followed by gynecologists (13.3%), and urologists (6.8%). Notably, 64.5% of initial therapy prescriptions filled by gynecologists and 32.1% by GPs were first-choice antibiotics. CONCLUSION: A high proportion of prescribed treatments for the initial uUTI episode were not recommended by German uUTI guidelines as first-choice antibiotics. Prescribing adherence varied by physician specialty; specialists showed greater adherence to treatment guidelines versus GPs. This study provides a novel and multi-dimensional picture of uUTI treatment in Germany.

Uncomplicated urinary tract infections are one of the most common infections in women. Doctors around the world use different types of antibiotics to treat people with uncomplicated urinary tract infections. We performed this study to find out more about how doctors in Germany use antibiotics to treat uncomplicated urinary tract infections. We looked at health records from female patients (aged 12+) in Germany. Overall, we examined 144,645 records. We found that around one in ten women use antibiotics to treat an uncomplicated urinary tract infection every year. We then checked to see if the doctors were giving people the right type of antibiotic, the right dose, and the right length of course. To do this, we checked against guidelines that were written by experts in Germany. We found that only one in three patients (35%) received treatment that met the guidelines. We also looked to see what differences there were between different types of doctors. For example, if general practitioners (family doctors) used different antibiotics to specialist doctors in hospitals. Four out of five patients (82%) were treated by general practitioners. We found that specialists were more likely to stick to the guidelines than general practitioners. Finally, we looked at how many patients recovered well after their first course of antibiotics. More than four out of five patients (80%) recovered well. Interestingly, more than half of the patients who had a good recovery (59%) received antibiotics that were not recommended by the guidelines.

[Validation study of MEP questionnaire for simplified detection of exacerbation of chronic obstructive pulmonary disease]. / Validierungsstudie des MEP-Fragebogens zur erleichterten Erkennung von COPD-Exazerbationen.

The Questionnaire "Monitoring of Exacerbation Probability" (MEP) provides a novel simple tool to assist detection and semiquantitative numerical documentation of exacerbation (ECOPD) in daily routine. In a prospective multi-center trial involving 3751 visits of 810 patients in 21 centers, MEP was evaluated and compared to the application of the EXACT-Pro questionnaire under real world conditions. The population of COPD patients included in this study is a typical COPD population demographically and clinically. Defining a MEP score of one or more as a positive test result, we found a sensitivity of 91% and a specificity of 66%. Additionally, MEP results correlated clearly with EXACT-Pro results. This qualifies the MEP questionnaire as a valid tool for the detection of ECOPD and longitudinal characterization of COPD patients.

Single Cell Phenotyping Reveals Heterogeneity Among Hematopoietic Stem Cells Following Infection.

The hematopoietic stem cell (HSC) niche provides essential microenvironmental cues for the production and maintenance of HSCs within the bone marrow. During inflammation, hematopoietic dynamics are perturbed, but it is not known whether changes to the HSC-niche interaction occur as a result. We visualize HSCs directly in vivo, enabling detailed analysis of the 3D niche dynamics and migration patterns in murine bone marrow following Trichinella spiralis infection. Spatial statistical analysis of these HSC trajectories reveals two distinct modes of HSC behavior: (a) a pattern of revisiting previously explored space and (b) a pattern of exploring new space. Whereas HSCs from control donors predominantly follow pattern (a), those from infected mice adopt both strategies. Using detailed computational analyses of cell migration tracks and life-history theory, we show that the increased motility of HSCs following infection can, perhaps counterintuitively, enable mice to cope better in deteriorating HSC-niche microenvironments following infection. Stem Cells 2017;35:2292-2304.

Bistable Epigenetic States Explain Age-Dependent Decline in Mesenchymal Stem Cell Heterogeneity.

The molecular mechanisms by which heterogeneity, a major characteristic of stem cells, is achieved are yet unclear. We here study the expression of the membrane stem cell antigen-1 (Sca-1) in mouse bone marrow mesenchymal stem cell (MSC) clones. We show that subpopulations with varying Sca-1 expression profiles regenerate the Sca-1 profile of the mother population within a few days. However, after extensive replication in vitro, the expression profiles shift to lower values and the regeneration time increases. Study of the promoter of Ly6a unravels that the expression level of Sca-1 is related to the promoter occupancy by the activating histone mark H3K4me3. We demonstrate that these findings can be consistently explained by a computational model that considers positive feedback between promoter H3K4me3 modification and gene transcription. This feedback implicates bistable epigenetic states which the cells occupy with an age-dependent frequency due to persistent histone (de-)modification. Our results provide evidence that MSC heterogeneity, and presumably that of other stem cells, is associated with bistable epigenetic states and suggest that MSCs are subject to permanent state fluctuations. Stem Cells 2017;35:694-704.

Radiographic Study of the Prevalence and Distribution of Hypodontia Associated with Unilateral and Bilateral Clef Lip and Palate in a Hungarian Population.

BACKGROUND Cleft defects are one of the most frequent birth-deformities of the orofacial region and they are commonly associated with anomalies of the tooth structure, size, shape, formation, eruption, and tooth number. The aim of our study was to evaluate the prevalence, distribution, and potential association of combined hypodontia in cleft-affected patients with regard to all types of teeth in both jaws in the permanent dentition. MATERIAL AND METHODS This retrospective radiographic analysis included patients with various types of clefts treated orthodontically in the Department of Orofacial Orthopedics and Orthodontics at Heim Pàl Children's Hospital, Budapest. There were 150 patients (84 males, 66 females) with non-syndromic unilateral (UCLP; n=120 patients) or bilateral (BCLP; n=30 patients) cleft formation (lip, alveolus and palate) who met the inclusion criteria. Statistical analysis was performed using the chi-square test and Fisher's exact test (significance level p<0.05). RESULTS Hypodontia was significantly more frequent in patients with cleft-sided lateral incisor (104 patients, 69%), with a total of 235 missing teeth, followed by the second premolars of the upper and lower jaw. A significant correlation of congenital missing teeth was observed in left-sided clefts between the upper and lower second premolar in the cleft area CONCLUSIONS Hypodontia inside and outside the cleft area was frequently observed. This should affect the therapy plans, especially if the cleft-sided premolar is also absent. Further comprehensive research including numerous random samples is necessary for better estimating other possible associations.

Quantification and modeling of stem cell-niche interaction.

Adult stem cells persist lifelong in the organism, where they are responsible for tissue homeostasis and repair. It is commonly assumed that their maintenance and function are facilitated in local environments called "stem cell niches." Although there is convincing evidence that a variety of niche components determine stem cell fate, the regulatory details of stem cell-niche interactions are widely unknown. To pave the way for a substantiated discussion of these interactions, we first focus on the stem cells themselves and describe the stem cell defining criteria and their implications. The fate of the cells that fulfill these criteria is regulated by a broad spectrum of factors and regulatory mechanisms. A summary of established components and their action is given exemplary for the hematopoietic system. The complexity resulting from the interplay of various cell types, signaling molecules, and extracellular structures can be boiled down to important key features as exemplified by the presented model of hematopoietic stem cell organization. Although neglecting many details, we show that this and similar models have the power to yield intriguing results as proven by the agreement of the presented model with experimental data and the predictions derived from model simulations. Finally, we will discuss the paradigm of systems biology and give a summary of the techniques that promise to unveil further details of the organization principles of stem cell niches at different levels. The synergistic effect of the described techniques together with the integration of their results into a unified model that allows quantitative evaluation and predictions may lead to a better and more systematic understanding of the most relevant niche elements and their interactions.

In vivo time-lapse imaging shows diverse niche engagement by quiescent and naturally activated hematopoietic stem cells.

Hematopoietic stem cells (HSCs) maintain the turnover of mature blood cells during steady state and in response to systemic perturbations such as infections. Their function critically depends on complex signal exchanges with the bone marrow (BM) microenvironment in which they reside, but the cellular mechanisms involved in HSC-niche interactions and regulating HSC function in vivo remain elusive. We used a natural mouse parasite, Trichinella spiralis, and multipoint intravital time-lapse confocal microscopy of mouse calvarium BM to test whether HSC-niche interactions may change when hematopoiesis is perturbed. We find that steady-state HSCs stably engage confined niches in the BM whereas HSCs harvested during acute infection are motile and therefore interact with larger niches. These changes are accompanied by increased long-term repopulation ability and expression of CD44 and CXCR4. Administration of a CXCR4 antagonist affects the duration of HSC-niche interactions. These findings suggest that HSC-niche interactions may be modulated during infection.

Merging concepts - coupling an agent-based model of hematopoietic stem cells with an ODE model of granulopoiesis.

BACKGROUND: Hematopoiesis is a complex process involving different cell types and feedback mechanisms mediated by cytokines. This complexity stimulated various models with different scopes and applications. A combination of complementary models promises to provide their mutual confirmation and to explain a broader range of scenarios. Here we propose a combination of an ordinary differential equation (ODE) model of human granulopoiesis and an agent-based model (ABM) of hematopoietic stem cell (HSC) organization. The first describes the dynamics of bone marrow cell stages and circulating cells under various perturbations such as G-CSF treatment or chemotherapy. In contrast to the ODE model describing cell numbers, our ABM focuses on the organization of individual cells in the stem population. RESULTS: We combined the two models by replacing the HSC compartment of the ODE model by a difference equation formulation of the ABM. In this hybrid model, regulatory mechanisms and parameters of the original models were kept unchanged except for a few specific improvements: (i) Effect of chemotherapy was restricted to proliferating HSC and (ii) HSC regulation in the ODE model was replaced by the intrinsic regulation of the ABM. Model simulations of bleeding, chronic irradiation and stem cell transplantation revealed that the dynamics of hybrid and ODE model differ markedly in scenarios with stem cell damage. Despite these differences in response to stem cell damage, both models explain clinical data of leukocyte dynamics under four chemotherapy regimens. CONCLUSIONS: ABM and ODE model proved to be compatible and were combined without altering the structure of both models. The new hybrid model introduces model improvements by considering the proliferative state of stem cells and enabling a cell cycle-dependent effect of chemotherapy. We demonstrated that it is able to explain and predict granulopoietic dynamics for a large variety of scenarios such as irradiation, bone marrow transplantation, chemotherapy and growth factor applications. Therefore, it promises to serve as a valuable tool for studies in a broader range of clinical applications, in particular where stem cell activation and proliferation are involved.

Plasma-free vs deconjugated metanephrines for diagnosis of phaeochromocytoma.

BACKGROUND: The diagnosis of phaeochromocytoma is commonly performed by the measurements of plasma-free normetanephrine and metanephrine. Plasma-deconjugated normetanephrine and metanephrine have been proposed as alternative, equivalent, but easier to measure biomarkers. OBJECTIVE: The aim of this study was to compare the diagnostic performance of plasma-free vs deconjugated normetanephrine and metanephrine in patients tested for phaeochromocytoma. METHODS: The study population included a reference group of 262 normotensive and hypertensive volunteers, 198 patients with phaeochromocytoma and 528 patients initially suspected of having the tumour, but with negative investigations after at least 2 years of follow-up. Measurements were performed using liquid chromatography with electrochemical detection. RESULTS: Plasma concentrations of free normetanephrine were 17-fold higher in patients with phaeochromocytoma than in the reference population, a 72% larger (P < 0·001) difference than that for the 10-fold higher levels of plasma-deconjugated normetanephrine. In contrast, relative increases in plasma concentrations of free and deconjugated metanephrine were similar. Using upper cut-offs established in the reference population, measurements of plasma-free metabolites provided superior diagnostic performance than deconjugated metabolites according to measures of both sensitivity (97% vs 92%, P = 0·002) and specificity (93% vs 89%, P = 0·012). The area under the receiver operating characteristic curve for the free metabolites was larger than that for the deconjugated metabolites (0·986 vs 0·965, P < 0·001). CONCLUSION: Measurements of plasma-free normetanephrine and metanephrine are superior to the deconjugated metabolites for diagnosis of phaeochromocytoma.

Individual fates of mesenchymal stem cells in vitro.

BACKGROUND: In vitro cultivated stem cell populations are in general heterogeneous with respect to their expression of differentiation markers. In hematopoietic progenitor populations, this heterogeneity has been shown to regenerate within days from isolated subpopulations defined by high or low marker expression. This kind of plasticity has been suggested to be a fundamental feature of mesenchymal stem cells (MSCs) as well. Here, we study MSC plasticity on the level of individual cells applying a multi-scale computer model that is based on the concept of noise-driven stem cell differentiation. RESULTS: By simulation studies, we provide detailed insight into the kinetics of MSC organisation. Monitoring the fates of individual cells in high and low oxygen culture, we calculated the average transition times of individual cells into stem cell and differentiated states. We predict that at low oxygen the heterogeneity of a MSC population with respect to differentiation regenerates from any selected subpopulation in about two days. At high oxygen, regeneration becomes substantially slowed down. Simulation results on the composition of the functional stem cell pool of MSC populations suggest that most of the cells that constitute this pool originate from more differentiated cells. CONCLUSIONS: Individual cell-based models are well-suited to provide quantitative predictions on essential features of the spatio-temporal organisation of MSC in vitro. Our predictions on MSC plasticity and its dependence on the environment motivate a number of in vitro experiments for validation. They may contribute to a better understanding of MSC organisation in vitro, including features of clonal expansion, environmental adaptation and stem cell ageing.