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In this paper, we introduce a compact, single-sided stray field sensor for NMR relaxometry applications. The sensor consists of four main components: the magnet, the RF coil, the spectrometer, and the translation stage. Our proposed magnet, an improved design of the Profile NMR-MOUSE, is designed for low weight, compactness, and magnetic field homogeneity, achieved through various shim strategies using a mixed genetic algorithm. The magnet comprises eight NdFeB blocks, generating a magnetic field of 0.424T within the sensitive region, positioned 12 mm above the magnet surface. For high spatial resolution measurements, we optimized the sensor performance by using a custom-designed rf coil, providing maximum sensitivity, lateral selectivity, and a dead time of less than 20µs. Moreover, we utilized 3D-printed structures to precisely align the sensitive slice within the object, using an experimental approach based on CPMG measurements. The presented setup achieved a spatial resolution of 50µm, with resolution changes proportional to acquisition time. We demonstrate the sensor's versatility and high resolution with measurements on materials such as cosmetics, elastomers, glue, and wood, verifying the good performance of our design, our alignment strategy, and the measuring scheme., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declarations. Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. The project was approved by the ethics committees at Charité – Universitätsmedizin Berlin (EA2/192/17) and the Medical Association of North Rhine (2017429). Consent to participate: Written informed consent was obtained from all individual participants included in the study. Consent to publish: Not applicable. Competing interests: The authors have no relevant financial or non-financial interests to disclose.

Treatment modifications and contact restrictions were common during the COVID-19 pandemic and can be stressors for mental health. There is a lack of studies assessing pandemic-related risk factors for anxiety and depression of cancer patients and survivors systematically in multifactorial models. A total of 2391 participants, mean age 65.5 years, ≤5 years post-diagnosis of either lung, prostate, breast, colorectal cancer, or leukemia/lymphoma, were recruited in 2021 via the Baden-Württemberg Cancer Registry, Germany. Sociodemographic information, pandemic-related treatment modifications, contact restrictions, and anxiety/depression (Hospital Anxiety and Depression Scale, HADS) were assessed via self-administered questionnaire. Clinical information (diagnosis, stage, and treatment information) was obtained from the cancer registry. Overall, 22% of participants reported oncological care modifications due to COVID-19, mostly in follow-up care and rehabilitation. Modifications of active cancer treatment were reported by 5.8%. Among those, 50.5% had subclinical anxiety and 55.4% subclinical depression (vs. 37.4% and 45.4%, respectively, for unchanged active treatment). Age <60 years, female sex, lung cancer, low income, and contact restrictions to peer support groups or physicians were identified as independent risk factors for anxiety. Risk factors for depression were lung cancer (both sexes), leukemia/lymphoma (females), recurrence or palliative treatment, living alone, low income, and contact restrictions to relatives, physicians, or caregivers. The study demonstrates that changes in active cancer treatment and contact restrictions are associated with impaired mental well-being. The psychological consequences of treatment changes and the importance for cancer patients to maintain regular contact with their physicians should be considered in future responses to threats to public health., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Cancer treatments, although life prolonging, are associated with side effects. The occurrence, duration, and severity of side effects vary, depending on treatment received. Long-term effects refer to effects that manifest during treatment and persist long after treatment has ended. Late effects are complications that occur after treatment has ended. These effects can have a negative impact on the functioning and quality of life of persons living with and beyond cancer. This overview aims to provide a non-exhaustive overview of the long-term and late effects associated with the traditional mainstay of cancer treatments (surgery, radiotherapy, chemotherapy) and newer treatments such as immunotherapy. In conclusion, long-term and late effects of cancer treatment can be associated with a high burden for those affected, including a reduction in their ability to function and health-related quality of life. Given the large and further growing number of cancer survivors and the abundance of long-term and late effects, it is essential to develop and implement risk-adapted, multidisciplinary survivorship care programmes., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Platelets play a crucial role in tissue regeneration, and their involvement in liver regeneration is well-established. However, the specific contribution of platelet-derived Transforming Growth Factor Beta 1 (TGFβ1) to liver regeneration remains unexplored. This study investigated the role of platelet-derived TGFβ1 in initiating liver regeneration following 2/3 liver resection. Using platelet-specific TGFβ1 knockout (Plt.TGFβ1 KO) mice and wild-type littermates (Plt.TGFβ1 WT) as controls, the study assessed circulating levels and hepatic gene expression of TGFβ1, Platelet Factor 4 (PF4), and Thrombopoietin (TPO) at early time points post-hepatectomy (post-PHx). Hepatocyte proliferation was quantified through Ki67 staining and PCNA expression in total liver lysates at various intervals, and phosphohistone-H3 (PHH3) staining was employed to mark mitotic cells. Circulating levels of hepatic mitogens, Hepatocyte Growth Factor (HGF), and Interleukin-6 (IL6) were also assessed. Results revealed that platelet-TGFβ1 deficiency significantly reduced total plasma TGFβ1 levels at 5 h post-PHx in Plt.TGFβ1 KO mice compared to controls. While circulating PF4 levels, liver platelet recruitment and activation appeared normal at early time points, Plt.TGFβ1 KO mice showed more stable circulating platelet numbers with higher numbers at 48 h post-PHx. Notably, hepatocyte proliferation was significantly reduced in Plt.TGFβ1 KO mice. The results show that a lack of TGFβ1 in platelets leads to an unbalanced expression of IL6 in the liver and to strongly increased HGF levels 48 h after liver resection, and yet liver regeneration remains reduced. The study identifies platelet-TGFβ1 as a regulator of hepatocyte proliferation and platelet homeostasis in the early stages of liver regeneration., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

A strategy for pandemic preparedness is the development of antivirals against a wide set of viral targets with complementary mechanisms of action. SARS-CoV-2 nsp3-mac1 is a viral macrodomain with ADP-ribosylhydrolase activity, which counteracts host immune response. Targeting the virus' immunomodulatory functionality offers a differentiated strategy to inhibit SARS-CoV-2 compared to approved therapeutics, which target viral replication directly. Here we report a fragment-based lead generation campaign guided by computational approaches. We discover tool compounds which inhibit nsp3-mac1 activity at low nanomolar concentrations, and with responsive structure-activity relationships, high selectivity, and drug-like properties. Using our inhibitors, we show that inhibition of nsp3-mac1 increases ADP-ribosylation, but surprisingly does not translate to demonstrable antiviral activity in cell culture and iPSC-derived pneumocyte models. Further, no synergistic activity is observed in combination with interferon gamma, a main protease inhibitor, nor a papain-like protease inhibitor. Our results question the extent to which targeting modulation of innate immunity-driven ADP-ribosylation can influence SARS-CoV-2 replication. Moreover, these findings suggest that nsp3-mac1 might not be a suitable target for antiviral therapeutics development.

In the restoration or rehabilitation of traditional buildings, compatible materials with known characteristics must be used. However, the existing literature lacks comprehensive studies on the characterisation of Persian mud-straw plaster, focusing primarily on Persian adobe. Moreover, previous research on Persian adobe has primarily employed XRF and XRD tests, neglecting ion chromatography, moisture sorption isotherm determination, and thermogravimetric analysis with differential scanning calorimetry. Consequently, there is a shortage of information regarding the elemental composition, mineralogical characteristics, moisture sorption behaviour, and thermal properties of Persian mud-straw plaster, as well as Persian adobe bricks. This paper aims to address this research gap by examining historical and new adobe bricks and mud-straw plaster used in Iran, utilising a comprehensive array of analytical techniques. The results from XRF analysis reveal relatively similar chemical compositions across all samples, while XRD analysis indicates predominantly similar mineral phases. Ion chromatography results demonstrate higher conductivity and chloride concentrations in the mud-straw samples than the adobe samples, with higher values for new samples than historical ones. Freshly used straw, clay, or soil may have higher chloride concentrations caused by the arid climate and soil salinisation in the area. Additionally, moisture sorption isotherm determination results show that adobe and mud-straw plaster with a higher salt load of chlorides have significantly higher moisture absorption. The increased straw quantity in the samples increases the moisture content. Furthermore, thermogravimetric analysis and differential scanning calorimetry indicate that, at low heating, adobe and mud-straw plaster lose water due to dehydration, and at high heating, they lose carbon dioxide due to decarboxylation. The comprehensive characterisation of Persian adobe and mud-straw plaster in this study fills a significant gap in the literature and offers invaluable insights for informing restoration and rehabilitation processes, ensuring the compatibility of the materials used.

Background: Fragmented and complex healthcare systems make it difficult to provide continuity of care for patients with advanced cancer near the end of life. Nurse-based cross-sectoral navigation support has the potential to increase patients' quality of life. The objective of this paper was to evaluate associations between navigation support and health care utilization, and the associated costs of care., Methods: The evaluation is based on claims data from 37 statutory health insurance funds. Non-randomized recruitment of the intervention group (IG) took place between 2018 and 2019 in four German hospitals. The comparison group (CG) was defined ex post. It comprises nonparticipating clients of the involved health insurance funds matched on age, gender, and diagnosis in a 1:4 ratio to the IG. Healthcare resource utilization was compared using incident rate ratios (IRRs) based on negative binomial regression models. Linear mixed models were performed to compare differences in lengths of hospital stays and costs between groups., Results: A total of 717 patients were included (IG: 149, CG: 568). IG patients showed shorter average lengths of hospital stays (IG: 11 days [95% CI: 10, 13] vs. CG: 15 days [95% CI: 14, 16], p < 0.001). In the IG, 21% fewer medications were prescribed and there were on average 15% fewer outpatient doctor contacts per month. Average billed costs in the IG were 23% lower than in the CG (IG: 6754 EUR [95% CI: 5702, 8000] vs. CG: 8816 EUR [95% CI: 8153, 9533], p < 0.001)., Conclusions: The intervention was associated with decreased costs mainly as a result of a non-intended navigation effect. The social care nurses had navigated patients within the hospital early, needs-oriented and effectively but interpreted their function less cross-sectorally. Linkage of hospital-based navigators with the outpatient care sector needs further exploration., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Chronic gastric infection with Helicobacter pylori can lead to progressive tissue changes that culminate in cancer, but how H. pylori adapts to the changing tissue environment during disease development is not fully understood. In a transgenic mouse gastric metaplasia model, we found that strains from unrelated individuals differed in their ability to infect the stomach, to colonize metaplastic glands, and to alter the expression of the metaplasia-associated protein TFF3. H. pylori isolates from different stages of disease from a single individual had differential ability to colonize healthy and metaplastic gastric glands. Exposure to the metaplastic environment selected for high gastric colonization by one of these strains. Complete genome sequencing revealed a unique alteration in the frequency of a variant allele of the putative adhesin sabB , arising from a recombination event with the related sialic acid binding adhesin (SabA) gene. Mutation of sabB in multiple H. pylori strain backgrounds strongly reduced adherence to both normal and metaplastic gastric tissue, and highly attenuated stomach colonization in mice. Thus, the changing gastric environment during disease development promotes bacterial adhesin gene variation associated with enhanced gastric colonization. IMPORTANCE Chronic infection with Helicobacter pylori is the primary risk factor for developing stomach cancer. As disease progresses H. pylori must adapt to a changing host tissue environment that includes induction of new cell fates in the cells that line the stomach. We tested representative H. pylori isolates collected from the same patient during early and later stages of disease in a mouse model where we can rapidly induce disease-associated tissue changes. Only the later-stage H. pylori strains could robustly colonize the diseased stomach environment. We also found that the ability to colonize the diseased stomach was associated with genetic variation in a putative cell surface adhesin gene called sabB . Additional experiments revealed that SabB promotes binding to stomach tissue and is critical for stomach colonization by the late-stage strains. Thus, H. pylori diversifies its genome during disease progression and these genomic changes highlight critical factors for bacterial persistence.

Purpose: Sexual function is crucial for the quality of life and can be highly affected by preoperative therapy and surgery. The aim of this study was to identify potential risk factors for poor sexual function and quality of life., Methods: Female patients were asked to complete the Female Sexual Function Index (FSFI-6). Male patients were demanded to answer the International Index of Erectile Function (IIEF-5)., Results: In total, 79 patients filled in the questionary, yielding a response rate of 41.57%. The proportion of women was represented by 32.91%, and the median age was 76.0 years (66.0-81.0). Sexual dysfunction appeared in 88.46% of female patients. Severe erectile dysfunction occurred in 52.83% of male patients. Univariate analysis showed female patients (OR: 0.17, 95%CI: 0.05-0.64, p = 0.01), older age (OR: 0.34, 95%CI 0.11-1.01, p = 0.05), tumor localization under 6cm from the anal verge (OR: 4.43, 95%CI: 1.44-13.67, p = 0.01) and extension of operation (APR and ISR) (OR: 0.13, 95%CI: 0.03-0.59, p = 0.01) as significant risk factors for poor outcome. Female patients (OR: 0.12, 95%CI: 0.03-0.62, p = 0.01) and tumors below 6 cm from the anal verge (OR: 4.64, 95%CI: 1.18-18.29, p = 0.03) were shown to be independent risk factors for sexual dysfunction after multimodal therapy in the multivariate analysis. Quality of life was only affected in the case of extensive surgery ( p = 0.02)., Conclusion: Higher Age, female sex, distal tumors and extensive surgery (APR, ISR) are revealed risk factors for SD in this study. Quality of life was only affected in the case of APR or ISR.

This study aims to improve emergency department (ED) care for patients suffering from atraumatic abdominal pain. An application-supported pathway for the ED will be implemented, which supports quick, evidence-based, and standardized diagnosis and treatment steps for patients with atraumatic abdominal pain at the ED. A mixed-methods multicentre cluster randomized controlled stepped wedge trial design will be applied. A total of 10 hospitals with EDs (expected n = 2.000 atraumatic abdominal pain patients) will consecutively (every 4 months) be randomized to apply the intervention. Inclusion criteria for patients are a minimum age of 18 years, suffering from atraumatic abdominal pain and being insured with a German statutory health insurance. Primary outcomes: acute pain score at time of discharge from ED, duration of treatment at the ED, patient-reported satisfaction. Secondary endpoints include patient safety and quality of care parameters, process evaluation parameters, and costs and cost-effectiveness parameters. Quantitative data will be gathered from patient-surveys, clinical records, and routine data from hospital information systems as well as from a participating German statutory health insurance. Descriptive and analytic statistical analysis will be performed to provide summaries and associations for primary patient-reported outcomes, process measures, quality measures, and costs. Qualitative data collection consists of participatory patient observations and semi-structured expert interviews, which will be inductively analysed. Findings will be disseminated in publications in peer-reviewed journals, on conferences, as well as via a project website. To ensure data protection, appropriate technical and organisational measures will be taken. Trial registration: DRKS00021052., Competing Interests: The authors have declared that no competing interests exist.

Background: Robotic surgery represents a novel approach for the treatment of colorectal cancers and has been established as an important and effective method over the last years. The aim of this work was to evaluate the effect of a robotic program on oncological findings compared to conventional laparoscopic surgery within the first three years after the introduction., Methods: All colorectal cancer patients from two centers that either received robotic-assisted or conventional laparoscopic surgery were included in a comparative study. A propensity-score-matched analysis was used to reduce confounding differences., Results: A laparoscopic resection (LR Group) was performed in 82 cases, and 93 patients were treated robotic-assisted surgery (RR Group). Patients' characteristics did not differ between groups. In right-sided resections, an intracorporeal anastomosis was significantly more often performed in the RR Group (LR Group: 5 (26.31%) vs. RR Group: 10 (76.92%), p = 0.008). Operative time was shown to be significantly shorter in the LR Group (LR Group: 200 min (150-243) vs. 204 min (174-278), p = 0.045). Conversions to open surgery did occur more often in the LR Group (LR Group: 16 (19.51%) vs. RR Group: 5 (5.38%), p = 0.004). Postoperative morbidity, the number of harvested lymph nodes, quality of resection and postoperative tumor stage did not differ between groups., Conclusion: In this study, we could clearly demonstrate robotic-assisted colorectal cancer surgery as effective, feasible and safe regarding postoperative morbidity and oncological findings compared to conventional laparoscopy during the introduction of a robotic system.

Purpose: Given the psychosocial burdens patients in advanced stages of cancer face, innovative care concepts are needed. At the same time, such vulnerable patient groups are difficult to reach for participation in intervention studies and randomized patient inclusion may not be feasible. This article aims to identify systematic biases respectively selection effects occurring during the recruitment phase and to discuss their potential causes based on a non-randomized, multicenter intervention study with patients in advanced stages of cancer., Methods: Patients diagnosed with at least one of 16 predefined cancers were recruited at four hospitals in three German cities. The effect of social care nurses' continuous involvement in acute oncology wards was measured by health-related quality of life (EORTC QLQ-C30), information and participation preferences, decisional conflicts, doctor-patient communication, health literacy and symptom perception. Absolute standardized mean difference was calculated as a standardized effect size to test baseline characteristics balance between the intervention and control groups., Results: The study enrolled 362 patients, 150 in the intervention and 212 in the control group. Except for gender, both groups differed in relevant socio-demographic characteristics, e.g. regarding age and educational background. With respect to the distribution of diagnoses, the intervention group showed a higher symptom burden than the control group. Moreover, the control group reported better quality of life at baseline compared to the intervention group (52.6 points (SD 21.7); 47.8 points (SD 22.0), ASMD = 0.218, p = 0.044)., Conclusion: Overall, the intervention group showed more social and health vulnerability than the control group. Among other factors, the wide range of diagnoses included and structural variation between the recruiting clinics increased the risk for bias. We recommend a close, continuous monitoring of relevant social and health-related characteristics during the recruitment phase as well as the use of appropriate statistical analysis strategies for adjustment, such as propensity score methods., Trial Registration: German Clinical Trials Register (DRKS-ID: DRKS00013640 ); registered on 29th December 2017., (© 2022. The Author(s).)

Extensive clinical data from liver-mediated gene therapy trials have shown that dose-dependent immune responses against the vector capsid may impair or even preclude transgene expression if not managed successfully with prompt immune suppression. The goal of this preclinical study was to generate an adeno-associated viral (AAV) vector capable of expressing therapeutic levels of B-domain deleted factor VIII (FVIII) at the lowest possible vector dose to minimize the potential Risk of a capsid-mediated immune response in the clinical setting. Here, we describe the studies that identified the investigational agent SPK-8011 , currently being evaluated in a phase 1/2 study (NCT03003533) in individuals with hemophilia A. In particular, the potency of our second-generation expression cassettes was evaluated in mice and in non-human primates using two different bioengineered capsids (AAV-Spark100 and AAV-Spark200). At 2 weeks after gene transfer, primates transduced with 2 × 10 12 vg/kg AAV-Spark100-FVIII or AAV-Spark200-FVIII expressed FVIII antigen levels of 13% ± 2% and 22% ± 6% of normal, respectively. Collectively, these preclinical results validate the feasibility of lowering the AAV capsid dose for a gene-based therapeutic approach for hemophilia A to a dose level orders of magnitude lower than the first-generation vectors in the clinic., Competing Interests: S.M.A., R.T., M.D., M.W., S.K., J.S., J.F., M.C., Y.W., C.W., L.E., K.A.H., and X.M.A. are current or former employees of Spark Therapeutics. K.A.H., X.M.A., L.E., and D.E.S. are inventors on issued and pending patents related to AAV viral vectors for which they have received royalty payments., (© 2021 The Authors.)

Background: Cognitive dysfunction has been reported in acute psychiatric patients for a long time. The detection of cognitive deficits is crucial both for clinical treatment and for predicting the psychosocial functional level in the further course of the disease. The SCIP is a well-evaluated screening instrument for the examination of cognitive performance in psychiatric patients. We recently integrated the SCIP into our routine admission and discharge assessments on two inpatient wards, and we examined the cognitive profiles of patients with psychotic and affective disorders over the course of their admission., Methods: Shortly after admission, and prior to discharge, patients were routinely referred for examination with the SCIP. A total of 529 assessments were completed on admission, and 227 returned for SCIP at the time of discharge. After standardization of the test results against a normative sample, we examined the normalized test values in terms of percentages of pathological cognitive performance based on the total SCIP score, and each of the SCIP subscale scores. We conducted cluster analysis to identify cognitive subgroups within the clinical sample., Results: More than 70% of the SCIP results on admission were pathological. At discharge, improvements were observed, especially on tests with attention and speed components. Cluster analysis identified two groups. The cluster with chronic patients showed poorer results at admission, but greater improvement and reached the level of the others at discharge., Conclusions: The SCIP appears to have value in routine diagnostic assessments, and in the quantification of improvements in cognitive performance during an inpatient stay. The greatest benefit was observed in chronically ill patients with many previous stays., Trial Registration: DRKS00019825 (retrospectively registered on 03.12.2019)., (© 2021. The Author(s).)

Objective: The objective of this study was to evaluate an extended role for the physiotherapist in primary care in referring patients to plain X-ray., Methods: This prospective cohort study was set in a single region in Sweden. It included 20 physiotherapists who were educated in a 1-day training in performing referral to X-ray, along with 107 patients with musculoskeletal disorders who were referred to X-ray. We evaluated referral quality and patient and physiotherapist satisfaction and calculated healthcare and patient costs., Results: All referrals fulfilled the basic requirements of quality, and 78% were classified as good, fulfilling all criteria. Both patients and physiotherapists were satisfied with the extended role for the physiotherapist that decreased the waiting time to diagnosis and to adequate treatment. Costs were reduced for patients (by €53/patient) and healthcare (by €6286.2/107 patients). The cost to visit a physician was twice that of a physiotherapist visit., Conclusions: An extended role for physiotherapists in primary care in referring patients to X-ray was effective and safe for patients and reduced costs for patients and for healthcare. Physiotherapists in primary care were able to refer patients to X-ray after a 1 day of training, and the extended role freed up 45 min of physician time for each patient with a musculoskeletal disorder in need of an X-ray., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society for Quality in Health Care.)

Background: Patient-reported outcome measures (PROMs) are commonly-used surrogates for clinical outcomes in cancer research. When researching severe diseases such as cancer, it is difficult to avoid the problem of incomplete questionnaires from drop-outs or missing data from patients who pass away during the observation period. The aim of this exploratory study was to explore patient characteristics and the patient-reported outcomes associated with the time-to-dropout., Methods: In an Oncological Social Care Project (OSCAR) study, the condition of the participants was assessed four times within 12 months (t0: baseline, t1: 3 months, t2: 6 months, and t3: 12 months) by validated PROMs. We performed competing-risk regressions based on Fine and Gray's proportional sub-distribution hazards model for exploring factors associated with time-to-dropout. Death was considered a competing risk., Results: Three hundred sixty-two participants were analyzed in the study. 193 (53.3%) completed a follow-up after 12 months, 67 (18.5%) patients dropped out, and 102 patients (28.2%) died during the study period. Poor subjective social support was related to a higher risk of drop-out (SHR = 2.10; 95%CI: 1.01-4.35). Lower values in health-related quality of life were related to drop-out and death. The sub-scales global health status/QoL, role functioning, physical functioning, and fatigue symptom in the EORTC QLQ-C30 were key characteristics of early drop-out., Conclusion: Severely affected cancer patients with poor social support and poor quality of life seem more likely to drop out of studies than patients with higher levels of social support and a better quality of life. This should be considered when planning studies to assess advanced cancer patients. Methods of close continued monitoring should be actively used when patient experiences a substantial deterioration in their health-related quality of life and symptoms during the study. Results for such studies have to be interpreted with caution in light of specific drop-out mechanisms., Trial Registration: OSCAR study was registered to the German Clinical Trials Register (DRKS-ID: DRKS00013640 ). Registered 29 December 2017.

Domain boundaries are a determining factor in the performance of organic electronic devices since they can trap mobile charge carriers. We point out the possibility of time-dependent motion of these boundaries and suggest that their thermal fluctuations can be a source of dynamic disorder in organic films. In particular, we study the C8-BTBT monolayer films with several different domain boundaries. After characterizing the crystallography and diversity of structures in the first layer of C8-BTBT on Au(111), we focus on quantifying the domain boundary fluctuations in the saturated monolayer. We find that the mean squared displacement of the boundary position grows linearly with time at early times but tends to saturate after about 7 s. This behavior is ascribed to confined diffusion of the interface position based on fits and numerical integration of a Langevin equation for the interface motion.

We present the results from a white-box machine learning approach to detect cardiac arrhythmias using electrocardiographic data. A C5.0 is trained to recognize four classes using common features. The four classes are (i) atrial fibrillation and atrial flutter, (ii) tachycardias (iii), sinus bradycardia and (iv) sinus rhythm. Data from 10,646 subjects, 83% of whom have at least one arrhythmia and 17% of whom exhibit a normal sinus rhythm, are used. The C5.0 is trained using 10-fold cross-validation and is able to achieve a balanced accuracy of 95.35%. By using the white-box machine learning approach, a clear and comprehensible tree structure can be revealed, which has selected the 5 most important features from a total of 24 features. These 5 features are ventricular rate, RR-Interval variation, atrial rate, age and difference between longest and shortest RR-Interval. The combination of ventricular rate, RR-Interval variation and atrial rate is especially relevant to achieve classification accuracy, which can be disclosed through the tree. The tree assigns unique values to distinguish the classes. These findings could be applied in medicine in the future. It can be shown that a white-box machine learning approach can reveal granular structures, thus confirming known linear relationships and also revealing nonlinear relationships. To highlight the strength of the C5.0 with respect to this structural revelation, the results of further white-box machine learning and black-box machine learning algorithms are presented., Competing Interests: The authors have declared that no competing interests exist.

Here, we report a case of COVID-19-related acute necrotizing encephalopathy where SARS-CoV-2 RNA was found in CSF 19 days after symptom onset after testing negative twice. Although monocytes and protein levels in CSF were only marginally increased, and our patient never experienced a hyperinflammatory state, her neurologic function deteriorated into coma. MRI of the brain showed pathologic signal symmetrically in central thalami, subinsular regions, medial temporal lobes, and brain stem. Extremely high concentrations of the neuronal injury markers neurofilament light and tau, as well as an astrocytic activation marker, glial fibrillary acidic protein, were measured in CSF. Neuronal rescue proteins and other pathways were elevated in the in-depth proteomics analysis. The patient received IV immunoglobulins and plasma exchange. Her neurologic status improved, and she was extubated 4 weeks after symptom onset. This case report highlights the neurotropism of SARS-CoV-2 in selected patients and emphasizes the importance of repeated lumbar punctures and CSF analyses in patients with suspected COVID-19 and neurologic symptoms., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Pulmonary hypertension (PH) in patients with bronchopulmonary dysplasia (BPD) results from vasoconstriction and/or vascular remodeling, which can be regulated by mitogen-activated protein kinases (MAPKs). MAPKs are deactivated by dual-specificity phosphatases (DUSPs). We hypothesized that single-nucleotide polymorphisms (SNPs) in DUSP genes could be used to predict PH in BPD., Methods: Preterm infants diagnosed with BPD (n = 188) were studied. PH was defined by echocardiographic criteria. Genomic DNA isolated from patient blood samples was analyzed for 31 SNPs in DUSP genes. Clinical characteristics and minor allele frequencies were compared between BPD-PH (cases) and BPD-without PH (control) groups. Biomarker models to predict PH in BPD using clinical and SNP data were tested by calculations of area under the ROC curve., Results: In our BPD cohort, 32% (n = 61) had PH. Of the DUSP SNPs evaluated, DUSP1 SNP rs322351 was less common, and DUSP5 SNPs rs1042606 and rs3793892 were more common in cases than in controls. The best fit biomarker model combines clinical and DUSP genetic data with an area under the ROC curve of 0.76., Conclusion: We identified three DUSP SNPs as potential BPD-PH biomarkers. Combining clinical and DUSP genetic data yields the most robust predictor for PH in BPD.

Background: Differences in the susceptibility of preterm infants to develop necrotizing enterocolitis (NEC) implicate potential genetic differences in response to the inflammatory stimuli leading to NEC. Dual specificity phosphatases (DUSPs) are a key suppressor pathway of the mitogen-activated protein kinase (MAPK) pro-inflammatory signaling pathway. We hypothesized that inherited single nucleotide polymorphisms (SNPs) in DUSP genes contribute to NEC susceptibility in premature infants., Methods: Patients admitted between 2010 and 2015 born at <  32 weeks GA and≤1,500 g BW with stage II+NEC (cases; n = 50) and age, weight-matched controls (n = 38) were included. Blood samples were collected for DNA isolation. Agena Mass Array assay was used to examine 31 SNPs in 9 different DUSP genes. Calculated minor allele frequencies (MAF) for cases and controls were compared using χ2 and logistic regression., Results: The presence of the rs704074 SNP was associated with a 48% decreased risk of developing NEC (OR 0.52; 95% CI 0.27- 1.01, p = 0.04). The odds of surgical NEC decreased by 78% (OR 0.22; 95% CI 0.06- 0.84, p = 0.027) for each copy of rs704074/G allele in patients with NEC., Conclusion: In this small single-center pilot study, DUSP-6 SNP (rs704074) was associated with a lower risk of developing NEC and surgical NEC, the most severe form of NEC, in preterm infants.

Background: Cancer patients experience psychological and social distress due to their medical treatment and social issues. However, continuous and specialized social support is still lacking. In Germany, a group of company health insurance funds has developed an approach to support cancer patients with monthly structured interviews conducted by specially trained Social Care Nurses. The nurses will identify patient needs in order to provide help with medical, personal, and social matters. One aim of the scientific evaluation is to analyze the effect of the consultations on various patient-reported outcomes, especially quality of life. The evaluation concept will be described in this study protocol., Methods/design: The evaluation is a non-randomized, controlled, multi-center intervention study with a mixed-method design. It consists of three research modules which include primary data from questionnaires, and claims data from the health insurance funds. In Module 1, cancer patients will be recruited to form an intervention group (OSCAR, n = 150) and a control group (n = 200) in four study centers for a period of 1 year. One baseline and three follow-up questionnaires will be conducted to survey the patient-reported outcomes. Relevant secondary outcomes are health literacy, participation, and physician-patient communication. In Module 2, claims data will be used to analyze cost effects and thereby assess effectivity and hospitalization. Module 3 will involve a qualitative analysis of project diaries kept by the Social Care Nurses. The diaries will record the nurses' practical experiences and the benefits of deploying OSCAR across the German healthcare system., Discussion: OSCAR is an innovative way of providing cancer patients with continuous support to improve their quality of life. The evaluation concept aims to assess the effects of the monthly consultations by the Social Care Nurses on the patients, and will use a mixed-method design. The results are important for assessing the transferability of OSCAR to the healthcare system as a whole., Trial Registration: German Clinical Trials Register (DRKS-ID: DRKS00013640 ). Registered 29 December 2017.

Aim: Evaluation of German-language guidelines for aphasia and dysarthria rehabilitation, and comparison with international guidelines., Methods: The quality of the 6 included guidelines, as found through a comprehensive literature search, was sytematically evaluated using AGREE II. Quality ratings were compared to the results of a systematic review of 19 English-language guidelines., Results: The quality of German-language guidelines was heterogeneous. In 2 out of 6 evaluation domains and in the overall assessment, no German-language guideline reached the cut-off of 66,67% for good guideline quality. Apart from the domain Editorial Independence, results remained behind those of the international reference guidelines., Conclusion: In some cases, quality can be improved by simple means. It is more resource-intensive, but crucial to document search strategies and how evidence was used in guideline development. A harmonization of the German-language guidelines seems desirable., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: To investigate the suitability of the German version of the Manchester Triage System (MTS) as a potential tool to redirect emergency department (ED) patients to general practitioner care. Such tools are currently being discussed in the context of reorganisation of emergency care in Germany., Design: Prospective cohort study., Setting: Single centre University Hospital Emergency Department., Participants: Adult, non-surgical ED patients., Exposure: A non-urgent triage category was defined as a green or blue triage category according to the German version of the MTS., Primary and Secondary Outcome Measures: Surrogate parameters for short-term risk (admission rate, diagnoses, length of hospital stay, admission to the intensive care unit, in-hospital and 30-day mortality) and long-term risk (1-year mortality)., Results: A total of 1122 people presenting to the ED participated in the study. Of these, 31.9% (n=358) received a non-urgent triage category and 68.1% (n=764) were urgent. Compared with non-urgent ED presentations, those with an urgent triage category were older (median age 60 vs 56 years, p=0.001), were more likely to require hospital admission (47.8% vs 29.6%) and had higher in-hospital mortality (1.6% vs 0.8%). There was no significant difference observed between non-urgent and urgent triage categories for 30-day mortality (1.2% [n=4] vs 2.2% [n=15]; p=0.285) or for 1-year mortality (7.9% [n=26] vs 10.5% [n=72]; p=0.190). Urgency was not a significant predictor of 1-year mortality in univariate (HR=1.35; 95% CI 0.87 to 2.12; p=0.185) and multivariate regression analyses (HR=1.20; 95% CI 0.77 to 1.89; p=0.420)., Conclusions: The results of this study suggest the German MTS is unsuitable to safely identify patients for redirection to non-ED based GP care., Trial Registration Number: U1111-1119-7564; Post-results., Competing Interests: Competing interests: This study was supported by Thermofisher Scientific. AS, JS, JF, MB, TL and MM report grants from Thermoficher Scientific, during the conduct of the study; grants from Roche Diagnostics, grants from Thermofisher Scientific, grants from Novartis, grants from Cardiorentis, grants from Governmental institutions, from Foundations, outside the submitted work. MM reports grants from Thermoficher Scientific, during the conduct of the study; grants and personal fees from Roche Diagnostics, grants and personal fees from Thermofisher Scientific, grants and personal fees from Novartis, grants from Cardiorentis, grants from Governmental institutions, grants from Foundations, personal fees from Bayer Healthcare, personal fees from Boehringer Ingelheim, personal fees from Daiichi Sankyo, personal fees from Astra Yeneca, outside the submitted work. FG, LH and FT have nothing to disclose., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: For several years, Emergency Departments (ED) in Germany have observed increasing patient numbers, resulting in ED crowding. This leads to the question of whether patients with nonurgent conditions could also receive adequate treatment in primary care. Our objective was to develop a quantitative questionnaire to investigate in a larger patient group the reasons for this and to describe the implications for a patient survey in the ED., Methods: The development of the questionnaire was based on a literature search and the results of the qualitative EPICS-2 study. Two pretest surveys were conducted in three EDs at the Charité - Universitätsmedizin Berlin. We included patients aged ≥ 18 years with outpatient treatment and the categories blue (nonurgent), green (standard), or yellow (urgent) according to the Manchester Triage System (MTS)., Results: In total, 189 patients were recruited in two surveys (pretest 1: n = 89, pretest 2 n = 100). The final questionnaire includes 24 items, which were evaluated and adapted during both pretests. The items evaluate basic clinical characteristics, reasons for choosing the ED, prior contacts in primary care, utilization of primary care after-hours services as well as sociodemographic characteristics. Data from the hospital information system were used to link the survey data with clinical characteristics., Conclusions: The questionnaire is based on reasons for ED utilization. We recommend the written, self-applied questionnaire for patient surveys with plausibility checks conducted by staff. It is necessary to consider the heterogenic study surroundings in the ED, which requires a lot of flexibility during data collection.

Aim: Pulmonary hypertension significantly increases morbidity and mortality in infants with bronchopulmonary dysplasia. The frequency of single nucleotide polymorphisms in arginase-1 (ARG1 rs2781666) and dimethylarginine dimethylaminohydrolase-1 (DDAH1 rs480414) genes has been found to differ in a cohort of bronchopulmonary dysplasia patients with pulmonary hypertension (cases) and without pulmonary hypertension (controls). Therefore, we tested the hypothesis that combining these genotypes with phenotypic data would better predict pulmonary hypertension in bronchopulmonary dysplasia patients., Methods: Bronchopulmonary dysplasia patients (n = 79) born at <35 weeks gestation were studied. Pulmonary hypertension was diagnosed by echocardiographic criteria (n = 20). ROC curves to predict pulmonary hypertension in bronchopulmonary dysplasia were generated from genotype and/or clinical data., Results: Cases were born at an earlier gestation and weighed less at birth than did controls. ROC curves for rs2781666 had an AUC of 0.61, while rs480414 had an AUC of 0.66. Together, the AUC was 0.70. When clinical data were added to the genetic model, AUC was 0.73., Conclusion: These findings demonstrate that ROC predictive modelling of pulmonary hypertension in bronchopulmonary dysplasia improves with inclusion of both genotypic and phenotypic data. Further refinement of these types of models could facilitate the implementation of precision medicine approaches to pulmonary hypertension in bronchopulmonary dysplasia., (©2018 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: There are few treatment options in metastatic colorectal cancer (mCRC) after progression on standard chemotherapy. Third and fourth line therapies typically consist of regorafenib or trifluridine-tipiracil, however, clinical benefit of these medications is limited, as progression free survival is approximately 1.9 months for regorafenib (Grothey et al. 2013) and 2.0 months for trifluridine-tipiracil (Mayer et al. 2015). Another choice in this setting may include the re-initiation of previously used chemotherapy, therefore in this study we assessed the efficacy and tolerability of chemotherapy re-challenge., Methods: This was a retrospective, cohort study assessing patients with mCRC who were 18-89 years of age and treated with re-challenge chemotherapy. Re-challenge chemotherapy was defined as re-initiation of oxaliplatin or irinotecan-based regimens at least nine months from the end of initial exposure. A minimum of four chemotherapy cycles was required to qualify as initial exposure. The key endpoints of this study were clinical benefit rate (CBR), defined as the proportion of patients with partial response or stable disease, and time to progression (TTP)., Results: A total of 67 chemotherapy re-challenges were accounted for in 51 patients. The overall CBR was 70.7%. Partial responses occurred in 50.7% cases. The TTP was 6.0 months. For the 51 cases of first re-challenge, the CBR was 75.5% and TTP was 6.5 months. Fourteen patients had a second re-challenge, and in these patients, the CBR was 61.5% and TTP was 4.1 months., Conclusions: Oxaliplatin or irinotecan-based re-challenge should be considered as a third or fourth line treatment option in select patients with mCRC. CBR and especially TTP compare favorably to approved third line therapies such as regorafenib or trifluridine-tipiracil., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Eight resistance-trained men completed three protocols separated by 48-96 hours. Each protocol included 36 repetitions with the same rest duration, but the frequency and length of rest periods differed. The cluster sets of four (CS4) protocol included 30 s of rest after the 4th, 8th, 16th, 20th, 28th, and 32nd repetition in addition to 120 s of rest after the 12th and 24th repetition. For the other two protocols, the total 420 s rest time of CS4 was redistributed to include nine sets of four repetitions (RR4) with 52.5 s of rest after every four repetitions, or 36 sets of single repetitions (RR1) with 12 s of rest after every repetition. Mean (MF) and peak (PF) force, velocity (MV and PV), and power output (MP and PP) were measured during 36 repetitions and were collapsed into 12 repetitions for analysis. Repeated measures ANOVA 3 (protocol) x 12 (repetition) showed a protocol x repetition interaction for PF, MV, PV, MP, and PP (p-values from <0.001 to 0.012). No interaction or main effect was present for MF. During RR1, MV, PV, MP, and PP were maintained, but decreased throughout every 4-repetition sequence during CS4 and RR4. During CS4 and RR4, PF was less following a rest period compared to subsequent repetitions, whereas PF was maintained during RR1. These data indicate that rest redistribution results in similar average kinetics and kinematics, but if total rest time is redistributed to create shorter but more frequent sets, kinetics and kinematics may remain more constant.

Background  The increasing number of low-acuity visits to Emergency Departments (ED) is an important issue in Germany and contributes to ED crowding. A sustainable solution needs deeper knowledge of patients' underlying rationales. Methods  To explore patients' motives we conducted 31 semi-structured face-to-face interviews with low-acuity ED patients in a rural region in Saxony-Anhalt. Subsequently we interviewed 12 General Practitioners (GP)s about their perspectives on patients visiting ED with low-acuity conditions and referring patients to ED. A qualitative content analysis approach was used for data analysis. Results  All patients were connected to a GP. One third had visited ED because of 24/7 availability when consultation hours and working times overlapped. Another third had addressed EDs full range of laboratory and imaging technology with a subjective need for fast diagnosis. One group reported that they had been referred to the ED by their GP. The interviewed GPs classified patients' ED usage for time-constraints as impatience and growing demand, while they expressed greater understanding for patients striving to ED for anxiety reasons. Most GPs sometimes referred patients to ED for diagnostic reasons. Conclusion  The findings demonstrate that ED usage with non-urgent conditions takes place for different reasons. Therefore, ED plays a pivotal role not only in emergency care, but also in ambulant care. The growing demand for ambulant care indicates a need for changed health care structures., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: The point-of-care test Roche CARDIAC POC Troponin T (PoC TnT) is an improved assay which has been developed for the Roche cobas h 232 system., Methods: We performed a multicentre evaluation (four sites) to assess the analytical performance of the PoC TnT assay and to compare it with the central laboratory Elecsys® troponin T high sensitive (lab cTnT-hs) assay., Results: The relative mean differences found in method comparisons of PoC TnT vs. lab cTnT-hs ranged from -4.1% to +6.8%. Additionally, there was good concordance between PoC TnT and lab cTnT-hs for the number of samples with troponin T values below the measuring range of 40 ng/L. Lot-to-lot differences of PoC TnT ranged from -8.6% to +4.6%. Within-series coefficients of variation (CV) resulting from 81 ten-fold measurements with patient samples were 9.3%, 11.8%, and 12.9% in the low (40 to < 200 ng/L), medium (200 to < 600 ng/L), and high (600 to 2000 ng/L) measuring range, respectively. Using the system quality control, the mean CV for between-day imprecision was 11.3%. No interference was observed by triglycerides (up to 11.4 mmol/L), bilirubin (up to 376 µmol/L), hemoglobin (up to 0.12 mmol/L), biotin (up to 30 µg/L), rheumatoid factor (up to 200 IU/mL), or with 52 standard or cardiovascular drugs at therapeutic concentrations. There was no influence on the results by varying hematocrit values in a range from 25% to 53%. However, interferences with human anti-mouse antibodies were found. No significant influence on the results was found with PoC TnT by using sample volumes between 135 to 165 µL. High troponin T concentrations up to 500 µg/L did not lead to false low results, indicating no high-concentration hook effect. No cross-reactivity was found between the PoC TnT assay and human skeletal troponin T up to 1000 µg/L (< 0.05%). Diagnostic sensitivity and specificity data of a subpopulation (23 patients) of this study are in agreement with results of another large pre-hospital study., Conclusions: The PoC TnT assay showed good analytical performance with excellent concordance with the calibration and reference laboratory method. It should therefore be suitable for its intended use in point-of-care settings.

Objectives: The increasing number of low-acuity visits to emergency departments (ED) is an important issue in Germany, despite the fact that all costs of inpatient and outpatient treatment are covered by mandatory health insurance. We aimed to explore the motives of patients categorised with low-acuity conditions for visiting an ED., Methods: We conducted a qualitative study in two urban and one rural ED. We recruited a purposive sample of adults, who were assigned to the lowest two categories in the Manchester triage system. One-to-one interviews took place in the ED during patients' waiting time for treatment. Interview transcripts were analysed using the qualitative data management software MAXQDA. A qualitative content analysis approach was taken to identify motives and to compare the rural with the urban sites., Results: A total of 86 patients were asked to participate; of these, n=15 declined participation and n=7 were excluded because they were admitted as inpatients, leaving a final sample of 40 female and 24 male patients. We identified three pathways leading to an ED visit: (1) without primary care contact, (2) after unsuccessful attempts to see a resident specialist or general practitioner (GP) and (3) recommendation to visit the ED by an outpatient provider. The two essential motives were (1) convenience and (2) health anxiety, triggered by time constraints and focused usage of multidisciplinary medical care in a highly equipped setting. All participants from the rural region were connected to a GP, whom they saw more or less regularly, while more interviewees from the urban site did not have a permanent GP. Still, motives to visit the ED were in general the same., Conclusions: We conclude that the ED plays a pivotal role in ambulatory acute care which needs to be recognised for adequate resource allocation., Trial Registration Number: DRK S00006053., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Aim: Pulmonary hypertension (PH) develops in 25-40% of bronchopulmonary dysplasia (BPD) patients, substantially increasing mortality. We have previously found that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) production, is elevated in patients with BPD-associated PH. ADMA is metabolised by N(ᴳ) ,N(ᴳ) -dimethylarginine dimethylaminohydrolase (DDAH). Presently, we test the hypothesis that there are single nucleotide polymorphisms (SNPs) in DDAH1 and/or DDAH2 associated with the development of PH in BPD patients., Methods: BPD patients were enrolled (n = 98) at Nationwide Children's Hospital. Clinical characteristics and 36 SNPs in DDAH1 and DDAH2 were compared between BPD-associated PH patients (cases) and BPD-alone patients (controls)., Results: In BPD patients, 25 (26%) had echocardiographic evidence of PH (cases). In this cohort, DDAH1 wild-type rs480414 was 92% sensitive and 53% specific for PH in BPD, and the DDAH1 SNP rs480414 decreased the risk of PH in an additive model of inheritance (OR = 0.39; 95% CI [0.18-0.88], p = 0.01)., Conclusion: The rs480414 SNP in DDAH1 may be protective against the development of PH in patients with BPD. Furthermore, the DDAH1 rs480414 may be a useful biomarker in developing predictive models for PH in patients with BPD., Competing Interests: The authors declare no conflict of interest., (©2015 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Simian tuberculosis is one of the most important bacterial diseases of non-human primates. Outbreaks of tuberculosis have been reported in primate colonies almost as long as these animals have been used experimentally or kept in zoological gardens. Significant progress has been made in reducing the incidence of tuberculosis in captive non-human primates, but despite reasonable precautions, outbreaks continue to occur. The most relevant reason is the high incidence of tuberculosis (TB) amongst the human population, in which tuberculosis is regarded as an important re-emerging disease. Furthermore, many non-human primate species originate from countries with a high burden of human TB. Therefore, Mycobacterium tuberculosis remains a significant threat in animals imported from countries with high rates of human infection. We report an outbreak of tuberculosis among a group of rhesus monkeys (Macaca mulatta) living in a closed, long-term colony. The outbreak coincided with reactivation of a TB infection in a co-worker who never had direct access to the animal house or laboratories. Eleven of 26 rhesus monkeys developed classical chronic active tuberculosis with typical caseous granulomata of varying size within different organs. The main organ system involved was the lung, suggesting an aerosol route of infection. Such an outbreak has significant economic consequences due to animal loss, disruption of research and costs related to disease control. Precautionary measures must be improved in order to avoid TB in non-human primate colonies., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aims: Heart failure (HF) continues to be a leading cause of morbidity and mortality in industrialized countries. Data on the epidemiology of HF are largely lacking for Germany. The aims of this study were to estimate the incidence and prevalence of HF in Germany, to estimate 1-year all-cause mortality in patients who received their first diagnosis of HF in hospital and to assess related risk factors., Methods: The study was based on data for the years 2004-2006 from three German statutory health insurance providers, comprising data of more than six million people. The study sample was not restricted to a specific age group. The incidence rate of HF in 2006 was assessed in patients who did not have a diagnosis of HF or had not received medications for HF in the previous 2 years. One-year all-cause mortality in patients who received their first diagnosis of HF in hospital was analysed using Kaplan-Meier method and Cox proportional hazard model. Case identification was based on confirmed outpatient diagnoses, main and secondary hospital discharge diagnoses as well as medications for HF., Results: The age- and sex-standardized incidence rate of HF was 2.7 per 1000 person years. Age- and sex-standardized prevalence of HF was 1.7% in 2004, 1.9% in 2005 and 1.7% in 2006. The 1-year all-cause mortality was 23% among patients who received their first HF diagnosis during a hospitalization in 2006., Conclusion: Our study revealed an incidence and prevalence of HF in Germany which were largely comparable to those from other countries. Due to the poor prognosis of HF, high readmission rates and an aging society, HF remains highly relevant in the context of health care planning.

Objectives: Survivin, an antiapoptotic gene inhibited by p53, is overexpressed in human cancers and correlates with chemotherapy resistance. Here, we investigated the mutual regulatory mechanism between MGMT (O-methylguanine DNA methyltransferase) and survivin., Methods: This study used standard techniques for protein and messenger RNA levels, promoter activity, protein-DNA interaction, cell viability, and correlative animal model., Results: O-benzylguanine (BG), a potent inhibitor of MGMT (a DNA repair protein), curtails the expression of survivin in pancreatic cancer. Silencing MGMT by small interfering RNA down-regulates survivin transcription. p53 inhibition enhances MGMT and survivin expressions. When p53 was silenced, BG-induced MGMT inhibition was not associated with the down-regulation of survivin, underscoring the regulatory role of p53 in the MGMT-survivin axis. O-benzylguanine inhibits survivin and PCNA (proliferating cell nuclear antigen) at messenger RNA and protein levels in PANC-1 and L3.6pl cells and decreases survivin promoter activity via increased p53 recruitment to the survivin promoter. In orthotopic pancreatic xenografts established in nude mice, BG ± gemcitabine (GEM) decrease survivin expression in tumor tissue; protein levels and immunohistochemistry show significant decrease in survivin and PCNA levels, which correlate with increased sensitivity to GEM., Conclusions: MGMT inhibition is associated with decrease in survivin expression and increase in sensitivity to GEM in pancreatic cancer.

Background: Patients with homozygous familial hypercholesterolemia (HoFH) are at extremely elevated risk for early cardiovascular disease because of exposure to elevated low-density lipoprotein cholesterol (LDL-C) plasma levels from birth. Lowering LDL-C by statin therapy is the cornerstone for cardiovascular disease prevention, but the residual risk in HoFH remains high, emphasizing the need for additional therapies. In the present study, we evaluated the effect of serial infusions with CER-001, a recombinant human apolipoprotein A-I (apoA-I)-containing high-density lipoprotein-mimetic particle, on carotid artery wall dimensions in patients with HoFH., Methods and Results: Twenty-three patients (mean age 39.4 ± 13.5 years, mean LDL-C 214.2 ± 81.5 mg/dL) with genetically confirmed homozygosity or compound heterozygosity for LDLR, APOB, PCSK9, or LDLRAP1 mutations received 12 biweekly infusions with CER-001 (8 mg/kg). Before and 1 hour after the first infusion, lipid values were measured. Magnetic resonance imaging (3-T magnetic resonance imaging) scans of the carotid arteries were acquired at baseline and after 24 weeks to assess changes in artery wall dimensions. After CER-001 infusion, apoA-I increased from 114.8 ± 20.7 mg/dL to 129.3 ± 23.0 mg/dL. After 24 weeks, mean vessel wall area (primary end point) decreased from 17.23 to 16.75 mm(2) (P = .008). A trend toward reduction of mean vessel wall thickness was observed (0.75 mm at baseline and 0.74 mm at follow-up, P = .0835)., Conclusions: In HoFH, 12 biweekly infusions with an apoA-I-containing high-density lipoprotein-mimetic particle resulted in a significant reduction in carotid mean vessel wall area, implying that CER-001 may reverse atherogenic changes in the arterial wall on top of maximal low-density lipoprotein-lowering therapy. This finding supports further clinical evaluation of apoA-I-containing particles in patients with HoFH., (Copyright © 2015 Mosby, Inc. All rights reserved.)

The CDH1 gene, which encodes the cell-to-cell adhesion protein E-cadherin, is frequently mutated in lobular breast cancer (LBC) and diffuse gastric cancer (DGC). However, because E-cadherin is a tumor suppressor protein and lost from the cancer cell, it is not a conventional drug target. To overcome this, we have taken a synthetic lethal approach to determine whether the loss of E-cadherin creates druggable vulnerabilities. We first conducted a genome-wide siRNA screen of isogenic MCF10A cells with and without CDH1 expression. Gene ontology analysis demonstrated that G-protein-coupled receptor (GPCR) signaling proteins were highly enriched among the synthetic lethal candidates. Diverse families of cytoskeletal proteins were also frequently represented. These broad classes of E-cadherin synthetic lethal hits were validated using both lentiviral-mediated shRNA knockdown and specific antagonists, including the JAK inhibitor LY2784544, Pertussis toxin, and the aurora kinase inhibitors alisertib and danusertib. Next, we conducted a 4,057 known drug screen and time course studies on the CDH1 isogenic MCF10A cell lines and identified additional drug classes with linkages to GPCR signaling and cytoskeletal function that showed evidence of E-cadherin synthetic lethality. These included multiple histone deacetylase inhibitors, including vorinostat and entinostat, PI3K inhibitors, and the tyrosine kinase inhibitors crizotinib and saracatinib. Together, these results demonstrate that E-cadherin loss creates druggable vulnerabilities that have the potential to improve the management of both sporadic and familial LBC and DGC., (©2015 American Association for Cancer Research.)

Aim: To test the hypothesis that there are single-nucleotide polymorphisms (SNPs) in genes of the l-arginine/nitric oxide pathway associated with pulmonary hypertension (PH) in neonates with bronchopulmonary dysplasia (BPD)., Methods: Neonates with BPD were enrolled (n = 140) and clinical characteristics compared between case (BPD + PH) and control (BPD) groups. DNA was isolated from blood leucocytes and assayed for 17 SNPs in l-arginine/nitric oxide pathway genes by Sequenom massarray. Genes included carbamoyl-phosphate synthetase, ornithine transcarbamylase, argininosuccinate synthase, nitric oxide synthase and arginase. SNPs were selected from the National Center for Biotechnology Information database for their putative functionality. Calculated minor allele frequencies (MAF) of cases and controls were compared using χ2 and logistic regression., Results: Of the 140 patients with BPD, 26% had echocardiographic evidence of PH. Ventilation days were longer for cases than controls (mean 31 vs. 15 days, p < 0.05). Of the 17 SNPs, rs2781666 in arginase I gene was less common in cases (MAF = 0.23) than controls (MAF = 0.37, p = 0.04). The odds of PH decreased by 43% (p = 0.047) for each copy of the SNP minor allele in arginase I gene in patients with BPD., Conclusion: Arginase I SNP (rs2781666) may be associated with protection against pulmonary hypertension in preterm neonates with BPD., (©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Federal health monitoring deals with the state of health and the health-related behavior of populations and is used to inform politics. To date, the routine data from statutory health insurances (SHI) have rarely been used for federal health monitoring purposes. SHI routine data enable analyses of disease frequency, risk factors, the course of the disease, the utilization of medical services, and mortality rates. The advantages offered by SHI routine data regarding federal health monitoring are the intersectoral perspective and the nearly complete absence of recall and selection bias in the respective population. Further, the large sample sizes and the continuous collection of the data allow reliable descriptions of the state of health of the insurants, even in cases of multiple stratification. These advantages have to be weighed against disadvantages linked to the claims nature of the data and the high administrative hurdles when requesting the use of SHI routine data. Particularly in view of the improved availability of data from all SHI insurants for research institutions in the context of the "health-care structure law", SHI routine data are an interesting data source for federal health monitoring purposes.

Whole body vibration (WBV) training is an increasingly popular training method that is strongly promoted for weight loss, but scientific data on its effectiveness, particularly in obese subjects, are sparse. 14 obese women (BMI: 37.4 ± 1.3 kg/m2) randomized to 2 different groups (each n=7) participated in a 6-week endurance training program that was either combined or not combined with additional WBV training. Anthropometric measures, phase angle and body composition (assessed by bioelectrical impedance analysis; BIA), and resting energy expenditure (REE) were obtained before and after the training program. Body weight did not change during the training period (P=0.87), but waist circumference decreased in both groups (P=0.007; WBV: -3.4 ± 1.4 cm; no-WBV: -1.7 ± 0.7 cm) independent of WBV training (P=0.29 for group×time interaction). BIA revealed an enhancing effect of WBV training in comparison to no-WBV training on the phase angle (+0.20 ± 0.12° vs. -0.19 ± 0.12°; P=0.04) and calculated body cell mass (+0.8 ± 0.2 vs. -0.3 ± 0.4 kg; P=0.02), while calculated percentage fat mass decreased in both conditions (P=0.05) to similar extent (P=0.59; WBV: -0.8 ± 0.2%; no-WBV: -0.4 ± 0.5%). REE increased across the training (P=0.01; WBV: +77 ± 33 kcal/24 h; no-WBV: +68 ± 34 kcal/24 h), with this increase again not depending on WBV condition (P=0.85). Results of our pilot study in obese women provide preliminary evidence for a beneficial effect of WBV, when added to endurance training, on the bioelectrical phase angle, an increasingly recognized marker of individual's health status., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: Aurora Health Care (AHC) is the largest health care system in Wisconsin, with 14 acute care hospitals. In early 2010, a group of 18 medical oncologists became affiliated with AHC. This affiliation added 13 medical oncology infusion clinics to our existing 12 sites. In the era of health care reform and declining reimbursement, we need an objective method and criteria to evaluate our 25 outpatient medical oncology sites. We developed financial, clinical, and strategic tools for the evaluation and management of our cancer subservice lines and outpatient sites. The key to our success has been the direct involvement of stakeholders with a vested interest in the services in the selection of the criteria and evaluation process., Methods: We developed our objective metrics for evaluation based on strategic, financial, operational, and patient experience criteria. Strategic criteria included: population trends, full-time equivalent (FTE) medical oncologists/primary care physicians, FTE radiation oncologists, FTE oncologic surgeons, new annual cases of patients with cancer, and market share trends. Financial criteria per site included: physician work relative value units, staff FTE by type, staff salaries, and profit and loss. Operational criteria included: facility by type (clinic v hospital based), hours of operation, and facility detail (eg, No. of chairs, No. of procedure and examination rooms, square footage). Patient experience criteria included: nursing model primary/nurse navigators, multidisciplinary support at site, Press Ganey (South Bend, IN; health care performance improvement company) results, and employee engagement score., Results: The outcome of our data analysis has resulted in the development of recommendations for AHC senior leadership and geographic market leadership to consider the consolidation of four sites (phase one, four sites; phase two, two sites) and priority strategic sites to address capacity issues that limit growth. The recommendations if implemented would result in significant cost savings, currently being quantified as a result of consolidation and improved efficiency. A reinvestment of these cost savings would be required to address facility expansion and program enhancement to maximize patient-centered expert care consistently across all of our remaining sites of service.

Background/objectives: Consisting of ≈10(14) microbial cells, the intestinal microbiota represents the largest and the most complex microbial community inhabiting the human body. However, the influence of regular diets on the microbiota is widely unknown., Subjects/methods: We examined faecal samples of vegetarians (n=144), vegans (n=105) and an equal number of control subjects consuming ordinary omnivorous diet who were matched for age and gender. We used classical bacteriological isolation, identification and enumeration of the main anaerobic and aerobic bacterial genera and computed absolute and relative numbers that were compared between groups., Results: Total counts of Bacteroides spp., Bifidobacterium spp., Escherichia coli and Enterobacteriaceae spp. were significantly lower (P=0.001, P=0.002, P=0.006 and P=0.008, respectively) in vegan samples than in controls, whereas others (E. coli biovars, Klebsiella spp., Enterobacter spp., other Enterobacteriaceae, Enterococcus spp., Lactobacillus spp., Citrobacter spp. and Clostridium spp.) were not. Subjects on a vegetarian diet ranked between vegans and controls. The total microbial count did not differ between the groups. In addition, subjects on a vegan or vegetarian diet showed significantly (P=0.0001) lower stool pH than did controls, and stool pH and counts of E. coli and Enterobacteriaceae were significantly correlated across all subgroups., Conclusions: Maintaining a strict vegan or vegetarian diet results in a significant shift in the microbiota while total cell numbers remain unaltered.

Background: Gastrointestinal infections have been proposed to predict subsequent irritable bowel syndrome (IBS) but large-scale infectious events are rare and long-term data are missing., Methods: We identified 576 individuals with a Salmonella or Campylobacter infection between 2000 and 2009 that were followed by a short postal questionnaire asking for the presence of current symptoms in 2010. In case of agreement (n = 90), an extended postinfectious (PI)-IBS questionnaire was mailed including the Hospital Anxiety Depression Scale and the Patient Health Questionnaire., Key Results: A total of 189 patients reported back (36%); 98 had a Salmonella and 91 had a Campylobacter infection, of which 56 reported persistent symptoms (9.7% of the initial sample). Fifty-one patients returned the PI-IBS questionnaire. Of 48 patients with complete data, 15 reported no or mild symptoms of abdominal pain or discomfort while 17 had moderate and 16 severe symptoms. Twenty-two met Rome IBS criteria, 14 (29%) reported GI symptoms before the infection. Patients with moderate and/or severe PI-IBS symptoms were significantly more often females, were more often infected by Salmonella than by Campylobacter, had more severe symptoms during the initial infection, and had more often GI symptoms prior to the infection. They reported higher anxiety, depression, and somatisation scores, but were not different with respect to acute stool habits., Conclusions & Inferences: Nearly 10% of patients with an intestinal bacterial infection report postinfectious symptoms up to 10 years after the infectious event. They represent a clinically important population with high psychiatric comorbidity and somatic symptom burden., (© 2011 Blackwell Publishing Ltd.)

Introduction: Despite considerable research efforts, the epidemiological characteristics of post-infectious symptoms of the irritable bowel syndrome-type (PI-IBS) are not yet well defined. Estimates of its incidence after gastrointestinal (GI) infection show considerable variation and the number of patients with a history of a GI infection among all patients with IBS is practically unknown. This review aims at summarizing published estimates (i) on the prevalence of PI-IBS among all IBS patients and (ii) on PI-IBS incidence after GI infection, critically discusses methodological differences that may explain the variation of the presented findings and gives an overview on currently identified risk factors for the development of PI-IBS., Methods: A systematic literature review was perfomed of studies indexed in PUBMED that assessed the epidemiology and risk factors of PI-IBS., Results: The reported incidence of PI-IBS ranges for epidemic infections between 7 and 36 %, for individual infections between 4 and 36 % and for traveller's diarrhea from 4 to 14 %. Estimates of the prevalence of PI-IBS range from as low as 7 % to more than ⅓ of all IBS patients, depending on the study design. The predictors and biomarkers are varying among the studies., Conclusion: PI-IBS appears to be common following infectious enteritis and among all IBS patients, but precise estimates are still lacking., (© Georg Thieme Verlag KG Stuttgart · New York.)

Emerging evidence suggests that fetuin-A, a liver-derived glycoprotein, represents an important factor in the pathophysiology of the metabolic syndrome, type 2 diabetes and cardiovascular disease. So far circulating fetuin-A was found to be increased in fatty liver disease, however, the precise mechanisms regulating fetuin-A expression and secretion are largely unknown. Here we assessed serum fetuin-A levels in 14 non-diabetic, obese women (BMI 36.5 ± 1.5 kg/m (2)) before and after a 6-week aerobic exercise program. Despite decreasing waist circumference (from 114.9 ± 3.5 to 112.3 ± 3.2 cm; P = 0.006) and body fat content (from 44.1 ± 1.5% to 43.4 ± 1.5%; P = 0.022) regular exercise 3-times per week over a 6-week period did not affect serum fetuin-A levels (before vs. after: 0.440 ± 0.018 vs. 0.440 ± 0.014 μg/ml; P = 0.767). Thus, our data provide evidence against a major role of exercise in the regulation of serum fetuin-A levels in non-diabetic obese women., (© Georg Thieme Verlag KG Stuttgart · New York.)

Cadmium, copper, iron, and zinc levels were measured in the kidneys of 115 grey wolves (Canis lupus) from Idaho, Montana and Alaska (United States), and from the Northwest Territories (Canada). No significant differences in the levels of iron or copper were observed between locations, but wolf kidneys from more northern locations had significantly higher cadmium levels (Alaska > Northwest Territories > Montana ≈ Idaho), and wolves from Alaska showed significantly higher zinc than other locations. Additionally, female wolves in Alaska had higher iron levels than males, and adult wolves in Montana had higher copper levels than subadults.

A number of real-time PCR assays for direct detection of methicillinresistant (MRSA) in clinical specimens are targeting staphylococcal cassette chromosome mec (SCCmec) right extremity sequences and the S. aureus chromosomal orfX gene sequences located to the right of the SCCmec integration site. When testing 184 MRSA strains of human and animal origin from geographically distinct locations, we identified several characteristic single-nucleotide polymorphisms (SNPs) within the SCCmec-orfX junction of livestock-associated (LA) MRSA CC398 which serve as suitable strain markers for screening purposes. Within an assay time of 60 minutes and an additional 10 minutes for the melting curve analysis, all MRSA CC398 isolates were correctly identified by their characteristic T(m) value in the commercial LightCycler MRSA Advanced test. Studies to confirm the diagnostic accuracy of the SNP-based strain identification assay with a larger collection of clinical and LA-MRSA strains are ongoing.