Development and validation of a haematuria cancer risk score to identify patients at risk of harbouring cancer.

BACKGROUND: A lack of consensus exists amongst national guidelines regarding who should be investigated for haematuria. Type of haematuria and age-specific thresholds are frequently used to guide referral for the investigation of haematuria. OBJECTIVES: To develop and externally validate the haematuria cancer risk score (HCRS) to improve patient selection for the investigation of haematuria. METHODS: Development cohort comprise of 3539 prospectively recruited patients recruited at 40 UK hospitals (DETECT 1; ClinicalTrials.gov: NCT02676180) and validation cohort comprise of 656 Swiss patients. All patients were aged >18 years and referred to hospital for the evaluation of visible and nonvisible haematuria. Sensitivity and specificity of the HCRS in the validation cohort were derived from a cut-off identified from the discovery cohort. RESULTS: Patient age, gender, type of haematuria and smoking history were used to develop the HCRS. HCRS validation achieves good discrimination (AUC 0.835; 95% CI: 0.789-0.880) and calibration (calibration slope = 1.215) with no significant overfitting (P = 0.151). The HCRS detected 11.4% (n = 8) more cancers which would be missed by UK National Institute for Health and Clinical Excellence guidelines. The American Urological Association guidelines would identify all cancers with a specificity of 12.6% compared to 30.5% achieved by the HCRS. All patients with upper tract cancers would have been identified. CONCLUSION: The HCRS offers good discriminatory accuracy which is superior to existing guidelines. The simplicity of the model would facilitate adoption and improve patient and physician decision-making.

Improved survival in metastatic germ-cell cancer.

Background: The prognostic score of the International Germ-Cell Cancer Collaborative Group (IGCCCG) in metastatic germ-cell cancers (mGCC) relies on treatments delivered before 1990. It is unclear, if this score is still relevant to contemporary cohorts of patients who receive modern-type chemotherapy and supportive care. Patients and methods: All patients who underwent cisplatin/etoposide-based first-line chemotherapy for mGCC at the University Hospital Zurich (USZ) between 1991 and 2016 were identified retrospectively. Clinical characteristics were extracted from medical charts and patients classified according to the IGCCCG score. International germ cell consensus classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 1997; 15: 594-603.). Progression-free survival (PFS) and overall survival (OS) probabilities at 5 years served as outcome parameters. Results: The study cohort consisted of 204 patients at a median age of 32 years and a median follow-up of 4.2 years. According to the IGCCCG score, PFS in the contemporary USZ cohort was 71% overall: 83% for good-risk, 69% for intermediate-risk and 30% for poor-risk patients, P < 0.001. OS for the entire cohort was 88%. In respect to OS, we observed no difference between good- and intermediate-risk patients (94% versus 91%, P = 0.62), but a statistically significant difference between those two risk groups and poor-risk patients, who had an OS of only 65%, P < 0.001. Conclusions: Within the contemporary USZ cohort of mGCC patients no improvements in PFS probabilities were observed compared with the ones predicted by the IGCCCG score for any prognostic category, but marked improvements in OS probabilities for intermediate- and poor-risk patients, possibly due to better salvage treatments.

[Prelabour Rupture of Membranes at Term: In- or Outpatient Management? A Survey in Birth Institutions in the German-Speaking Part of Switzerland]. / Vorzeitiger spontaner Blasensprung am Termin: Hospitalisation oder ambulantes Management? Eine Erhebung in Deutschschweizer Geburtsinstitutionen.

Approximately 8-10% of pregnant women experience prelabour rupture of membranes at term (tPROM). The ideal timing to induce labour as a means to shorten the time interval to birth and thus to reduce maternal and neonatal risk of infection is a controversial topic. A distinction is made between an active and an expectant approach. There is little evidence comparing in- and outpatient management in the expectant approach. The goal of this investigation was to determine the current management approach in birth institutions in the German-speaking part of Switzerland. In this cross-sectional study, a self-designed online questionnaire was distributed to obstetricians and midwives in leading positions at all obstetric institutions in Switzerland. Outcome measures were: the currently offered approach at tPROM, experience with outpatient expectant management and the willingness to introduce outpatient management as an option for pregnant women. From a total of n=85 Swiss German birth institutions, n=47 (55%) responded to the questionnaire. 53% (n=25) provide outpatient expectant management. The women's satisfaction was seen as a decisive advantage. The respondents furthermore ascribed advantages for maternal outcome but no advantage for fetal outcome. 73% (n=16) of respondents working in institutions that hospitalize exclusively stated their willingness to introduce outpatient management provided that there was evidence of maternal and fetal outcome and that expectant mothers were satisfied. The number of birth institutions offering outpatient management is surprisingly high. In future studies examining general management at tPROM, the question of outpatient management should be included. Even though this survey seems to justify outpatient management under strict quality control conditions, prospective studies to assess safety issues are urgently needed.

Frequent PD-L1 expression in testicular germ cell tumors.

BACKGROUND: Many testicular germ cell cancers are curable despite metastatic disease, but about 10-15% of patients fail cisplatin-based first-line treatment. Immunotherapy is considered as additional treatment approach for these patients. Inhibition of the interaction between Programmed Death Receptor 1 (PD-1) and Programmed Death Receptor Ligand 1 (PD-L1) enhances T-cell responses in vitro and mediates clinical antitumour activity. We analysed the expression of PD-L1 in testicular germ cell tumours to evaluate its potential as target for immunotherapeutic strategies. METHODS: Immunohistochemistry was performed in 479 formalin-fixed paraffin-embedded specimens using a rabbit monoclonal antibody (E1L3N). The tissue microarray consisted of 208 pure seminomas, 121 non-seminomas, 20 intratubular germ cell neoplasia unclassified (IGCNU) and 20 specimens of non-neoplastic testicular tissue. RESULTS: Programmed Death Receptor Ligand-1 expression was found in 73% of all seminomas and in 64% of all non-seminomas. None of 20 IGCNU and none of 20 normal tissue specimens exhibited PD-L1 expression. PD-L1 positive stromal cells were only detected in seminomas, but not in non-seminomas. The anti PD-L1 antibody showed a pre-dominantly membranous staining pattern in testicular tumour cells, as well as expression in stromal cells. CONCLUSIONS: This frequent expression of PD-L1 in human testicular germ cell tumours suggests that patients with testicular germ cell tumours could profit from immunotherapeutic strategies using anti-PD1 and anti-PDL1 antibodies.

Burden of meticillin-resistant Staphylococcus aureus infections at a Swiss University hospital: excess length of stay and costs.

BACKGROUND: Meticillin-resistant Staphylococcus aureus (MRSA) infections increase hospital costs primarily by prolonging patient length of stay (LOS). AIM: To estimate the health-economic burden of MRSA infections at a Swiss University hospital using different analytical approaches. METHODS: Excess LOS was estimated by: (i) multistate modelling comparing MRSA-infected and MRSA-free patients with MRSA infection as time-dependent exposure; (ii) matching MRSA-infected patients with a cohort of MRSA-uninfected patients. The economic impact was assessed by: (i) comparing cost estimates between MRSA-infected and MRSA-free patients and multiplying excess LOS by bed-day cost; (ii) comparing real costs between MRSA-infected and MRSA-colonized non-infected patients. FINDINGS: The crude mean LOS was 37.3, 33.0 and 8.8 days for MRSA-infected, MRSA-colonized and MRSA-free patients, respectively. Excess LOS attributable to MRSA infection was 11.5 [95% confidence interval (CI): 7.9-15] or 15.3 days according to multistate modelling and matched analysis, respectively. The likelihood of discharge after MRSA infection was significantly reduced (adjusted hazard ratio: 0.69; 95% CI: 0.59-0.81). Average bed-day costs for MRSA-infected patients were 1.49- and 1.26-fold higher than for the general population hospitalized in acute wards and MRSA-colonized patients, respectively. MRSA infection resulted in an average additional cost of about 800 Swiss francs per day. CONCLUSIONS: This analysis emphasizes the financial impact of MRSA infections, demonstrates the importance of accounting for time-dependent bias and confirms that multistate modelling is a valid strategy for estimating excess LOS and costs after MRSA infection.

[Epidemiology and clinical implications of carbapenemase-producing bacteria in Switzerland]. / Carbapénémases: implications cliniques et épidémiologiques pour la Suisse.

The emergence and global dissemination of carbapenemases represents a major threat to public health. Switzerland has not been spared; we report a case-series of four patients hospitalised in our institution colonised with carbapenemase-producing bacteria. Infections caused by carbapenemase-producing Enterobacteriaceae limit therapeutic options and increase mortality. Detection of carbapenemases is also a challenge for laboratories. It is imperative to implement stringent infection control measures in order to prevent epidemics at the hospital level.

Validity and responsiveness of the Core Outcome Measures Index (COMI) for the neck.

PURPOSE: Patient-orientated outcome questionnaires are essential to evaluate treatment success. To compare different treatments, hospitals, and surgeons, standardised questionnaires are required. The present study examined the validity and responsiveness of the Core Outcome Measurement Index for neck pain (COMI-neck), a short, multidimensional outcome instrument. METHODS: Questionnaires were completed by patients with degenerative problems of the cervical spine undergoing cervical disc arthroplasty before (N = 89) and 3 months after (N = 75) surgery. The questionnaires comprised the EuroQol-Five Dimension (EQ-5D), the North American Spine Society Cervical Spine Outcome Assessment Instrument (NASS-cervical) and the COMI-neck. RESULTS: The COMI and NASS-cervical scores displayed no notable floor or ceiling effects at any time point whereas for the EQ-5D, the highest values [corrected] were reached in around 32.5% of patients at follow-up. With one exception (symptom-specific well-being), the individual COMI items and the COMI summary score correlated to the expected extent (R = 0.4-0.8) with the scores of the chosen reference questionnaires. The area under the curve (AUC) generated by ROC analysis was significantly higher for the COMI (0.96) than for any other instrument/subscale when self reported treatment outcome was used as the external criterion, dichotomised as "good" (operation helped a lot/helped) versus "poor" (operation helped only a little/didn't help/made things worse). The COMI had a high effect size (standardised response mean; SRM) (2.34) for the good global outcome group and a low SRM for the poor outcome group (0.34). The EQ-5D and the NASS-cervical lacked this ability to differentiate between the two groups, showing less distinct SRMs for good and poor outcome groups. CONCLUSIONS: This study provides evidence that the COMI-neck is a valid and responsive questionnaire in the population of patients examined. Further investigations should examine its applicability in other patient groups with less severe neck pain or undergoing other treatment modalities.

Surveillance of extended-spectrum-beta-lactamase-producing Enterobacteriaceae in a Swiss Tertiary Care Hospital.

BACKGROUND: Extended spectrum beta-lactamase producing enterobacteriaceae (ESBL-E) are increasing worldwide, but there is sparse data on patient-to-patient transmission and the prevalence among risk groups in Switzerland. A prospective, observational cohort study was performed to: 1) assess the prevalence of ESBL-E at admission among at-risk groups; 2) evaluate nosocomial cross-transmission in acute care (ACF) versus long-term care facilities (LTCF); and 3) evaluate prevalent mutations of the detected beta-lactamase genes. METHODS: Predefined risk groups were screened either on admission or after having been in contact with index patients diagnosed with ESBL-E by clinical cultures. Three patient categories were distinguished: patients previously known to be ESBL-E carrier (category I); patients transferred from countries with known high ESBL-E prevalence and thus at risk for ESBL-E carriage (category II); and roommates of index patients (category III). RESULTS: A total of 93 patients with ESBL-E were identified: Sixty-two percent (31/50) of category I patients were positive when screened upon rehospitalisation (category I); eighteen percent (22/124) of category II patients; and eight out of 177 category III patients (4.5%) of which five showed identical ESBL-E strains or shared the same beta-lactamase gene as their index cases. The incidence density of transmission was 0.9/1000 exposure-days, with more transmissions in ACF than in LTCF (4.2 vs 0.4/1000 exposure days). CTX-M-15 was the predominant beta-lactamase gene (60%) among the index patients. CONCLUSIONS: The prevalence of ESBL-E carriage among patients coming from regions with endemic rates or those previously identified as carriers is high; on-admission screening should be considered for these high risk populations. Documented nosocomial ESBL-E transmission was low.

Biomechanical evaluation of the less invasive stabilization system for the internal fixation of distal femur fractures.

OBJECTIVE: Comparison between a Less Invasive Stabilization System (LISS) using monocortical screws with angular stability and two conventional plate systems Condylar Buttress Plate (CBP) and Dynamic Condylar Screw (DCS) for the treatment of distal femoral fractures with respect to biomechanical properties. DESIGN: Biomechanical study using paired cadaver femurs. In Test Configuration 1 (distal test), a ten-millimeter gap at the diaphysis-metaphysis junction simulates a supracondylar femoral fracture. Test Configuration 2 (proximal test) has the same configuration, but the gap was cut in the isthmic region. Proximal and distal plate ends were fixed to corresponding cortical bone fragments in both tests. Optical displacement transducers served to quantify the system's ability to withstand a stepwise increased load. Reversible (deflection) and irreversible deformation (subsidence) of the bone-plate construct was investigated. RESULTS: In Test Configuration 1, LISS showed less irreversible deformation in 72 percent of the left-right comparisons. No correlation between bone mineral density, cross-section area of bones and the measured response of the construct under load was found between pairs. In Test Configuration 2, 83 percent of the left-right comparisons showed less permanent deformation but a higher elastic deformation for LISS. CONCLUSIONS: These results suggest an enhanced ability to withstand high loads when using the monocortical screw fixation technique with angular stability. A higher elastic deformation of LISS compared with conventional plating systems in distal femoral fractures can be explained by the lower bending stiffness caused by different design and material properties.

ELF3 encodes a circadian clock-regulated nuclear protein that functions in an Arabidopsis PHYB signal transduction pathway.

Many aspects of plant development are regulated by photoreceptor function and the circadian clock. Loss-of-function mutations in the Arabidopsis EARLY FLOWERING 3 (ELF3) and PHYTOCHROME B (PHYB) genes cause early flowering and influence the activity of circadian clock-regulated processes. We demonstrate here that the relative abundance of the ELF3 protein, which is a novel nucleus-localized protein, displays circadian regulation that follows the pattern of circadian accumulation of ELF3 transcript. Furthermore, the ELF3 protein interacts with PHYB in the yeast two-hybrid assay and in vitro. Genetic analyses show that ELF3 requires PHYB function in early morphogenesis but not for the regulation of flowering time. This suggests that ELF3 is a component of a PHYB signaling complex that controls early events in plant development but that ELF3 and PHYB control flowering via independent signal transduction pathways.

Augmentation of mechanical properties in osteoporotic vertebral bones--a biomechanical investigation of vertebroplasty efficacy with different bone cements.

Recent clinical trials have reported favorable early results for transpedicular vertebral cement reinforcement of osteoporotic vertebral insufficiencies. There is, however, a lack of basic data on the application, safety and biomechanical efficacy of materials such as polymethyl-methacrylate (PMMA) and calciumphospate (CaP) cements. The present study analyzed 33 vertebral pairs from five human cadaver spines. Thirty-nine vertebrae were osteoporotic (bone mineral density < 0.75 g/cm2), 27 showed nearly normal values. The cranial vertebra of each pair was augmented with either PMMA (Palacos E-Flow) or experimental brushite cement (EBC), with the caudal vertebra as a control. PMMA and EBC were easy to inject, and vertebral fillings of 20-50% were achieved. The maximal possible filling was inversely correlated to the bone mineral density (BMD) values. Cement extrusion into the spinal canal was observed in 12% of cases. All specimens were subjected to axial compression tests in a displacement-controlled mode. From load-displacement curves, the stiffness, S, and the maximal force before failure, Fmax, were determined. Compared with the native control vertebrae, a statistically significant increase in vertebral stiffness and Fmax was observed by the augmentation. With PMMA the stiffness increased by 174% (P = 0.018) and Fmax by 195% (P = 0.001); the corresponding augmentation with EBC was 120% (P = 0.03) and 113% (P = 0.002). The lower the initial BMD, the more pronounced was the augmentation effect. Both PMMA and EBC augmentation reliably and significantly raised the stiffness and maximal tolerable force until failure in osteoporotic vertebral bodies. In non-porotic specimens, no significant increase was achieved.

A role for flavin monooxygenase-like enzymes in auxin biosynthesis.

Although auxin is known to regulate many processes in plant development and has been studied for over a century, the mechanisms whereby plants produce it have remained elusive. Here we report the characterization of a dominant Arabidopsis mutant, yucca, which contains elevated levels of free auxin. YUCCA encodes a flavin monooxygenase-like enzyme and belongs to a family that includes at least nine other homologous Arabidopsis genes, a subset of which appears to have redundant functions. Results from tryptophan analog feeding experiments and biochemical assays indicate that YUCCA catalyzes hydroxylation of the amino group of tryptamine, a rate-limiting step in tryptophan-dependent auxin biosynthesis.

RSF1, an Arabidopsis locus implicated in phytochrome A signaling.

In Arabidopsis, phytochrome A (phyA) is the major photoreceptor both for high irradiance responses to far-red light and broad spectrum very low fluence responses, but little is known of its signaling pathway(s). rsf1 was isolated as a recessive mutant with reduced sensitivity to far-red inhibition of hypocotyl elongation. At the seedling stage rsf1 mutants are affected, to various degrees, in all described phyA-mediated responses. However, in adult rsf1 plants, the photoperiodic flowering response is normal. The rsf1 mutant has wild-type levels of phyA suggesting that RSF1 is required for phyA signaling rather than phyA stability or biosynthesis. RSF1 thus appears to be a major phyA signaling component in seedlings, but not in adult, Arabidopsis plants.

Periodic accumulation of cdc15 mRNA is not necessary for septation in Schizosaccharomyces pombe.

Analysis of Schizosaccharomyces pombe mutants that are defective in septum formation and cytokinesis has identified the product of the cdc15 gene as a key element in formation of a division septum. S. pombe cells lacking cdc15p function cannot assemble a functional medial ring, and do not make a division septum. cdc15 mRNA accumulates periodically during the cell cycle, peaking after entry into mitosis, and increased expression of the gene in G2-arrested cells can promote F-actin ring formation. Here, we have investigated the effects of mutations that block cell division upon the expression of cdc15 in synchronised cell populations, and analysed the expression of cdc15 when septum formation is induced by ectopic activation of the septation signalling network. We concluded the following: (i) the septation signalling network genes are not required for periodic accumulation of cdc15 mRNA; (ii) induction of septum formation in G2-arrested cells by activation of the septation signalling network does not result in accumulation of cdc15 mRNA, which is therefore not a prerequisite for septum formation; (iii) failure to turn off septum formation at the end of mitosis results in continued expression of cdc15; and (iv) periodic accumulation of cdc15 mRNA is mediated by a 97 bp region 5' to the mRNA start site.

Absence of GAP-43 can protect neurons from death.

The main function of GAP-43 is thought to be regulating growth cone motility and axon guidance signals. GAP-43 is highly expressed during development and in regenerating nerves and in particular regions of the adult brain. We here present the first evidence that GAP-43 can modulate guidance signals emanating from Semaphorin III (SemaIII) in cultured NGF-dependent sensory neurons. We further show that absence of GAP-43 dramatically increases resistance of specific sensory neurons to apoptotic stimuli in vitro. NGF-dependent sensory neurons from GAP-43 (+/-) and null mutant mice are strongly protected against SemaIII-induced death. Furthermore, NGF- and BDNF-dependent neurons, but not NT-3-dependent neurons, from GAP-43 null mutant mice are much more resistant to apoptosis induced by trophic factor deprivation. We also show that early postnatal Purkinje cells from GAP-43 (+/-) mice are more resistant to cell death in organotypic cultures. We conclude that GAP-43 can influence neuronal survival and modulate repulsive axon guidance signals.

Activation tagging in Arabidopsis.

Activation tagging using T-DNA vectors that contain multimerized transcriptional enhancers from the cauliflower mosaic virus (CaMV) 35S gene has been applied to Arabidopsis plants. New activation-tagging vectors that confer resistance to the antibiotic kanamycin or the herbicide glufosinate have been used to generate several tens of thousands of transformed plants. From these, over 30 dominant mutants with various phenotypes have been isolated. Analysis of a subset of mutants has shown that overexpressed genes are almost always found immediately adjacent to the inserted CaMV 35S enhancers, at distances ranging from 380 bp to 3.6 kb. In at least one case, the CaMV 35S enhancers led primarily to an enhancement of the endogenous expression pattern rather than to constitutive ectopic expression, suggesting that the CaMV 35S enhancers used here act differently than the complete CaMV 35S promoter. This has important implications for the spectrum of genes that will be discovered by this method.

Phytochromes as light-modulated protein kinases.

Many phytochrome responses in plants are induced by red light and inhibited by far-red light. To explain the biochemical basis of these observations, it was speculated that plant phytochromes are light-regulated enzymes more than 40 years ago. The search for such an enzymatic activity has a long and rather tumultuous history. Biochemical data in the late 1980s had suggested that oat phytochrome might be a light-regulated protein kinase. The topic was the subject of intense debate, but solid experimental data backing the kinase model has been published recently. Two lines of research played a key role in this finding: the production of biologically active highly purified recombinant phytochrome and the discovery of phytochromes in prokaryotes. This review discusses the key steps of this discovery, and suggests some hypotheses for the role of protein kinase activity in photomorphogenesis.

Prevention of nuclear localization of activated caspases correlates with inhibition of apoptosis.

The caspase family proteases are principal components of the apoptotic pathway. In this study we demonstrate that caspase-1-like proteases and interleukin-1 beta are important for death induced by various stimuli in cell lines, primary fibroblasts and primary sensory neurons. Furthermore, we show by immunohistochemistry that during the cell death process endogenous caspase-1-like proteases translocate into the nucleus. This translocation is stimulated by interleukin-1 receptor activation. Translocation of caspase-1-like proteases and cell death can be partially prevented by blocking the interleukin-1 receptor with the interleukin-1 receptor antagonist. This finding offers for the first time a mechanistic explanation for the protective effect of the interleukin-1 receptor antagonist against cell death. Furthermore, our data suggest that caspase-1-like proteases have a function in the nucleus which is necessary for completion of the cell death program. In cultured DRG neurons from embryonic mice the combined inhibition of caspases and the interleukin-1 receptor have an additive effect and fully prevent semaphorin III-induced neuronal death. This shows that endogenous caspases work together with IL-1 beta in Semaphorin III-induced neuronal death. We hypothesize that the cell death process involves a double activation step, probably including an interleukin-1 autocrine loop. This model can explain our finding that combined inhibition of caspases and interleukin-1 receptor is necessary to strongly inhibit the cell death process.