Successful interdisciplinary management of the misdeployment of two self-expanding stents into the internal carotid artery: a case report

<p>Abstract</p> <p>Introduction</p> <p>With the widespread use of carotid artery stenting, previously unknown technical mistakes of this treatment modality are now being encountered. There are multiple strategies for the treatment of in-stent restenosis. With regard to surgical management, endarterectomy and patch plasty are favored. To the best of our knowledge, this report is the first description of a complete stent removal by the eversion technique.</p> <p>Case presentation</p> <p>We report the case of a 63-year-old Caucasian man with misdeployment of two stents into his stenotic proximal internal carotid artery, resulting in a high-grade mechanical obstruction of the internal carotid artery lumen. With the contralateral internal carotid artery already occluded and associated stenoses of both proximal and distal vertebral arteries, an interdisciplinary therapeutic concept was applied. Bilateral balloon angioplasty and stenting of the proximal and distal stenotic vertebral arteries were carried out to provide sufficient posterior collateral blood flow, followed by successful surgical stentectomy and carotid endarterectomy using the eversion technique. Duplex scanning and neurological assessments were normal over a 12-month follow-up period.</p> <p>Conclusions</p> <p>Interdisciplinary treatment is a recommended option to protect patients from further impairment. Further evaluation in larger studies is highly recommended.</p

Outcome of ATP-based tumor chemosensitivity assay directed chemotherapy in heavily pre-treated recurrent ovarian carcinoma

BACKGROUND: We wished to evaluate the clinical response following ATP-Tumor Chemosensitivity Assay (ATP-TCA) directed salvage chemotherapy in a series of UK patients with advanced ovarian cancer. The results are compared with that of a similar assay used in a different country in terms of evaluability and clinical endpoints. METHODS: From November 1998 to November 2001, 46 patients with pre-treated, advanced ovarian cancer were given a total of 56 courses of chemotherapy based on in-vitro ATP-TCA responses obtained from fresh tumor samples or ascites. Forty-four patients were evaluable for results. Of these, 18 patients had clinically platinum resistant disease (relapse < 6 months after first course of chemotherapy). There was evidence of cisplatin resistance in 31 patients from their first ATP-TCA. Response to treatment was assessed by radiology, clinical assessment and tumor marker level (CA 125). RESULTS: The overall response rate was 59% (33/56) per course of chemotherapy, including 12 complete responses, 21 partial responses, 6 with stable disease, and 15 with progressive disease. Two patients were not evaluable for response having received just one cycle of chemotherapy: if these were excluded the response rate is 61%. Fifteen patients are still alive. Median progression free survival (PFS) was 6.6 months per course of chemotherapy; median overall survival (OAS) for each patient following the start of TCA-directed therapy was 10.4 months (95% confidence interval 7.9-12.8 months). CONCLUSION: The results show similar response rates to previous studies using ATP-TCA directed therapy in recurrent ovarian cancer. The assay shows high evaluability and this study adds weight to the reproducibility of results from different centre

Effect of heptavalent pneumococcal conjugate vaccination on invasive pneumococcal disease in preterm born infants

<p>Abstract</p> <p>Background</p> <p>Evidence for protection of preterm born infants from invasive pneumococcal disease (IPD) by 7-valent pneumococcal conjugate vaccination (PCV7) is relatively sparse. Data from randomized trials is based on relatively small numbers of preterm born children.</p> <p>Methods</p> <p>We report data from active prospective surveillance of IPD in children in Germany. The cohorts of preterm born children in 2000 and 2007 and the respective whole birth cohorts are compared regarding occurrence of IPD.</p> <p>Results</p> <p>After introduction of PCV7 we observed a reduction in the rate of IPD in preterm born infants comparing the 2000 and 2007 birth cohort. The rate of IPD among the whole birth cohorts was reduced from 15.0 to 8.5 notifications per 100,000 (<it>P </it>< .001). The impact among the preterm birth cohort was comparable: A reduction in notification rate from 26.1 to 16.7 per 100,000 comparing the 2000 with the 2007 preterm birth cohort (<it>P </it>= .39). Preterm born infants with IPD were either unvaccinated or vaccinated delayed or incomplete.</p> <p>Conclusions</p> <p>This adds to evidence that PCV7 also protects preterm born infants effectively from IPD. Preterm born infants should receive pneumococcal vaccination according to their chronological age.</p

Increased expression of transcription factor TFAP2α correlates with chemosensitivity in advanced bladder cancer

<p>Abstract</p> <p>Background</p> <p>The standard treatment for patients with advanced transitional cell carcinoma of the bladder is platin based chemotherapy. Only approximately 50% of the patients respond to chemotherapy. Therefore, molecular predictive markers for identification of chemotherapy sensitive subgroups of patients are highly needed. We selected the transcription factor <it>TFAP2α </it>from a previously identified gene expression signature for chemotherapy response.</p> <p>Methods</p> <p><it>TFAP2α </it>expression and localization was assessed by immunohistochemistry using a tissue microarray (TMA) containing 282 bladder cancer tumors from patients with locally advanced (pT2-T4_band N_1-3) or metastatic (M₁) disease. All patients had received cisplatin containing chemotherapy. Furthermore, QPCR analysis of three <it>TFAP2α </it>isoforms was performed on tumor specimens of advanced muscle invasive bladder cancers (T2-4). Using the bladder cell lines T24 and SW780 the relation of <it>TFAP2α </it>and cisplatin and gemcitabine sensitivity as well as cell proliferation was examined using siRNA directed <it>TFAP2α </it>knockdown.</p> <p>Results</p> <p>TFAP2α protein expression was analyzed on a TMA with cores from 282 advanced bladder cancer tumors from patients treated with cisplatin based combinational chemotherapy. <it>TFAP2α </it>was identified as a strong independent predictive marker for a good response and survival after cisplatin-containing chemotherapy in patients with advanced bladder cancer. Strong TFAP2α nuclear and cytoplasmic staining predicted good response to chemotherapy in patients with lymph node metastasis, whereas weak TFAP2α nuclear staining predicted good response in patients without lymph node metastasis. In vitro studies showed that siRNA mediated knockdown of TFAP2α increased the proliferation of SW780 cells and rendered the cells less sensitive to cisplatin and gemcitabine. In contrast to that T24 bladder cells with mutated p53 showed to be more drug sensitive upon TFAP2α depletion.</p> <p>Conclusions</p> <p>High levels of nuclear and cytoplasmic TFAP2α protein were a predictor of increased overall survival and progression free survival in patients with advanced bladder cancer treated with cisplatin based chemotherapy. TFAP2α knockdown increased the proliferation of the SW780 bladder cells and reduced cisplatin and gemcitabine induced cell death. The inverse effect was observed in the <it>TP53 </it>mutated T24 cell line where TFAP2α silencing augmented cisplatin and gemcitabine sensitivity and did not stimulate proliferation.</p

Customer’s Acceptance of Humanoid Robots in Services: The Moderating Role of Risk Aversion

The emerging introduction of humanoid robots in service encounters is becoming a reality in the present and the short-term. Owing to this unstoppable advance, there is a need to better understand customers’ perceptions and reactions toward humanoid agents in service encounters. To shed some light on this underexplored phenomenon, this research investigates how the interaction between robot and customer’s features may contribute to a successful introduction of this disruptive innovation. Results of an empirical study with a sample of 168 US customers reveal that customer’s perceptions of robot’s human-likeness increase the intentions to use humanoid service robots. Interestingly, customers’ risk aversion moderates this relationship. Specifically, the study found that highly risk-averse customers tend to avoid using humanoids when they are perceived as highly mechanical-like. The discussion highlights the main contributions of the research, which combine previous knowledge on human–robot interaction and risk aversion from a marketing approach. Managerial implications derived from the research findings and the avenues opened for further research are described at the end

On the relation between action selection and movement control in 5- to 9-month-old infants

Although 5-month-old infants select action modes that are adaptive to the size of the object (i.e., one- or two-handed reaching), it has largely remained unclear whether infants of this age control the ensuing movement to the size of the object (i.e., scaling of the aperture between hands). We examined 5-, 7-, and 9-month-olds’ reaching behaviors to gain more insight into the developmental changes occurring in the visual guidance of action mode selection and movement control, and the relationship between these processes. Infants were presented with a small set of objects (i.e., 2, 3, 7, and 8 cm) and a large set of objects (i.e., 6, 9, 12, and 15 cm). For the first set of objects, it was found that the infants more often performed two-handed reaches for the larger objects based on visual information alone (i.e., before making contact with the object), thus showing adaptive action mode selection relative to object size. Kinematical analyses of the two-handed reaches for the second set of objects revealed that inter-trial variance in aperture between the hands decreased with the approach toward the object, indicating that infants’ reaching is constrained by the object. Subsequent analysis showed that between hand aperture scaled to object size, indicating that visual control of the movement is adjusted to object size in infants as young as 5 months. Individual analyses indicated that the two processes were not dependent and followed distinct developmental trajectories. That is, adaptive selection of an action mode was not a prerequisite for appropriate aperture scaling, and vice versa. These findings are consistent with the idea of two separate and independent visual systems (Milner and Goodale in Neuropsychologia 46:774–785, 2008) during early infancy

Estimation of the incidence of genital warts and the cost of illness in Germany: A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Human papillomavirus (HPV) is a necessary cause of cervical cancer. HPV is also responsible for benign <it>condylomata acuminata</it>, also known as genital warts. We assessed the incidence of genital warts in Germany and collected information on their management to estimate the annual cost of disease.</p> <p>Methods</p> <p>This was a multi-centre observational (cross-sectional) study of genital warts in Germany. Data were collected from gynecologists, dermatologists, and urologists seeing patients with genital warts between February and April 2005. The number of patients with new and recurrent genital warts was used to estimate the incidence in Germany. We assessed resource use for patients with genital warts seen during a two-month period as well as retrospective resource use twelve months prior to the inclusion visit through a chart review. The mean costs of treatment of patients with genital warts from third-party payer and societal perspectives were estimated, and the total annual cost of genital warts was then calculated.</p> <p>Results</p> <p>For the incidence calculation 217 specialists provided information on 848 patients and 214 specialists provided resource use data for 617 patients to assess resource consumption. The incidence of new and recurrent cases of genital warts was 113.7 and 34.7 per 100 000, respectively, for women aged 14–65 years consulting gynecologists. The highest incidence was observed in women aged 14–25 years (171.0 per 100 000) for new cases and in women aged 26–45 years (53.1 per 100 000) for recurrent cases. The sample size for males was too small to allow a meaningful estimate of the incidence. The mean direct cost per patient with new genital warts was estimated at 378 euros (95% CI: 310.8–444.9); for recurrent genital warts at 603 euros (95% CI: 436.5–814.5), and for resistant genital warts at 1,142 euros (95% CI: 639.6–1752.3). The overall cost to third-party payers was estimated at 49.0 million euros, and the total societal cost at 54.1 million euros, corresponding to an average cost per patient of 550 euros and 607 euros, respectively.</p> <p>Conclusion</p> <p>The societal burden and costs of managing and treating genital warts in Germany are considerable. A vaccination programme using the quadrivalent human papillomavirus vaccine could provide a substantial health benefit and reduce the costs associated with genital warts in Germany.</p

The Antioxidant Protein Peroxiredoxin 4 Is Epigenetically Down Regulated in Acute Promyelocytic Leukemia

The antioxidant peroxiredoxin (PRDX) protein family comprises 6 members, which are implicated in a variety of cellular responses, including growth factor signal transduction. PRDX4 resides in the endoplasmic reticulum (ER), where it locally controls oxidative stress by reducing H2O2levels. We recently provided evidence for a regulatory function of PRDX4 in signal transduction from a myeloid growth factor receptor, the granulocyte colony-stimulating factor receptor (G-CSFR). Upon activation, the ligand-induced G-CSFR undergoes endocytosis and routes via the early endosomes where it physically interacts with ER-resident PRDX4. PRDX4 negatively regulates G-CSFR mediated signaling. Here, we investigated whether PRDX4 is affected in acute myeloid leukemia (AML); genomic alterations and expression levels of PRDX4 were investigated. We show that genomic abnormalities involving PRDX4 are rare in AML. However, we find a strong reduction in PRDX4 expression levels in acute promyelocytic leukemia (APL) compared to normal promyelocytes and different molecular subtypes of AML. Subsequently, the possible role of DNA methylation and histone modifications in silencing of PRDX4 in APLs was investigated. We show that the reduced expression is not due to methylation of the CpG island in the promoter region of PRDX4 but correlates with increased trimethylation of histone 3 lysine residue 27 (H3K27me3) and lysine residue 4 (H3K4me3) at the transcriptional start site (TSS) of PRDX4, indicative of a bivalent histone code involved in transcriptional silencing. These findings suggest that the control of G-CSF responses by the antioxidant protein PRDX4 may be perturbed in APL

Divergent Roles of Clock Genes in Retinal and Suprachiasmatic Nucleus Circadian Oscillators

The retina is both a sensory organ and a self-sustained circadian clock. Gene targeting studies have revealed that mammalian circadian clocks generate molecular circadian rhythms through coupled transcription/translation feedback loops which involve 6 core clock genes, namely Period (Per) 1 and 2, Cryptochrome (Cry) 1 and 2, Clock, and Bmal1 and that the roles of individual clock genes in rhythms generation are tissue-specific. However, the mechanisms of molecular circadian rhythms in the mammalian retina are incompletely understood and the extent to which retinal neural clocks share mechanisms with the suprachiasmatic nucleus (SCN), the central neural clock, is unclear. In the present study, we examined the rhythmic amplitude and period of real-time bioluminescence rhythms in explants of retina from Per1-, Per2-, Per3-, Cry1-, Cry2-, and Clock-deficient mice that carried transgenic PERIOD2::LUCIFERASE (PER2::LUC) or Period1::luciferase (Per1::luc) circadian reporters. Per1-, Cry1- and Clock-deficient retinal and SCN explants showed weakened or disrupted rhythms, with stronger effects in retina compared to SCN. Per2, Per3, and Cry2 were individually dispensable for sustained rhythms in both tissues. Retinal and SCN explants from double knockouts of Cry1 and Cry2 were arrhythmic. Gene effects on period were divergent with reduction in the number of Per1 alleles shortening circadian period in retina, but lengthening it in SCN, and knockout of Per3 substantially shortening retinal clock period, but leaving SCN unaffected. Thus, the retinal neural clock has a unique pattern of clock gene dependence at the tissue level that it is similar in pattern, but more severe in degree, than the SCN neural clock, with divergent clock gene regulation of rhythmic period

A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM): a multi-cohort machine learning study

BACKGROUND: Differentiating between self-resolving viral infections and bacterial infections in children who are febrile is a common challenge, causing difficulties in identifying which individuals require antibiotics. Studying the host response to infection can provide useful insights and can lead to the identification of biomarkers of infection with diagnostic potential. This study aimed to identify host protein biomarkers for future development into an accurate, rapid point-of-care test that can distinguish between bacterial and viral infections, by recruiting children presenting to health-care settings with fever or a history of fever in the previous 72 h. METHODS: In this multi-cohort machine learning study, patient data were taken from EUCLIDS, the Swiss Pediatric Sepsis study, the GENDRES study, and the PERFORM study, which were all based in Europe. We generated three high-dimensional proteomic datasets (SomaScan and two via liquid chromatography tandem mass spectrometry, referred to as MS-A and MS-B) using targeted and untargeted platforms (SomaScan and liquid chromatography mass spectrometry). Protein biomarkers were then shortlisted using differential abundance analysis, feature selection using forward selection-partial least squares (FS-PLS; 100 iterations), along with a literature search. Identified proteins were tested with Luminex and ELISA and iterative FS-PLS was done again (25 iterations) on the Luminex results alone, and the Luminex and ELISA results together. A sparse protein signature for distinguishing between bacterial and viral infections was identified from the selected proteins. The performance of this signature was finally tested using Luminex assays and by calculating disease risk scores. FINDINGS: 376 children provided serum or plasma samples for use in the discovery of protein biomarkers. 79 serum samples were collected for the generation of the SomaScan dataset, 147 plasma samples for the MS-A dataset, and 150 plasma samples for the MS-B dataset. Differential abundance analysis, and the first round of feature selection using FS-PLS identified 35 protein biomarker candidates, of which 13 had commercial ELISA or Luminex tests available. 16 proteins with ELISA or Luminex tests available were identified by literature review. Further evaluation via Luminex and ELISA and the second round of feature selection using FS-PLS revealed a six-protein signature: three of the included proteins are elevated in bacterial infections (SELE, NGAL, and IFN-γ), and three are elevated in viral infections (IL18, NCAM1, and LG3BP). Performance testing of the signature using Luminex assays revealed area under the receiver operating characteristic curve values between 89·4% and 93·6%. INTERPRETATION: This study has led to the identification of a protein signature that could be ultimately developed into a blood-based point-of-care diagnostic test for rapidly diagnosing bacterial and viral infections in febrile children. Such a test has the potential to greatly improve care of children who are febrile, ensuring that the correct individuals receive antibiotics. FUNDING: European Union's Horizon 2020 research and innovation programme, the European Union's Seventh Framework Programme (EUCLIDS), Imperial Biomedical Research Centre of the National Institute for Health Research, the Wellcome Trust and Medical Research Foundation, Instituto de Salud Carlos III, Consorcio Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Grupos de Refeencia Competitiva, Swiss State Secretariat for Education, Research and Innovation