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Background: In Europe, health-care policies are determined at a national level and differ between countries. This analysis from a prospective, longitudinal, non-interventional study aimed to describe patterns in the clinical monit...
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Background: In Europe, health-care policies are determined at a national level and differ between countries. This analysis from a prospective, longitudinal, non-interventional study aimed to describe patterns in the clinical monitoring and treatment of chronic hepatitis B (CHB) in five European countries. Methods: Country-specific cohorts of adult patients with compensated CHB managed in clinics in Germany, France, Poland, Romania and Turkey were followed for up to 2 years between March 2008 and December 2010. Results: A total of 1,267 patients were included. Baseline age and gender distribution were similar across countries for patients who were treated (n=567) and untreated (n=700) at baseline. Most treated patients were receiving monotherapy at baseline, most frequently with entecavir or tenofovir in Germany, France and Turkey, and with lamivudine in Poland and Romania. Use of pegylated interferon was more frequent in Poland and Romania than in other countries. In Romania monotherapy with entecavir increased after it became reimbursed in 2008. Hospitalizations during follow-up were more frequent in Romania (1.45 hospital days/patient-year) and Poland (1.81 days/patient-year) than in Turkey, France and Germany (0.00, 0.05 and 0.10 days/patient-year, respectively); clinic visits were more frequent in Poland (3.20 versus 0.30-1.78 visits/patient-year across other countries). Conclusions: These results illustrate country-specific patterns in the management of CHB patients across Europe. Observed monitoring patterns, hospitalization rates and other health-care utilization may be related to cost and reimbursement issues; however, further study in individual countries would be required to confirm these (post hoc) observations.
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EGF receptor (EGFR) promotes tumor growth as well as radio- and chemoresistance in various human malignancies including squamous cell carcinomas (SCC). In addition to deactivation of prosurvival signaling, cetuximab-mediated EGFR ...
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EGF receptor (EGFR) promotes tumor growth as well as radio- and chemoresistance in various human malignancies including squamous cell carcinomas (SCC). In addition to deactivation of prosurvival signaling, cetuximab-mediated EGFR targeting might concomitantly induce self-attenuating signaling bypasses. Identification of such bypass mechanisms is key to improve the efficacy of targeted approaches. Here, we show great similarity of EGFR signaling and radiation survival in cetuximab-treated SCC cells grown in a more physiologic three-dimensional extracellular matrix and as tumor xenografts in contrast to conventional monolayer cell cultures. Using phosphoproteome arrays, we observed strong induction of JNK2 phosphorylation potentially resulting from cetuximab-inhibited EGFR through c-jun-NH2-kinase (JNK)-interacting protein-4 (JIP-4), which was identified using an immunoprecipitation-mass spectrometric approach. Inhibition of this signaling bypass by JIP-4 or JNK2 knockdown or pharmacologic JNK2 inhibition enhanced cetuximab efficacy and tumor cell radiosensitivity. Our findings add new facets to EGFR signaling and indicate signaling bypass possibilities of cancer cells to improve their survival on cetuximab treatment. By deactivation of cetuximab-self-attenuating JNK2-dependent signaling, the cytotoxicity, and radiosensitizing potential of cetuximab can be augmented.
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The impact and consequences of damage generation into genomic DNA, especially in the form of DNA double-strand breaks, and of the DNA-damage response (DDR) pathways that are promptly activated, have been elucidated in great detail...
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The impact and consequences of damage generation into genomic DNA, especially in the form of DNA double-strand breaks, and of the DNA-damage response (DDR) pathways that are promptly activated, have been elucidated in great detail. Most of this research, however, has been performed on proliferating, often cancerous, cell lines. In a mammalian body, the majority of cells are terminally differentiated (TD), and derives from a small pool of self-renewing somatic stem cells. Here, we comparatively studied DDR signaling and radiosensitivity in neural stem cells (NSC) and their TD-descendants, astrocytes-the predominant cells in the mammalian brain. Astrocytes have important roles in brain physiology, development and plasticity. We discovered that NSC activate canonical DDR upon exposure to ionizing radiation. Strikingly, astrocytes proved radioresistant, lacked functional DDR signaling, with key DDR genes such as ATM being repressed at the transcriptional level. Nevertheless, astrocytes retain the expression of non-homologous end-joining (NHEJ) genes and indeed they are DNA repair proficient. Unlike in NSC, in astrocytes DNA-PK seems to be the PI3K-like protein kinase responsible for γH2AX signal generation upon DNA damage. We also demonstrate the lack of functional DDR signaling activation in vivo in astrocytes of irradiated adult mouse brains, although adjacent neurons activate the DDR.
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The structural and functional repertoire of small non-protein-coding RNAs (ncRNAs) is central for establishing gene regulation networks in cells and organisms. Here, we show that an mRNA-derived 18-nucleotide-long ncRNA is capable...
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The structural and functional repertoire of small non-protein-coding RNAs (ncRNAs) is central for establishing gene regulation networks in cells and organisms. Here, we show that an mRNA-derived 18-nucleotide-long ncRNA is capable of downregulating translation in Saccharomyces cerevisiae by targeting the ribosome. This 18-mer ncRNA binds to polysomes upon salt stress and is crucial for efficient growth under hyperosmotic conditions. Although the 18-mer RNA originates from the TRM10 locus, which encodes a tRNA methyltransferase, genetic analyses revealed the 18-mer RNA nucleotide sequence, rather than the mRNA-encoded enzyme, as the translation regulator. Our data reveal the ribosome as a target for a small regulatory ncRNA and demonstrate the existence of a yet unkown mechanism of translation regulation. Ribosome-targeted small ncRNAs are found in all domains of life and represent a prevalent but so far largely unexplored class of regulatory molecules.
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Background: Chronic hepatitis B (CHB) is an important health concern, but there are few studies describing its management in different countries. This prospective, longitudinal, non-interventional study aimed to assess differences...
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Background: Chronic hepatitis B (CHB) is an important health concern, but there are few studies describing its management in different countries. This prospective, longitudinal, non-interventional study aimed to assess differences in CHB management in five European countries (Germany, France, Poland, Romania and Turkey). Methods: Data were collected from CHB patients' records between 2008 and 2010. Patients were stratified by treatment status at baseline (treated or untreated). The primary objective was to estimate the probability of a CHB management modification (treatment initiation or change) among patients from each country during a 2-year follow-up. Results: A total of 1,267 patients were included (567 treated, 700 untreated). Baseline characteristics between countries and treatment status groups were broadly comparable. Most patients had an alanine aminotransferase measurement in the 12 months prior to baseline; proportions of patients with an HBV DNA assessment varied by country and treatment status. The Kaplan-Meier-estimated probability of any treatment modification ranged from 9.4% (Turkey) to 30.1% (Poland) at 12 months and 10.0% (Turkey) to 40.0% (Poland) at 24 months. Modifications were more common in treated than untreated patients. The most frequently reported reasons for modifying treatment were HBV-DNA-related. The majority of treated patients were treated with monotherapy; however, choice of therapy differed between countries. Conclusions: This is the first longitudinal study describing CHB management in European countries. Differences were observed in treatment and monitoring between countries, but alanine aminotransferase and HBV DNA levels consistently emerged as key tests in the management of CHB in all five countries.
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OBJECTIVE: Variation in emergency department head computed tomography (CT) use in patients with atraumatic headaches between hospitals is being measured nationwide. However, the magnitude of interphysician variation within a hospi...
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OBJECTIVE: Variation in emergency department head computed tomography (CT) use in patients with atraumatic headaches between hospitals is being measured nationwide. However, the magnitude of interphysician variation within a hospital is currently unknown. We hypothesized that there was significant variation in the rates of physician head CT use, both overall and for patients diagnosed with atraumatic headaches. METHODS: This cross-sectional study was conducted in the emergency department of a large urban academic hospital, and institutional review board approval was obtained. All emergency department visits from 2009 were analyzed, and the primary outcome measure was whether or not head CT was performed. Logistic regression was used to control for patient, physician, and visit characteristics potentially associated with head CT ordering. The degree of interphysician variability was tested, both before and after controlling for these variables. RESULTS: Of 55,286 emergency department patient encounters, 4919 (8.9%) involved head CT examinations. Unadjusted head CT ordering rates per physician ranged from 4.4% to 16.9% overall and from 15.2% to 61.7% in patients diagnosed with atraumatic headaches, with both rates varying significantly between physicians. Two-fold variation in head CT ordering overall (6.5%-13.5%) and approximately 3-fold variation in head CT ordering for atraumatic headaches (21.2%-60.1%) persisted even after controlling for pertinent variables. CONCLUSION: Emergency physicians vary significantly in their use of head CT both overall and in patients with atraumatic headaches. Further studies are needed to identify strategies to reduce interphysician variation in head CT use.
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The adaptors DOCK8 and MyD88 have been linked to serological memory. Here we report that DOCK8-deficient patients had impaired antibody responses and considerably fewer CD27 + memory B cells. B cell proliferation and immunoglobuli...
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The adaptors DOCK8 and MyD88 have been linked to serological memory. Here we report that DOCK8-deficient patients had impaired antibody responses and considerably fewer CD27 + memory B cells. B cell proliferation and immunoglobulin production driven by Toll-like receptor 9 (TLR9) were considerably lower in DOCK8-deficient B cells, but those driven by the costimulatory molecule CD40 were not. In contrast, TLR9-driven expression of AICDA (which encodes the cytidine deaminase AID), the immunoglobulin receptor CD23 and the costimulatory molecule CD86 and activation of the transcription factor NF-κB, the kinase p38 and the GTPase Rac1 were intact. DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells. After ligation of TLR9, DOCK8 became tyrosine-phosphorylated by Pyk2, bound the Src-family kinase Lyn and linked TLR9 to a Src-kinase Syk-transcription factor STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation. Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells.
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Background An increasing number of octogenarians are referred for cardiac surgical procedures. In this subset of patients, information on the health-related quality of life (HrQoL) is critical for decision making. However, there i...
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Background An increasing number of octogenarians are referred for cardiac surgical procedures. In this subset of patients, information on the health-related quality of life (HrQoL) is critical for decision making. However, there is a paucity of prospective data. Thus, we sought to prospectively evaluate the HrQoL in octogenarians undergoing cardiac surgery. Methods A prospective HrQoL analysis was performed in 106 elective patients (median age 83.0 ± 2.6 years, range 80-91.8 years, 59.4% male) undergoing cardiac surgery. The standardized SF-36 Health Survey questionnaire was answered preoperatively, and three and 12 months postoperatively. Preoperative data, perioperative outcome, and postoperative morbidity were analyzed. Results SF-36 scores for physical functioning (44.3 ± 2.3 vs. 52.0 ± 2.7; p < 0.001), role physical (25.2 ± 3.3 vs. 41.5 ± 4.1; p < 0.001), bodily pain (57.8 ± 3.2 vs. 70.7 ± 2.8; p < 0.01), general health (54.9 ± 1.7 vs. 59.6 ± 1.7; p < 0.001), vitality (41.1 ± 2.1 vs. 50.6 ± 2.1; p < 0.001), and mental health (67.5 ± 2.0 vs. 72.4 ± 1.9; p < 0.05) significantly improved from baseline to three months. Social functioning (75.4 ± 2.6 vs. 76.1 ± 2.5; p = 0.79) and role emotional (56.8 ± 4.5 vs. 58.0 ± 4.6; p = 0.29) improved slightly without reaching statistical significance. Correspondingly, at three months, physical component scores increased significantly compared to baseline (34.3 ± 1.0 vs. 39.4 ± 1.0; p < 0.001). SF-36 scores remained stable between three months and one year. No significant change was seen in the mental component score from baseline to three months (48.6 ± 1.2 vs. 49.8 ± 1.1; p = 0.18). Conclusions Physical HrQoL is significantly improved in octogenarians three months after cardiac surgery remaining stable at one year postoperatively when compared to baseline.
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Background: Lowering low-density lipoprotein (LDL) cholesterol in patients with diabetes mellitus (DM) and cardiovascular disease (CVD) is critical to lowering morbidity and mortality. To increase the percentage of patients with D...
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Background: Lowering low-density lipoprotein (LDL) cholesterol in patients with diabetes mellitus (DM) and cardiovascular disease (CVD) is critical to lowering morbidity and mortality. To increase the percentage of patients with DM and CVD at target LDL (<100 mg/dL), we launched an expanded team-based quality improvement programme in which centralised registered nurses (RNs) followed a detailed protocol to adjust cholesterol-lowering medications. Despite the growing use of team-based approaches to improve quality of care, little remains known about how best to implement them. Program evaluation: To share our experiences and lessons from operating a team-based programme, we conducted a retrospective observational analysis of administrative and clinical data on programme performance. We measured: primary care physician (PCP) and patient acceptance of the programme, number of medication adjustments, change in LDL, per cent of patients achieving target, time to LDL target and the efforts required to achieve these goals. Results: Using administrative data, we initially identified 374 potential patients for enrolment. Chart review revealed that 203 (54%) were clinically eligible. PCPs agreed to enrol 74% (150/203) of these patients. Thirty-six per cent of PCP-approved patients (54/150) could not be reached via phone and 5.3% (8/150) declined enrolment. Of patients enrolled (n=64), 50% did not complete the programme. Of those enrolled, median LDL decreased by 21 mg/dL and 52% (33/64) achieved the LDL target. Programme RNs spent 12 023 min on programme activities, of which 44.4% (5539) was related to nonenrolled patients. Conclusions: Our adoption of a centralised expanded team-based programme for the management of LDL cholesterol uncovered many barriers to efficiency and success. Even though expanded team programmes may be supported by PCPs, the administrative efforts required to identify, enrol and continually engage eligible patients raise many concerns regarding efficiency and highlight infrastructure changes needed for successful team-based approaches.
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The objective of this study was to evaluate the switch to once-daily darunavir/ritonavir 800/100mg in treatment-experienced patients with suppressed HIV-1 replication on a twice-daily ritonavir-boosted protease-inhibitor (bid PI/r...
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The objective of this study was to evaluate the switch to once-daily darunavir/ritonavir 800/100mg in treatment-experienced patients with suppressed HIV-1 replication on a twice-daily ritonavir-boosted protease-inhibitor (bid PI/r) containing regimen, that is in a setting where genotypic resistance test cannot be performed. In this open label, non-comparative, multicenter study, patients on a bid PI/r-containing triple combination, with suppressed viral replication, were switched to once-daily darunavir/r 800/100mg containing triple combination. The primary endpoint was the proportion of patients with plasma HIV-RNA<50copies/ml 24 weeks after the switch. Intensive darunavir pharmacokinetic evaluation was performed at Week 4 (W4) in 11 patients. Eighty-five patients were enrolled. All had HIV-RNA<50copies/ml at screening with a pre-exposure to a median of 2 PI/r (1-5). By intent-to-treat analysis (missing=failure), 78/85 patients (92%, 95% CI [83;96]) maintained an HIV-RNA<50copies/ml at W24. Seven patients experienced protocol-defined treatment failure between baseline and W24: Two had confirmed low-level viral rebound, one discontinued study treatment for adverse event, three withdrew their consent, and one was lost to follow-up. By on-treatment analysis, 78/80 patients (97%, 95% CI [91;99]) maintained an HIV-RNA<50copies/ml at W24. Results were similar at Week 48. The median area under the darunavir plasma concentration-time curve measured in 11 patients was 61,380nghr/ml; darunavir median trough concentration 1,340ng/ml and darunavir half-life was 12.2hr. Tolerability of once-daily darunavir/r 800/100mg was excellent. Optimally suppressed, treatment-experienced patients can switch safely from a twice-daily PI/r regimen to a once-daily darunavir/r 800/100mg containing regimen.
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