Among the large Member States of the European Union (EU), the Federal Republic of Germany has been distinctive in its commitment to integration and enlargement and has always played a key role in ...European integration. The traumatic experience of the short century from 1870 to 1945, when Germany had twice attempted to assert its power unilaterally, meant, however, that the Federal Republic was a reflexive multilateralist who made a practice of leading from behind. There was a self- and external perception of Germany pursuing a European vocation (Paterson, 2010). It therefore avoided a discourse of national interest: the European interest was seen as the national interest. Its preferred mode of presenting European initiatives was in tandem with France. All of these elements have come under pressure in recent years, but the eurozone crisis has proved to be a tipping point for classic German Europeanism while simultaneously Germany has been pushed somewhat reluctantly centre stage to become Europe's reluctant hegemon. In this article we will examine how this tipping point was arrived at, how the German government has performed in this new role and the implications for Germany and the wider EU. Adapted from the source document.
This article explores the growing perception, prompted by the eurozone crisis, of Germany as a hegemonic power in the European Union. The article explores the realignments in the power balance within ...the European Union (EU) by making an original application of the insights from the literature on hegemony. It reviews the evidence for Germany playing a hegemonic role, but then emphasizes three sets of constraints. First, German pre-eminence is largely confined to the economic sphere. Even in this area Germany has not acted fully in line with the role ascribed by hegemonic stability theory. Second, its pre-eminence in the EU encounters problems of international legitimacy. Third, growing constraints arising from German domestic politics further hamper playing the role of hegemon. In consequence, Germany is intrinsically a reluctant hegemon: one whose economic leadership is recognized but politically contested. The conclusion considers the significance of these findings on the EU's most important member state.
Throughout the 1970s and 1980s, West Germany was considered to be one of the world's most successful economic and political systems. In his seminal 1987 analysis of West Germany's 'semisovereign' ...system of governance, Peter Katzenstein attributed this success to a combination of a fragmented polity, consensus politics and incremental policy changes. However, unification in 1990 has both changed Germany's institutional configuration and created economic and social challenges on a huge scale. This 2005 volume therefore asks whether semisovereignty still exists in contemporary Germany and, crucially, whether it remains an asset in terms of addressing these challenges. By shadowing and building on the original study, an eminent team of British, German and American scholars analyses institutional changes and the resulting policy developments in key sectors, with Peter Katzenstein himself providing the conclusion. Together, the chapters provide a landmark assessment of the outcomes produced by one of the world's most important countries.
Culturing experiments were performed on sediment samples from the Ythan Estuary, N. E. Scotland, to assess the impacts of ocean acidification on test surface ornamentation in the benthic foraminifer ...Haynesina germanica. Specimens were cultured for 36 weeks at either 380, 750 or 1000 ppm atmospheric CO2. Analysis of the test surface using SEM imaging reveals sensitivity of functionally important ornamentation associated with feeding to changing seawater CO2 levels. Specimens incubated at high CO2 levels displayed evidence of shell dissolution, a significant reduction and deformation of ornamentation. It is clear that these calcifying organisms are likely to be vulnerable to ocean acidification. A reduction in functionally important ornamentation could lead to a reduction in feeding efficiency with consequent impacts on this organism's survival and fitness.
Forces play diverse roles in vascular development, homeostasis and disease. VE-cadherin at endothelial cell-cell junctions links the contractile acto-myosin cytoskeletons of adjacent cells, serving ...as a tension-transducer. To explore tensile changes across VE-cadherin in live zebrafish, we tailored an optical biosensor approach, originally established in vitro. We validate localization and function of a VE-cadherin tension sensor (TS) in vivo. Changes in tension across VE-cadherin observed using ratio-metric or lifetime FRET measurements reflect acto-myosin contractility within endothelial cells. Furthermore, we apply the TS to reveal biologically relevant changes in VE-cadherin tension that occur as the dorsal aorta matures and upon genetic and chemical perturbations during embryonic development.
Purpose
Bisphosphonates reduce bone metastases in postmenopausal women with early-stage breast cancer but carry the risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We describe risk ...factors for BRONJ and compare BRONJ provoked by infection or trauma with spontaneous lesions, which carry a better prognosis.
Methods
SWOG 0307 randomized women with stage I–III breast cancer to receive zoledronic acid (ZA), clodronate (CL), or ibandronate (IB) for 3 years, implemented BRONJ prevention guidelines, and collected information about dental health and development of BRONJ. All statistical tests were two-sided.
Results
Of 6018 women, 48 developed BRONJ. Infection was present in 21 (43.8%). Median time to BRONJ was 2.1 years for ZA, 2.0 years for IB, and 3.4 years for clodronate (
p
= 0.04). BRONJ was associated with bisphosphonate type (28/2231 (1.26%) for ZA, 8/2235 (0.36%) for CL, 12/1552 (0.77%) for IB), dental calculus (OR 2.03), gingivitis (OR 2.11), moderate/severe periodontal disease (OR 2.87), and periodontitis > 4 mm (OR 2.20) (
p
< 0.05). Of 57 lesions, BRONJ occurred spontaneously in 20 (35.1%) and was provoked by dental extraction in 20 (35.1%), periodontal disease in 14 (24.6%), denture trauma in 6 (10.5%), and dental surgery in 2 (3.5%). Spontaneous BRONJ occurred more frequently at the mylohyoid ridge. There were no differences in dental disease, infection, or bisphosphonate type between spontaneous and provoked BRONJ.
Conclusion
ZA and worse dental health were associated with increased incidence of BRONJ, with a trend toward additive risk when combined. BRONJ incidence was lower than in similar studies, with prevention strategies likely linked to this.
Clinical trial number
NCT00127205
Registration date
July 2005
Abstract
Background
Adjuvant bisphosphonates, when given in a low-estrogen environment, can decrease breast cancer recurrence and death. Treatment guidelines include recommendations for adjuvant ...bisphosphonates in postmenopausal patients. SWOG/Alliance/Canadian Cancer Trials Group/ECOG-ACRIN/NRG Oncology study S0307 compared the efficacy of three bisphosphonates in early-stage breast cancer.
Methods
Patients with stage I–III breast cancer were randomly assigned to 3 years of intravenous zoledronic acid, oral clodronate, or oral ibandronate. The primary endpoint was disease-free survival (DFS) with overall survival as a secondary outcome. All statistical tests were two-sided.
Results
A total of 6097 patients enrolled. Median age was 52.7 years. Prior to being randomly assigned, 73.2% patients indicated preference for oral vs intravenous formulation. DFS did not differ across arms in a log-rank test (P = .49); 5-year DFS was 88.3% (zoledronic acid: 95% confidence interval CI = 86.9% to 89.6%), 87.6% (clodronate: 95% CI = 86.1% to 88.9%), and 87.4% (ibandronate: 95% CI = 85.6% to 88.9%). Additionally, 5-year overall survival did not differ between arms (log rank P = .50) and was 92.6% (zoledronic acid: 95% CI = 91.4% to 93.6%), 92.4% (clodronate: 95% CI = 91.2% to 93.5%), and 92.9% (ibandronate: 95% CI = 91.5% to 94.1%). Bone as first site of recurrence did not differ between arms (P = .93). Analyses based on age and tumor subtypes showed no treatment differences. Grade 3/4 toxicity was 8.8% (zoledronic acid), 8.3% (clodronate), and 10.5% (ibandronate). Osteonecrosis of the jaw was highest for zoledronic acid (1.26%) compared with clodronate (0.36%) and ibandronate (0.77%).
Conclusions
We found no evidence of differences in efficacy by type of bisphosphonate, either in overall analysis or subgroups. Despite an increased rate of osteonecrosis of the jaw with zoledronic acid, overall toxicity grade differed little across arms. Given that patients expressed preference for oral formulation, efforts to make oral agents available in the United States should be considered.
Summary
B‐cell maturation antigen (BCMA, also termed TNFRSF17) is an attractive therapeutic target due to its restricted expression on normal and malignant plasma cells (PC). GSK2857916 (or ...J6M0‐MMAF) is a BCMA‐specific antibody conjugated to the microtubule‐disrupting agent monomethyl auristatin F (MMAF) via a protease‐resistant linker. To evaluate the clinical potential of this agent, tumour cells from seventy multiple myeloma (MM) patients were assessed for BCMA expression by immunohistochemistry and flow cytometry. All patients tested expressed BCMA, at varying levels, and both surface and intracellular expression were observed. BCMA expression is maintained through relapse, extramedullary spread and in residual disease post therapy. BCMA levels may also be prognostically useful as higher levels of BCMA were associated with poorer outcomes, even taking into account genetic risk. We observed rapid internalization of surface BCMA and newly expressed protein by 1 h, suggesting a mechanism for J6M0‐MMAF activity even with low surface antigen. J6M0‐MMAF mediated cytotoxicity of MM cells varied with dose and antigen levels, with clonogenic progenitors killed at lower doses than mature cells. In comparison, J6M0‐MMAF killing of primary CD138+ myeloma cells occurred with slower kinetics. Our observations support BCMA to be a promising therapeutic target in MM for novel therapies such as J6M0‐MMAF.
Fever, Hypotension, and a Worsening Necrotic Wound Peterson, Danielle M; Damsky, William E; Vesely, Matthew D
JAMA : the journal of the American Medical Association,
04/2022, Letnik:
327, Številka:
15
Journal Article
Recenzirano
On the day of giving birth via a normal vaginal delivery, a healthy woman in her 20s developed painful swelling on her right thigh, at the site of a methergine injection administered 1 day prior. ...Despite 3 days of treatment with an oral antibiotic (cefalexin), her thigh pain and swelling did not improve, and she was readmitted to the hospital and intravenous clindamycin was started. Wound cultures and blood cultures obtained during incision and drainage performed on hospital day 1 were negative for bacterial, mycobacterial, and fungal organisms. The following day, her temperature was 39.4 degrees C, blood pressure was 86/42 mm Hg, and heart rate was 131/min. She was transferred to the intensive care unit for presumed septic shock, and her antibiotics were changed to vancomycin and meropenem. Surgical debridement of the right thigh was performed on hospital day 3.
To determine, with novel software, the feasibility of measuring the tortuosity and width of retinal veins and arteries from digital retinal images of infants at risk of retinopathy of prematurity ...(ROP).
The Computer-Aided Image Analysis of the Retina (CAIAR) program was developed to enable semiautomatic detection of retinal vasculature and measurement of vessel tortuosity and width from digital images. CAIAR was tested for accuracy and reproducibility of tortuosity and width measurements by using computer-generated vessel-like lines of known frequency, amplitude, and width. CAIAR was then tested by using clinical digital retinal images for correlation of vessel tortuosity and width readings compared with expert ophthalmologist grading.
When applied to 16 computer-generated sinusoidal vessels, the tortuosity measured by CAIAR correlated very well with the known values. Width measures also increased as expected. When the CAIAR readings were compared with five expert ophthalmologists' grading of 75 vessels on 10 retinal images, moderate correlation was found in 10 of the 14 tortuosity output calculations (Spearman rho = 0.618-0.673). Width was less well correlated (rho = 0.415).
The measures of tortuosity and width in CAIAR were validated using sequential model vessel analysis. On comparison of CAIAR output with assessments made by expert ophthalmologists, CAIAR correlates moderately with tortuosity grades, but less well with width grades. CAIAR offers the opportunity to develop an automated image analysis system for detecting the vascular changes at the posterior pole, which are becoming increasingly important in diagnosing treatable ROP.
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