Gravitational wave background from Standard Model physics: qualitative features

Because of physical processes ranging from microscopic particle collisions to macroscopic hydrodynamic fluctuations, any plasma in thermal equilibrium emits gravitational waves. For the largest wavelengths the emission rate is proportional to the shear viscosity of the plasma. In the Standard Model at 0T > 16 GeV, the shear viscosity is dominated by the most weakly interacting particles, right-handed leptons, and is relatively large. We estimate the order of magnitude of the corresponding spectrum of gravitational waves. Even though at small frequencies (corresponding to the sub-Hz range relevant for planned observatories such as eLISA) this background is tiny compared with that from non-equilibrium sources, the total energy carried by the high-frequency part of the spectrum is non-negligible if the production continues for a long time. We suggest that this may constrain (weakly) the highest temperature of the radiation epoch. Observing the high-frequency part directly sets a very ambitious goal for future generations of GHz-range detectors.

Standard Model thermodynamics across the electroweak crossover

Even though the Standard Model with a Higgs mass mH = 125GeV possesses no bulk phase transition, its thermodynamics still experiences a "soft point" at temperatures around T = 160GeV, with a deviation from ideal gas thermodynamics. Such a deviation may have an effect on precision computations of weakly interacting dark matter relic abundances if their mass is in the few TeV range, or on leptogenesis scenarios operating in this temperature range. By making use of results from lattice simulations based on a dimensionally reduced effective field theory, we estimate the relevant thermodynamic functions across the crossover. The results are tabulated in a numerical form permitting for their insertion as a background equation of state into cosmological particle production/decoupling codes. We find that Higgs dynamics induces a non-trivial "structure" visible e.g. in the heat capacity, but that in general the largest radiative corrections originate from QCD effects, reducing the energy density by a couple of percent from the free value even at T > 160GeV.

Bevacizumab, Pemetrexed, and Cisplatin, or Bevacizumab and Erlotinib for Patients With Advanced Non-Small-Cell Lung Cancer Stratified by Epidermal Growth Factor Receptor Mutation: Phase II Trial SAKK19/09

Treatment allocation by epidermal growth factor receptor mutation status is a new standard in patients with metastatic nonesmall-cell lung cancer. Yet, relatively few modern chemotherapy trials were conducted in patients characterized by epidermal growth factor receptor wild type. We describe the results of a multicenter phase II trial, testing in parallel 2 novel combination therapies, predefined molecular markers, and tumor rebiopsy at progression. Objective: The goal was to demonstrate that tailored therapy, according to tumor histology and epidermal growth factor receptor (EGFR) mutation status, and the introduction of novel drug combinations in the treatment of advanced nonesmall-cell lung cancer are promising for further investigation. Methods: We conducted a multicenter phase II trial with mandatory EGFR testing and 2 strata. Patients with EGFR wild type received 4 cycles of bevacizumab, pemetrexed, and cisplatin, followed by maintenance with bevacizumab and pemetrexed until progression. Patients with EGFR mutations received bevacizumab and erlotinib until progression. Patients had computed tomography scans every 6 weeks and repeat biopsy at progression. The primary end point was progression-free survival (PFS) ≥ 35% at 6 months in stratum EGFR wild type; 77 patients were required to reach a power of 90% with an alpha of 5%. Secondary end points were median PFS, overall survival, best overall response rate (ORR), and tolerability. Further biomarkers and biopsy at progression were also evaluated. Results: A total of 77 evaluable patients with EGFR wild type received an average of 9 cycles (range, 1-25). PFS at 6 months was 45.5%, median PFS was 6.9 months, overall survival was 12.1 months, and ORR was 62%. Kirsten rat sarcoma oncogene mutations and circulating vascular endothelial growth factor negatively correlated with survival, but thymidylate synthase expression did not. A total of 20 patients with EGFR mutations received an average of 16.

Dexmedetomidine versus standard care sedation with propofol or midazolam in intensive care: an economic evaluation.

INTRODUCTION Dexmedetomidine was shown in two European randomized double-blind double-dummy trials (PRODEX and MIDEX) to be non-inferior to propofol and midazolam in maintaining target sedation levels in mechanically ventilated intensive care unit (ICU) patients. Additionally, dexmedetomidine shortened the time to extubation versus both standard sedatives, suggesting that it may reduce ICU resource needs and thus lower ICU costs. Considering resource utilization data from these two trials, we performed a secondary, cost-minimization analysis assessing the economics of dexmedetomidine versus standard care sedation. METHODS The total ICU costs associated with each study sedative were calculated on the basis of total study sedative consumption and the number of days patients remained intubated, required non-invasive ventilation, or required ICU care without mechanical ventilation. The daily unit costs for these three consecutive ICU periods were set to decline toward discharge, reflecting the observed reduction in mean daily Therapeutic Intervention Scoring System (TISS) points between the periods. A number of additional sensitivity analyses were performed, including one in which the total ICU costs were based on the cumulative sum of daily TISS points over the ICU period, and two further scenarios, with declining direct variable daily costs only. RESULTS Based on pooled data from both trials, sedation with dexmedetomidine resulted in lower total ICU costs than using the standard sedatives, with a difference of €2,656 in the median (interquartile range) total ICU costs-€11,864 (€7,070 to €23,457) versus €14,520 (€7,871 to €26,254)-and €1,649 in the mean total ICU costs. The median (mean) total ICU costs with dexmedetomidine compared with those of propofol or midazolam were €1,292 (€747) and €3,573 (€2,536) lower, respectively. The result was robust, indicating lower costs with dexmedetomidine in all sensitivity analyses, including those in which only direct variable ICU costs were considered. The likelihood of dexmedetomidine resulting in lower total ICU costs compared with pooled standard care was 91.0% (72.4% versus propofol and 98.0% versus midazolam). CONCLUSIONS From an economic point of view, dexmedetomidine appears to be a preferable option compared with standard sedatives for providing light to moderate ICU sedation exceeding 24 hours. The savings potential results primarily from shorter time to extubation. TRIAL REGISTRATION ClinicalTrials.gov NCT00479661 (PRODEX), NCT00481312 (MIDEX).

Standard cystectomy fits all: truth or myth?

Radical cystectomy (RC) with pelvic lymph node dissection (PLND) followed by urinary diversion is the treatment of choice for muscle-invasive bladder cancer (BC) and non-invasive BC refractory to transurethral resection of the bladder (TUR-B) and/or intravesical instillation therapies. Since the morbidity and possible mortality of this surgery are relevant, care must be taken in the preoperative selection of patients for the various organ-sparing procedures (e.g., bladder-sparing, nerve sparing, seminal vesicle sparing) and various types of urinary diversion. The patient’s performance status and comorbidities, along with individual tumor characteristics, determine possible surgical steps during RC. This individualized approach to RC in each patient can maximize oncological safety and minimize avoidable side effects, rendering ‘standard’ cystectomy a surgery of the past.

In vitro analysis of osteogenic inhibition in non-union spinal fusion caused by nucleus pulposus cells.

Discectomy and spinal fusion is the gold standard for spinal surgery to relieve pain. However, fusion can be hindered for yet unknown reasons that lead to non-fusions with pseudo-arthrosis. Clinical observations indicate that presence of residual intervertebral disc (IVD) tissue might hinder the ossification. We hypothesize that BMP-antagonists are constantly secreted by IVD cells and potentially prevent the ossification process. Furthermore, L51P, the engineered BMP2 variant, stimulates osseo-induction of bone marrow-derived mesenchymal stem cells (MSC) by antagonizing BMP-inhibitors. Human MSCs, primary nucleus pulposus (NPC) and annulus pulposus cells (AFC) were isolated and expanded in monolayer cultures up to passage 3. IVD cells were seeded in 1.2% alginate beads (4Mio/mL) and separated by culture inserts from MSCs. MSCs were kept in 1:control medium, 2:osteogenic medium±alginate beads, 3:osteogenic medium+NPC (±L51P) and 4:osteogenic medium+AFC (±L51P) for 21 days. Relative gene expression of bone-related genes, alkaline phosphatase assay and histological staining were performed. Osteogenesis of MSCs was hindered as shown by reduced alizarin red staining in the presence of NPC. No such inhibition was observed if co-cultured with alginate only or in the presence of AFC. The results were confirmed on the RNA and protein level. Addition of L51Pto the co- cultures, however, induced mineralization of MSCs in presence of NPC. We demonstrated that NPC secrete BMP-antagonists that prevent osteogenesis of MSCs and L51P can antagonize BMP-antagonists and induce bone formation.

Investigation of bone inhibition in non-union spinal fusion caused by intervertebral disc cells in vitro

Introduction: Discectomy and spinal fusion is the gold standard for spinal surgery to relieve pain. However, fusion can be hindered for yet unknown reasons that lead to non-fusions with pseudo-arthrose. It is hence appealing to develop biomaterials that can enhance bone formation. Clinical observations indicate that presence of residual intervertebral disc (IVD) tissue might hinder the ossification. We hypothesize that BMP-antagonists are constantly secreted by IVD cells and potentially prevent the ossification process. Furthermore, L51P, the engineered BMP2 variant, stimulates osteoinduction of bone marrow-derived mesenchymal stem cells (MSC) by antagonizing BMP-inhibitors. Methods: Human MSCs, primary nucleus pulposus (NPC) and annulus pulposus cells (AFC) were isolated and expanded in monolayer cultures up to passage 3. IVD cells were seeded in 1.2% alginate beads (4Mio/mL) and separated by culture inserts from MSCs in a co-culture set-up. MSCs were kept in 1:control medium, 2:osteogenic medium+alginate control, 3:osteogenic medium+NPC (±L51P) and 4:osteogenic medium+AFC (±L51P) for 21 days. Relative gene expression of bone-related genes, Alkaline Phosphatase (ALP) assay and histological staining were performed. Results: Osteogenesis of MSCs was hindered as shown by reduced alizarin red staining in the presence of NPC. No such inhibition was observed if co-cultured with alginate only or in the presence of AFC. The results were confirmed on the RNA and protein level. Addition of L51P to the co-cultures induced mineralization of MSCs, however a reduced ALP was observed. Conclusion: We demonstrated that NPC secrete BMP-antagonists that prevent osteogenesis of MSCs and L51P can antagonize BMP-antagonists and induce bone formation.

Mapping tibiofemoral gonarthrosis: an MRI analysis of non-traumatic knee cartilage defects

OBJECTIVE Arthroscopy is "the gold standard" for the diagnosis of knee cartilage lesions. However, it is invasive and expensive, and displays all the potential complications of an open surgical procedure. Ultra-high-field MRI now offers good opportunities for the indirect assessment of the integrity and structural changes of joint cartilage of the knee. The goal of the present study is to determine the site of early cartilaginous lesions in adults with non-traumatic knee pain. METHODS 3-T MRI examinations of 200 asymptomatic knees with standard and three-dimensional double-echo steady-state (3D-DESS) cartilage-specific sequences were prospectively studied for early degenerative lesions of the tibiofemoral joint. Lesions were classified and mapped using the modified Outerbridge and modified International Cartilage Repair Society classifications. RESULTS A total of 1437 lesions were detected: 56.1% grade I, 33.5% grade II, 7.2% grade III and 3.3% grade IV. Cartographically, grade I lesions were most common in the anteromedial tibial areas; grade II lesions in the anteromedial L5 femoral areas; and grade III in the centromedial M2 femoral areas. CONCLUSION 3-T MRI with standard and 3D-DESS cartilage-specific sequences demonstrated that areas predisposed to early osteoarthritis are the central, lateral and ventromedial tibial plateau, as well as the central and medial femoral condyle. ADVANCES IN KNOWLEDGE In contrast with previous studies reporting early cartilaginous lesions in the medial tibial compartment and/or in the medial femoral condyle, this study demonstrates that, regardless of grade, lesions preferentially occur at the L5 and M4 tibial and L5 and L2 femoral areas of the knee joint.

Long-term ticagrelor monotherapy versus standard dual antiplatelet therapy followed by aspirin monotherapy in patients undergoing biolimus-eluting stent implantation: rationale and design of the GLOBAL LEADERS trial

AIMS The GLOBAL LEADERS trial is a superiority study in patients undergoing percutaneous coronary intervention, with a uniform use of Biolimus A9-eluting stents (BES) and bivalirudin. GLOBAL LEADERS was designed to assess whether a 24-month antithrombotic regimen with ticagrelor and one month of acetylsalicylic acid (ASA), compared to conventional dual antiplatelet therapy (DAPT), improves outcomes. METHODS AND RESULTS Patients (n >16,000) are randomised (1:1 ratio) to ticagrelor 90 mg twice daily for 24 months plus ASA ≤100 mg for one month versus DAPT with either ticagrelor (acute coronary syndrome) or clopidogrel (stable coronary artery disease) for 12 months plus ASA ≤100 mg for 24 months. The primary outcome is a composite of all-cause mortality or non-fatal, new Q-wave myocardial infarction at 24 months. The key safety endpoint is investigator-reported class 3 or 5 bleeding according to the Bleeding Academic Research Consortium (BARC) definitions. Sensitivity analysis will be carried out to explore potential differences in outcome across geographic regions and according to specific angiographic and clinical risk estimates. CONCLUSIONS The GLOBAL LEADERS trial aims to assess the role of ticagrelor as a single antiplatelet agent after a short course of DAPT for the long-term prevention of cardiac adverse events, across a wide spectrum of patients, following BES implantation.

Post-colonial (American?) English Presence on the North-Western Pacific Island of Kosrae: A cross-linguistic analysis of the overlaps and divergences of Kosraean English compared to standard American English

Kosrae is the most remote island of the Federated States of Micronesia (FSM), with a population of less than 7,000 inhabitants, located in the Pacific Ocean between Hawaii and Guam. FSM is an independent sovereign nation consisting of four states in total: Pohnpei, Chuuk, Yap, and Kosrae. Having passed through the hands of Spain, Germany and Japan, the United States gained administrative control of FSM after WWII, as commissioned by the UN. The FSM became an independent nation in 1986 while still retaining affiliation with the US under a ‘Compact of Free Association’. Now both Kosraean and English are considered to be the two official languages and the variety of Kosraean English which has arisen proves for an interesting comparative study. In order to obtain the relevant data, I spent three months on the island of Kosrae, interviewing 90 local speakers, ranging in age (16-70), occupation, sex and time spent off island. The 45 minute long interviews were informal but supported by participant information to capture relevant data and conversations were guided in a way that aimed to reveal language and cultural attitudes. With reference to these samples, I examine the effects of American English on the language use in Kosrae. This paper aims to present a broad analysis of phonological, morphosyntactic and pragmatic features, such as pro-dropping, discourse markers and other practices in order to demonstrate the similarities and differences between the two varieties, which are coming to shape the variety developing on Kosrae. Having transcribed conversations using the tool Elan, I will put particular focus on [h] deletion and insertion, a rare occurrence found in a variety of post-colonial American English which I believe is of particular interest. I assess the presence of English in Kosrae with reference to sociological influences, past and present. First, I discuss the extralinguistic factors which have shaped the English that is currently used on Kosrae, including migration between US and FSM, and English as a language of administration, social media usage and visual media presence. Secondly, I assess the use of English in this community in light of Schneider’s (2007) ‘Dynamic Model’, with reference to America’s contribution as an ‘exploitation colony’ as defined by Mufwene (2001). Finally, an overview of the salient linguistic characteristics of Kosraean English, based on the data collected will be presented and compared to features associated with standard American English in view of examining overlap and divergence. The overall objective is to present a cross-linguistic description of a hitherto unexamined English emerging in a postcolonial environment with a juxtaposed contact variety. Mufwene, Salikoko S. 2001. The ecology of language evolution. Cambridge: Cambridge University Press. Schneider, E. (2007). Postcolonial Englishes. Cambridge: Cambridge University Press. Segal, H.G. (1989) Kosrae, The Sleeping Lady Awakens. Kosrae: Kosrae Tourist Division, Dept. Of Conservation and Development. Keywords: American English, Global English, Pacific English, Morphosyntactic, Phonological, Variation, Discourse

The timing of extraction of non-restorable first permanent molars: a systematic review.

AIM To identify the ideal timing of first permanent molar extraction to reduce the future need for orthodontic treatment. MATERIALS AND METHODS A computerised database and subsequent manual search was performed using Medline database, Embase and Ovid, covering the period from January 1946 to February 2013. Two reviewers (JE and ME) extracted the data independently and evaluated if the studies matched the inclusion criteria. Inclusion criteria were specification of the follow-up with clinical examination or analysis of models, specification of the chronological age or dental developmental stage at the time of extraction, no treatment in between, classification of the treatment result into perfect, good, average and poor. The search was limited to human studies and no language limitations were set. RESULTS The search strategy resulted in 18 full-text articles, of which 6 met the inclusion criteria. By pooling the data from maxillary sites, good to perfect clinical outcome was estimated in 72% (95% confidence interval 63%-82%). Extractions at the age of 8-10.5 years tended to show better spontaneous clinical outcomes compared to the other age groups. By pooling the data from mandibular sites, extractions performed at the age of 8-10.5 and 10.5-11.5 years showed significantly superior spontaneous clinical outcome with a probability of 50% and 59% likelihood, respectively, to achieve good to perfect clinical result (p<0.05) compared to the other age groups (<8 years of age: 34%, >11.5 years of age: 44%). CONCLUSION Prevention of complications after first permanent molars extractions is an important issue. The overall success rate of spontaneous clinical outcome for maxillary extraction of first permanent molars was superior to mandibular extraction. Extractions of mandibular first permanent molars should be performed between 8 and 11.5 years of age in order to achieve a good spontaneous clinical outcome. For the extraction in the maxilla, no firm conclusions concerning the ideal extraction timing could be drawn.

Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06)

BACKGROUND Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer (mCRC) patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after completing first-line chemotherapy. PATIENTS AND METHODS In an open-label, phase III multicentre trial, patients with mCRC without disease progression after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned to continuing bevacizumab at a standard dose or no treatment. CT scans were done every 6 weeks until disease progression. The primary end point was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significance level of 10% and a statistical power of 85%. RESULTS The intention-to-treat population comprised 262 patients: median follow-up was 36.7 months. The median TTP was 4.1 [95% confidence interval (CI) 3.1-5.4] months for bevacizumab continuation versus 2.9 (95% CI 2.8-3.8) months for no continuation; HR 0.74 (95% CI 0.58-0.96). Non-inferiority could not be demonstrated. The median overall survival was 25.4 months for bevacizumab continuation versus 23.8 months (HR 0.83; 95% CI 0.63-1.1; P = 0.2) for no continuation. Severe adverse events were uncommon in the bevacizumab continuation arm. Costs for bevacizumab continuation were estimated to be ∼30,000 USD per patient. CONCLUSIONS Non-inferiority could not be demonstrated for treatment holidays versus continuing bevacizumab monotheray, after 4-6 months of standard first-line chemotherapy plus bevacizumab. Based on no impact on overall survival and increased treatment costs, bevacizumab as a single agent is of no meaningful therapeutic value. More efficient treatment approaches are needed to maintain control of stabilized disease following induction therapy. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, number NCT00544700.

Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial

BACKGROUND One of the standard options in the treatment of stage IIIA/N2 non-small-cell lung cancer is neoadjuvant chemotherapy and surgery. We did a randomised trial to investigate whether the addition of neoadjuvant radiotherapy improves outcomes. METHODS We enrolled patients in 23 centres in Switzerland, Germany and Serbia. Eligible patients had pathologically proven, stage IIIA/N2 non-small-cell lung cancer and were randomly assigned to treatment groups in a 1:1 ratio. Those in the chemoradiotherapy group received three cycles of neoadjuvant chemotherapy (100 mg/m(2) cisplatin and 85 mg/m(2) docetaxel) followed by radiotherapy with 44 Gy in 22 fractions over 3 weeks, and those in the control group received neoadjuvant chemotherapy alone. All patients were scheduled to undergo surgery. Randomisation was stratified by centre, mediastinal bulk (less than 5 cm vs 5 cm or more), and weight loss (5% or more vs less than 5% in the previous 6 months). The primary endpoint was event-free survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030771. FINDINGS From 2001 to 2012, 232 patients were enrolled, of whom 117 were allocated to the chemoradiotherapy group and 115 to the chemotherapy group. Median event-free survival was similar in the two groups at 12·8 months (95% CI 9·7-22·9) in the chemoradiotherapy group and 11·6 months (8·4-15·2) in the chemotherapy group (p=0·67). Median overall survival was 37·1 months (95% CI 22·6-50·0) with radiotherapy, compared with 26·2 months (19·9-52·1) in the control group. Chemotherapy-related toxic effects were reported in most patients, but 91% of patients completed three cycles of chemotherapy. Radiotherapy-induced grade 3 dysphagia was seen in seven (7%) patients. Three patients died in the control group within 30 days after surgery. INTERPRETATION Radiotherapy did not add any benefit to induction chemotherapy followed by surgery. We suggest that one definitive local treatment modality combined with neoadjuvant chemotherapy is adequate to treat resectable stage IIIA/N2 non-small-cell lung cancer. FUNDING Swiss State Secretariat for Education, Research and Innovation (SERI), Swiss Cancer League, and Sanofi.

Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics.

BACKGROUND Endometriosis, the growth of endometrial tissue outside the uterine cavity, is associated with chronic pelvic pain, subfertility and an increased risk of ovarian cancer. Current treatments include the surgical removal of the lesions or the induction of a hypoestrogenic state. However, a reappearance of the lesion after surgery is common and a hypoestrogenic state is less than optimal for women of reproductive age. Additional approaches are required. Endometriosis lesions exist in a unique microenvironment characterized by increased concentrations of hormones, inflammation, oxidative stress and iron. This environment influences cell survival through the binding of membrane receptors and a subsequent cascading activation of intracellular kinases that stimulate a cellular response. Many of these kinase signalling pathways are constitutively activated in endometriosis. These pathways are being investigated as therapeutic targets in other diseases and thus may also represent a target for endometriosis treatment. METHODS To identify relevant English language studies published up to 2015 on kinase signalling pathways in endometriosis, we searched the Pubmed database using the following search terms in various combinations; 'endometriosis', 'inflammation', 'oxidative stress', 'iron', 'kinase', 'NF kappa', 'mTOR', 'MAPK' 'p38', 'JNK', 'ERK' 'estrogen' and progesterone'. Further citing references were identified using the Scopus database and finally current clinical trials were searched on the clinicaltrials.gov trial registry. RESULTS The current literature on intracellular kinases activated by the endometriotic environment can be summarized into three main pathways that could be targeted for treatments: the canonical IKKβ/NFκB pathway, the MAPK pathways (ERK1/2, p38 and JNK) and the PI3K/AKT/mTOR pathway. A number of pharmaceutical compounds that target these pathways have been successfully trialled in in vitro and animal models of endometriosis, although they have not yet proceeded to clinical trials. The current generation of kinase inhibitors carry a potential for adverse side effects. CONCLUSIONS Kinase signalling pathways represent viable targets for endometriosis treatment. At present, however, further improvements in clinical efficacy and the profile of adverse effects are required before these compounds can be useful for long-term endometriosis treatment. A better understanding of the molecular activity of these kinases, including the specific extracellular compounds that lead to their activation in endometriotic cells specifically should facilitate their improvement and could potentially lead to new, non-hormonal treatments of endometriosis.