The proliferation of life on earth is based on the ability of single cells to divide into two daughter cells. During cell division, the plasma membrane undergoes a series of morphological ...transformations which ultimately lead to membrane fission. Here, we show that analogous remodeling processes can be induced by low densities of proteins bound to the membranes of cell-sized lipid vesicles. Using His-tagged fluorescent proteins, we are able to precisely control the spontaneous curvature of the vesicle membranes. By fine-tuning this curvature, we obtain dumbbell-shaped vesicles with closed membrane necks as well as neck fission and complete vesicle division. Our results demonstrate that the spontaneous curvature generates constriction forces around the membrane necks and that these forces can easily cover the force range found in vivo. Our approach involves only one species of membrane-bound proteins at low densities, thereby providing a simple and extendible module for bottom-up synthetic biology.
Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment with vincristine, etoposide, ...prednisone, and doxorubicin (OEPA) followed by cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) and radiotherapy, but long-term treatment effects affect survival and quality of life. We aimed to investigate whether radiotherapy can be omitted in patients with morphological and metabolic adequate response to OEPA and whether modified consolidation chemotherapy reduces gonadotoxicity.
Our study was designed as a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial, and was carried out at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed intermediate-stage (treatment group 2) and advanced-stage (treatment group 3) classical Hodgkin lymphoma who were younger than 18 years and stratified according to risk using Ann Arbor disease stages IIAE, IIB, IIBE, IIIA, IIIAE, IIIB, IIIBE, and all stages IV (A, B, AE, and BE) were included in the study. Patients with early disease (treatment group 1) were excluded from this analysis. All patients were treated with two cycles of OEPA (1·5 mg/m2 vincristine taken intravenously capped at 2 mg, on days 1, 8, and 15; 125 mg/m2 etoposide taken intravenously on days 1–5; 60 mg/m2 prednisone taken orally on days 1–15; and 40 mg/m2 doxorubicin taken intravenously on days 1 and 15). Patients were randomly assigned to two (treatment group 2) or four (treatment group 3) cycles of COPP (500 mg/m2 cyclophosphamide taken intravenously on days 1 and 8; 1·5 mg/m2 vincristine taken intravenously capped at 2 mg, on days 1 and 8; 40 mg/m2 prednisone taken orally on days 1 to 15; and 100 mg/m2 procarbazine taken orally on days 1 to 15) or COPDAC, which was identical to COPP except that 250 mg/m2 dacarbazine administered intravenously on days 1 to 3 replaced procarbazine. The method of randomisation (1:1) was minimisation with stochastic component and was centrally stratified by treatment group, country, trial sites, and sex. The primary endpoint was event-free survival, defined as time from treatment start until the first of the following events: death from any cause, progression or relapse of classical Hodgkin lymphoma, or occurrence of secondary malignancy. The primary objectives were maintaining 90% event-free survival at 5 years in patients with adequate response to OEPA treated without radiotherapy and to exclude a decrease of 8% in event-free survival at 5 years in the embedded COPDAC versus COPP randomisation to show non-inferiority of COPDAC. Efficacy analyses are reported per protocol and safety in the intention-to-treat population. The trial is registered with ClinicalTrials.gov (trial number NCT00433459) and EUDRACT (trial number 2006-000995-33), and is closed to recruitment.
Between Jan 31, 2007, and Jan 30, 2013, 2102 patients were recruited. 737 (35%) of the 2102 recruited patients were in treatment group 1 (early-stage disease) and were not included in our analysis. 1365 (65%) of the 2102 patients were in treatment group 2 (intermediate-stage disease; n=455) and treatment group 3 (advanced-stage disease; n=910). Of these 1365, 1287 (94%) patients (435 34% of 1287 in treatment group 2 and 852 66% of 1287 in treatment group 3) were included in the titration trial per-protocol analysis. 937 (69%) of 1365 patients were randomly assigned to COPP (n=471) or COPDAC (n=466) in the embedded trial. Median follow-up was 66·5 months (IQR 62·7–71·7). Of 1287 patients in the per-protocol group, 514 (40%) had an adequate response to treatment and were not treated with radiotherapy (215 49% of 435 in treatment group 2 and 299 35% of 852 in treatment group 3). 773 (60%) of 1287 patients with inadequate response were scheduled for radiotherapy (220 51% of 435 in the treatment group 2 and 553 65% of 852 in treatment group 3. In patients who responded adequately, event-free survival rates at 5 years were 90·1% (95% CI 87·5–92·7). event-free survival rates at 5 years in 892 patients who were randomly assigned to treatment and analysed per protocol were 89·9% (95% CI 87·1–92·8) for COPP (n=444) versus 86·1% (82·9–89·4) for COPDAC (n=448). The COPDAC minus COPP difference in event-free survival at 5 years was −3·7% (−8·0 to 0·6). The most common grade 3–4 adverse events (intention-to-treat population) were decreased haemoglobin (205 15% of 1365 patients during OEPA vs 37 7% of 528 treated with COPP vs 20 2% of 819 treated with COPDAC), decreased white blood cells (815 60% vs 231 44% vs 84 10%), and decreased neutrophils (1160 85% vs 223 42% vs 174 21%). One patient in treatment group 2 died of sepsis after the first cycle of OEPA; no other treatment-related deaths occurred.
Our results show that radiotherapy can be omitted in patients who adequately respond to treatment, when consolidated with COPP or COPDAC. COPDAC might be less effective, but is substantially less gonadotoxic than COPP. A high proportion of patients could therefore be spared radiotherapy, eventually reducing the late effects of treatment. With more refined criteria for response assessment, the number of patients who receive radiotherapy will be further decreased.
Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder Gießen, Kinderkrebsstiftung Mainz, Tour der Hoffnung, Menschen für Kinder, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Decorating GUVs, used as minimal synthetic cell models, with photoswitchable proteins allows controlling the adhesion between them and their assembly into multicellular structures with light. ...Thereby, the chemical communication between a sender and a receiver GUV, which strongly depends on their spatial proximity, can also be photoregulated.
Light controlled adhesions between sender and receiver GUVs, used as minimal synthetic cells, photoregulates their spatial proximity and chemical communication.
Homoepitaxy provides an ideal testing ground for fundamental concepts in film growth. The rich variety of complex far-from-equilibrium morphologies which can form during deposition contrasts with the ...simple equilibrium structure of homoepitaxial films. These complex morphologies result from the inhibition on the time-scale of deposition of various equilibrating surface diffusion processes. A sophisticated framework for analysis of such phenomena derives from the concepts and methodology of Statistical Physics. Kinetic Monte Carlo (KMC) simulation of suitable atomistic lattice–gas models has elucidated the growth behavior of numerous specific systems. In this review, we describe in detail
submonolayer nucleation and growth of two-dimensional islands during deposition. The traditional mean-field treatment is quite successful in capturing the behavior of mean island densities, but it fails to predict island size distributions. The latter are provided by simulation of appropriate atomistic models, as well as by suitable hybrid models. Recent developments towards providing reliable analytic beyond-mean-field theories are also discussed.
Kinetic roughening of multilayer films during deposition is also described with particular emphasis on the formation of mounds (multilayer stacks of 2D islands) induced by step-edge barriers to downward transport. We describe results for mound evolution from realistic atomistic simulations, predictions of phenomenological continuum theories, and efforts to derive more reliable coarse-grained formulations. For both regimes, we demonstrate how atomistic modeling can be used extract key activation barriers by comparison with experimental data from scanning tunneling microscopy and surface sensitive diffraction. Significantly, suitable tailored atomistic models are often shown to have predictive capability for growth over a broad range of temperatures. Finally, we comment briefly on other deposition processes such as heteroepitaxial growth and chemisorption.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background Previously, we assessed selective digestive tract decontamination (SDD) and selective oropharyngeal decontamination (SOD) on survival and prevention of bacteraemia in patients in ...intensive-care units. In this analysis, we aimed to assess effectiveness of these interventions for prevention of respiratory tract colonisation and bacteraemia with highly resistant microorganisms acquired in intensive-care units. Methods We did an open-label, clustered group-randomised, crossover study in 13 intensive-care units in the Netherlands between May, 2004, and July, 2006. Participants admitted to intensive-care units with an expected duration of mechanical ventilation of more than 48 h or an expected stay of more than 72 h received SOD (topical tobramycin, colistin, and amphotericin B in the oropharynx), SDD (SOD antibiotics in the oropharynx and stomach plus 4 days' intravenous cefotaxime), or standard care. The computer-randomised order of study regimens was applied by an independent clinical pharmacist who was masked to intensive-care-unit identity. We calculated crude odds ratios (95% CI) for rates of bacteraemia or respiratory tract colonisation with highly resistant microorganisms in patients who stayed in intensive-care units for more than 3 days (ie, acquired infection). This trial is registered at http://isrctn.org , number ISRCTN35176830. Findings Data were available for 5927 (>99%) of 5939 patients, of whom 5463 (92%) were in intensive-care units for more than 3 days. 239 (13%) of 1837 patients in standard care acquired bacteraemia after 3 days, compared with 158 (9%) of 1758 in SOD (odds ratio 0·66, 95% CI 0·53–0·82), and 124 (7%) of 1868 in SDD (0·48, 0·38–0·60). Eight patients acquired bacteraemia with highly resistant microorganisms during SDD, compared with 18 patients (with 19 episodes) during standard care (0·41, 0·18–0·94; rate reduction RR 59%, absolute risk reduction ARR 0·6%) and 20 during SOD (0·37, 0·16–0·85; RR 63%, ARR 0·7%). Of the patients staying in intensive-care units for more than 3 days, we obtained endotracheal aspirate cultures for 881 (49%) patients receiving standard care, 886 (50%) receiving SOD, and 828 (44%) receiving SDD. 128 (15%) patients acquired respiratory tract colonisation with highly resistant microorganisms during standard care, compared with 74 (8%) during SDD (0·58, 0·43–0·78; RR 38%, ARR 5·5%) and 88 (10%) during SOD (0·65, 0·49–0·87; RR 32%, ARR 4·6%). Acquired respiratory tract colonisation with Gram-negative bacteria or cefotaxime-resistant and colistin-resistant pathogens was lowest during SDD. Interpretation Widespread use of SDD and SOD in intensive-care units with low levels of antibiotic resistance is justified. Funding None.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Children and adolescents with early-stage classical Hodgkin lymphoma have a 5-year event-free survival of 90% or more with vincristine, etoposide, prednisone, and doxorubicin (OEPA) plus ...radiotherapy, but late complications of treatment affect survival and quality of life. We investigated whether radiotherapy can be omitted in patients with adequate morphological and metabolic responses to OEPA.
The EuroNet-PHL-C1 trial was designed as a titration study and recruited patients at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed stage IA, IB, and IIA classical Hodgkin lymphoma younger than 18 years of age were assigned to treatment group 1 to be treated with two cycles of OEPA (vincristine 1·5 mg/m2 intravenously, capped at 2 mg, on days 1, 8, and 15; etoposide 125 mg/m2 intravenously, on days 1–5; prednisone 60 mg/m2 orally on days 1–15; and doxorubicin 40 mg/m2 intravenously on days 1 and 15). If no adequate response (a partial morphological remission or greater and PET negativity) had been achieved after two cycles of OEPA, involved-field radiotherapy was administered at a total dose of 19·8 Gy (usually in 11 fractions of 1·8 Gy per day). The primary endpoint was event-free survival. The primary objective was maintaining a 5-year event-free survival rate of 90% in patients with an adequate response to OEPA without radiotherapy. We performed intention-to-treat and per-protocol analyses. The trial was registered at ClinicalTrials.gov (NCT00433459) and with EUDRACT, (2006–000995-33) and is completed.
Between Jan 31, 2007, and Jan 30, 2013, 2131 patients were registered and 2102 patients were enrolled onto EuroNet-PHL-C1. Of these 2102 patients, 738 with early-stage disease were allocated to treatment group 1. Median follow-up was 63·3 months (IQR 60·1–69·8). We report on 714 patients assigned to and treated on treatment group 1; the intention-to-treat population comprised 713 patients with 323 (45%) male and 390 (55%) female patients. In 440 of 713 patients in the intention-to-treat group who had an adequate response and did not receive radiotherapy, 5-year event-free survival was 86·5% (95% CI 83·3–89·8), which was less than the 90% target rate. In 273 patients with an inadequate response who received radiotherapy, 5-year event-free survival was 88·6% (95% CI 84·8–92·5), for which the 95% CI included the 90% target rate. The most common grade 3–4 adverse events were neutropenia (in 597 88% of 680 patients) and leukopenia (437 61% of 712). There were no treatment-related deaths.
On the basis of all the evidence, radiotherapy could be omitted in patients with early-stage classical Hodgkin lymphoma and an adequate response to OEPA, but patients with risk factors might need more intensive treatment.
Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder, Gießen, Kinderkrebsstiftung Mainz of the Journal Oldtimer Markt, Tour der Hoffnung, Menschen für Kinder, Mitteldeutsche Kinderkrebsforschung, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
F-FDG PET/MRI might be the diagnostic method of choice for Hodgkin lymphoma patients, as it combines significant metabolic information from PET with excellent soft-tissue contrast from MRI and avoids ...radiation exposure from CT. However, a major issue is longer examination times than for PET/CT, especially for younger children needing anesthesia. Thus, a targeted selection of suitable whole-body MRI sequences is important to optimize the PET/MRI workflow.
The initial PET/MRI scans of 84 EuroNet-PHL-C2 study patients from 13 international PET centers were evaluated. In each available MRI sequence, 5 PET-positive lymph nodes were assessed. If extranodal involvement occurred, 2 splenic lesions, 2 skeletal lesions, and 2 lung lesions were also assessed. A detection rate was calculated dividing the number of visible, anatomically assignable, and measurable lesions in the respective MRI sequence by the total number of lesions.
Relaxation time-weighted (T2w) transverse sequences with fat saturation (fs) yielded the best result, with detection rates of 95% for nodal lesions, 62% for splenic lesions, 94% for skeletal lesions, and 83% for lung lesions, followed by T2w transverse sequences without fs (86%, 49%, 16%, and 59%, respectively) and longitudinal relaxation time-weighted contrast-enhanced transverse sequences with fs (74%, 35%, 57%, and 55%, respectively).
T2w transverse sequences with fs yielded the highest detection rates and are well suited for accurate whole-body PET/MRI in lymphoma patients. There is no evidence to recommend the use of contrast agents.
Abstract
Background
Appropriate use of available inpatient beds is an ongoing challenge for US hospitals. Historical capacity goals of 80% to 85% may no longer serve the intended purpose of ...maximizing the resources of space, staff, and equipment. Numerous variables affect the input, throughput, and output of a hospital. Some of these variables include patient demand, regulatory requirements, coordination of patient flow between various systems, coordination of processes such as bed management and patient transfers, and the diversity of departments (both inpatient and outpatient) in an organization.
Methods
Mayo Clinic Health System in the Southwest Minnesota region of the US, a community-based hospital system primarily serving patients in rural southwestern Minnesota and part of Iowa, consists of 2 postacute care and 3 critical access hospitals. Our inpatient bed usage rates had exceeded 85%, and patient transfers from the region to other hospitals in the state (including Mayo Clinic in Rochester, Minnesota) had increased. To address these quality gaps, we used a blend of Agile project management methodology, rapid Plan-Do-Study-Act cycles, and a proactive approach to patient placement in the medical-surgical units as a quality improvement initiative.
Results
During 2 trial periods of the initiative, the main hub hospital (Mayo Clinic Health System hospital in Mankato) and other hospitals in the region increased inpatient bed usage while reducing total out-of-region transfers.
Conclusion
Our novel approach to proactively managing bed capacity in the hospital allowed the region’s only tertiary medical center to increase capacity for more complex and acute cases by optimizing the use of historically underused partner hospital beds.
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CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The fatigue behaviour of two glass fibre-reinforced epoxy composite materials with a cross-ply layup is investigated in the very high cycle fatigue (VHCF) regime with up to
10
8
load cycles. In ...addition to the influence on the fatigue lifetime, different materials can also cause a different damage phenomenology. One reference fibre (OC111A) and one fibre with increased fibre–matrix adhesion (SE2020) are tested. The experimental and numerical investigations show that the damage threshold is shifted to higher loads with increased fibre–matrix adhesion, but the damage mode of delaminations becomes more important.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In this paper, we introduce a variational integrator for higher order finite element models. The solution quality of finite element simulation strongly depends on the approximation in time and space. ...A variational integrator is robust due to conservation of both the balance of total linear momentum and the balance of total angular momentum. It also binds the error in the balance of total energy. We extend the variational integrator to an integrator that conserves the balance of total energy as well. However, the approximation in time cannot mend the approximation error in space. Therefore, we use a higher order approximation in space to obtain a better solution compared to the real live model that should be simulated. We show different numerical examples with Dirichlet and Neumann boundaries. For the Dirichlet boundaries we use the Lagrange multiplier method and for the Neumann boundaries we introduce the forces on the nodes by constant pressure.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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