The mechanisms of drug–receptor interactions and the controlled delivery of drugs via biodegradable and biocompatible nanoparticulate carriers are active research fields in nanomedicine. Many ...clinically used drugs target G-protein coupled receptors (GPCRs) due to the fact that signaling via GPCRs is crucial in physiological and pathological processes and thus central for the function of biological systems. In this letter, a fast and reliable ratiometric fluorescence lifetime imaging microscopy (rmFLIM) approach is described to analyze the distribution of protein–ligand complexes in the cellular context. Binding of the fluorescently labeled antagonist naloxone to the G-protein coupled μ-opioid receptor is used as an example. To show the broad applicability of the rmFLIM method, we extended this approach to investigate the distribution of polymer-based nanocarriers in histological liver sections.
The history and current status of suture techniques to correct a broad or bulbous nasal tip are reviewed. General principles for suture techniques to control tip shape are discussed; they include ...leaving an approximately 6-mm-wide lateral crus. The algorithm presented includes four sutures, all of which are not necessary in every case. These sutures include (1) the transdomal suture (to narrow the individual domes), (2) the interdomal suture (to provide symmetry and tip strength and sometimes to narrow the tip complex), (3) the lateral crural mattress suture (to reduce lateral crural convexity), and (4) the columella-septal suture (to prevent tip drop and adjust tip projection). The lateral crural mattress suture is the newest of these sutures. It specifically controls undesirable convexity of the lateral crus. The four-suture algorithm is principally designed for primary open rhinoplasties. However, it is also recommended for secondary rhinoplasties. A minor modification is suggested for use in closed rhinoplasties. The algorithm is intended to reduce the difficulty of determining which of the currently available rhinoplasty sutures are useful and in what order they should be used. Illustrative cases are provided. The advantages and disadvantages of this particular algorithm, compared with others that have been proposed, are also reviewed.
Improved lifetime of microchannel-plate PMTs Lehmann, A.; Britting, A.; Eyrich, W. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
12/2014, Letnik:
766
Journal Article
Recenzirano
The charged particle identification at the PANDA experiment will be mainly performed with DIRC detectors. Because of their advantageous properties the preferred photon sensors are MCP-PMTs. However, ...until recently these devices showed serious aging problems which resulted in a diminishing quantum efficiency (QE) of the photo cathode. By applying innovative countermeasures against the aging causes, the manufacturers recently succeeded in drastically improving the lifetime of MCP-PMTs. Especially the application of an ALD coating technique to seal the material of the micro-channels proves very powerful and results in a lifetime of approximately 6C/cm2 integrated anode charge without a substantial QE degradation for the latest PHOTONIS XP85112. This paper will present a comparative measurement of the lifetime of several older and recent MCP-PMTs demonstrating this progress.
Iron storage diseases are rare conditions of dysregulated iron metabolism in man and animals. A genetic basis has been confirmed only for human haemochromatosis. Iron storage disease was diagnosed in ...six related, 2-year-old male red deer of the same herd. These animals presented with weight loss and rough hair coats. Haematological examination was unremarkable. At necropsy examination, gross lesions were restricted to cachexia. Microscopical examination revealed severe, diffuse hepatocellular necrosis and iron accumulation in hepatocytes, Kupffer cells, cardiac myocytes and renal tubular cells in all affected animals. Four animals also had moderate bridging fibrosis in the liver. Hepatic iron concentrations were increased (1108–2275
mg/kg wet weight; reference range 100–200
mg/kg). Drinking water in rusty iron tubs in the deer park contained eight times more iron than the accepted level for human drinking water. To test for a possible genetic basis of increased iron uptake and storage in red deer, the cervid haemochromatosis gene (
HFE) was identified. Sequence comparisons between the six diseased animals and three healthy free-ranging unrelated animals failed to identify differences in the
HFE sequences. Furthermore, the disease was not associated with common amino acid substitutions reported in human patients with haemochromatosis, including C282Y and H63D. Polymorphisms in other non-
HFE genes involved in iron metabolism may have led to a higher sensitivity to iron and this, together with the high iron content of the drinking water, may have been the cause of the observed iron storage in these red deer.
Anomalous Aortic Origin of a Coronary Artery Poynter, Jeffrey A.; Williams, William G.; McIntyre, Susan ...
World journal for pediatric & congenital heart surgery,
01/2014, Letnik:
5, Številka:
1
Journal Article
Recenzirano
Background:Anomalous aortic origin of a coronary artery (AAOCA) is a common congenital heart lesion that may be rarely associated with myocardial ischemia and sudden death in the young. ...Evidence-based criteria for managing young patients with AAOCA are lacking. The Congenital Heart Surgeons Society (CHSS) established a multicenter registry of patients with AAOCA aged ≤30 years to develop these criteria.Methods:All institutional members of the CHSS are eligible to enroll patients. Patients were enrolled retrospectively if diagnosis of AAOCA occurred between January 1, 1998, and January 20, 2009, and prospectively from January 20, 2009 forward. The first phase of analysis explored possible associations between demographics, symptoms, coronary anatomy, and management using correlation analysis and logistic regression.Results:As of June 2012, 198 patients were enrolled from CHSS member institutions (median age at diagnosis = 10.2 years; 64% male). Data were extracted from clinical records. Fifty-four percent were symptomatic at presentation (most commonly chest pain, N = 78). The AAOCA was diagnosed at autopsy in two patients who presented with sudden death (one with anomalous aortic origin of the left coronary artery AAOLCA; one with a single ostium above a commissure giving rise to both left and right coronary arteries). Imaging reports documented anomalous aortic origin of the right coronary artery (AAORCA) in 144 patients, AAOLCA in 51 patients, and AAOLCA/AAORCA in 1 patient. Surgery or autopsy without surgery was performed in 106 patients (71 AAORCA 67%; 31 AAOLCA 29%; and 4 AAORCA/AAOLCA 4%) at a median age of 12.6 years. Overall, 52% of patients with AAORCA versus 67% with AAOLCA had surgery. Most surgical operative reports described an intramural segment of the coronary artery with anomalous origin. Surgery correlated with symptoms, older age, and presence of an intramural segment in the setting of AAOLCA.Conclusions:Management decisions, including surgical referral, are associated with patient symptoms and coronary morphology. Information derived from annual follow-up of surgically and nonsurgically managed patients enrolled in the registry will eventually form the basis for development of evidence-based protocols to address the spectrum of risk and inform clinical decision making in this heterogeneous population of young patients.
Highlights • All admitted patients from 10 independent Point Prevalence Surveys (PPS). • Actual direct healthcare costs were calculated, not templates, nor estimates. • The 30-days Follow-up showed ...more re-admissions in the group with HAI. • Patients with HAI had a greater portion of bed days and costs than average. • Patients with HAI had a higher one year mortality rate than other patients.
Introduction
We previously reported the results of the phase III randomized HOVON-87/NMSG-18 study for Newly Diagnosed Multiple Myeloma patients not eligible for stem cell transplantation (nte-NDMM). ...The efficacy of melphalan, prednisolone and either thalidomide followed by thalidomide maintenance (MPT-T) versus lenalidomide followed by lenalidomide maintenance (MPR-R) was found to be comparable, being consistent across subgroups defined by age, cytogenetic risk and ISS 1. As frailty is known to affect clinical outcome, we investigated the impact of frailty on outcome.
Methods
Frailty was assessed by a modification of the IMWG frailty score based on age, the Charlson Comorbidity Index (retrospectively retrieved from the list of comorbidities that were present at entry) and the WHO performance as a proxy for (instrumental) Activities of Daily Living ((i)ADL). To assess the effect of frailty on progression free survival (PFS) and OS, the logrank test was used, while the chi-squared test was used to evaluate the association of frailty with discontinuation rate and toxicity.
Results
All 637 eligible patients from the HOVON-87/NMSG-18 trial were included in the analysis. Median age was 73 years; 66% of patients were ≤ 75 years, 24% were 76-80 years and 10% were > 80 years. A CCI of 0, 1, 2 and ≥3 was found in 61, 20, 7 and 4% of patients respectively (8% unknown). The most common comorbidities were diabetes mellitus without end organ complications (12%) and myocardial infarction (6%). A WHO performance of 0, 1 and ≥ 2 was observed in 35, 47 and 16% respectively (3% unknown).
Univariate analyses showed that older age (>80 years: HR 1.59 95% CI 1.12-2.25), a higher CCI (CCI ≥2: HR 1.41 95% CI 1.01-1.95); and a poor WHO performance (WHO ≥2: HR 2.05 1.49-2.82) were associated with an inferior OS. HR's were 1.07 95% CI 0.82-1.40 and 1.27 95% CI 0.98-1.65 for age 76-80 years and WHO performance respectively. For age and the CCI the IMWG frailty score classification was used. For the WHO, scores were assigned based on the HR: WHO 0; 0 points, WHO 1; 1 point and WHO ≥2; 2 points. Fit patients were defined as a proxy frailty score of 0, unfit as a score of 1 and frail as a score of ≥2, comparable to the IMWG frailty score.
Using this modified IMWG frailty score, 135 patients were fit (21%), 199 were unfit (31%) and 259 were frail (41%) (7% unknown). The median OS was found to be significantly different in fit versus unfit versus frail patients; 58, 55 and 46 months respectively (p=0.004). In contrast no significant difference in median PFS was found; 26, 20 and 21 months respectively (p=0.30).
The inferior OS for the frail might be partly explained by higher discontinuation rate of induction therapy; 50%, versus 43% in unfit, and 34% in fit patients (p=0.011), being mainly due to excessive toxicity (25, 23 and 16% respectively). The cumulative incidence of treatment discontinuation on protocol (induction plus maintenance), corrected for death and progressive disease which were considered as competing risks, is depicted in figure 1B. Discontinuation rate at 2 years for fit, unfit, and frail patients were 48%, 48%, and 59% respectively (p=0.06). There were significantly more grade ≥3 adverse events on protocol in frail and unfit patients (both 86%) as compared to fit patients (77%, p=0.039). Especially more grade ≥3 infections were found in frail (28% versus 18% in unfit and 13% in fit). In contrast, frailty was not associated with hematological toxicity.
Conclusion
We here present a modified frailty score, using the WHO performance instead of the (i)ADL, combined with age and the CCI, that enables the identification of frail MM patients with an inferior OS, a higher discontinuation rate and a higher rate of grade ≥ 3 toxicity. This non-laborious modified frailty score can be easily implemented in clinical trials and allows to compare the outcome of frail patients in nte-NDMM trials, which will hopefully result in frailty-adapted therapy in clinical daily practice.
Reference:
1. Zweegman S, Holt vd B, Mellqvist U, et al. Blood 2016;127(9):1109-16
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Mellqvist:Celgene: Honoraria; janssen: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Sandoz: Other: participation advisory board; Amgen: Honoraria, Other: participation advisory board. Abildgaard:Takeda: Research Funding. Plesner:Janssen: Research Funding; Janssen, Takeda: Consultancy; Janssen, Genmab: Membership on an entity's Board of Directors or advisory committees. Van De Donk:Janssen, Celgene, Bristol-Myers Squibb, Amgen: Research Funding. Sonneveld:Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding; Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria; Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy. Waage:Celgene, Takeda: Honoraria. Zweegman:Celgene: Other: advisory board participation, Research Funding; Janssen: Other: advisory board participation, Research Funding; Takeda: Other: advisory board participation, Research Funding; Amgen: Other: advisory board participation.
Pionic hydrogen and deuterium Gotta, D.; Amaro, F.D.; Anagnostopoulos, D.F. ...
EPJ Web of conferences,
2022, Letnik:
262
Journal Article
Recenzirano
Odprti dostop
The strong-interaction effects both in pionic hydrogen and deuterium atoms have been re-determined with improved precision. The hadronic shift and width in pionic hydrogen together with the hadronic ...shift in pionic deuterium constitute a one-fold constraint for the two independent pion-nucleon scattering lengths. Furthermore, the hadronic width in pionic deuterium measures the transition strength of s-wave pions on an isoscalar nucleon-nucleon pair which is an independent quantity not related to the pion-nucleon scattering lengths. The experiment was performed at the Paul Scherrer Institute by stopping a high-intensity low-energy pion beam in gaseous targets using the cyclotron trap. The X-rays emitted by the πH and πD atoms were analysed with a high resolution Bragg spectrometer equipped with spherically bent crystals. The pion-nucleon scattering lengths and other physical quantities extracted from the atom data are in good agreement with the results obtained from pionnucleon and nucleon-nucleon scattering experiments and confirm that a consistent picture is achieved for the low-energy pion-nucleon sector with respect to the expectations of chiral perturbation theory.
Randomized controlled trials are becoming increasingly difficult to organize and conduct efficiently. This, in turn, hinders the ability to derive the highest level of evidence. Often, investigators ...forget or remain unaware of essential practices that will help them fulfill their study goals. This article emphasizes the common issues that a study team experiences during the planning and conducting of randomized controlled trials. The authors sought to share remedies to overcome these issues with the experience garnered in conducting several multicenter clinical trials and observational studies. In addition, the authors list resources from sponsors such as the National Institutes of Health and the U.S. Food and Drug Administration that study teams can apply to undertake studies effectively.
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