G-Protein-vermittelte Signalwege in der akuten myeloischen Leukämie

Mittels quantitativer PCR wurde die Expression der G-Proteine Galpha12 und Galpha13 und RGS-Proteine RGS2, RGS16 und p115Rho-GEF im Knochenmark von Patienten mit AML untersucht. Dabei zeigte sich in den Patientenproben eine signifikant erniedrigte RGS2-Expression und erhöhte Galpha12- und Galpha13-Expression. Für vier der untersuchten Gene konnte eine Korrelation der Genexpresssion mit dem FAB-Typ gezeigt werden. Beim Vergleich der Genexpressionshöhe zwischen Patienten mit und ohne ITD-Mutationen von Flt3 zeigte sich in der Gruppe mit Mutationen eine signifikant erniedrigte RGS2-Expression. Die Höhe der RGS2- und der RGS16-Expression korrelierte mit der Prognose: Patienten mit hoher RGS2-Expression zeigten ein vermindertes Gesamtüberleben, Patienten mit hoher RGS16-Expression ein vermindertes rezidivfreies Überleben. Diese Ergebnisse zeigen, dass G-Proteine und RGS-Proteine, über deren Rolle in der Hämatopoese bislang wenig bekannt war, in Leukämien vielfältig reguliert sind

Technology Decisions Under Architectural Uncertainty: Informing Investment Decisions Through Tradespace Exploration

Although NASA has yet to choose an architecture for human spaceflight beyond Earth orbit, they must pursue near-term investment in the enabling technologies that will be required for these future systems. Given this architectural uncertainty, it is difficult to define the value proposition of technology investments. This paper proposes a method for evaluating technology across a tradespace defined by architectural decisions. Main effects analysis is taken from design of experiments to quantify the influence that a technology has on the system being considered. This analysis also identifies couplings between technologies that are mutually exclusive or mutually beneficial. This method is applied to the architecture tradespace of transportation for future human exploration at Mars with a set of possible propellant, propulsion, and aerobraking technologies. The paper demonstrates that the evaluation of technologies against an individual reference architecture is flawed when the range of architectures being pursued remains diverse. Furthermore, it is shown that comparisons between fuzzy Pareto optimal architectures and heavily dominated architectures will distort the evaluated benefit of a technology. The resulting tradespace can be structured as the sequence in which technology decisions should be made, in order of their impact on the tradespace and their coupling to other decisions.United States. National Aeronautics and Space Administration (Massachusetts Institute of Technology Research Grant

‘They’re more like ordinary stroppy British women’: Attitudes and expectations of maternity care professionals to UK-born ethnic minority women

Objective To explore the attitudes and expectations of maternity care professionals to UK-born ethnic minority mothers. Methods Qualitative in-depth interviews with 30 professionals from eight NHS maternity units in England that provide services for large proportions of women of black Caribbean, black African, Indian, Pakistani and Irish descent. Results All the professionals reported providing care to both UK-born and migrant mothers from ethnic minorities. Most of them felt that they could differentiate between UK-born and migrant mothers based mainly on language fluency and accent. ‘Westernized dress’ and ‘freedom’ were also cited as indicators. Overall, professionals found it easier to provide services to UK-born mothers and felt that their needs were more like those of white English mothers than those of migrant mothers. UK-born mothers were generally thought to be assertive and expressive, and in control of care-related decision-making whereas some South Asian Muslim women were thought to be constrained by family influences. Preconceived ideas about ethnic minority mothers' tolerance of pain in labour, use of pharmacological pain relief measures and mode of delivery were recurring themes. Women's education and social class were felt to be major influences on the uptake of maternity care, regardless of ethnicity. Conclusions Professionals appeared to equate the needs of UK-born ethnic minority women with those of white English women. Overall, this has positive implications for care provision. Despite this, specific behavioural expectations and unconscious stereotypical views were evident and have the potential to affect clinical practice

General Practitioners' views on the provision of nicotine replacement therapy and bupropion.

BACKGROUND: Nicotine replacement therapies (NRT) and a new drug, bupropion, are licensed in several countries as aids to smoking cessation. General practitioners (GPs) play a crucial role in recommending or prescribing these medications. In the UK there has been discussion about whether the medications should be reimbursable by the National Health Service (NHS). This study assessed English GPs' attitudes towards reimbursement of NRT and bupropion. METHODS: Postal survey of a randomly selected national sample of GPs; 376 GPs completed the questionnaire after one reminder; effective response rate: 53%. There was no difference between the responses of GPs who responded to the initial request and those who responded only after a reminder suggesting minimal bias due to non-response. RESULTS: Attitudes of GPs were remarkably divided on most issues relating to the medications. Forty-three percent thought that bupropion should not be on NHS prescription while 42% thought that it should be (15% did not know); Fifty percent thought that NRT should not be on NHS prescription while 42% thought it should be (8% did not know). Requiring that smokers attend behavioural support programmes to be eligible to receive the medications on NHS prescription made no appreciable difference to the GPs' views. GPs were similarly divided on whether having the medications reimbursable would add unacceptably to their workload or offer a welcome opportunity to discuss smoking with their patients. A principal components analysis of responses to the individual questions on NRT and bupropion revealed that GPs' attitudes could be understood in terms of a single 'pro-con' dimension accounting for 53% of the total variance which made no distinction between the two medications. CONCLUSIONS: GPs in England appear to be divided in their attitudes to medications to aid smoking cessation and appear not to discriminate in their views between different types of medication or different aspects of their use. This suggests that their attitudes are generated by quite fundamental values. Addressing these values may be important in encouraging GPs to adhere more closely to national and international guidelines

Impact of the frequency of online verifications on the patient set-up accuracy and set-up margins

<p>Abstract</p> <p>Purpose</p> <p>The purpose of the study was to evaluate the patient set-up error of different anatomical sites, to estimate the effect of different frequencies of online verifications on the patient set-up accuracy, and to calculate margins to accommodate for the patient set-up error (ICRU set-up margin, SM).</p> <p>Methods and materials</p> <p>Alignment data of 148 patients treated with inversed planned intensity modulated radiotherapy (IMRT) or three-dimensional conformal radiotherapy (3D-CRT) of the head and neck (n = 31), chest (n = 72), abdomen (n = 15), and pelvis (n = 30) were evaluated. The patient set-up accuracy was assessed using orthogonal megavoltage electronic portal images of 2328 fractions of 173 planning target volumes (PTV). In 25 patients, two PTVs were analyzed where the PTVs were located in different anatomical sites and treated in two different radiotherapy courses. The patient set-up error and the corresponding SM were retrospectively determined assuming no online verification, online verification once a week and online verification every other day.</p> <p>Results</p> <p>The SM could be effectively reduced with increasing frequency of online verifications. However, a significant frequency of relevant set-up errors remained even after online verification every other day. For example, residual set-up errors larger than 5 mm were observed on average in 18% to 27% of all fractions of patients treated in the chest, abdomen and pelvis, and in 10% of fractions of patients treated in the head and neck after online verification every other day.</p> <p>Conclusion</p> <p>In patients where high set-up accuracy is desired, daily online verification is highly recommended.</p

COVID-19 Patients Require Prolonged Extracorporeal Membrane Oxygenation Support for Survival Compared With Non-COVID-19 Patients

OBJECTIVES: To investigate the ICU survival of venovenous extracorporeal membrane oxygenation (ECMO) patients suffering from COVID-19–related acute respiratory distress syndrome (ARDS) versus ECMO patients without COVID-19 (non-COVID-19)–related ARDS. DESIGN: Preliminary analysis of data from two prospective ECMO trials and retrospective analysis of a cohort of ARDS ECMO patients. SETTING: Single-center ICU. PATIENTS: Adult ARDS ECMO patients, 16 COVID-19 versus 23 non-COVID-19 patients. Analysis of retrospective data from 346 adult ARDS ECMO patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: COVID-19 and non-COVID-19 ARDS patients did not differ with respect to preexisting disease or body mass index. ICU survival rate was 62% for COVID-19 ECMO patients and 70% for non-COVID-19 ECMO patients. COVID-19 ECMO survivors were supported with ECMO for a median of 43 days (interquartile range [IQR], 18–58 d) versus 16 days (IQR, 19–39 d; p = 0.03) for non-COVID-19 patients. The median duration of ECMO therapy for all ARDS patients between 2007 and 2018 was 15 days (IQR, 6–28 d). The subgroup of patients suffering from any viral pneumonia received ECMO support for a median of 16 days (IQR, 9–27 d), survivors of influenza pneumonia received ECMO support for 13 days (IQR, 7–25 d). CONCLUSIONS: COVID-19 patients required significant longer ECMO support compared with patients without COVID-19 to achieve successful ECMO weaning and ICU survival

Upk3b is dispensable for development and integrity of urothelium and mesothelium

The mesothelium, the lining of the coelomic cavities, and the urothelium, the inner lining of the urinary drainage system, are highly specialized epithelia that protect the underlying tissues from mechanical stress and seal them from the overlying fluid space. The development of these epithelia from simple precursors and the molecular characteristics of the mature tissues are poorly analyzed. Here, we show that uroplakin 3B (Upk3b), which encodes an integral membrane protein of the tetraspanin superfamily, is specifically expressed both in development as well as under homeostatic conditions in adult mice in the mesothelia of the body cavities, i.e., the epicardium and pericardium, the pleura and the peritoneum, and in the urothelium of the urinary tract. To analyze Upk3b function, we generated a creERT2 knock-in allele by homologous recombination in embryonic stem cells. We show that Upk3bcreERT2 represents a null allele despite the lack of creERT2 expression from the mutated locus. Morphological, histological and molecular analyses of Upk3b-deficient mice did not detect changes in differentiation or integrity of the urothelium and the mesothelia that cover internal organs. Upk3b is coexpressed with the closely related Upk3a gene in the urothelium but not in the mesothelium, leaving the possibility of a functional redundancy between the two genes in the urothelium only

Treatment results for hypopharyngeal cancer by different treatment strategies and its secondary primary- an experience in Taiwan

<p>Abstract</p> <p>Purpose</p> <p>The aim of this study was to evaluate treatment results in our hypopharyngeal cancer patients.</p> <p>Patients and Methods</p> <p>A total of three hundred and ninety five hypopharyngeal cancer patients received radical treatment at our hospital; 96% were male. The majority were habitual smokers (88%), alcohol drinkers (73%) and/or betel quid chewers (51%). All patients received a CT scan or MRI for tumor staging before treatment. The stage distribution was stage I: 2 (0.5%); stage II: 22 (5.6%); stage III: 57 (14.4%) and stage IV: 314 (79.5%). Radical surgery was used first in 81 patients (20.5%), and the remaining patients (79.5%) received organ preservation-intended treatment (OPIT). In the OPIT group, 46 patients received radiotherapy alone, 156 patients received chemotherapy followed by radiotherapy (CT/RT) and 112 patients received concomitant chemo-radiotherapy (CCRT).</p> <p>Results</p> <p>The five-year overall survival rates for stages I/II, III and IV were 49.5%, 47.4% and 18.6%, respectively. There was no significant difference in overall and disease-specific survival rates between patients who received radical surgery first and those who received OPIT. In the OPIT group, CCRT tended to preserve the larynx better (p = 0.088), with three-year larynx preservation rates of 44.8% for CCRT and 27.2% for CT/RT. Thirty-seven patients developed a second malignancy, with an annual incidence of 4.6%.</p> <p>Conclusions</p> <p>There was no survival difference between OPIT and radical surgery in hypopharyngeal cancer patients at our hospital. CCRT may offer better laryngeal preservation than RT alone or CT/RT. However, prospective studies are still needed to confirm this finding. Additionally, second primary cancers are another important issue for hypopharyngeal cancer management.</p