Dielectronic satellite spectra of heliumlike argon, recorded with a high-resolution x-ray crystal spectrometer at the National Spherical Torus Experiment, were found to be inconsistent with existing ...predictions resulting in unacceptable values for the power balance and suggesting the unlikely existence of non-Maxwellian electron energy distributions. These problems were resolved with calculations from a new atomic code. It is now possible to perform reliable electron-temperature measurements and to eliminate the uncertainties associated with determinations of non-Maxwellian distributions.
A protocol of a pilot randomised trial Yoong, Sze Lin; Brown, Andrew D; Leung, Gloria K. W ...
PloS one,
05/2024, Letnik:
19, Številka:
5
Journal Article
Recenzirano
Over a quarter of children aged 2-17 years living in Australia are overweight or obese, with a higher prevalence reported in regional and remote communities. Systems thinking approaches that seek to ...support communities to generate and implement locally appropriate solutions targeting intertwined environmental, political, sociocultural, and individual determinants of obesity have the potential to ameliorate this. There have however been reported challenges with implementation of such initiatives, which may be strengthened by incorporating implementation science methods. This pilot randomised controlled trial protocol outlines the development and proposed evaluation of a multicomponent implementation strategy (Action-RESPOND). to increase the implementation of community-based systems thinking child obesity prevention initiatives The target of this intervention is ten rural and regional communities (or local government areas as the unit of allocation) within Northeast Victoria who were participants in a whole-of-systems intervention (RESPOND). Action-RESPOND builds on this intervention by assessing the impact of offering additional implementation strategies to five communities relative to usual care. The development of the multicomponent implementation strategy was informed by the Promoting Action on Research Implementation in Health Services (PARIHS) framework and consists of seven implementation strategies primarily delivered via 'facilitation' methods. Implementation strategies aimed to ensure initiatives implemented are i) evidence-based, ii) address community's specific needs and iii) are suitable for local context. Strategies also aimed to increase the community's capacity to implement, through iv) improving the health promotion team's implementation knowledge and skills, fostering v) leadership, vi) physical resources and vii) community culture to drive implementation. The feasibility, acceptability, potential impact, and cost of the strategy will be assessed at baseline and follow up using surveys administered to key representatives within the community and internal records maintained by the research team. By leveraging an existing community-based whole-of-systems intervention, Action-RESPOND offers a unique opportunity to collect pilot feasibility and early empirical data on how to apply implementation and systems science approaches to support obesity prevention in rural and regional communities in Victoria.
Summary Background Preoperative (neoadjuvant) chemotherapy and radiotherapy are more effective than similar postoperative treatment for oesophageal, gastric, and rectal cancers, perhaps because of ...more effective micrometastasis eradication and reduced risk of incomplete excision and tumour cell shedding during surgery. The FOxTROT trial aims to investigate the feasibility, safety, and efficacy of preoperative chemotherapy for colon cancer. Methods In the pilot stage of this randomised controlled trial, 150 patients with radiologically staged locally advanced (T3 with ≥5 mm invasion beyond the muscularis propria or T4) tumours from 35 UK centres were randomly assigned (2:1) to preoperative (three cycles of OxMdG oxaliplatin 85 mg/m2 , l-folinic acid 175 mg, fluorouracil 400 mg/m2 bolus, then 2400 mg/m2 by 46 h infusion repeated at 2-weekly intervals followed by surgery and a further nine cycles of OxMdG) or standard postoperative chemotherapy (12 cycles of OxMdG). Patients with KRAS wild-type tumours were randomly assigned (1:1) to receive panitumumab (6 mg/kg; every 2 weeks with the first 6 weeks of chemotherapy) or not. Treatment allocation was through a central randomisation service using a minimised randomisation procedure including age, radiological T and N stage, site of tumour, and presence of defunctioning colostomy as stratification variables. Primary outcome measures of the pilot phase were feasibility, safety, and tolerance of preoperative therapy, and accuracy of radiological staging. Analysis was by intention to treat. This trial is registered, number ISRCTN 87163246. Findings 96% (95 of 99) of patients started and 89% (85 of 95) completed preoperative chemotherapy with grade 3–4 gastrointestinal toxicity in 7% (seven of 94) of patients. All 99 tumours in the preoperative group were resected, with no significant differences in postoperative morbidity between the preoperative and control groups: 14% (14 of 99) versus 12% (six of 51) had complications prolonging hospital stay (p=0·81). 98% (50 of 51) of postoperative chemotherapy patients had T3 or more advanced tumours confirmed at post-resection pathology compared with 91% (90 of 99) of patients following preoperative chemotherapy (p=0·10). Preoperative therapy resulted in significant downstaging of TNM5 compared with the postoperative group (p=0·04), including two pathological complete responses, apical node involvement (1% one of 98 vs 20% ten of 50, p<0·0001), resection margin involvement (4% four of 99 vs 20% ten of 50, p=0·002), and blinded centrally scored tumour regression grading: 31% (29 of 94) vs 2% (one of 46) moderate or greater regression (p=0·0001). Interpretation Preoperative chemotherapy for radiologically staged, locally advanced operable primary colon cancer is feasible with acceptable toxicity and perioperative morbidity. Proceeding to the phase 3 trial, to establish whether the encouraging pathological responses seen with preoperative therapy translates into improved long-term oncological outcome, is appropriate. Funding Cancer Research UK.
The objective of this study was to assess the role of pulmonary fat embolism caused by intramedullary pressurization of the femoral canal in the development of acute lung injury in the setting of ...acute hemorrhagic shock and resuscitation.
Thirty New Zealand White rabbits were randomly assigned to one of four groups: (1) nine animals in which hemorrhagic shock was induced by carotid bleeding, resuscitation was performed, and the femoral canal was reamed and pressurized with bone cement to induce fat embolism (hemorrhagic shock and resuscitation/fat embolism HR/FE group); (2) six animals in which shock was induced by carotid bleeding, resuscitation was performed, and a sham knee incision was made and closed without drilling, reaming, or pressurization (hemorrhagic shock and resuscitation HR group); (3) eight animals in which no hemorrhage or shock was induced but the femoral canal was reamed and pressurized with bone cement to induce fat embolism (fat embolism FE group); and (4) seven animals that had a three-hour ventilation period followed by a sham knee incision (control group). The animals were ventilated for four hours following closure. Flow cytometry with use of antibodies against CD45 and CD11b was performed to test neutrophil activation in whole blood. Histological examination of lung specimens was also performed. Plasma and bronchoalveolar lavage fluid were analyzed for monocyte chemotactic peptide-1 and interleukin-8 levels with use of the ELISA (enzyme-linked immunosorbent assay) method.
Three animals in the HR/FE group died immediately after canal pressurization and were excluded. CD11b mean channel fluorescence was significantly elevated, as compared with baseline, only in the HR/FE group at two hours (p = 0.025) and four hours (p = 0.024) after knee closure. Histological analysis showed that only the HR/FE (p < 0.001) and HR (p = 0.010) groups had significantly greater infiltration of alveoli by polymorphonuclear leukocytes as compared with that in the controls. No significant differences in plasma cytokine levels were found between the groups. Only the HR/FE group had significantly higher interleukin-8 (p = 0.020) and monocyte chemotactic peptide-1 (p = 0.004) levels in the bronchoalveolar lavage fluid as compared with those in the controls.
Fat embolism from canal pressurization alone did not activate a pulmonary inflammatory response. The combination of hemorrhagic shock, resuscitation, and fat embolism elicited neutrophil activation, infiltration of alveoli by polymorphonuclear leukocytes, and inflammatory cytokine expression in bronchoalveolar lavage fluid.
The low dust temperatures (<14 K) of Planck Galactic cold clumps (PGCCs) make them ideal targets to probe the initial conditions and very early phase of star formation. "TOP-SCOPE" is a joint survey ...program targeting ∼2000 PGCCs in J = 1-0 transitions of CO isotopologues and ∼1000 PGCCs in 850 m continuum emission. The objective of the "TOP-SCOPE" survey and the joint surveys (SMT 10 m, KVN 21 m, and NRO 45 m) is to statistically study the initial conditions occurring during star formation and the evolution of molecular clouds, across a wide range of environments. The observations, data analysis, and example science cases for these surveys are introduced with an exemplar source, PGCC G26.53+0.17 (G26), which is a filamentary infrared dark cloud (IRDC). The total mass, length, and mean line mass (M/L) of the G26 filament are ∼6200 M☉, ∼12 pc, and ∼500 M☉ pc−1, respectively. Ten massive clumps, including eight starless ones, are found along the filament. The most massive clump as a whole may still be in global collapse, while its denser part seems to be undergoing expansion owing to outflow feedback. The fragmentation in the G26 filament from cloud scale to clump scale is in agreement with gravitational fragmentation of an isothermal, nonmagnetized, and turbulent supported cylinder. A bimodal behavior in dust emissivity spectral index (β) distribution is found in G26, suggesting grain growth along the filament. The G26 filament may be formed owing to large-scale compression flows evidenced by the temperature and velocity gradients across its natal cloud.
Objectives. To determine whether diagnostic triage by general practitioners (GPs) or rheumatology nurses (RNs) can improve the positive predictive value of referrals to early arthritis clinics ...(EACs). Methods. Four GPs and two RNs were trained in the assessment of early inflammatory arthritis (IA) by four visits to an EAC supervised by hospital rheumatologists. Patients referred to one of three EACs were recruited for study and assessed independently by a GP, an RN and one of six rheumatologists. Each assessor was asked to record their clinical findings and whether they considered the patient to have IA. Each was then asked to judge the appropriateness of the referral according to predetermined guidelines. The rheumatologists had been shown previously to have a satisfactory level of agreement in the assessment of IA. Results. Ninety‐six patients were approached and all consented to take part in the study. In 49 cases (51%), the rheumatologist judged that the patient had IA and that the referral was appropriate. The assessments of GPs and RNs were compared with those of the rheumatologists. Levels of agreement were measured using the kappa value, where 1.0 represents total unanimity. The kappa value was 0.77 for the GPs when compared with the rheumatologists and 0.79 for the RNs. Significant stiffness in the morning or after rest and objective joint swelling were the most important clinical features enabling the GPs and RNs to discriminate between IA and non‐IA conditions. Conclusion. Diagnostic triage by GPs or RNs improved the positive predictive value of referrals to an EAC with a degree of accuracy approaching that of a group of experienced rheumatologists.
We have used site-directed mutagenesis and a recombinant expression system for thrombin-activable fibrinolysis inhibitor (TAFI) in order to identify the thrombin cleavage site in activated TAFI ...(TAFIa) and to determine the relative contribution of proteolytic cleavage and thermal instability in regulation of TAFIa activity in clots. Arg-330 of TAFIa had been proposed to be the thrombin cleavage site based on studies with trypsin, but mutation of this residue to Gln did not prevent thrombin-mediated cleavage nor did mutation to Gln of the nearby Arg-320 residue. However, mutation of Arg-302 to Gln abolished thrombin-mediated cleavage of TAFIa. All TAFIa variants were susceptible to plasmin cleavage. Interestingly, all Arg to Gln substitutions decreased the thermal stability of TAFIa. The antifibrinolytic potential of the TAFI mutants in vitrocorrelates with the thermal stability of their respective TAFIa species, indicating that this property plays a key role in regulating the activity if TAFIa. Incubation of TAFIa under conditions that result in complete thermal inactivation of the enzyme accelerates subsequent thrombin- and plasmin-mediated cleavage of TAFIa. Moreover, the extent of cleavage of TAFIa by thrombin does not affect the rate of decay of TAFIa activity. Collectively, these studies point to a role for the thermal instability, but not for proteolytic cleavage, of TAFIa in regulation of its activity and, thus, of its antifibrinolytic potential. Finally, we propose a model for the thermal instability of TAFIa.
Reported herein are semi-empirical calculations of the molecular geometry of TCDD, TCPT, TCPT-sulfoxide (TCPT-O), TCPT-sulfone (TCPT-O
2),
N-methyl-TCPT (Me-TCPT),
N-methyl-TCPT-sulfoxide ...(Me-TCPT-O), and
N-methyl-TCPT-sulfone (Me-TCPT-O
2), the characterization of their AhR binding affinity in rat hepatic cytosol, and their ability to induce EROD activity in a rat hepatoma cell line
in vitro.
Semi-empirical calculations yielded detailed information about the stereochemistry and the preferred conformation of each of these compounds. These results in combination with observations reported in this paper were used to determine structure–activity relationships.
In vitro displacement of
3H-TCDD was measured by increasing concentrations of the respective ligands. This assay revealed a strong binding affinity of TCPT to the AhR with a
K
i value of 1.08 nM. TCDD had a
K
i value of 0.54 nM. The affinity of TCPT derivatives for the AhR decreased with increasing degree of oxidation. Moreover,
N-methylation further lowered the affinity, so that the
N-methyl sulfone derivative of TCPT displayed the highest
K
i at ∼
1200 nM (=
460.4 ng/ml).
A corresponding trend was observed regarding the potency of TCPT and derivatives to induce EROD activity
in vitro. However, the potencies were considerably lower than that of TCDD. Enzyme induction was measured in a rat hepatoma cell line H4IIEC/T3 by quantification of ethoxyresorufin-
O-deethylase (EROD) activity. Induction was measured at 12, 24, 48 and 72 h to determine time dependence. Sulfoxidated and
N-methylated phenothiazines displayed a lower potency than their respective parent compounds. TCPT and all derivatives induced enzyme activity at an efficacy similar to TCDD at all time points measured.
The reported findings clearly separate the induction of EROD activity by TCPT and derivatives from their binding affinities to the AhR. In contrast, a direct correlation between the two is generally assumed in drug development, leading to – in our view – unwarranted termination of drug candidates. Therefore, a lack of such a correlation for TCPT and derivatives in fact supports their further development as possible drug leads.
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