Pain in critically ill patients in the intensive care unit (ICU) is common. However, pain assessment in critically ill patients often is complicated because these patients are unable to communicate ...effectively. Therefore, we designed a study (a) to determine the inter-rater reliability of the Numerical Rating Scale (NRS) and the Behavioral Pain Scale (BPS), (b) to compare pain scores of different observers and the patient, and (c) to compare NRS, BPS, and the Visual Analog Scale (VAS) for measuring pain in patients in the ICU.
We performed a prospective observational study in 113 non-paralyzed critically ill patients. The attending nurses, two researchers, and the patient (when possible) obtained 371 independent observation series of NRS, BPS, and VAS. Data analyses were performed on the sample size of patients (n = 113).
Inter-rater reliability of the NRS and BPS proved to be adequate (kappa = 0.71 and 0.67, respectively). The level of agreement within one scale point between NRS rated by the patient and NRS scored by attending nurses was 73%. However, high patient scores (NRS > or = 4) were underestimated by nurses (patients 33% versus nurses 18%). In responsive patients, a high correlation between NRS and VAS was found (rs = 0.84, P < 0.001). In ventilated patients, a moderate positive correlation was found between the NRS and the BPS (rs = 0.55, P < 0.001). However, whereas 6% of the observations were NRS of greater than or equal to 4, BPS scores were all very low (median 3.0, range 3.0 to 5.0).
The different scales show a high reliability, but observer-based evaluation often underestimates the pain, particularly in the case of high NRS values (> or = 4) rated by the patient. Therefore, whenever this is possible, ICU patients should rate their pain. In unresponsive patients, primarily the attending nurse involved in daily care should score the patient's pain. In ventilated patients, the BPS should be used only in conjunction with the NRS nurse to measure pain levels in the absence of painful stimuli.
Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and ...generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non-small-cell lung cancer (NSCLC) receiving nivolumab in this trial.
Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle.
Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting > 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis.
Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing.
Functional diagnostic examinations such as clinical functional analysis and manual structural analysis ('orthopedic tests') allow the dentist to establish a structured diagnosis. Previously, the ...process of correlating findings with the appropriate diagnoses was guided by human thought processes alone. The experimental diagnostic randomized controlled trial (RCT) in this study investigated whether computer-aided diagnosis (CADx) of temporomandibular disorders (TMD) offers quality advantages over traditional diagnosis (TRAD).
Thirty-nine 5th-year dental students (examiners) at a university in Hamburg, Germany, received joint training in the diagnosis of TMD by clinical functional analysis and manual structural analysis ('orthopedic tests'). This study is based on anonymized data from 10 patients who were consecutively recruited at a specialized TMJ treatment center. The examiners were randomly allocated to two groups. Each examiner established a structured diagnosis through a traditional diagnostic method and by computer-aided diagnosis (CMDfact 4 functional diagnostics software) of five cases, each using the AB/BA crossover design. The diagnoses established by each individual examiner were then compared with the corresponding reference diagnoses (gold standard) and with those of the other examiners.
Cohen's kappa coefficient analysis showed that median agreement with the reference diagnoses was significantly higher (P < 0.001) with computer assistance (median 0.692) than without it (0.553). Fleiss' kappa showed that the median interexaminer consistency of diagnoses was significantly higher (P < 0.001) with computer assistance (0.497) than with traditional diagnostic methods alone (0.271). Likewise, the number of false-positive and false-negative diagnoses was significantly lower with computer assistance (P < 0.001).
This study determined that dentists who are less experienced and not specialized in dental functional diagnostics achieve a significantly better and more consistent diagnostic quality with computer assistance by means of the system used in this study. Therefore, it seems advisable to extend computer-aided diagnostics to further functional examination techniques (condylar position analysis and jaw motion analysis).
BackgroundThe phase I first-in-human study ENGAGE-1 evaluated the humanized IgG1 OX40 agonistic monoclonal antibody GSK3174998 alone (Part 1 (P1)) or in combination with pembrolizumab (Part 2 (P2)) ...in patients with advanced solid tumors.MethodsGSK3174998 (0.003–10 mg/kg) ± pembrolizumab (200 mg) was administered intravenously every 3 weeks using a continuous reassessment method for dose escalation. Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics, immunogenicity, pharmacodynamics, and clinical activity.Results138 patients were enrolled (45 (P1) and 96 (P2, including 3 crossovers)). Treatment-related adverse events occurred in 51% (P1) and 64% (P2) of patients, fatigue being the most common (11% and 24%, respectively). No dose-toxicity relationship was observed, and maximum-tolerated dose was not reached. Dose-limiting toxicities (P2) included Grade 3 (G3) pleural effusion and G1 myocarditis with G3 increased troponin. GSK3174998 ≥0.3 mg/kg demonstrated pharmacokinetic linearity and >80% receptor occupancy on circulating T cells; 0.3 mg/kg was selected for further evaluation. Limited clinical activity was observed for GSK3174998 (P1: disease control rate (DCR) ≥24 weeks 9%) and was not greater than that expected for pembrolizumab alone (P2: overall response rate 8%, DCR ≥24 weeks 28%). Multiplexed immunofluorescence data from paired biopsies suggested that increased infiltration of natural killer (NK)/natural killer T (NKT) cells and decreased regulatory T cells (Tregs) in the tumor microenvironment may contribute to clinical responses: CD16+CD56–CD134+ NK /NKT cells and CD3+CD4+FOXP3+CD134+ Tregs exhibited the largest magnitude of change on treatment, whereas CD3+CD8+granzyme B+PD-1+CD134+ cytotoxic T cells were the least variable. Tumor gene expression profiling revealed an upregulation of inflammatory responses, T-cell proliferation, and NK cell function on treatment with some inflammatory cytokines upregulated in peripheral blood. However, target engagement, evidenced by pharmacologic activity in peripheral blood and tumor tissue, did not correlate with clinical efficacy. The low number of responses precluded identifying a robust biomarker signature predictive of response.ConclusionsGSK3174998±pembrolizumab was well tolerated over the dose range tested and demonstrated target engagement. Limited clinical activity does not support further development of GSK3174998±pembrolizumab in advanced cancers.Trial registration numberNCT02528357.
Martensitic transformation and the low temperature plastic deformation proceed by the easiest coordinated atom movements, i.e. those which produce the least amount of energy dissipation. The two ...requirements, namely that the correct martensitic crystal structure results, and in addition that an undistorted interface between the matrix and the martensite is necessary, lead in general to more than one shear system. As will be discussed, the selection of the shear systems to comply with the transformation crystallography underlies the same selection principles as deformation by slip. Three examples are presented: the Cu-Zn based noble metal alloys, the Ni-Ti based ones and the Fe alloys. Whereas plastic deformation is induced by applied stresses, the martensitic transformation is controlled by a change in Gibbs free energy, but can be modified by applying stresses. The creation of transformation strains leads to an interaction with applied stresses. The different types of interaction between applied stress, transformation strain and associated plastic deformation are discussed for the three alloy groups.
Three aspects related to the martensitic transformation are discussed, using the Cu–Zn based alloys as prototypes. The first is concerned with the similarities to the plastic deformation by ...dislocations, since both proceed by coordinated atom movements. In the second, the changes in stability due to long-range order are compared with reference to the disordered high temperature equilibrium phases. Finally, the ordering and annealing behavior of the vacancies, which control the time dependent aging in the martensite, are related to their ordered arrangement in the high temperature cubic equilibrium γ phases.
Because of overpopulation of African elephants in South Africa and the consequent threat to biodiversity, the need for a method of population control has become evident. In this regard, the potential ...use of the porcine zona pellucida (pZP) vaccine as an effective means for population control is explored. While potential effects of pZP treatment on social behavior of African elephants have been investigated, no examination of the influence of pZP vaccination on the endocrine correlates in treated females has been undertaken. In this study, ovarian activity of free-ranging, pZP-treated African elephant females was monitored noninvasively for 1 yr at Thornybush Private Nature Reserve, South Africa, by measuring fecal 5α-pregnan-3β-ol-20-on concentrations via enzyme immunoassay. A total of 719 fecal samples from 19 individuals were collected over the study period, averaging 38 samples collected per individual (minimum, maximum: 16, 52). Simultaneously, behavioral observations were made to record the occurrence of estrous behavior for comparison. Each elephant under study showed 5α-pregnan-3β-ol-20-on concentrations rising above baseline at some period during the study indicating luteal activity. Average 5α-pregnan-3β-ol-20-on concentrations were 1.61 ± 0.46 μg/g (mean ± SD). Within sampled females, 42.9% exhibited estrous cycles within the range reported for captive African elephants, 14.3% had irregular cycles, and 42.9% did not appear to be cycling. Average estrous cycle duration was 14.72 ± 0.85 wk. Estrous behavior coincided with the onset of the luteal phase and a subsequent rise in 5α-pregnan-3β-ol-20-on concentrations. Average 5α-pregnan-3β-ol-20-on levels positively correlated with rainfall. No association between average individual 5α-pregnan-3β-ol-20-on concentrations or cyclicity status with age or parity were detected. Earlier determination of efficacy was established via fecal hormone analysis with no pregnancies determined 22 mo post-treatment and onward. Results indicate the presence of ovarian activity amongst pZP-treated female African elephants in 2 yr after initial immunization. Further study should now be aimed toward investigating the long-term effects of pZP vaccination on the reproductive function of female African elephants.
Stability of martensite in noble metal alloys Ahlers, M.
Materials science & engineering. A, Structural materials : properties, microstructure and processing,
05/2003, Letnik:
349, Številka:
1-2
Journal Article
Recenzirano
The stability of the martensite is controlled by the electron concentration and by the electronegativity, which is described in terms of pair interchange energies. Although the contribution of the ...conduction electrons determines the difference in stability between the disordered equilibrium face centred cubic and body centred cubic phases at elevated temperatures, they are only partly responsible for the enthalpy difference between the β phase matrix and the martensite. For a quantitative evaluation of the martensitic transformation it is therefore necessary to have also information on the differences in electronegativity, which control a large fraction of the enthalpy of mixing of the disordered phases, and contribute to the changes from long-range ordering. Long-range ordering takes place generally at lower temperatures in the β phase matrix, and is inherited in the martensite after the diffusionless transformation. The aim of this paper is to derive pair interchange energies that permit to describe quantitatively the martensitic transformation in noble metal alloys. As their prototypes the binary Cu–Zn, Cu–Al and ternary Cu–Zn–Al alloys are analysed in detail, because most information is available for them. It will be shown that for the quantitative description of the enthalpy of formation of the martensite and of the equilibrium phases, pair interchange energies are required which include important contributions also from more distant than first and second nearest neighbour pairs. However, the difference in enthalpy of formation between the martensite and the high temperature β phase can be well described by composition independent nearest and next nearest neighbour pair interchange energies alone.
BACKGROUND:Although morphine is used frequently to treat pain in the intensive care unit, its pharmacokinetics has not been adequately quantified in critically ill patients. We evaluated the ...glucuronidation and elimination clearance of morphine in intensive care patients compared with healthy volunteers based on the morphine and morphine-3-glucuronide (M3G) concentrations.
METHODS:A population pharmacokinetic model with covariate analysis was developed with the nonlinear mixed-effects modeling software (NONMEM 7.3). The analysis included 3012 morphine and M3G concentrations from 135 intensive care patients (117 cardiothoracic surgery patients and 18 critically ill patients), who received continuous morphine infusions adapted to individual pain levels, and 622 morphine and M3G concentrations from a previously published study of 20 healthy volunteers, who received an IV bolus of morphine followed by a 1-hour infusion.
RESULTS:For morphine, a 3-compartment model best described the data, whereas for M3G, a 1-compartment model fits best. In intensive care patients with a normal creatinine concentration, a decrease of 76% was estimated in M3G clearance compared with healthy subjects, conditional on the M3G volume of distribution being the same in intensive care patients and healthy volunteers. Furthermore, serum creatinine concentration was identified as a covariate for both elimination clearance of M3G in intensive care patients and unchanged morphine clearance in all patients and healthy volunteers.
CONCLUSIONS:Under the assumptions in the model, M3G elimination was significantly decreased in intensive care patients when compared with healthy volunteers, which resulted in substantially increased M3G concentrations. Increased M3G levels were even more pronounced in patients with increased serum creatinine levels. Model-based simulations show that, because of the reduction in morphine clearance in intensive care patients with renal failure, a 33% reduction in the maintenance dose would result in morphine serum concentrations equal to those in healthy volunteers and intensive care patients with normal renal function, although M3G concentrations remain increased. Future pharmacodynamic investigations are needed to identify target concentrations in this population, after which final dosing recommendations can be made.
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