When do combinations of diuretics make sense?

Diuretics are commonly prescribed by physicians to contract the ECF volume. In two clinical situations combining different classes of diuretics make sense: First, if a loop diuretic at maximal dose alone does not lead to sufficient diuresis or second, if the side effect of a diuretic needs to be corrected by adding a diuretic of another class. The latter is clinically often used to counteract loop or thiazide diuretic-induced hypokalemia by the addition of a potassium sparing diuretic. Key to a reasonable combination of diuretics is understanding of the pharmaco-kinetics and knowledge of the molecular targets of the diuretics involved.

Which Combinations Of New Venture Firms Resources Payoff? A Configurational Perspective

Baldauf, Artur; Schweiger, Simone A.; Wuethrich, Adrian

Changes in skill variety predict job satisfaction and psychosomatic complaints

Purpose Skill variety in terms of opportunities for utilizing different skills is an important element of job design; it is associated with well-being and health, but most pertinent research is cross-sectional. Positive associations with well-being, and with intellectual flexibility, have been shown longitudinally, but these studies focus on levels of skill variety at time 1 and do not use changes in skill variety as a predictor. We expect changes in skill variety to be associated with well-being in terms of higher job satisfaction and fewer psychosomatic complaints. Design/Methodology Skill variety, job satisfaction, and psychosomatic complaints were assessed in 2005, 2006, 2007, and 2010 (N = 317 young employees). Data were analyzed using latent growth modeling. Results Skill variety decreased over the first three years after labor market entry. Initial levels of skill variety predicted higher job satisfaction in 2010. Steeper decreases in skill variety from 2005 to 2007 predicted lower levels of job satisfaction and more psychosomatic complaints three years later. Limitations This longitudinal study used only self-report. Research/Practical Implications Our results extend the often found association between challenging work content and job satisfaction in terms of a) showing it for young employees, b) longitudinally, c) not only for initial level but also for changes, and d) for psychosomatic complaints; they underscore the importance of maintaining a high level of challenging work content beyond the initial phase by enriching work as routine increases. Originality/Value Compared to the few existing longitudinal studies, we focus on changes and their relations with well-being.

Assessment of Skill and Portability in Regional Marine Biogeochemical Models: Role of Multiple Planktonic Groups

Application of biogeochemical models to the study of marine ecosystems is pervasive, yet objective quantification of these models' performance is rare. Here, 12 lower trophic level models of varying complexity are objectively assessed in two distinct regions (equatorial Pacific and Arabian Sea). Each model was run within an identical one-dimensional physical framework. A consistent variational adjoint implementation assimilating chlorophyll-a, nitrate, export, and primary productivity was applied and the same metrics were used to assess model skill. Experiments were performed in which data were assimilated from each site individually and from both sites simultaneously. A cross-validation experiment was also conducted whereby data were assimilated from one site and the resulting optimal parameters were used to generate a simulation for the second site. When a single pelagic regime is considered, the simplest models fit the data as well as those with multiple phytoplankton functional groups. However, those with multiple phytoplankton functional groups produced lower misfits when the models are required to simulate both regimes using identical parameter values. The cross-validation experiments revealed that as long as only a few key biogeochemical parameters were optimized, the models with greater phytoplankton complexity were generally more portable. Furthermore, models with multiple zooplankton compartments did not necessarily outperform models with single zooplankton compartments, even when zooplankton biomass data are assimilated. Finally, even when different models produced similar least squares model-data misfits, they often did so via very different element flow pathways, highlighting the need for more comprehensive data sets that uniquely constrain these pathways.

Is choking under pressure a consequence of skill-focus or increased distractibility? Results from a tennis serve task

It has been repeatedly demonstrated that athletes often choke in high pressure situations because anxiety can affect attention regulation and in turn performance. There are two competing theoretical approaches to explain the negative anxiety-performance relationship. According to skillfocus theories, anxious athletes’ attention is directed at how to execute the sport-specific movements which interrupts execution of already automatized movements in expert performers. According to distraction theories, anxious athletes are distractible and focus less on the relevant stimuli. We tested these competing assumptions in a between-subject design, as semi-professional tennis players were either assigned to an anxiety group (n = 25) or a neutral group (n = 28), and performed a series of second tennis serves into predefined target areas. As expected, anxiety was negatively related to serve accuracy. However, mediation analyses with the bootstrapping method revealed that this relationship was fully mediated by self-reported distraction and not by skill-focus.

Establishing the skill of climate field reconstruction techniques for precipitation with pseudoproxy experiments

This study aims at assessing the skill of several climate field reconstruction techniques (CFR) to reconstruct past precipitation over continental Europe and the Mediterranean at seasonal time scales over the last two millennia from proxy records. A number of pseudoproxy experiments are performed within the virtual reality ofa regional paleoclimate simulation at 45 km resolution to analyse different aspects of reconstruction skill. Canonical Correlation Analysis (CCA), two versions of an Analog Method (AM) and Bayesian hierarchical modeling (BHM) are applied to reconstruct precipitation from a synthetic network of pseudoproxies that are contaminated with various types of noise. The skill of the derived reconstructions is assessed through comparison with precipitation simulated by the regional climate model. Unlike BHM, CCA systematically underestimates the variance. The AM can be adjusted to overcome this shortcoming, presenting an intermediate behaviour between the two aforementioned techniques. However, a trade-off between reconstruction-target correlations and reconstructed variance is the drawback of all CFR techniques. CCA (BHM) presents the largest (lowest) skill in preserving the temporal evolution, whereas the AM can be tuned to reproduce better correlation at the expense of losing variance. While BHM has been shown to perform well for temperatures, it relies heavily on prescribed spatial correlation lengths. While this assumption is valid for temperature, it is hardly warranted for precipitation. In general, none of the methods outperforms the other. All experiments agree that a dense and regularly distributed proxy network is required to reconstruct precipitation accurately, reflecting its high spatial and temporal variability. This is especially true in summer, when a specifically short de-correlation distance from the proxy location is caused by localised summertime convective precipitation events.

Combinations of dexmedetomidine and alfaxalone with butorphanol in cats: application of an innovative stepwise optimisation method to identify optimal clinical doses for intramuscular anaesthesia

OBJECTIVES The aim of this study was to optimise dexmedetomidine and alfaxalone dosing, for intramuscular administration with butorphanol, to perform minor surgeries in cats. METHODS Initially, cats were assigned to one of five groups, each composed of six animals and receiving, in addition to 0.3 mg/kg butorphanol intramuscularly, one of the following: (A) 0.005 mg/kg dexmedetomidine, 2 mg/kg alfaxalone; (B) 0.008 mg/kg dexmedetomidine, 1.5 mg/kg alfaxalone; (C) 0.012 mg/kg dexmedetomidine, 1 mg/kg alfaxalone; (D) 0.005 mg/kg dexmedetomidine, 1 mg/kg alfaxalone; and (E) 0.012 mg/kg dexmedetomidine, 2 mg/kg alfaxalone. Thereafter, a modified 'direct search' method, conducted in a stepwise manner, was used to optimise drug dosing. The quality of anaesthesia was evaluated on the basis of composite scores (one for anaesthesia and one for recovery), visual analogue scales and the propofol requirement to suppress spontaneous movements. The medians or means of these variables were used to rank the treatments; 'unsatisfactory' and 'promising' combinations were identified to calculate, through the equation first described by Berenbaum in 1990, new dexmedetomidine and alfaxalone doses to be tested in the next step. At each step, five combinations (one new plus the best previous four) were tested. RESULTS None of the tested combinations resulted in adverse effects. Four steps and 120 animals were necessary to identify the optimal drug combination (0.014 mg/kg dexmedetomidine, 2.5 mg/kg alfaxalone and 0.3 mg/kg butorphanol). CONCLUSIONS AND RELEVANCE The investigated drug mixture, at the doses found with the optimisation method, is suitable for cats undergoing minor clinical procedures.

Trade Costs, Quality, and The Skill Premium

We develop a monopolistic competition model with nonhomothetic factor input bundles where increasing quality requires increasing use of skilled workers. As a result more skill abundant countries export higher quality, higher priced goods. Using a multicountry dataset we test and confirm the findings in Schott (2004) of a positive effect of skill abundance on unit values identified with US data. We extend the core model with per unit trade costs leading to the Washington-apples effect that goods shipped over larger distance are of higher quality. The combination of high-quality goods being relatively skill intensive with the Washington-apples effect implies that countries at a larger distance from their trading partners display a higher skill premium. Simulating our model we find that a doubling of distance of a country relative to all its trading partners raises the skill premium in a country by about 2.3 percent.

Bayesian adaptive designs for drug combinations in early phase clinical trials

Treating patients with combined agents is a growing trend in cancer clinical trials. Evaluating the synergism of multiple drugs is often the primary motivation for such drug-combination studies. Focusing on the drug combination study in the early phase clinical trials, our research is composed of three parts: (1) We conduct a comprehensive comparison of four dose-finding designs in the two-dimensional toxicity probability space and propose using the Bayesian model averaging method to overcome the arbitrariness of the model specification and enhance the robustness of the design; (2) Motivated by a recent drug-combination trial at MD Anderson Cancer Center with a continuous-dose standard of care agent and a discrete-dose investigational agent, we propose a two-stage Bayesian adaptive dose-finding design based on an extended continual reassessment method; (3) By combining phase I and phase II clinical trials, we propose an extension of a single agent dose-finding design. We model the time-to-event toxicity and efficacy to direct dose finding in two-dimensional drug-combination studies. We conduct extensive simulation studies to examine the operating characteristics of the aforementioned designs and demonstrate the designs' good performances in various practical scenarios.^

Skill distribution and comparative advantage: a comparison of China and India

This paper empirically examines the different comparative advantages of two emerging economic giants, China and India, in relation to the different skill distribution patterns in each country. By utilizing industry export data on China and India from 1983 to 2000, we find that a country with a greater dispersion of skills (i.e., India, especially in the earlier years) has higher exports in industries with shorter production chains, whereas a country with a more equal dispersion of skills (i.e., China, especially in the later years) is found to have higher exports in industries with longer production chains. The causal relationship is fairly robust across different specifications. This empirical evidence supports our assumption that the likely mechanism for these results is the negative impact of low-skilled workers on input quality, which accumulates and becomes larger as the length of production chains and the proportion of low-skilled workers in the economy increase.

Skill sorting, inter-industry skill wage premium, and production chains: evidence from India 1999-2000

This paper proposes a mechanism that links industry’s technological characteristics (i.e. quality of non-labor inputs, which is proxied by the length of industry production chains), industry-specific skill wage premium, and skill sorting across industries. It is hypothesized that high-skilled workers are sorted into industries where they can receive a higher skill wage premium, by working with better quality non-labor input. The quality of non-labor inputs is assumed to be worse in industries with longer production chains due to the increased involvement of low-skilled labor and poor infrastructure over the sequential production. By examining Indian wage and employment data for 1999-2000, empirical evidence to support this mechanism can be obtained: First, the skill wage premium is lower [higher] in industries with longer [shorter] production chains. Second, the skill wage premium is lower [higher] in industries with a higher [lower] proportion of low-skilled workers producing inputs outside their own industry. Third, the proportion of high-skilled workers is larger in industries with shorter production chains and lower ratio of low-skilled labor involved, i.e., a skill sorting trend can be observed.