Learning curves, taking instructions, and patient safety: using a theoretical domains framework in an interview study to investigate prescribing errors among trainee doctors

ABSTRACT: BACKGROUND: Prescribing errors are a major source of morbidity and mortality and represent a significant patient safety concern. Evidence suggests that trainee doctors are responsible for most prescribing errors. Understanding the factors that influence prescribing behavior may lead to effective interventions to reduce errors. Existing investigations of prescribing errors have been based on Human Error Theory but not on other relevant behavioral theories. The aim of this study was to apply a broad theory-based approach using the Theoretical Domains Framework (TDF) to investigate prescribing in the hospital context among a sample of trainee doctors. METHOD: Semistructured interviews, based on 12 theoretical domains, were conducted with 22 trainee doctors to explore views, opinions, and experiences of prescribing and prescribing errors. Content analysis was conducted, followed by applying relevance criteria and a novel stage of critical appraisal, to identify which theoretical domains could be targeted in interventions to improve prescribing. RESULTS: Seven theoretical domains met the criteria of relevance: "social professional role and identity," "environmental context and resources," "social influences," "knowledge," "skills," "memory, attention, and decision making," and "behavioral regulation." From critical appraisal of the interview data, "beliefs about consequences" and "beliefs about capabilities" were also identified as potentially important domains. Interrelationships between domains were evident. Additionally, the data supported theoretical elaboration of the domain behavioral regulation. CONCLUSIONS: In this investigation of hospital-based prescribing, participants' attributions about causes of errors were used to identify domains that could be targeted in interventions to improve prescribing. In a departure from previous TDF practice, critical appraisal was used to identify additional domains that should also be targeted, despite participants' perceptions that they were not relevant to prescribing errors. These were beliefs about consequences and beliefs about capabilities. Specifically, in the light of the documented high error rate, beliefs that prescribing errors were not likely to have consequences for patients and that trainee doctors are capable of prescribing without error should also be targeted in an intervention. This study is the first to suggest critical appraisal for domain identification and to use interview data to propose theoretical elaborations and interrelationships between domains.     

The dynamic role of bone morphogenetic proteins in neural stem cell fate and maturation

The bone morphogenetic proteins (BMPs) are a group of powerful morphogens that are critical for development of the nervous system. The effects of BMP signaling on neural stem cells are myriad and dynamic, changing with each stage of development. During early development inhibition of BMP signaling differentiates neuroectoderm from ectoderm, and BMP signaling helps to specify neural crest. Thus modulation of BMP signaling underlies formation of both the central and peripheral nervous systems. BMPs secreted from dorsal structures then form a gradient which helps pattern the dorsal-ventral axis of the developing spinal cord and brain. During forebrain development BMPs sequentially induce neurogenesis and then astrogliogenesis and participate in neurite outgrowth from immature neurons. BMP signaling also plays a critical role in maintaining adult neural stem cell niches in the subventricular zone (SVZ) and subgranular zone (SGZ). BMPs are able to exert such diverse effects through closely regulated temporospatial expression and interaction with other signaling pathways.     

Toward using δ13C of ecosystem respiration to monitor canopy physiology in complex terrain

In 2005 and 2006, air samples were collected at the base of a Douglas-fir watershed to monitor seasonal changes in the delta13CO2 of ecosystem respiration (delta13C(ER)). The goals of this study were to determine whether variations in delta13C(ER) correlated with environmental variables and could be used to predict expected variations in canopy-average stomatal conductance (Gs). Changes in delta13C(ER) correlated weakly with changes in vapor pressure deficit (VPD) measured 0 and 3-7 days earlier and significantly with soil matric potential (psi(m)) (P value <0.02) measured on the same day. Midday G (s) was estimated using sapflow measurements (heat-dissipation method) at four plots located at different elevations within the watershed. Values of midday Gs from 0 and 3-7 days earlier were correlated with delta13C(ER), with the 5-day lag being significant (P value <0.05). To examine direct relationships between delta13C(ER) and recent Gs, we used models relating isotope discrimination to stomatal conductance and photosynthetic capacity at the leaf level to estimate values of stomatal conductance ("Gs-I") that would be expected if respired CO2 were derived entirely from recent photosynthate. We compared these values with estimates of Gs using direct measurement of transpiration at multiple locations in the watershed. Considering that the approach based on isotopes considers only the effect of photosynthetic discrimination on delta13C(ER), the magnitude and range in the two values were surprisingly similar. We conclude that: (1) delta13C(ER) is sensitive to variations in weather, and (2) delta13C(ER) potentially could be used to directly monitor average, basin-wide variations in Gs in complex terrain if further research improves understanding of how delta13C(ER) is influenced by post-assimilation fractionation processes.     

An information-theoretic analysis of genetics, gender and age in cancer patients

Germline genetics, gender and hormonal-signaling pathways are all well described modifiers of cancer risk and progression. Although an improved understanding of how germline genetic variants interact with other cancer risk factors may allow better prevention and treatment of human cancer, measuring and quantifying these interactions is challenging. In other areas of research, Information Theory has been used to quantitatively describe similar multivariate interactions. We implemented a novel information-theoretic analysis to measure the joint effect of a high frequency germline genetic variant of the p53 tumor suppressor pathway (MDM2 SNP309 T/G) and gender on clinical cancer phenotypes. This analysis quantitatively describes synergistic interactions among gender, the MDM2 SNP309 locus, and the age of onset of tumorigenesis in p53 mutation carriers. These results offer a molecular and genetic basis for the observed sexual dimorphism of cancer risk in p53 mutation carriers and a model is proposed that suggests a novel cancer prevention strategy for p53 mutation carriers.     

Metaproteomics provides functional insight into activated sludge wastewater treatment

Background

Through identification of highly expressed proteins from a mixed culture activated sludge system this study provides functional evidence of microbial transformations important for enhanced biological phosphorus removal (EBPR).

Methodology/Principal Findings

A laboratory-scale sequencing batch reactor was successfully operated for different levels of EBPR, removing around 25, 40 and 55 mg/l P. The microbial communities were dominated by the uncultured polyphosphate-accumulating organism “Candidatus Accumulibacter phosphatis”. When EBPR failed, the sludge was dominated by tetrad-forming α-Proteobacteria. Representative and reproducible 2D gel protein separations were obtained for all sludge samples. 638 protein spots were matched across gels generated from the phosphate removing sludges. 111 of these were excised and 46 proteins were identified using recently available sludge metagenomic sequences. Many of these closely match proteins from “Candidatus Accumulibacter phosphatis” and could be directly linked to the EBPR process. They included enzymes involved in energy generation, polyhydroxyalkanoate synthesis, glycolysis, gluconeogenesis, glycogen synthesis, glyoxylate/TCA cycle, fatty acid β oxidation, fatty acid synthesis and phosphate transport. Several proteins involved in cellular stress response were detected.

Conclusions/Significance

Importantly, this study provides direct evidence linking the metabolic activities of “Accumulibacter” to the chemical transformations observed in EBPR. Finally, the results are discussed in relation to current EBPR metabolic models.     

Structure and regulation of the vacuolar ATPases

The vacuolar (H(+))-ATPases (V-ATPases) are ATP-dependent proton pumps responsible for both acidification of intracellular compartments and, for certain cell types, proton transport across the plasma membrane. Intracellular V-ATPases function in both endocytic and intracellular membrane traffic, processing and degradation of macromolecules in secretory and digestive compartments, coupled transport of small molecules such as neurotransmitters and ATP and in the entry of pathogenic agents, including envelope viruses and bacterial toxins. V-ATPases are present in the plasma membrane of renal cells, osteoclasts, macrophages, epididymal cells and certain tumor cells where they are important for urinary acidification, bone resorption, pH homeostasis, sperm maturation and tumor cell invasion, respectively. The V-ATPases are composed of a peripheral domain (V(1)) that carries out ATP hydrolysis and an integral domain (V(0)) responsible for proton transport. V(1) contains eight subunits (A-H) while V(0) contains six subunits (a, c, c', c', d and e). V-ATPases operate by a rotary mechanism in which ATP hydrolysis within V(1) drives rotation of a central rotary domain, that includes a ring of proteolipid subunits (c, c' and c'), relative to the remainder of the complex. Rotation of the proteolipid ring relative to subunit a within V(0) drives active transport of protons across the membrane. Two important mechanisms of regulating V-ATPase activity in vivo are reversible dissociation of the V(1) and V(0) domains and changes in coupling efficiency of proton transport and ATP hydrolysis. This review focuses on recent advances in our lab in understanding the structure and regulation of the V-ATPases.     

Plant structural defences against browsing birds: a legacy of New Zealand's extinct moas

Browsing by large vertebrates has been a major force in the evolution of terrestrial plants but Holocene extinctions of the browsers have left a legacy of broken biotic partnerships. Ratite birds were the largest herbivores in several regions, such as the moas of New Zealand. Many woody plants there have a distinct form of branching, described as "divaricate", with thin, wide angled, branches intertwining to form a tangled canopy. Divaricate branching has been interpreted as a form of protection against climate extremes or as an anachronistic defense against the extinct moas. Here we report the first experimental evidence that many of these plants are defended against extant ratite browsers. In feeding experiments on two tree species with different (heteroblastic) juvenile and adult branch morphology, emus and ostriches obtained adequate feeding rates from adult shoots but sub-maintenance feeding rates from juvenile shoots with the ratite-resistant traits. Divaricate juvenile shoots suffered 30–70% less biomass removal to the birds than adult shoots. Ratites browse by a distinctive clamping and tugging action. Structural defence traits that exploit the limitations of this feeding mode include narrow, strong, elastic branches that resist being torn off, wide branching angle ("divaricate") that makes shoots difficult to swallow, and small, widely spaced leaves. This novel plant architectural defence has developed in at least 20% of the native woody flora of New Zealand, including 10 heteroblastic tree species that exhibit the ratite-resistant strategy until they reach ca 3 metres height. It is also a major axis of variation amongst homoblastic woody shrub species. The defences are useless against mammalian browsers that shear shoots, contributing to marked decreases in the abundances of ratite-resistant species in New Zealand after the introduction of mammals.     

Relaxin-like bioactivity of ovine Insulin 3 (INSL3) analogues.

Relaxin is an insulin-like peptide consisting of two separate chains (A and B) joined by two inter- and one intrachain disulfide bonds. Binding to its receptor requires an Arg-X-X-X-Arg-X-X-Ile motif in the B-chain. A related member of the insulin superfamily, INSL3, has a tertiary structure that is predicted to be similar to relaxin. It also possesses an Arg-X-X-X-Arg motif within its B-chain, although this is displaced by four amino acids towards the C-terminus from the corresponding position within relaxin. We have previously shown that synthetic INSL3 itself does not display relaxin-like activity although analogue (Analogue A) with an introduced arginine residue in the B-chain giving it an Arg cassette in the exact relaxin position does possess weak activity. In order to identify further the structural features that impart relaxin function, solid phase peptide synthesis was used to prepare three additional analogues for bioassay. Each of these contained point substitutions within the arginine cassette. Analogue D contained the full human relaxin binding cassette, Analogue G consisted of the native INSL3 sequence containing an Arg to Ala substitution, and Analogue E was a further modification of Analogue A, with the same substitution. Each analogue was fully chemically characterized by a number of criteria. Detailed circular dichroism spectroscopy analyses showed that the changes caused little alteration of secondary structure and, hence, overall conformation. However, each analogue displayed only weak relaxin-like activity. These results indicate that while the arginine cassette is vital for relaxin-like activity, there are additional, as yet unidentified structural requirements for relaxin binding.