Clindamycin binding to ribosomes revisited: foot printing and computational detection of two binding sites within the peptidyl transferase center.

Clindamycin is a semi-synthetic lincosamide, active against most Gram-positive bacteria and some protozoa. It binds to the 50S ribosomal subunit and inhibits early peptide chain elongation. By kinetic analysis it has been shown that clindamycin (I) competitively interacts with the A-site of translating ribosomes (C) to form the encounter complex CI, which then slowly isomerizes to a tighter complex, termed C*I. As the final complex is capable of synthesizing peptide bonds with decreased velocity, it was assumed that in C*I complex the drug is fixed near the P-site of the ribosome. In the present study, two series of chemical foot printing experiments were carried out. In the first series, clindamycin and ribosomal complex C were incubated for 1 s and then DMS or kethoxal was added (CI probing). In the second series, complex C was preincubated with clindamycin for 1 min before the addition of DMS or kethoxal (C*I probing). It was found that clindamycin in CI complex protects A2451 and A2602 from chemical probing, both located within the A-site of the catalytic center. In contrast, it strongly protects G2505 in C*I complex, which is a discrete foot print of peptidyl-tRNA bound to the P-site. In both CI and C*I complexes, clindamycin also protects nucleotides A2058 and A2059, located next to the entrance of the exit-tunnel where the nascent peptide leaves the ribosome. Polyamines negatively affect the protection of G2505, but favor the protection of A2451 and A2602 nucleotides. Structure modeling confirms the kinetic and chemical foot printing results and suggests that clindamycin mode of action is more complex than a simple competitive inhibition of peptide bond formation.

From cognition to the system: developing a multilevel taxonomy of patient safety in general practice.

The paper describes the process of developing a taxonomy of patient safety in general practice. The methodologies employed included fieldwork, task analysis and confidential reporting of patient-safety events in five West Midlands practices. Reported events were traced back to their root causes and contributing factors. The resulting taxonomy is based on a theoretical model of human cognition, includes multiple levels of classification to reflect the chain of causation and considers affective and physiological influences on performance. Events are classified at three levels. At level one, the information-processing model of cognition is used to classify errors. At level two, immediate causes are identified, internal and external to the individual. At level three, more remote causal factors are classified as either 'work organization' or 'technical' with subcategories. The properties of the taxonomy (validity, reliability, comprehensiveness) as well as its usability and acceptability remain to be tested with potential users.

Sources of variability in uncertain medical decisions in the ICU: a process tracing study.

BACKGROUND: Consistency of medical decision making (equity) is an important component of quality of care. When patients with chronic obstructive pulmonary disease (COPD) present with an exacerbation needing respiratory support they may die if it is not provided. However, if the disease has reached its terminal stage, ventilation will prolong the process of dying. The ventilation outcome is uncertain and there is evidence of variability when this decision is made, the sources of which are not well understood. OBJECTIVES: To identify sources of variability and propose ways of tackling them in order to promote equity in this type of medical decision. METHODS: Six case histories were selected from hospital records of COPD patients. Fourteen senior doctors from seven hospitals in the West Midlands participated. A process tracing approach was used which consisted of (1) withholding case information until specifically requested by the doctors, (2) estimating survival during the decision making process, and (3) concurrent questioning regarding information interpretation and its impact on survival estimates and decisions. RESULTS: The observed decision variability was attributed to doctors attaching importance to different information, gathering different information, and interpreting information differently. There were significant differences between doctors in the amount of information requested. CONCLUSIONS: Differences in information gathering and interpretation by clinicians can result in different decisions being made about the same patient. This variation may exist for other uncertain medical decisions and may be tackled by providing clinicians with prognostic models in the form of usable decision aids.

Variation in intubation decisions for patients with chronic obstructive pulmonary disease in one critical care network.

BACKGROUND: Anecdotal evidence suggests variation in intubation decisions for chronic obstructive pulmonary disease (COPD) patients with respiratory failure, but little is known about the extent of or reasons for this variability. AIM: To describe clinician decision-making for patients with exacerbations of COPD considered for intubation. DESIGN: Telephone simulation study. METHODS: Consultants responsible for COPD admissions in the Heart of England Critical Care network were asked to decide whether or not to admit three patients with COPD to ICU on the basis of information conveyed over the telephone. Consultants were also asked to predict patients survival in ICU hospital and at 180 days on the assumption that the patient did receive ICU care. RESULTS: Of the 120 consultants, 98 (82%) took part; 89% would admit patient 1, 64% patient 2, and 40% patient 3. The prediction of survival if ICU admission had occurred differed significantly between admitters and non-admitters. Mean predicted post-ICU hospital survival for patient 1 was 46% (95%CI 43-49) for admitters, and 13% (95%CI 6-19) for non-admitters (p < 0.001). The respective figures for patient 2 were 38% (95%CI 34-42) vs. 12% (95%CI 8-15) (p < 0.001), and for patient 3, 28% (95%CI 24-33) vs. 13% (95%CI 10-16) (p < 0.001). For a housebound COPD patient in their mid 70s, the mean (SD) threshold of predicted hospital survival below which consultants would recommend not admitting to ICU was 22% (13.2%). CONCLUSIONS: Consultants differed markedly in their admitting decisions about identical patients. Objective outcome prediction models might improve equity in ICU bed use for patients with COPD.

Abstract and reduced-context representations in fault-finding training.

The ability to transfer problem-solving expertise to new situations is regarded as an important practical skill but it is known to be sensitive to contextual differences. Employing abstract and reduced-context training tasks has been proposed as a method of fostering transferable skill but the evidence supporting this approach is limited. The research reported here aimed at assessing the effectiveness of training with diagnostic tasks of varying degrees of contextual detail. The criterion test used to measure training effectiveness was a context-rich diagnostic task that involved locating faults in a representation of a water supply and drainage system (WSDS). In the first study reported (baseline study), subjects were trained and tested on the WSDS task. Various training interventions were employed and a set of diagnostic heuristics proved to be the most effective. Two pilot studies were then carried out to determine whether training with abstract diagnostic tasks could produce transfer to the criterion test, the WSDS. Little evidence of transfer was found; therefore, it was decided to incorporate some context into training but not so much as to obscure important, conceptual task features. This was achieved by constructing reduced-context representations (RCO) of the WSDS at more than one level of abstraction (main study). Training with those representations took less time than training with the WSDS but transfer to the criterion test (the WSDS) was equally efficient. During training with the RCO representations, a technique of refusing costly test information was employed which is thought to have helped subjects discover efficient search strategies and consistently transfer them to the criterion test. This was contrasted with the verbal diagnostic heuristics of the baseline study, which had proved to be effective, but which were not always transferred consistently to the criterion test. This raises the question as to whether diagnostic strategies are necessarily best conveyed solely in verbal form, if the intention is to train transferable skill.

Fragmentation of treatment and the potential for human error in neonatal intensive care.

Neonatal intensive care involves continuous monitoring of highly unstable patients in order to plan and deliver effective care and treatment. Making care and treatment decisions depends upon using information obtained in many different ways. Analysis of care and treatment tasks shows how much staff need to rely on one another for crucial information. This problem becomes more acute as personnel change shifts, yet are still obliged to maintain continuity of care. Effective sharing of information is done through the medium of shared records, shift handovers, ward rounds, and informal verbal exchanges. This article describes strategies for understanding the tasks involved in neonatal intensive care, considers issues of task fragmentation, identifies the communication systems designed to minimize the effects of this fragmentation, and reviews problems associated with those systems that give rise to the potential for human error.

Perceived risk of future pathology associated with pathology-free third molars: a comparison of oral and maxillofacial surgeons and family dentists.

OBJECTIVE: To examine and compare practitioners' judgements of risk of future pathology associated with pathology-free disease asymptomatic third molars. SUBJECTS: 10 oral and maxillofacial surgeons and 18 family dentists (90% male) with experience ranging from 5-28 years. METHOD: Participants were presented with periapical radiographs of 36 asymptomatic, disease-free mandibular third molars and were informed of the age and sex of the patients and the degree of eruption of the third molars. Participants were asked to assess likelihood of future pathology in general, and more specifically, likelihood of root resorption, pericoronitis, periodontitis, cystic change and neoplasia if the third molar was left in situ. RESULTS: There was significant variation between the 28 raters but not between the two groups. Excepting assessment of future cystic change, there was no evidence that oral and maxillofacial surgeons and family dentists rated the 36 cases in consistently different ways. CONCLUSIONS: Practitioners varied very considerably in their judgment of the risks of pathology associated with asymptomatic disease-free third molars. Specialisation, did not account for this variation.

Intra-observer reliability regarding removal of asymptomatic third molars.

OBJECTIVE: To investigate reliability of practitioners' removal decisions and judgements of risk of pathology associated with asymptomatic third molars. SUBJECTS: 10 oral surgeons and 18 family dentists from South Wales with experience ranging from 5 to 28 years. METHOD: Participants were presented with periapical radiographs of 36 asymptomatic, mandibular third molars and were informed of the age and sex of the patients and the degree of eruption of the third molars. Participants were asked to assess, using visual analogue scales, the likelihood of future pathology if the third molars were left in situ and to indicate if they should be removed or not. To assess intra-observer reliability, the 36 cases were duplicated and presented to the participants on a different occasion, a month later. The same questions were asked as on the first occasion. RESULTS: Significant correlations (Pearsons correlation coefficients) were found between initial and repeat assessments of all measures but there was little agreement about the need for removal (Kappa values: 0.54 for oral surgeons and 0.41 for the family dentists). For every item studied, changes in position on the visual analogue scale of two-thirds or more of the total length occurred from the first to the second assessment. CONCLUSION: Treatment decisions about whether or not to remove asymptomatic third molars were not made on a rational basis. Since similar conclusions were recorded in a previous Swedish study, it is inferred that until further high quality evidence of disease prediction is published, decisions to remove third molars prophylactically cannot be made reliably.

Agreement between practitioners concerning removal of asymptomatic third molars.

OBJECTIVE: To investigate and compare agreement within two groups of dental practitioners, family dentists and oral surgeons, in their decisions regarding removal of asymptomatic mandibular third molars. SUBJECTS: Ten oral surgeons and 18 family dentists from South Wales with experience ranging from 5 to 28 years. METHODOLOGY: Participants were presented with periapical radiographs of 36 asymptomatic, mandibular third molars and were informed of the age and gender of the patients and the degree of eruption of the third molars. Participants were asked to indicate whether they thought that the third molar should be removed or not. The degree of agreement between participants was measured by kappa indices for multiple raters. RESULTS: The kappa indices were 0.14 for the oral surgeons and 0.09 for the family dentists, indicating poor agreement beyond chance. Although in most cases the participants decided not to remove the third molar, they did so inconsistently, that is, they did not make this decision on the same cases. There were also differences in the inclination of the participants to suggest removal of the 36 third molars. CONCLUSION: Poor inter-observer agreement suggested that treatment decisions regarding asymptomatic third molars are based more on subjective beliefs and habitual practices than on rational decision making.

Treatment strategies for lower third molars following orthodontic care.

To examine the extent to which orthodontists consider it appropriate to refer post-orthodontic patients for lower third molar treatment. The subjects were 10 orthodontists from hospital, specialist practice and community setting. Participants were presented with 15 case histories of orthodontic patients (including full records) and asked to state whether they would have referred the case to an oral surgeon for management of their third molars. Data were analysed using multi-kappa measure. Two-hundred-and-sixty-two decisions of 300 (88%) were not to refer cases for third molar management. Little consensus was seen between orthodontists on which post-orthodontic cases referral (kappa = 0.14). Some clinicians referred cases much more frequently than others (Kruskall-Wallis = 46.84, P < 0.001) and some clinicians referred much more frequently (Kruskall-Wallis = 85.57, P < 0.001). This group of orthodontists did not refer post-orthodontic cases for third molar management and little consensus was observed regarding which cases did warrant removal.