Can Safe Clinical Thinking be Taught?

OBJECTIVES: To determine if: (a) safe clinical decision making can be taught to undergraduate final year medical students and (b) if such students can be taught to specifically recognise illness severity from nominal clinical data. 
METHODS: 115 final year undergraduate medical students completed a 3 hour interactive Safe Thinking Workshop which focussed entirely on nontechnical skills such as potential perceptive pitfalls, attention to detail, teamwork and safe clinical decision making. The study involved students inspecting and interpreting a set of arterial blood gas results relating to a patient with acute respiratory distress, then answering a short questionnaire addressing biochemical diagnosis, clinical diagnosis and effective management. A separate question was embedded in the questionnaire to determine if astute students could determine the severity of the illness from the CO2 value provided. The study group (n = 58) completed the questionnaire immediately after the Safe Thinking Workshop, whilst the control group (n = 57) completed the questionnaire prior to the Workshop.
RESULTS: The mean total score for study students was 80.51%, with a mean total score of 63.86% for the control group (Student’s t-test; p<0.05). Correct classification of illness severity was observed in 10.35% of study students, compared with 3.51% of control students (p<0.05). 
CONCLUSION: These results suggest that safe clinical decision making and recognition of illness severity can be fostered by specific teaching in the nontechnical skill areas described above.

FoodCAP: acid-labile protein adducts of heterocyclic amines in human blood are not viable biomarkers of HCA dietary exposure

Intake of heterocyclic amines (HCAs, carcinogens produced during cooking of meat/fish, the most abundant being PhIP, DiMeIQx and MeIQx) is influenced by many factors including type/thickness of meat and cooking method/temperature/duration. Thus, assessment of HCA dietary exposure is difficult. Protein adducts of HCAs have been proposed as potential medium-term biomarkers of exposure, e.g. PhIP adducted to serum albumin or haemoglobin. However, evidence is still lacking that HCA adducts are viable biomarkers in humans consuming normal diets. The FoodCAP project, supported by World Cancer Research Fund, developed a highly sensitive mass spectrometric method for hydrolysis, extraction and detection of acid-labile HCAs in blood and assessed their validity as biomarkers of exposure. Multiple acid/alkaline hydrolysis conditions were assessed, followed by liquid-liquid extraction, clean-up by cation-exchange SPE and quantification by UPLC-ESI-MS/ MS. Blood was analysed from volunteers who completed food diaries to estimate HCA intake based on the US National Cancer Institute’s CHARRED database. Standard HCAs were recovered quantitatively from fortified blood. In addition, PhIP/MeIQx adducts bound to albumin and haemoglobin prepared in vitro using a human liver microsome system were also detectable in blood fortified at low ppt concentrations. However, except for one sample (5pg/ml PhIP), acid-labile PhIP, 7,8-DiMeIQx, 4,8-DiMeIQx and MeIQx were not observed above the 2pg/ml limit of detection in plasma (n=35), or in serum, whole blood or purified albumin, even in volunteers with high meat consumption (nominal HCA intake >2µg/day). It is concluded that HCA blood protein adducts are not viable biomarkers of exposure. Untargeted metabolomic analyses may facilitate discovery of suitable markers.

Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial

Background: Ataluren was developed to restore functional protein production in genetic disorders caused by nonsense mutations, which are the cause of cystic fibrosis in 10% of patients. This trial was designed to assess the efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis. 

Methods: This randomised, double-blind, placebo-controlled, phase 3 study enrolled patients from 36 sites in 11 countries in North America and Europe. Eligible patients with nonsense-mutation cystic fibrosis (aged ≥6 years; abnormal nasal potential difference; sweat chloride >40 mmol/L; forced expiratory volume in 1 s [FEV₁] ≥40% and ≤90%) were randomly assigned by interactive response technology to receive oral ataluren (10 mg/kg in morning, 10 mg/kg midday, and 20 mg/kg in evening) or matching placebo for 48 weeks. Randomisation used a block size of four, stratified by age, chronic inhaled antibiotic use, and percent-predicted FEV₁. The primary endpoint was relative change in percent-predicted FEV₁ from baseline to week 48, analysed in all patients with a post-baseline spirometry measurement. This study is registered with ClinicalTrials.gov, number NCT00803205. 

Findings: Between Sept 8, 2009, and Nov 30, 2010, 238 patients were randomly assigned, of whom 116 in each treatment group had a valid post-baseline spirometry measurement. Relative change from baseline in percent-predicted FEV₁ did not differ significantly between ataluren and placebo at week 48 (-2·5% vs -5·5%; difference 3·0% [95% CI -0·8 to 6·3]; p=0·12). The number of pulmonary exacerbations did not differ significantly between treatment groups (rate ratio 0·77 [95% CI 0·57-1·05]; p=0·0992). However, post-hoc analysis of the subgroup of patients not using chronic inhaled tobramycin showed a 5·7% difference (95% CI 1·5-10·1) in relative change from baseline in percent-predicted FEV₁ between the ataluren and placebo groups at week 48 (-0·7% [-4·0 to 2·1] vs -6·4% [-9·8 to -3·7]; nominal p=0·0082), and fewer pulmonary exacerbations in the ataluern group (1·42 events [0·9-1·9] vs 2·18 events [1·6-2·7]; rate ratio 0·60 [0·42-0·86]; nominal p=0·0061). Safety profiles were generally similar for ataluren and placebo, except for the occurrence of increased creatinine concentrations (ie, acute kidney injury), which occurred in 18 (15%) of 118 patients in the ataluren group compared with one (<1%) of 120 patients in the placebo group. No life-threatening adverse events or deaths were reported in either group. I

nterpretation: Although ataluren did not improve lung function in the overall population of nonsense-mutation cystic fibrosis patients who received this treatment, it might be beneficial for patients not taking chronic inhaled tobramycin. 

Funding: PTC Therapeutics, Cystic Fibrosis Foundation, US Food and Drug Administration's Office of Orphan Products Development, and the National Institutes of Health. 

Characterisation of a two-dimensional liquid-filled ion chamber detector array using flattened and unflattened beams for small fields, small MUs and high dose-rates

In this study, the PTW 1000SRS array with Octavius 4D phantom was characterised for FF and FFF beams. MU linearity, field size, dose rate, dose per pulse (DPP) response and dynamic conformal arc treatment accuracy of the 1000SRS array were assessed for 6MV, 6FFF and 10FFF beams using a Varian TrueBeam STx linac. The measurements were compared with a pinpoint IC, microdiamond IC and EBT3 Gafchromic film. Measured dose profiles and FWHMs were compared with film measurements. Verification of FFF volumetric modulated arc therapy (VMAT) clinical plans were assessed using gamma analysis with 3%/3 mm and 2%/2 mm tolerances (10% threshold). To assess the effect of cross calibration dose rate, clinical plans with different dose rates were delivered and analysed. Output factors agreed with film measurements to within 4.5% for fields between 0.5 and 1 cm and within 2.7% for field sizes between 1.5 and 10 cm and were highly correlated with the microdiamond IC detector. Field sizes measured with the 1000SRS array were within 0.5 mm of film measurements. A drop in response of up to 1.8%, 2.4% and 5.2% for 6MV, 6FFF and 10FFF beams respectively was observed with increasing nominal dose rate. With an increase in DPP, a drop of up to 1.7%, 2.4% and 4.2% was observed in 6MV, 6FFF and 10FFF respectively. The differences in dose following dynamic conformal arc deliveries were less than 1% (all energies) from calculated. Delivered VMAT plans showed an average pass percentage of 99.5(±0.8)% and 98.4(±3.4)% with 2%/2 mm criteria for 6FFF and 10FFF respectively. A drop to 97.7(±2.2)% and 88.4(±9.6)% were observed for 6FFF and 10FFF respectively when plans were delivered at the minimum dose rate and calibrated at the maximum dose rate. Calibration using a beam with the average dose rate of the plan may be an efficient method to overcome the dose rate effects observed by the 1000SRS array.