Evaluating the UK's first national prescribing assessment for GPs in training using an online survey.

BACKGROUND: GP trainees may not have experienced a systematic and comprehensive education in safe prescribing. Therefore, a self-assessment prescribing review was developed. AIM: To determine whether the assessment was feasible, had face validity, and did not disadvantage particular groups of participants. DESIGN & SETTING: An online survey that evaluates the opinions of GPs in training of a prescribing assessment in the UK. All full-time UK trainees who started their final year of GP training in August 2019 undertook the prescribing assessment along with their trainers, after which they completed an online anonymous feedback questionnaire. METHOD: The questionnaire completed by trainees sought their opinions of the assessment, and collected ethnicity and disability data. The trainer questionnaire was similar but did not include any demographic information. RESULTS: The questionnaire was completed by 1741 trainees and 1576 trainers. There was no evidence that ethnic group and disability were related to aspects of the review. Most of the trainees (76.4%, n = 1330) and trainers (82.0%, n = 1293) agreed or strongly agreed that the prescribing review was helpful for assessing and learning about the trainee's prescribing. However, most participants (63.2%, n = 1092) took >4 hours to review their prescriptions. A majority of trainees (90.2%, n = 1571) reported that completing the assessment had resulted in a change in their prescribing practice. CONCLUSION: The majority of trainers and trainees reported that the prescribing assessment was helpful. The study was not able to assess whether there had been an actual change in practice that resulted in an error reduction.

Comparison of the effectiveness of exclusively facilitated clinical teaching as an alternative to traditional practice-based primary care placements.

INTRODUCTION: COVID-19 presented major challenges to undergraduate GP placement capacity and there was an increased reliance on clinical training using facilitated simulation. The authors present a novel comparison of the effectiveness and cost-effectiveness of delivering a one-week primary care course using entirely GP-facilitated clinical teaching outside the GP setting against traditional practice-based GP clinical education. METHODS: A one-week GP placement was redeveloped from a traditional teaching model (TT-M) to an exclusively facilitated teaching model (FT-M) delivered outside the GP practice setting, using principles of blended learning, flipped classroom methods, e-learning and simulation. Both teaching models, delivered in different locations during 2022 to pre-clinical students, were evaluated using student feedback surveys for attainment of learning outcomes and course satisfaction. RESULTS: The students reported their consultation skills and clinical knowledge (amalgamated mean score 4.36 for FT-M versus 4.63 for TT-M; P = 0.05), as well as preparation for the clinical phases (mean scores 4.35 for FT-M versus 4.41 for TT-M; P = 0.68), were well developed and similar for both courses. Students reported similar enjoyment across both teaching models (FT-M mean score 4.31 versus 4.41 for TT-M; P = 0.49). The costs for delivering teaching per 4-h session for 100 students were £1,379 and £5,551 for FT-M and TT-M, respectively. CONCLUSION: Delivery of a one-week primary care attachment to third year medical students using an FT-M was similarly effective and more cost effective than delivering it by a TT-M. FT-M potentially offers an important adjunct to clinical learning and resilience to capacity challenges for GP placements.

A first-order approximation of floodplain soil organic carbon stocks in a river network: The South Platte River, Colorado, USA as a case study.

The lack of watershed-scale estimates of floodplain carbon stocks limits recognition of the important role of floodplains and river corridor restoration in efforts to enhance carbon sequestration. We use the South Platte River watershed of Colorado, USA as a case study to illustrate spatial patterns of, and controls on, floodplain carbon stocks at the watershed scale. This case study illustrates the disproportionate importance of floodplains for soil carbon stocks relative to adjacent uplands and provides an example of how spatially explicit data can be used to prioritize floodplain restoration with regard to carbon sequestration. We use the hydrogeomorphic floodplain tool GFPLAIN to delineate the extent of 100-year floodplains in the South Platte River watershed. We distinguish elevation bands for the steppe, montane, subalpine, and alpine zones. We also differentiate bead (floodplain width/channel width ≥ 5) and string (floodplain width/channel width < 5) reaches within the montane and subalpine zones. Drawing on prior, field-based measurements of organic carbon stock in downed, dead wood and soil in these floodplain types, we estimate total floodplain organic carbon stock based on median values of stock in different floodplain types and the spatial extent of these floodplain types. This estimate includes organic carbon stocks in lake and reservoir sediments in the watershed. Soil constitutes the greatest reservoir of floodplain carbon. The total estimated area of floodplain is 2916 km2, which is 4.3 % of the total watershed area of the South Platte River. Our preferred estimate is 42.7 Tg C stock (likely range of 39.1-42.7 Tg). This equates to 11.1 % of a previously estimated overall carbon stock (above and belowground biomass and soil organic carbon) in the entire watershed of 384 Tg C. Floodplains are thus disproportionately important, relative to their surface area, in storing organic carbon in this semiarid watershed. Field measurements of floodplain soil organic carbon stocks from across the globe indicate that this finding is not unique to this watershed, with implications for prioritizing floodplain management and restoration as a means of enhancing carbon sequestration.

A river ran through it: Floodplains as America's newest relict landform.

Artificial levees are a major human modification of river corridors, but we still do not have a clear understanding of how artificial levees affect floodplain extent at regional and larger scales. We estimated changes in river-floodplain connectivity due to artificial levees in the contiguous United States (CONUS) using a combination of artificial levee databases, delineations of floodplain areas, and deletion of artificial levees from topography. Our results indicate that artificial levees do not only decrease floodplain extent but also alter locations of floodplain connectivity. Anthropogenically connected and disconnected locations are similar in land cover and are predominantly, in decreasing order of extent, cultivated, wetland, forested, and developed land cover types, with more than 30% of the entire floodplain area in the CONUS cultivated or developed. This study indicates that artificial levees cause complex changes in river-floodplain connectivity and can increase flooded areas in some rivers.

Levees don't protect, they disconnect: A critical review of how artificial levees impact floodplain functions.

Despite the recognition of floodplain importance in the scientific community, floodplains are not afforded the same legal protection as river channels. In the United States alone, flood-related economic losses were much higher in the second half of the 20th century than the first half despite the expenditure of billions of dollars on flood defenses. Partially to blame are the low appraisal and understanding of human impacts to floodplain functions. Here, we explore the impacts of levees on floodplain functions and analyze case studies of floodplain restoration through levee removal. Floodplain functions include (1) fluxes of water, solutes, and particulate materials; (2) enhanced spatial heterogeneity of hydrology and biogeochemistry; (3) enhanced habitat abundance and diversity; (4) enhanced biomass and biodiversity; and (5) hazard mitigation. Case studies of floodplain restoration involving artificial levee adjustment are heavily concentrated in North America, Europe, and Japan, and those case studies assess floodplain functions within 30 years of restoration. In the United States, restoration through levee removal comprises less than 1% of artificial levee length and 1-2% of disconnected floodplains. In Europe, restoration effectiveness was severely limited by upstream flow regulation. Most case studies were impacted by stressors outside the study site and took place in lowland alluvial rivers. Reconfiguration was successful at achieving limited aims while reconnection set floodplains on a trajectory to more fully restore floodplain functions. Case studies illustrated the tension between restoration scale and study resolution in time and space as well as the role of site-specific characteristics in determining restoration outcomes. Numerous knowledge gaps surrounding the integrative relationships between floodplain functions must be addressed in future studies. The ubiquity of flow regulation demands that future floodplain restoration occur in a whole-of-basin manner. Monitoring of restoration must take place for longer periods of time and include multiple functions.

The frequency and nature of prescribing problems by GPs-in-training (REVISiT): a retrospective review.

BACKGROUND: Prescribing errors can cause significant morbidity and occur in about 5% of prescriptions in English general practices. AIM: To describe the frequency and nature of prescribing problems in a cohort of GPs-in-training to determine whether they need additional prescribing support. DESIGN & SETTING: A primary care pharmacist undertook a retrospective review of prescriptions issued between 9 October 2014 and 11 March 2015 by 10 GPs in their final year of training from 10 practices in England. METHOD: Pre-existing standards and expert panel discussion were used to classify the appropriateness of prescribing. Data were imported into Stata (version 13) to perform descriptive analysis. An individualised report highlighting prescribing errors, suboptimal prescribing, and areas of good practice identified during the review was shared with the GPs-in-training and their trainers. This report was used to guide discussions during the GP-in-training's feedback session. RESULTS: A total of 1028 prescription items were reviewed from 643 consultations performed by 10 GPs-in-training. There were 92 prescribing errors (8.9%) and 360 episodes of suboptimal prescribing (35.0%). The most common types of error concerned medication dosages (n = 30, 32.6% of errors). CONCLUSION: Personalised review of prescribing revealed an error rate higher than recorded in a previous similar study mainly comprising GPs who had completed postgraduate training, and a substantially higher rate of suboptimal prescribing. A larger intervention study is now required to evaluate the effectiveness of receiving a personalised review of prescribing, and to assess its impact on patient safety.

Developing good practice by understanding how UK medical schools address low level concerns: a survey study.

In the literature, a distinction is made between low-level concerns and what is regarded as fitness to practise concerns. The General Medical Council expects all UK medical schools to have a transparent process in place about how concerns about its medical students are identified monitored and responded to. However, internationally, there is currently no well-established consensus on what is good practice in managing low-level concerns. Furthermore, currently, there is little information on how the UK medical schools vary in the processes they implement to monitor and respond to low-level concerns of their students. An online survey was developed and informed by the literature and sent to all UK medical schools to better understand their low-level concerns process. Of 39 medical schools invited, 25 participated. The data indicate variations between medical schools in the processes implemented. These variations can potentially influence the quality of the data; for example, whether there is a named person co-ordinating concerns between medical schools and placement providers. Furthermore, the data identify primary-care-based learning as offering missed opportunities where low-level concerns could be picked up. Key areas identified within the data for further work include how to quality assure that processes are equitable and how to bring more consistency to what sanctions are common and how these are decided up on.

The evaluation of an e-learning prescribing course for general practice.

Prescribed medication may lead to significant morbidity or mortality as a result of these medications causing adverse events, or because of a prescribing error. E-learning is a common tool used in supporting training in prescribing. This paper describes the development of an e-learning course and the subsequent evaluation undertaken by the users with the aim of obtaining an effective e-learning course for prescribing. The e-learning course was developed by general practitioners and pharmacists and focussed on the principles of good prescribing, examined the common reasons for prescribing errors, and was evaluated using self-reported quantitative and qualitative measures. Scores significantly increased on an assessment given before and after the course. The majority of respondents reported that the e-learning course had a positive impact on prescribing knowledge, skills and attitudes, with medication reviews the top area where a change in prescribing practice was reported. Over 90% of the respondents agreed that the e-learning course was easy to use and a useful part of their continuing professional education. This study shows that clinicians recognise the on-going need for training in prescribing, but the lack of training is one of the factors contributing to errors, which suggests that more education is needed, not just for GPs in training, but for qualified GPs as well.

A qualitative evaluation of a prescribing e-learning package for general practice.

BACKGROUND: The GMC PRACtiCe study identified a 1 in 20 error rate in prescriptions issued in general practice and identified a need for further training in prescribing. As a result, an e-Learning prescribing package was designed and launched to healthcare professionals through the Royal College of General Practitioners in January 2014. AIM: This part of the study explored the longer-term impact on prescribing knowledge, attitudes and behaviours of practitioners completing the eLearning prescribing package. METHOD: On completion of the e-Learning package, participants were asked to indicate their willingness to be contacted for a telephone interview. Semi-structured interviews were conducted which were audio recorded, transcribed verbatim and analysed using thematic analysis, aided by NVivo. Interviewees were invited to enter a prize draw to win Stockley's Drug Interaction textbook (provided courtesy of the Royal Pharmaceutical Society). RESULTS: Of the 120 participants who expressed an interest in being followed up for interview, seven prescribers were interviewed in 2014 and 2015. Reasons for completing the course were explored, and interviewees gave examples of changes made to their prescribing practice as a result of completing the e-Learning. This included the adoption of specific strategies to enhance safe practice, and enacting enhanced vigilance in key areas such as renal function monitoring. Some changes to the course content and presentation were also recommended. CONCLUSION: These interviews have highlighted the potential for using e-Learning for prescribing training and to achieve long-term changes in prescribing practice. However, further work is needed to generate substantive evidence of its impact on prescribing.

An improved cell-permeable fluorogenic substrate as the basis for a highly sensitive test for NAD(P)H quinone oxidoreductase 1 (NQO1) in living cells.

NAD(P)H:quinone oxidoreductase 1 (NQO1) is a flavoenzyme upregulated in response to oxidative stress and in some cancers. Its upregulation by compounds has been used as an indicator of their potential anti-cancer properties. In this study we have designed, produced and tested a fluorogenic coumarin conjugate which selectively releases highly fluorescent 4-methylumbelliferone (4-MU) in the presence of NQO1. It was found that measuring 4-MU release rapidly and specifically quantitated NQO1 levels in vitro and in live cells. Both the substrate and its products freely perfused through cell membranes and were non-toxic. The substrate was very specific with low background, and the assay itself could be done in less than 10minutes. This is the first assay to allow the quantitation of NQO1 in live cells which can then be retained for further experiments.

Studies relating to the synthesis, enzymatic reduction and cytotoxicity of a series of nitroaromatic prodrugs.

A series of N-nitroarylated-3-chloromethyl-1,2,3,4-tetrahydroisoquinoline derivatives, several of which also possessed a trifluoromethyl substituent, were prepared and assessed as potential nitroaromatic prodrugs. The enzymatic reduction of these compounds and their cytotoxicities were studied. The compounds were cytotoxic, but this is probably not related to their enzymatic reduction.

A BEME systematic review of UK undergraduate medical education in the general practice setting: BEME Guide No. 32.

BACKGROUND: General practice is increasingly used as a learning environment in undergraduate medical education in the UK. AIM: The aim of this project was to identify, summarise and synthesise research about undergraduate medical education in general practice in the UK. METHODS: We systematically identified studies of undergraduate medical education within a general practice setting in the UK from 1990 onwards. All papers were summarised in a descriptive report and categorised into two in-depth syntheses: a quantitative and a qualitative in-depth review. RESULTS: 169 papers were identified, representing research from 26 UK medical schools. The in-depth review of quantitative papers (n = 7) showed that medical students learned clinical skills as well or better in general practice settings. Students receive more teaching, and clerk and examine more patients in the general practice setting than in hospital. Patient satisfaction and enablement are similar whether a student is present or not in a consultation, however, patients experience lower relational empathy. Two main thematic groups emerged from the qualitative in-depth review (n = 10): the interpersonal interactions within the teaching consultation and the socio-cultural spaces of learning which shape these interactions. The GP has a role as a broker of the interactions between patients and students. General practice is a socio-cultural and developmental learning space for students, who need to negotiate the competing cultures between hospital and general practice. Lastly, patients are transient members of the learning community, and their role requires careful facilitation. CONCLUSIONS: General practice is as good, if not better, than hospital delivery of teaching of clinical skills. Our meta-ethnography has produced rich understandings of the complex relationships shaping possibilities for student and patient active participation in learning.

Spores of Clostridium engineered for clinical efficacy and safety cause regression and cure of tumors in vivo.

Spores of some species of the strictly anaerobic bacteria Clostridium naturally target and partially lyse the hypoxic cores of tumors, which tend to be refractory to conventional therapies. The anti-tumor effect can be augmented by engineering strains to convert a non-toxic prodrug into a cytotoxic drug specifically at the tumor site by expressing a prodrug-converting enzyme (PCE). Safe doses of the favored prodrug CB1954 lead to peak concentrations of 6.3 µM in patient sera, but at these concentration(s) known nitroreductase (NTR) PCEs for this prodrug show low activity. Furthermore, efficacious and safe Clostridium strains that stably express a PCE have not been reported. Here we identify a novel nitroreductase from Neisseria meningitidis, NmeNTR, which is able to activate CB1954 at clinically-achievable serum concentrations. An NmeNTR expression cassette, which does not contain an antibiotic resistance marker, was stably localized to the chromosome of Clostridium sporogenes using a new integration method, and the strain was disabled for safety and containment by making it a uracil auxotroph. The efficacy of Clostridium-Directed Enzyme Prodrug Therapy (CDEPT) using this system was demonstrated in a mouse xenograft model of human colon carcinoma. Substantial tumor suppression was achieved, and several animals were cured. These encouraging data suggest that the novel enzyme and strain engineering approach represent a promising platform for the clinical development of CDEPT.

The synthesis of 2-nitroaryl-1,2,3,4-tetrahydroisoquinolines, nitro-substituted 5,6-dihydrobenzimidazo[2,1-a]isoquinoline N-oxides and related heterocycles as potential bioreducible substrates for the enzymes NAD(P)H: quinone oxidoreductase 1 and E. coli nitroreductase.

A series of 2-nitroaryl-1,2,3,4-tetrahydroisoquinolines 10 and nitro-substituted 5,6-dihydrobenzimidazo[2,1-a]isoquinoline N-oxides 11 have been synthesised and evaluated as potential bioreducible substrates for the enzymes NAD(P)H: quinone oxidoreductase 1 (NQO1) and Escherichia coli nitroreductase (NR). Also prepared and evaluated were 2-(3,5-dinitropyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline 12 and 5,6-dihydro-10-nitropyrido[3″,2″:4',5']imidazo[2',1'-a]isoquinoline 12-oxide 13. Both compounds 10b and 13 were reduced faster by human NQO1 than by CB-1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide].

Synthesis and structure-activity relationships of nitrobenzyl phosphoramide mustards as nitroreductase-activated prodrugs.

A series of nitrobenzyl phosphoramide mustards and their analogs was designed and synthesized to explore their structure-activity relationships as substrates of nitroreductases from Escherichia coli and trypanosomes and as potential antiproliferative and antiparasitic agents. The position of the nitro group on the phenyl ring was important with the 4-nitrobenzyl phosphoramide mustard (1) offering the best combination of enzyme activity and antiproliferative effect against both mammalian and trypanosomatid cells. A preference was observed for halogen substitutions ortho to benzyl phosphoramide mustard but distinct differences were found in their SAR of substituted 4-nitrobenzyl phosphoramide mustards in E. coli nitroreductase-expressing cells and in trypanosomatids expressing endogenous nitroreductases.

Quinone oxidoreductase-2-mediated prodrug cancer therapy.

DNA-damaging agents are widely used in cancer treatment despite their lack of tumor specificity. Human NQO2 (quinone oxidoreductase-2) is an atypical oxidoreductase because no endogenous electron donor has been identified to date. The enzyme converts CB1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide], in the presence of the synthetic nicotinamide cofactor analog EP0152R, to a cytotoxic bifunctional alkylating agent. NQO2 activity in hepatocellular tumor tissue is higher than that in other cancer types by a factor of 6 and higher than that in bone marrow by a factor of 20. Structural data from x-ray crystallography and nuclear magnetic resonance spectroscopy allowed us to construct a model of CB1954 and EP0152R binding to NQO2, which suggested an optimal infusion schedule for a phase I trial combining the two agents. Thirty-two patients were treated, and diarrhea and serum transaminase concentrations defined a maximum tolerated dose for the drug combination. There was a clear pharmacokinetic interaction, with EP0152R inducing a marked increase in clearance of CB1954, in keeping with model predictions. We detected DNA interstrand cross-links caused by nitroreduced CB1954 in tumor biopsies from treated patients, demonstrating that the activated prodrug exerts its cytotoxic properties through DNA base alkylation.

Testing double mutants of the enzyme nitroreductase for enhanced cell sensitisation to prodrugs: effects of combining beneficial single mutations.

Prodrug activation gene therapy for cancer involves expressing prodrug-activating enzymes in tumour cells, so they can be selectively killed by systemically administered prodrug. For example, Escherichia colinfsB nitroreductase (E.C. 1.6.99.7)(NTR), sensitises cells to the prodrug CB1954 (5-[aziridin-1-yl]-2,4-dinitrobenzamide), which it converts to a potent DNA-crosslinking agent. However, low catalytic efficiency with this non-natural substrate appears to limit the efficacy of this enzyme prodrug combination for eliminating the target cancer cells. To improve this, we aim to engineer NTR for improved prodrug activation. Previously, a number of single amino acid substitutions at six positions around the active site of the enzyme were found to increase activity, resulting in up to approximately 5-fold enhanced cell sensitisation to CB1954. In this study we have made pairwise combinations among some of the best mutants at each of these 6 sites. A total of 53 double mutants were initially screened in E. coli, then the 7 most promising were inserted into an adenovirus vector and compared in SKOV3 human ovarian carcinoma cells for sensitisation to CB1954 and two alternative prodrugs. The most effective mutants, T41L/N71S and T41L/F70A, were 14-17-fold more potent than WT NTR at sensitising the cancer cells to CB1954. The best mutant for activation of the dinitrobenzamide mustard prodrug SN23862 was T41L/F70A (4.8-fold improvement); and S40A/F124M showed 1.7-fold improvement over WT with the nitrobenzylphosphoramide mustard prodrug LH7. In two tumour xenograft models using SKOV3 or human prostate carcinoma PC3, T41L/N71S NTR demonstrated greater CB1954-dependent anti-tumour activity than WT NTR.