Scientific Review of the Proarrhythmic Risks of Oligonucleotide Therapeutics: Are Dedicated ICH S7B/E14 Studies Needed for Low-Risk Modalities?

Oligonucleotide therapeutics (ONTs) represent a new modality with unique pharmacological and chemical properties that modulate gene expression with a high degree of target specificity mediated by complementary Watson-Crick base pair hybridization. To date, the proarrhythmic assessment of ONTs has been influenced by International Conference on Harmonization (ICH) E14 and S7B guidance. To document current hERG/QTc evaluation practices, we reviewed US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) Approval Packages (source: PharmaPendium.com) and collated preclinical and clinical studies for 17 marketed ONTs. In addition, clinical QTc data from 12 investigational ONTs were obtained from the literature. Of the marketed ONTs, eight were tested in the hERG assay with no inhibitory effect identified at the top concentration (range: 34-3,000 µM) tested. Fourteen of the ONTs were evaluated in nonhuman primate cardiovascular studies with 11 of them in dedicated telemetry studies. No effect on QTc intervals were observed (at high exposure multiples) in all studies. Clinically, four ONTs were evaluated in TQT studies; an additional six ONTs were assessed by concentration-QTc interval analysis, and six by routine safety electrocardiogram monitoring. None of the clinical studies identified a QTc prolongation risk; the same was true for the 12 investigational ONTs. A search of the FDA Adverse Event Database indicated no association between approved ONTs and proarrhythmias. Overall, the collective weight of evidence from 29 ONTs demonstrate no clinical proarrhythmic risk based on data obtained from ICH S7B/E14 studies. Thus, new ONTs may benefit from reduced testing strategies because they have no proarrhythmic risk, a similar cardiac safety profile as monoclonal antibodies, proteins, and peptides.

Prevalence and associations of prescribing of long-acting reversible contraception by general practitioner registrars: a secondary analysis of ReCEnT data.

OBJECTIVE: Long-acting reversible contraception (LARC) is the most effective form of contraception but use in Australia is low. Uptake of LARC prescribing by early-career general practitioners (GPs) has important implications for community reproductive health. We aimed to investigate the prevalence and associations of Australian GP registrars' LARC prescribing. METHODS: A cross-sectional analysis of the Registrar Clinical Encounters in Training (ReCEnT) cohort study 2010-2017. GP registrars collected data on 60 consecutive consultations on three occasions during their training. The outcome factor was prescription of LARC (compared with non-LARC). A secondary analysis was performed with problems involving prescription of LARC (compared with other problems). Associations with patient, practice, registrar and consultation independent variables were assessed by univariate and multivariable logistic regression. RESULTS: 1737 registrars recorded 5382 problems/diagnoses involving women aged 12-55 years in which contraception was prescribed. 1356 (25%) involved LARC. Significant multivariable associations of prescribing LARC included patient age (OR 2.85, 95% CI 3.17 to 3.74, for age 36-45 years compared with age 12-18 years), practice rurality - inner-regional (OR 1.47, 95% CI 1.22 to 1.79) and outer-regional/remote/very remote (OR 1.47 95% CI 1.15 to 1.87) compared with major cities, practices in areas of lower socioeconomic status (SES) (OR 0.93, 95% CI 0.91 to 0.96 for SES by decile), generating learning goals (OR 1.37, 95% CI 1.04 to 1.79), in-consultation assistance-seeking (OR 1.58, 95% CI 1.24 to 2.01), and the registrar having reproductive health-related postgraduate qualifications (OR 1.33, 95% CI 1.01 to 1.76). CONCLUSIONS: The prevalence of LARC prescribing by Australian GP registrars is higher than has been previously estimated in established GPs. Postgraduate qualifications in reproductive health are associated with prescribing LARC. Prescribing practice differs according to rurality and relative socioeconomic disadvantage.

General practice registrars' use of dermoscopy: Prevalence, associations and influence on diagnosis and confidence.

BACKGROUND AND OBJECTIVES: Dermoscopy increases accuracy for melanoma diagnosis by trained primary care physicians. We aimed to establish prevalence of dermatoscope use by general practice registrars, and identify factors associated with dermatoscope use and the implications of dermatoscope use for diagnosis and confidence in diagnosis. METHOD: This was a cross-sectional study nested within the Registrar Clinical Encounters in Training (ReCEnT) project, an ongoing multi-site cohort study of general practice registrars' consultations. The study was conducted during two six-monthly rounds of ReCEnT data collection in four regional training providers in 2014. RESULTS: Forty-nine per cent of registrars reported having dermoscopy training. Dermoscopy was used in 61% of consultations involving skin or pigmented lesion checks. Dermatoscope use changed provisional diagnosis in 22% of instances and increased diagnostic confidence in 55%. DISCUSSION: Dermoscopy is performed by general practice registrars in a modest proportion of skin and pigmented lesion checks. Its use influences registrars' diagnoses and increases their confidence in their diagnoses.

Emergency department referral patterns of Australian general practitioner registrars: a cross-sectional analysis of prevalence, nature and associations.

Objective Limited international evidence suggests general practice registrars' emergency department (ED) referral rates exceed those of established general practitioners (GPs). The aim of the present study was to fill an evidence gap by establishing the prevalence, nature and associations of Australian GP registrar ED referrals. Methods A cross-sectional analysis was performed of the Registrar Clinical Encounters in Training (ReCEnT) cohort study of GP registrars' consultation experiences, between 2010 and 2015. The outcome factor in logistic regression analysis was referral to an ED. Independent variables included patient-level, registrar-level, practice-level and consultation-level factors. Results In all, 1161 GP registrars (response rate 95.5%) contributed data from 166966 consultations, comprising 258381 individual problems. Based on responses, 0.5% of problems resulted in ED referral, of which nearly 25% comprised chest pain, abdominal pain and fractures. Significant (P < 0.05) associations of ED referral included patient age <15 and >34 years, the patient being new to the registrar, one particular regional training provider (RTP), in-consultation information or assistance being sought and learning goals being generated. Outer regional-, remote- or very remote-based registrars made significantly fewer ED referrals than more urban registrars. Of the problems referred to the ED, 45.5% involved the seeking of in-consultation information or assistance, predominantly from supervisors. Conclusions Registrars' ED referral rates are nearly twice those of established GPs. The findings of the present study suggest acute illnesses or injuries present registrars with clinical challenges and real learning opportunities, and highlight the importance of continuity of care, even for acute presentations. What is known about the topic? A GP's decision concerning continued community- versus hospital-based management of acute presentations demands careful consideration of a suite of factors, including implications for patient care and resource expenditure. General practice vocational training is a critical period for the development of GP registrars' long-term patterns of practice. Although limited international evidence suggests GP registrars and early career GPs refer patients to the ED at a higher rate than their more experienced peers, these studies involved small subject numbers and did not investigate associations of registrars making an ED referral. Relevant Australian studies focusing on GP registrars' ED referral patterns are lacking. What does this paper add? The present ongoing cohort study is the first to establish the patterns of ED referrals made by Australian GP registrars, encompassing five general practice RTPs across five states, with participating registrars practising in urban, rural, remote and very remote practices. Several significant associations were found with GP registrars making ED referrals, including patient age, continuity of care, the registrar's RTP, assistance sought by the registrar and rurality of the registrar's practice. What are the implications for practitioners? The higher likelihood of GP registrars seeing acute presentations than their more established practice colleagues, coupled with a demonstrated association of registrars seeking in-consultation assistance for such presentations, highlights the importance of GP supervisor accessibility in facilitating ED referral appropriateness and in the development of registrars' safe clinical practice.

General practice registrars' clinical exposure to dermatological procedures during general practice training: a cross-sectional analysis.

Australian general practitioners (GPs) commonly manage dermatological conditions requiring procedures. GP registrars have limited pre-vocational training exposure to dermatology and find skin problems challenging. We aimed to establish the prevalence, nature and associations of GP registrars' performance of skin procedures. We conducted a cross-sectional analysis from the Registrar Clinical Encounters in Training cohort study. Multivariable logistic regression was used to establish associations of our outcome (skin procedures, both including and excluding cryotherapy). Independent variables included patient and doctor demographics, diagnoses/problems managed and registrars' recourse to in-consultation assistance/information. A total of 1161 registrars provided data on 166,988 consultations, recording 2927 skin procedures (16.7% of all procedures; performed in 1.7% of consultations). Cryotherapy, excision, punch biopsy and shave biopsy were most common. More complex procedures were performed infrequently. Significant associations of performing procedures included rural/remote location (compared to major city), male patients, patient age 65+ (compared to age 15-34) and registrars seeking in-consultation information/assistance. Skin procedures were less likely for Aboriginal patients or those from non-English-speaking backgrounds. For non-cryotherapy procedures, rurality was not significantly associated, but significant differences were found between training regions. In summary, GP registrars perform fewer dermatological procedures compared to established GPs. Findings will inform GP vocational training in skin procedures.

Integration of cardiac energetics, function and histology from isolated rat hearts perfused with doxorubicin and doxorubicin-ol; a model for use in drug safety evaluations.

The isolated rat heart (Langendorff) assay combined with NMR spectroscopy and histology were used to elucidate functional, metabolic, and histological signs of cardiotoxicity resulting from acute exposure to clinically relevant concentrations of doxorubicin and its metabolite dox-ol. Doxorubicin blood concentrations and pharmacokinetic parameters were assessed following a clinically relevant dose of 2 mg/kg in order to select concentrations for isolated heart perfusions. Isolated rat hearts were exposed to 1 or 10 µM of doxorubicin or 0.3 µM dox-ol for at least 60 min using the Langendorff perfusion method. Effects on heart function were monitored using ECGs, left ventricular contraction parameters, and microscopic histology. Cardiac energetics (PCr, ATP, and Pi) were evaluated before, during, and after exposure to doxorubicin/dox-ol in perfused hearts using NMR spectroscopy. Cardiac effects were evident following clinically relevant concentrations of doxorubicin and dox-ol in isolated rat hearts demonstrated by altered heart function, energetic reserve, and microscopic lesions. A cardiac stress test utilizing isoproterenol resulted in enhanced functional response and reductions in PCr in doxorubicin versus vehicle treated hearts indicating possible alterations in the isoproterenol mediated pathway. Dox-ol treated hearts were similar to control with regard to function, but exhibited histologic findings. The use of combined Langendorff/NMR/histology methodologies allowed for comparison of multiple indices of cardiac function at one time in which cardiac effects were evident in multiple parameters. SHORT ABSTRACT: The isolated rat heart assay combined with NMR spectroscopy and histology was used to elucidate functional, metabolic, and histological signs of cardiotoxicity resulting from acute exposure to clinically relevant concentrations of doxorubicin and its metabolite dox-ol. Heart function was altered and microscopic signs of toxicity were evident with dox and dox-ol exposures. The use of combined Langendorff/NMR/histology assays allowed for comparison of multiple indices of cardiac function at one time in which cardiac effects were evident in multiple parameters.

Changes in Australian Early-Career General Practitioners' Benzodiazepine Prescribing: a Longitudinal Analysis.

BACKGROUND: Australian and international guidelines recommend benzodiazepines and related drugs (hereafter "benzodiazepines") as second-line, short-term medications only. Most benzodiazepines are prescribed by general practitioners (GPs; family physicians). Australian GP registrars ("trainees" or "residents" participating in a post-hospital training, apprenticeship-like, practice-based vocational training program), like senior GPs, prescribe benzodiazepines at high rates. Education within a training program, and experience in general practice, would be expected to reduce benzodiazepine prescribing. OBJECTIVE: To establish if registrars' prescribing of benzodiazepines decreases with time within a GP training program DESIGN: Longitudinal analysis from the Registrar Clinical Encounters in Training multi-site cohort study PARTICIPANTS: Registrars of five of Australia's 17 Regional Training Providers. Analyses were restricted to patients ≥ 16 years. MAIN MEASURES: The main outcome factor was prescription of a benzodiazepine. Conditional logistic regression was used, with registrar included as a fixed effect, to assess within-registrar changes in benzodiazepine-prescribing rates. The "time" predictor variable was "training term" (6-month duration Terms 1-4). To contextualize these "within-registrar" changes, a mixed effects logistic regression model was used, including a random effect for registrar, to assess within-program changes in benzodiazepine-prescribing rates over time. The "time" predictor variable was "year" (2010-2015). KEY RESULTS: Over 12 terms of data collection, 2010-2015, 1161 registrars (response rate 96%) provided data on 136,809 face-to-face office-based consultations. Two thousand six hundred thirty-two benzodiazepines were prescribed (for 1.2% of all problems managed). In the multivariable model, there was a significant reduction in within-program benzodiazepine prescribing over time (year) (p = < 0.001, OR = 0.94, CI = 0.90, 0.97). However, there was no significant change in 'within-registrar' prescribing over time (registrar Term) (p = 0.92, OR = 1.00 [95% CI = 0.94-1.06]). CONCLUSIONS: Despite a welcome temporal trend for reductions in overall benzodiazepine prescribing from 2010 to 2015, there is still room for improvement and our findings suggest a lack of effect of specific GP vocational training program education and, thus, an opportunity for targeted education.

Referrals to dietitians/nutritionists: A cross-sectional analysis of Australian GP registrars' clinical practice.

AIM: The present study aimed to describe referral patterns of general practitioner (GP) registrars to dietitians/nutritionists. There is a paucity of research regarding GP referral patterns to dietitians/nutritionists. Limited data show increasing referrals from established GPs to dietitians/nutritionists. There are no data on GP registrar (trainee) referrals. METHODS: This was a cross-sectional analysis of data from the Registrar Clinical Encounters in Training (ReCEnT) study. ReCEnT is an ongoing, multicentre, prospective cohort study of registrars, which documents 60 consecutive consultations of each registrar in each of the three six-month GP training terms. The outcome factor in this analysis was a problem/diagnosis resulting in dietitian/nutritionist referral (2010-2015). Independent variables were related to registrar, patient, practice and consultation. RESULTS: A total of 1124 registrars contributed data from 145 708 consultations. Of 227 190 problems/diagnoses, 587 (0.26% (confidence interval: 0.23-0.29)) resulted in dietitian/nutritionist referral. The most common problems/diagnoses referred related to overweight/obesity (27.1%) and type 2 diabetes (21.1%). Of referrals to a dietitian/nutritionist, 60.8% were for a chronic disease, and 38.8% were related to a Chronic Disease Management plan. Dietitian/nutritionist referral was significantly associated with a number of independent variables reflecting continuity of care, patient complexity, chronic disease, health equity and registrar engagement. CONCLUSIONS: Established patients with chronic disease and complex care needs are more likely than other patients to be referred by registrars to dietitians/nutritionists. Nutrition behaviours are a major risk factor in chronic disease, and we have found evidence for dietitian/nutritionist referrals representing one facet of engagement by registrars with patients' complex care needs.

Maintaining capacity for in-practice teaching and supervision of students and general practice trainees: a cross-sectional study of early career general practitioners.

Objectives Expanding learner cohorts of medical students and general practitioner (GP) vocational trainees and the impending retirement of the 'baby boomer' GP cohort threaten the teaching and supervisory capacity of the Australian GP workforce. Engaging newly qualified GPs is essential to sustaining this workforce training capacity. The aim of the present study was to establish the prevalence and associations of in-practice clinical teaching and supervision in early career GPs. Methods The present study was a cross-sectional questionnaire-based study of recent (within 5 years) alumni of three of Australia's 17 regional general practice training programs. The outcome factor was whether the alumnus taught or supervised medical students, GP registrars or other learners in their current practice. Logistic regression analysis was used to establish associations of teaching and supervision with independent variables comprising alumnus demographics, current practice characteristics and vocational training experiences. Results In all, 230 alumni returned questionnaires (response rate 37.4%). Of currently practising alumni, 52.4% (95% confidence interval (CI) 45.6-59.0%) reported current teaching or supervisory activities. Factors significantly (P<0.05) associated with alumni currently undertaking in-practice clinical teaching and supervision were: Australian medical graduation (odds ratio (OR) for international graduates 0.36; 95% CI 0.14-0.92), working in a regional or remote area (OR 2.75; 95% CI 1.24-6.11) and currently undertaking nursing home visits, home visits or after-hours work (OR 2.01; CI 1.02-3.94). Conclusions Rural-urban and country-of-graduation differences in the engagement of early career GPs in practice-based apprenticeship-like teaching or training should inform strategies to maintain workforce training capacity. What is known about the topic? Projected changes in the demand for and supply of clinical teaching and supervision within Australian general practice will require greater uptake of teaching and supervision by recently qualified GPs to ensure sustainability of this teaching model. Although interest in and undertaking of teaching roles have been documented for GP or family medicine trainees, studies investigating the engagement in these clinical roles by GPs during their early post-training period are lacking. What does this paper add? This paper is the first to document the prevalence of teaching and supervision undertaken by early career GPs as part of their regular clinical practice. We also demonstrate associations of practice rurality, country of medical graduation and undertaking non-practice-based clinical roles with GPs' engagement in teaching and supervisory roles. What are the implications for practitioners? Establishing current teaching patterns of GPs enables appropriate targeting of new strategies to sustain an effective teaching and supervisory capacity within general practice. The findings of the present study suggest that exploring focused strategies to facilitate and support international medical graduates to engage in teaching during their vocational training, aided by focused supervisor support, may be of particular value.

Reducing early career general practitioners' antibiotic prescribing for respiratory tract infections: a pragmatic prospective non-randomised controlled trial.

Background: Inappropriate antibiotic prescription and consequent antibacterial resistance is a major threat to healthcare. Objectives: To evaluate the efficacy of a multifaceted intervention in reducing early career general practitioners' (GPs') antibiotic prescribing for upper respiratory tract infections (URTIs) and acute bronchitis/bronchiolitis. Methods: A pragmatic non-randomized trial employing a non-equivalent control group design nested within an existing cohort study of GP registrars' (trainees') clinical practice. The intervention included access to online modules (covering the rationale of current clinical guidelines recommending non-prescription of antibiotics for URTI and bronchitis/bronchiolitis, and communication skills in management of acute bronchitis) followed by a face-to-face educational session. The intervention was delivered to registrars (and their supervisors) in two of Australia's seventeen regional GP training providers (RTPs). Three other RTPs were the control group. Outcomes were proportion of registrars' URTI consultations and bronchitis/bronchiolitis consultations prescribed antibiotics. Intention-to-treat analyses employed logistic regression within a Generalised Estimating Equation framework, adjusted for relevant independent variables. The predictors of interest were time; treatment group; and an interaction term for time-by-treatment group. The P value associated with an interaction term determined statistically significant differences in antibiotic prescribing. Results: Analyses include data of 217 intervention RTPs' and 311 control RTPs' registrars. There was no significant reduction in antibiotic prescribing for URTIs. For bronchitis/bronchiolitis, a significant reduction (interaction P value = 0.024) remained true for analysis adjusted for independent variables (P value = 0.040). The adjusted absolute reduction in prescribing was 15.8% (95% CI: 4.2%-27.5%). Conclusions: A multifaceted intervention reduced antibiotic prescribing for bronchitis/bronchiolitis but not URTIs.

GP registrar consultations addressing menopause-related symptoms: a cross-sectional analysis.

OBJECTIVE: To investigate the prevalence and associations of general practitioner registrars' (trainees') management of women with menopause-related symptoms. METHODS: A cross-sectional analysis from the Registrar Clinical Encounters in Training (ReCEnT) cohort study. In ReCEnT registrars collected data of 60 consecutive consultations on three occasions during training. The outcome factor was menopause-related problems/diagnoses (compared with other problems/diagnoses). Associations of registrar, patient, practice, and consultation-independent variables were assessed by univariate and multivariable logistic regression. RESULTS: In all, 1,333 registrars conducted 189,774 consultations involving 295,017 problems/diagnoses. Of these, there were 1,291 problems/diagnoses (0.44% of all problems/diagnoses) relating to menopause. Significant multivariable independent associations of a problem being menopause-related were registrar female sex (odds ratio [OR] 2.74, 95% confidence interval [CI] 2.30-3.26) and registrars working part-time (OR 0.84, 95% CI 0.72-0.98 for full-time work). Consultation-related associations included an increased number of problems addressed in the consultation (OR 1.29, 95% CI 1.21-1.37), and menopause-related problems/diagnoses not being new (OR 0.75, 95% CI 0.66-0.86). Significant educational associations were increased odds of recourse to in-consultation sources of information or assistance (OR 2.09, 95% CI 1.80-2.44) and of generating learning goals (OR 3.15, 95% CI 2.66-3.72). CONCLUSIONS: Registrars seek more assistance and further knowledge about menopause compared with other problems. Thus, they may find the area particularly challenging and could benefit from further education regarding managing menopause. Our findings may help inform the design of measures aimed at improving the delivery of menopause training for general practice registrars.

Management of transient ischemic attacks diagnosed by early-career general practitioners: A cross-sectional study.

Background Transient ischemic attack incurs a risk of recurrent stroke that can be dramatically reduced by urgent guideline-recommended management at the point of first medical contact. Aims This study describes the prevalence and associations of new transient ischemic attack presentations to general practice registrars and the management undertaken. Methods A cross-sectional analysis of the Registrar Clinical Encounters in Training cohort study. General practice registrars from five Australian states (urban to very remote practices) collected data on 60 consecutive patient encounters during each of their three six-month training terms. The proportion of problems managed being new transient ischemic attacks and proportion of transient ischemic attacks with guideline-recommended management were calculated. Univariate and multivariable logistic regression established associations of patient, registrar, and practice factors with a problem being a new transient ischemic attack. Results A total 1331 general practice registrars contributed data (response rate 95.8%). Of the 250,625 problems, there were 65 new transient ischemic attacks diagnosed (0.03% [95% confidence interval: 0.02-0.03%]). General practice registrars were more likely to seek help, generate learning goals, and spend more time for a new transient ischemic attack compared to other problems. Compliance with management guidelines was modest: 15.4% ordered brain and arterial imaging, 36.9% prescribed antiplatelet medication, and 3.1% prescribed antihypertensive medication. Conclusions Transient ischemic attack is a very infrequent presentation for general practice registrars, giving little clinical opportunity to reinforce training program education regarding guideline-recommended management. General practice registrars found transient ischemic attacks challenging and management was not ideal. Since most transient ischemic attacks first present to general practice and urgent management is essential, an enhanced model of care utilizing rapid access to specialist transient ischemic attack support and follow-up could improve guideline compliance.

Responses to clinical uncertainty in Australian general practice trainees: a cross-sectional analysis.

CONTEXT: Tolerance for ambiguity is essential for optimal learning and professional competence. General practice trainees must be, or must learn to be, adept at managing clinical uncertainty. However, few studies have examined associations of intolerance of uncertainty in this group. OBJECTIVES: The aim of this study was to establish levels of tolerance of uncertainty in Australian general practice trainees and associations of uncertainty with demographic, educational and training practice factors. METHODS: A cross-sectional analysis was performed on the Registrar Clinical Encounters in Training (ReCEnT) project, an ongoing multi-site cohort study. Scores on three of the four independent subscales of the Physicians' Reaction to Uncertainty (PRU) instrument were analysed as outcome variables in linear regression models with trainee and practice factors as independent variables. RESULTS: A total of 594 trainees contributed data on a total of 1209 occasions. Trainees in earlier training terms had higher scores for 'Anxiety due to uncertainty', 'Concern about bad outcomes' and 'Reluctance to disclose diagnosis/treatment uncertainty to patients'. Beyond this, findings suggest two distinct sets of associations regarding reaction to uncertainty. Firstly, affective aspects of uncertainty (the 'Anxiety' and 'Concern' subscales) were associated with female gender, less experience in hospital prior to commencing general practice training, and graduation overseas. Secondly, a maladaptive response to uncertainty (the 'Reluctance to disclose' subscale) was associated with urban practice, health qualifications prior to studying medicine, practice in an area of higher socio-economic status, and being Australian-trained. CONCLUSIONS: This study has established levels of three measures of trainees' responses to uncertainty and associations with these responses. The current findings suggest differing 'phenotypes' of trainees with high 'affective' responses to uncertainty and those reluctant to disclose uncertainty to patients. More research is needed to examine the relationship between clinical uncertainty and clinical outcomes, temporal changes in tolerance for uncertainty, and strategies that might assist physicians in developing adaptive responses to clinical uncertainty.

Prevalence and associations of general practitioners' ordering of "non-symptomatic" prostate-specific antigen tests: A cross-sectional analysis.

AIMS: Testing for asymptomatic prostate cancer with prostate specific antigen (PSA) is of uncertain benefit. Most relevant authorities recommend against screening, and for informed patient choice. We aimed to establish the prevalence and associations of "non-symptomatic" PSA-testing of men aged 40 or older by early-career general practitioners (GP registrars). METHODS: A cross-sectional analysis from the ReCEnT cohort study of registrars' consultations, 2010-2014 (analysed in 2016). Registrars record 60 consecutive consultations each 6-month training term. The outcome factor was ordering an "asymptomatic" PSA test (a PSA ordered for an indication that was not prostate-related symptoms or prostatic disease monitoring). Independent variables were patient, registrar, practice, consultation and educational factors. RESULTS: A total of 856 registrars contributed details of 21,372 individual consultations and 35,696 problems/diagnoses of males 40 or older. Asymptomatic PSAs were ordered for 1.8% (95%CI: 1.7-2.0%) of consultations and for 1.1% (95%CI: 1.0-1.2%) of problems/diagnoses. Multivariable associations of asymptomatic PSA testing (compared with problems/diagnoses for which a PSA was not ordered) included patient age (OR 2.32 [95%CI: 1.53-3.53] for 60-69 years compared with 40-49), patient ethnicity (OR 0.40 [95%CI: 0.19-0.86] for non-English speaking background), the patient being new to both the registrar and practice (ORs 1.46 [95%CI: 1.08-1.99] and 1.79 [95%CI: 1.03-3.10]), the number of problems/diagnoses addressed (OR 1.44 [95%CI: 1.25-1.66] for each extra problem) and more pathology tests being ordered (OR 1.88 [95%CI: 1.79-1.97] for each extra test). CONCLUSION: GP registrars frequently order "asymptomatic" PSA tests. Our findings suggest that non-compliance with current guidelines for PSA screening may be relatively common and that targeted education is warranted.

Changes in pathology test ordering by early career general practitioners: a longitudinal study.

OBJECTIVE: To assess the number of pathology tests ordered by general practice registrars during their first 18-24 months of clinical general practice. DESIGN: Longitudinal analysis of ten rounds of data collection (2010-2014) for the Registrar Clinical Encounters in Training (ReCEnT) study, an ongoing, multicentre, cohort study of general practice registrars in Australia. The principal analysis employed negative binomial regression in a generalised estimating equations framework (to account for repeated measures on registrars).Setting, participants: General practice registrars in training posts with five of 17 general practice regional training providers in five Australian states. The registrar participation rate was 96.4%. MAIN OUTCOME MEASURE: Number of pathology tests requested per consultation. The time unit for analysis was the registrar training term (the 6-month full-time equivalent component of clinical training); registrars contributed data for up to four training terms. RESULTS: 876 registrars contributed data for 114 584 consultations. The number of pathology tests requested increased by 11% (95% CI, 8-15%; P < 0.001) per training term. CONCLUSIONS: Contrary to expectations, pathology test ordering by general practice registrars increased significantly during their first 2 years of clinical practice. This causes concerns about overtesting. As established general practitioners order fewer tests than registrars, test ordering may peak during late vocational training and early career practice. Registrars need support during this difficult period in the development of their clinical practice patterns.

A 90-day oral toxicity study of glycolipids from Dacryopinax spathularia in Beagle dogs.

The subchronic toxicity of glycolipids from Dacryopinax spathularia (herein referred to as "AM-1") was studied in male and female Beagle dogs administered AM-1 by oral capsule at doses of 150, 500 or 1000 mg/kg/day for 90 days. AM-1 was well tolerated at all dosages and there were no test article-related effects on survival, clinical observations, neurological screening (functional observational battery) parameters, clinical pathology parameters, organ weights, macroscopic or microscopic evaluations. Test article-related changes were limited to minimal effects on food consumption and body weight changes in the 1000 mg/kg/day group females. Therefore, the no-observed-adverse-effect level (NOAEL) was considered to be 1000 mg/kg/day, the highest dosage level tested. These results add to the safety database for these naturally derived jelly mushroom glycolipids with potential for use as a food ingredient.

Procedural skills of Australian general practice registrars: A cross-sectional analysis.

BACKGROUND: Procedural skills are an essential component of general practice vocational training. The aim of this study was to investigate the type, frequency and rural or urban associations of procedures performed by general practice registrars, and to establish levels of concordance of procedures performed with a core list of recommended procedural skills in general practice training. METHODS: A cross-sectional analysis of a cohort study of registrars' consultations between 2010 and 2016 was undertaken. Registrars record 60 consecutive consultations during each six-month training term. The outcome was any procedure performed. RESULTS: In 182,782 consultations, 19,411 procedures were performed. Procedures (except Papanicolaou [Pap] tests) were performed more often in rural than urban areas. Registrars commonly sought help from supervisors for more complex procedures. The majority of procedures recommended as essential in registrar training were infrequently performed. DISCUSSION: Registrars have low exposure to many relevant clinical procedures. There may be a need for greater use of laboratory-based training and/or to review the expectations of the scope of procedural skills in general practice.

General practitioner trainees' in-consultation generation of clinical questions for later answering: prevalence and associations.

Background: As well as generating patient-specific questions, patient consultations are a rich source of questions relating to clinicians' need to acquire or maintain wider clinical knowledge. This is especially so for GP trainees. Objectives: To establish the prevalence and associations of GP trainees' generation of 'learning goals' (LGs: questions generated during clinical consultations for intended post-consultation answering). Also, to characterize the type of learning goals generated. Methods: A cross-sectional analysis (2010-15) of an ongoing cohort study of Australian GP trainees' consultations. Once each 6-month training term, trainees record detailed data of 60 consecutive consultations. The primary outcome was generation of an LG. Analysis was at the level of individual problem/diagnosis managed. The secondary outcome was the problems/diagnoses to which the LGs related. Results: One thousand one hundred and twenty-four trainees contributed data for 154746 consultations including 222307 problems/diagnoses. LGs were generated for 16.6% [95% confidence intervals (CI) = 16.4-16.7] of problems/diagnoses, in 22.1% (95% CI = 21.9-22.3%) of consultations. Associations of LGs included patient factors: younger age and having seen the trainee previously; trainee factors: earlier training stage, being overseas-trained and the trainee's training organization; consultation factors: longer duration, addressing a chronic disease, referring the patient, organizing follow-up, organizing investigations and accessing in-consultation information. LGs were commonly generated for skin (12.9% of all learning goals), musculoskeletal (12.7%) and respiratory (8.7%) problems. LGs were generated for 31.8% of male genital, 27.0% of neurological and 23.3% of eye problems. Conclusion: Australian GP trainees frequently generate questions in-consultation to be pursued post-consultation. Prevalence, 'complexity' and familiarity of clinical topic area influenced LG generation.

Protecting Pain Patients. The Evaluation of a Chronic Pain Educational Intervention.

INTRODUCTION: Advocacy and commercially funded education successfully reduced barriers to the provision of long-term opioid analgesia. The subsequent escalation of opioid prescribing for chronic noncancer pain has seen increasing harms without improved pain outcomes. METHODS: This was a one-group pretest-posttest design study. A multidisciplinary team developed a chronic pain educational package for general practitioner trainees emphasizing limitations, risk-mitigation, and deprescribing of opioids with transition to active self-care. This educational intervention incorporated prereadings, a resource kit, and a 90-minute interactional video case-based workshop incorporated into an education day. Evaluation was via pre- and postintervention (two months) questionnaires. Differences in management of two clinical vignettes were tested using McNemar's test. RESULTS: Of 58 eligible trainees, 47 (response rate = 81.0%) completed both questionnaires (36 of whom attended the workshop). In a primary analysis including these 47 trainees, therapeutic intentions of tapering opioid maintenance for pain (in a paper-based clinical vignette) increased from 37 (80.4%) pre-intervention to 44 (95.7%) postintervention (P = 0.039). In a sensitivity analysis including only trainees attending the workshop, 80.0% pre-intervention and 97.1% postintervention tapered opioids (P = 0.070). Anticipated initiation of any opioids for a chronic osteoarthritic knee pain clinical vignette reduced from 35 (74.5%) to 24 (51.1%; P = 0.012) in the primary analysis and from 80.0% to 41.7% in the sensitivity analysis (P = 0.001). CONCLUSIONS: Necessary improvements in pain management and opioid harm avoidance are predicated on primary care education being of demonstrable efficacy. This brief educational intervention improved hypothetical management approaches two months subsequently. Further research measuring objective changes in physician behavior, especially opioid prescribing, is indicated.

Antibiotic prescribing for acute otitis media and acute sinusitis: a cross-sectional analysis of the ReCEnT study exploring the habits of early career doctors in family practice.

Background: Antibiotic resistance is a public health concern, and is linked to over-prescribing. In self-limiting infections such as acute otitis media (AOM) and acute sinusitis, prescribing remains high despite strong guideline recommendations against the routine use of antibiotics. Early career General Practitioners may find evidence-based prescribing challenging. Aim: To establish the prevalence and associations of antibiotic prescribing for AOM and acute sinusitis by Australian vocational trainees in General Practice. Method: A cross-sectional analysis of data from the Registrar Clinical Encounters in Training (ReCEnT) study. This ongoing, multicentre prospective cohort study documents trainees' consultation-based clinical experiences. Univariate and logistic regression analyses were conducted on data recorded in consultations for AOM or acute sinusitis in nine collection periods during 2010-2014. Results: Data from 856 individual trainees (response rate 95.2%) were analysed. AOM was managed in 0.9% of encounters. Antibiotics were prescribed in 78.8% of cases. Prescribing was significantly associated with longer consultation time and first presentation for this problem. There was no significant association with patient age group. Acute sinusitis was managed in 0.9% of encounters. Antibiotics were prescribed in 71.2% of cases. Later-stage trainees and trainees who did not receive their primary medical qualification in Australia were more likely to prescribe an antibiotic for acute sinusitis. Conclusion: Early career GPs are not prescribing in an evidence-based manner. The complexity of guidelines for AOM and acute sinusitis may be confusing for prescribers, especially early career doctors struggling with inexperience and diagnostic uncertainty. Educational interventions are necessary to bring prescribing rates closer to quality benchmarks.