Medical Education - Research Publications
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Intravenous midazolam-droperidol combination, droperidol or olanzapine monotherapy for methamphetamine-related acute agitation: subgroup analysis of a randomized controlled trial
AIM: To examine the efficacy and safety of (1) midazolam-droperidol versus droperidol and (2) midazolam-droperidol versus olanzapine for methamphetamine-related acute agitation. DESIGN AND SETTING: A multi-centre, randomized, double-blind, controlled, clinical trial was conducted in two Australian emergency departments, between October 2014 and September 2015. PARTICIPANTS: Three hundred and sixty-one patients, aged 18-65 years, requiring intravenous medication sedation for acute agitation, were enrolled into this study. We report the results of a subgroup of 92 methamphetamine-affected patients. INTERVENTION AND COMPARATOR: Patients were assigned randomly to receive either an intravenous bolus of midazolam 5 mg-droperidol 5 mg combined, droperidol 10 mg or olanzapine 10 mg. Two additional doses were administered, if required: midazolam 5 mg, droperidol 5 mg or olanzapine 5 mg, respectively. MEASUREMENTS: The primary outcome was the proportion of patients sedated adequately at 10 minutes. Odds ratios with 95% confidence intervals (ORs, 95% CI) were estimated. FINDINGS: The baseline characteristics of patients in the three groups were similar. At 10 minutes, significantly more patients in the midazolam-droperidol group [29 of 34 (85.3%)] were sedated adequately compared with the droperidol group [14 of 30 (46.7%), OR = 6.63, 95% CI = 2.02-21.78] or with the olanzapine group [14 of 28 (50.0%), OR 5.80, 95% CI = 1.74-19.33]. The number of patients who experienced an adverse event (AE) in the midazolam-droperidol, droperidol and olanzapine groups was seven of 34, two of 30 and six of 28, respectively. The most common AE was oxygen desaturation. CONCLUSION: A midazolam-droperidol combination appears to provide more rapid sedation of patients with methamphetamine-related acute agitation than droperidol or olanzapine alone.
Low-dose rituximab and concurrent adjuvant therapy for pemphigus: Protocol and single-centre long-term review of nine patients
Pemphigus is an autoimmune B-cell mediated blistering disease associated with significant morbidity and mortality. Rituximab has proven effective for the treatment of steroid-refractory pemphigus, although there is controversy over the optimum dosing protocol. Additionally, effective disease control often requires long-term immunosuppression, even in disease-free periods. We present a case series of a single-centre long-term follow up of nine patients with pemphigus, treated with two 500-mg doses of rituximab separated by 14 days along with concurrent adjuvant therapy. In all these patients, low-dose rituximab resulted in B-cell depletion, along with a reduction in blistering disease. Three of these patients required repeat dosing cycles due to either relapsed disease or incomplete disease control following the first dosing cycle, and have remained disease free up to 154 weeks thus far. Six patients developed minor infections during the course of their treatment, but no major complications were observed.
Cystatin C estimated glomerular filtration rate and all-cause and cardiovascular disease mortality risk in the general population: AusDiab study
AIMS: Uncertainties about the role of cystatin C-based estimated glomerular filtration rate (eGFR) in the prediction of cardiovascular disease (CVD) beyond traditional CVD risk factors remain. We assessed contributions of eGFR to CVD and mortality in the general population. METHODS: Using 14 year follow-up data on 9353 adults without a reported history of CVD from the Australian Diabetes, Obesity and Lifestyle study, we assessed the contributions of eGFR (assessed by cystatin C (eGFRcysC ) and serum creatinine (eGFRcr ) and albuminuria (uACR) to total and CVD mortality. RESULTS: After adjusting for age, sex, CVD risk factors and uACR, compared with an eGFRcysC >90 mL/min per 1.73 m2 , eGFRcysC <60 mL/min per 1.73 m2 was associated with 56% and 73% increases in the risks for all-cause and CVD mortality, respectively. The respective changes for the c-statistic when eGFRcysC was added to a risk prediction model were 0.003 (95% confidence interval: 0.001 to 0.005) and 0.002 (95% confidence interval: -0.001 to 0.006). The net proportion of non-events assigned a lower-risk category significantly improved with the addition of eGFR (non-event net reclassification index eGFRcr : 1.0% and eGFRcysC : 1.5%) for all-cause mortality, but for CVD mortality, improvements were only significant when eGFR was combined with uACR. The net proportion of events assigned a higher-risk category was not significantly improved. CONCLUSION: In our community-based cohort, reduced eGFRcysC was associated with all-cause and CVD mortality. The addition of chronic kidney disease measures to risk prediction models improved overall risk stratification among those at low risk as opposed to those at high baseline risk of mortality.
TANGO - a screening tool to identify comorbidities on the causal pathway of nocturia.
OBJECTIVES: To develop a robust screening metric for use in identifying non-lower urinary tract comorbidities pertinent to the multidisciplinary assessment of patients with nocturia. METHODS: Variables having a significant risk association with nocturia of greater than once per night were identified. Discriminating items from validated and reliable tools measuring these comorbidities were identified. A self-completed 57-item questionnaire was developed and a medical checklist and pertinent clinical measures added. Pre-determined criteria were applied to retain or remove items in the development of the Short-Form (SF) screening tool. The tool was administered to 252 individuals with nocturia who were attending either a tertiary level Sleep, Continence, Falls or Rehabilitation service for routine care. Data collected were subjected to descriptive analysis; criteria were applied to reduce the number of items. Using pre-determined domains, a nocturia screening metric, entitled TANGO, was generated. The acronym TANGO stands for Targeting the individual's Aetiology of Nocturia to Guide Outcomes. RESULTS: The demographic characteristics of the sample are described, along with item endorsement levels. The statistical and structural framework to justify deleting or retaining of items from the TANGO Long-Form to the SF is presented. The resultant TANGO-SF patient-completed nocturia screening tool is reported. CONCLUSIONS: A novel all-cause diagnostic metric for identifying co-existing morbidities of clinical relevance to nocturia in patients who present across disciplines and medical specialties has been developed. TANGO has the potential to improve practice and smooth inequalities associated with a siloed approach to assessment and subsequent care of patients with nocturia.
Suspected atypical haemolytic uraemic syndrome in two post-partum patients with foetal-death in utero responding to eculizumab
BACKGROUND: Atypical haemolytic uraemic syndrome (aHUS) is a rare condition with the triad of microangiopathic haemolytic anaemia, thrombocytopenia and acute kidney injury. Other conditions that present in a similar manner peri-partum include thrombotic thrombocytopaenic purpura, and pregnancy associated conditions including HELLP syndrome (haemolysis, elevated liver enzymes and low platelets), severe pre-eclampsia and less commonly acute fatty liver of pregnancy. CASE REPORTS: We describe two cases of suspected aHUS, who presented post-partum with foetal death-in-utero at 33 and 37 weeks respectively. Both presented with the triad features of aHUS but had considerably different clinical courses. The first case required a prolonged ICU admission, needed intubation for neurological deterioration and dialysis for acute kidney injury, and developed complications including acute liver failure, septic shock, pancreatitis, and ischaemic colitis. Initial ADAMSTS13 activity was borderline-low (10.3%) and normal on repeat testing (42.6%), and there was no peri-partum pre-eclampsia. The other case remained clinically stable throughout her admission with creatinine peaking at 495, not requiring dialysis, minor liver transaminases derangement and was discharged after a week. Her ADAMSTS13 activity was normal (62%), and her pregnancy was complicated by peri-partum pre-eclampsia. Both eventually had a reduction in haemolysis with rapid and sustained reduction in LDH and normalised platelet counts, and complete recovery of renal function whilst receiving eculizumab therapy. CONCLUSIONS: It can be difficult to distinguish aHUS from other causes in peri-partum patients presenting with features of microangiopathic haemolytic anaemia, thrombocytopenia and acute kidney injury, and often, aHUS can be precipitated by pregnancy. In the setting of the clinical urgency to treat aHUS early with eculizumab, this presents a diagnostic challenge, as confirmatory tests for aHUS are not immediately available.
Spinal infections in older people: an analysis of demographics, presenting features, microbiology and outcomes
BACKGROUND: Clinical features of infection can become more atypical as we age. Spinal infections can be insidious, and timely diagnosis and treatment are essential to prevent adverse outcomes. AIMS: To explore differences in presentation and outcomes between younger and older patients with bacterial spinal infections. METHODS: Clinical, microbiological and radiological information was collected for patients with spinal infections (spondylodiscitis, vertebral osteomyelitis, septic discitis, facet joint septic arthritis and spinal epidural abscess) at a single metropolitan hospital between January 2008 and January 2015. Patients were excluded if they were under 18 years of age or if clinical and imaging findings were inconsistent with the diagnosis. Presenting features, investigations and outcomes were compared for patients ≥65 (older) or <65 (younger) years old. RESULTS: Of 53 identified patients, 34 (64%) were classified as older, with more males in both older (65%) and younger (79%) groups. Older patients presented later (median symptom duration 13 vs 4 days, P = 0.016). Back pain was nearly ubiquitous. Older patients presented less commonly with fevers (38 vs 63%) and rigors (24 vs 42%) but more commonly with hypotension (18 vs 5%), delirium (24 vs 11%), higher median inflammatory marker levels and variable microbiological findings, although these differences were not statistically significant. They had longer median lengths of stay (24 vs 14 days) and a higher likelihood of death or failure of medical treatment (HR 9.34, P = 0.031). Radicular pain was associated with poor outcome (HR 3.29, P = 0.046). CONCLUSION: Older patients with spinal infections present later, with higher inflammatory markers and fewer typical infective symptoms and signs; these may contribute to poorer outcomes. A low threshold for promptly investigating older patients with new or worsening back pain should be set.
Breast milk polyunsaturated fatty acids: associations with adolescent allergic disease and lung function
BACKGROUND: It has been hypothesized that n-3 PUFA in breast milk may assist immune and lung development. There are very limited data on possible long-term effects on allergic disease and lung function. The aim was to investigate associations of n-3 and n-6 PUFA levels in colostrum and breast milk with allergic disease and lung function at ages 12 and 18 years. METHODS: Polyunsaturated fatty acids were measured in 194 colostrum samples and in 118 three-month expressed breast milk samples from mothers of children enrolled in the Melbourne Atopy Cohort (MACS) Study, a high-risk birth cohort study. Associations with allergic diseases, skin prick tests and lung function assessed at 12 and 18 years were estimated using multivariable regression. RESULTS: Higher levels of n-3 but not n-6 PUFAs in colostrum were associated with a trend towards increased odds of allergic diseases, with strong associations observed for allergic rhinitis at 12 (OR = 5.69[95% CI: 1.83,17.60] per weight%) and 18 years (4.43[1.46,13.39]) and eczema at 18 years (9.89[1.44, 68.49]). Higher levels of colostrum n-3 PUFAs were associated with reduced sensitization (3.37[1.18, 9.6]), mean FEV1 (-166 ml [-332, -1]) and FEV1 /FVC ratio (-4.6%, [-8.1, -1.1]) at 12 years. CONCLUSION: Higher levels of colostrum n-3 PUFAs were associated with increased risks of allergic rhinitis and eczema up to 18 years, and sensitization and reduced lung function at 12 years. As residual confounding may have caused these associations, they should be replicated, but these results could indicate that strategies that increase maternal n-3 PUFA intake may not aid in allergic disease prevention.
Case-control study to investigate variables associated with incidents and adverse events in the emergency department
OBJECTIVE: To detect and analyse incidents (Is) and adverse events (AEs) in the ED. We hypothesised that I/AE are associated with patient load. METHODS: We undertook a case-control study in a tertiary level hospital ED (from 1 April 2012 to 31 March 2013). Three percent of patients were randomly selected and screened for I/AEs. I/AEs were adjudicated by consensus of four FACEMs. Controls were matched to cases 2:1. Logistic regression was used to analyse the data. RESULTS: We sampled 2167 patients. After exclusions, 217 I/AEs were detected and analysed. The I and AE rates were 6.0 and 4.1%, respectively. The serious AE rate was 0.8% and 30 day mortality was 0.1%. Diagnostic error occurred in 3.7% of all patients and adverse drug reactions in 2.5%. Seventy-seven percent of the I/AEs were judged preventable. ED occupancy of <35 patients was the reference group. Compared with this group, if 36-40 or 41-45 patients were in the ED, I/AEs were more likely to occur (odds ratio [OR] 2.37 [95% confidence interval (CI) 1.40-4.01, P < 0.0] and 1.8 [95% CI 1.03-3.15, P = 0.04], respectively) but not when there were >46 patients (OR 1.7, 95% CI 1.0-3.1). Higher hospital occupancy (90-99%) was a protective factor for sustaining an I/AE (OR 0.57, 95% CI 0.35-0.92, P = 0.02). CONCLUSION: I/AEs are common in the ED and a large proportion is preventable. Strategies for prevention are required. The relationship with patient load needs further clarification, since our data suggests increased I/AE rates with higher occupancy but not highest occupancy.
Timely initiation of chemotherapy: a systematic literature review of six priority cancers - results and recommendations for clinical practice
This review evaluated the association between time-to-chemotherapy (TTC) and survival in six priority cancers. A systematic review of the literature was undertaken for papers indexed in the MEDLINE and Cochrane Library databases from the earliest index until April 2014. The methodology used has been published in a separate paper (Guidelines for timely initiation of chemotherapy: a proposed framework for access to medical oncology and haematology cancer clinics and chemotherapy services). The optimal timing of chemotherapy in breast cancer is unclear as available studies are of low quality, report inconsistent results and are limited to the adjuvant setting. However, increased TTC may have a negative prognostic impact, and delays beyond 4 weeks should be avoided. Studies suggest that the optimal timing for initiation of adjuvant chemotherapy for surgically resected colorectal cancer is 4-8 weeks post-surgery. Timing of chemotherapy for metastatic colorectal cancer does not influence survival. There is a paucity of studies to guide the timing of chemotherapy for the treatment of lymphoma and myeloma; no definitive conclusions can be drawn, and clinician discretion should be applied. The optimal timing of chemotherapy in lung cancer is unclear; however, rapid tumour growth and poor disease prognosis suggest that delays should be avoided wherever possible. The optimal timing of chemotherapy in ovarian cancer is unclear as available studies are of low level, report inconsistent results and are limited to the post-surgery setting; however, increased TTC may have a negative prognostic impact; therefore, delays beyond 4 weeks should be avoided.
Aceruloplasminaemia: a disorder of diabetes and neurodegeneration
Aceruloplasminaemia is an autosomal recessive disorder of iron metabolism which is characterised by diabetes, neurodegeneration and anaemia. It should be considered in the differential diagnosis of adult onset, antibody-negative diabetes associated with persistent mild anaemia and hyperferritinaemia and/or progressive neuropsychiatric impairments.
Five-year efficacy and safety of tenofovir-based salvage therapy for patients with chronic hepatitis B who previously failed LAM/ADV therapy
BACKGROUND: Multidrug-resistant HBV continues to be an important clinical problem. The TDF-109 study demonstrated that TDF±LAM is an effective salvage therapy through 96 weeks for LAM-resistant patients who previously failed ADV add-on or switch therapy. We evaluated the 5-year efficacy and safety outcomes in patients receiving long-term TDF±LAM in the TDF-109 study. METHODS: A total of 59 patients completed the first phase of the TDF-109 study and 54/59 were rolled over into a long-term prospective open-label study of TDF±LAM 300 mg daily. RESULTS: Results are reported at the end of year 5 of treatment. At year 5, 75% (45/59) had achieved viral suppression by intent-to-treat analysis. Per-protocol assessment revealed 83% (45/54) were HBV DNA undetectable. Nine patients remained HBV DNA detectable, however 8/9 had very low HBV DNA levels (<264IU/mL) and did not meet virological criteria for virological breakthrough (VBT). One patient experienced VBT, but this was in the setting of documented non-compliance. The response was independent of baseline LAM therapy or mutations conferring ADV resistance. Four patients discontinued TDF, one patient was lost to follow-up and one died from hepatocellular carcinoma. CONCLUSIONS: Long-term TDF treatment appears to be safe and effective in patients with prior failure of LAM and a suboptimal response to ADV therapy. These findings confirm that TDF has a high genetic barrier to resistance is active against multidrug-resistant HBV, and should be the preferred oral anti-HBV agent in CHB patients who fail treatment with LAM and ADV.
In-training assessments: 'The difficulty is trying to balance reality and really tell the truth'
BACKGROUND: In-training assessments (ITA) aim to evaluate trainees' progress and give valuable feedback on their performance. Many factors can affect supervisors during their completion of assessments and these can influence the final results recorded. METHODS: This is the second part of a study of supervisors of the Australasian College of Dermatologists (ACD) and presents the qualitative data on their opinions of the ACD ITA process and the influences on their ITA ratings. RESULTS: Supervisors noted the benefits of this assessment tool, together with many limitations. Potential influences upon supervisor ratings included the relationship between the supervisor and trainee and the level of honesty in completing and delivery of the assessment. CONCLUSIONS: Many factors influence supervisors in the completion of the ITA. These include the impact of interpersonal relationships and concerns about the consequences of delivering a negative assessment, which sometimes lead supervisors to modify the assessment they deliver to the trainee. Further research is needed into honesty in assessment judgements.