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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

BACKGROUND: Maintenance anti-tumour necrosis factor-α (anti-TNFα) treatment for Crohn's disease is the standard of care for patients with an inadequate response to corticosteroids and immunomodulators. AIM: To compare the efficacy and safety of infliximab and adalimumab in clinical practice and assess the value of concomitant immunomodulator therapy. METHODS: We performed an observational cohort study in consecutive patients with Crohn's disease qualifying for anti-TNFα treatment in Australia and New Zealand between 2007 and 2011. Demographic and clinical data were prospectively recorded to identify independent factors associated with induction and maintenance of response to infliximab or adalimumab, or to either anti-TNFα therapy. RESULTS: Three hundred and twenty-seven patients (183 infliximab, 144 adalimumab) successfully applied for treatment. Eighty-nine percent responded in all groups and median maintenance of response was similar for the two agents. Concomitant immunomodulator with infliximab, but not adalimumab, demonstrated a significantly longer response overall (P = 0.002), and significantly fewer disease and treatment-related complications (P = 0.017). Corticosteroids at baseline, and/or in the preceding 12 months, were associated with a 9-13 times greater risk of disease flare during maintenance treatment as compared to no corticosteroids (P < 0.0001). Maintenance of response was similar in the anti-TNF naïve and anti-TNF experienced subgroups. CONCLUSIONS: In this large, real-life study, we demonstrate infliximab and adalimumab to have similar response characteristics. However, infliximab requires concomitant immunomodulator to achieve optimal maintenance of response comparable to adalimumab monotherapy. The results of this study will assist clinicians in further optimising patient care in their day-to-day clinical practice.

CONTEXT: Although their inclusion in medical curricula internationally is increasing, the medical humanities still face challenges to their role and place in the curriculum. Justifications supporting the inclusion of humanities content, methods and perspectives in medical curricula have generally been proposed along instrumental, intrinsic and critical lines. However, recent literature in the field has turned to 'ways of knowing' as representing an alternative, essentially epistemological, perspective on the matter. This involves the claim that the medical humanities align with and promote characteristic ways of understanding and practising medicine, which are not adequately represented in traditional disciplinary frameworks. DISCUSSION: Such epistemological arguments aim to move beyond generic claims of medicine as both an 'art' and a 'science' to explore the way in which the humanities support the ultimate objectives of a medical education, particularly in relation to claims about requisite knowledge and typical reasoning. Not only can this help focus attempts to identify and document relevant learning or clinical outcomes, but it can potentially uncover evidence from education outcomes research which may not have been the focus of previous inquiry in the medical humanities and which may in fact be associated, at least in part, with curricular activities formally associated with humanities disciplines. CONCLUSIONS: An epistemological view of the humanities in medical education offers a significant new way of conceptualising and communicating the potential role of the humanities in medical training. If clinical practice can be characterised as rational but interpretive, partly predictable yet fundamentally uncertain, and logical but also intuitive, it follows that educational training should facilitate such ways of knowing and thinking. An epistemological perspective enables the argument that the medical humanities are valuable not because they are more 'humane', but because they help constitute what it means to think like a doctor.

CONTEXT: For academic staff, responding to student concerns is an important responsibility. Professional staff, or non-academic staff who do administrative work in medical schools, are often the first to be approached by students, yet there is little research on how they manage student issues. Informed by the conceptual framework of emotional labour, we examined the experiences of professional staff, aiming to identify theoretical and practical insights for improving the provision of student support. We examined the scope of support provided, the impact of providing this support on staff and how these impacts can be managed. METHODS: Professional staff at two medical schools were invited to participate in semi-structured qualitative interviews. Interviews were transcribed and independently analysed for emergent themes. Data analysis continued with purposive sampling for maximum variation until thematic saturation was reached. Findings were returned to participants in writing and via oral presentations for member checking and refinement. RESULTS: Twenty-two female staff from clinical, teaching and commercial backgrounds at nine urban and rural teaching sites were interviewed. Participants described providing support for diverse concerns, from routine requests to life-threatening emergencies. Four major themes emerged: firstly, all described roles consistent with emotional labour. Secondly, student support was regarded as informal work, and not well recognised or defined. Consequently, many drew upon their personal orientation to provide support. Finally, we identified both positive and negative personal impacts, including ongoing distress after critical events. CONCLUSIONS: Professional staff perform a range of student support work, leading to emotional, personal and work impacts. In turn, they need support, recognition and training in this essential but under-recognised role. Emotional labour offers a conceptual framework for understanding the gendered nature and impact of this work and how it may be managed. We suggest practical strategies for promoting positive and preventing negative effects on staff from supporting medical students.

Genome-wide studies have identified allele A (adenine) of single nucleotide polymorphism (SNP) rs1006737 of the calcium-channel CACNA1C gene as a risk factor for both schizophrenia (SZ) and bipolar disorder (BD) as well as allele A for rs1344706 in the ZNF804A gene. These illnesses have also been associated with white matter abnormalities, reflected by reductions in fractional anisotropy (FA), measured using diffusion tensor imaging (DTI). We assessed the impact of the CACNA1C psychosis risk variant on FA in SZ, BD and health. 230 individuals (with existing ZNF804A rs1344706 genotype data) were genotyped for CACNA1C rs1006737 and underwent DTI. FA data was analysed with tract-based spatial statistics and threshold-free cluster enhancement significance correction (P < 0.05) to detect effects of CACNA1C genotype on FA, and its potential interaction with ZNF804A genotype and with diagnosis, on FA. There was no significant main effect of the CACNA1C genotype on FA, nor diagnosis by genotype(s) interactions. Nevertheless, when inspecting SZ in particular, risk allele carriers had significantly lower FA than the protective genotype individuals, in portions of the left middle occipital and parahippocampal gyri, right cerebellum, left optic radiation and left inferior and superior temporal gyri. Our data suggests a minor involvement of CACNA1C rs1006737 in psychosis via conferring susceptibility to white matter microstructural abnormalities in SZ. Put in perspective, ZNF804A rs1344706, not only had a significant main effect, but its SZ-specific effects were two orders of magnitude more widespread than that of CACNA1C rs1006737.

Zn2+ , the second most prevalent trace element in the body, is essential for supporting a wide range of biological functions. While the majority of Zn2+ in the brain is protein-bound, a significant proportion of free Zn2+ is found co-localized with glutamate in synaptic vesicles and is released in an activity-dependent manner. Clinical studies have shown Zn2+ levels are significantly lower in blood and cerebrospinal fluid of children that suffer febrile seizures. Likewise, investigations in multiple animal models demonstrate that low levels of brain Zn2+ increase seizure susceptibility. Recent work provides human genetic evidence that disruption of brain Zn2+ homeostasis at the level of the synapse is associated with increased seizure susceptibility. In this review, we have explored the clinical, functional and genetic data supporting the view that low synaptic Zn2+ increases cellular excitability and febrile seizure susceptibility. Finally, the review focuses on the potential of therapeutic Zn2+ supplementation for at risk patients.

BACKGROUND: The article describes the use of the mini clinical examination (mini-CEX) in a pilot study to introduce peer assessment in one allied health programme to explore students' capacity as clinical educators. Preparing today's pre-professional health students to be clinical educators by engaging them in peer teaching, learning and assessment may encourage them to become tomorrow's clinical educators. CONTEXT: Peer assessment is common among many undergraduate medical and allied health programmes, and is typically used as a means of providing students with feedback on their clinical skill development. We argue that peer assessment ought to be focused not only on the development of learners' clinical skills and knowledge, but also on preparing learners for their responsibilities as clinical educators. INNOVATION: Final-year Australian osteopathy students in our on-campus university clinic undertook, without training, peer assessment and provision of feedback related to clinical performance using a discipline-specific adaptation of the mini-CEX. The current study suggests that students are able to judge another's consultation skills and case management in that they identify what we know are common learning issues for students at this level. Peer assessment ought to be focused on preparing learners for their responsibilities as clinical educators IMPLICATION: Students may be willing to engage in peer assessment if they see the exercise as a way to improve patient care and to develop their skills as educators - potentially encouraging them to become clinical educators in the future.

BACKGROUND AND OBJECTIVE: Ultrasound has been shown to improve the accuracy and safety of pleural procedures. Studies to date have been performed in large, specialized units, where pleural procedures are performed by a small number of highly specialized physicians. There are no studies examining the safety and accuracy of ultrasound in the Australian healthcare system where procedures are performed by junior doctors with a high staff turnover. METHODS: We performed a retrospective review of the ultrasound database in the Respiratory Department at the Royal Melbourne Hospital to determine accuracy and complications associated pleural procedures. RESULTS: A total of 357 ultrasounds were performed between October 2010 and June 2013. Accuracy of pleural procedures was 350 of 356 (98.3%). Aspiration of pleural fluid was successful in 121 of 126 (96%) of patients. Two (0.9%) patients required chest tube insertion for management of pneumothorax. There were no recorded pleural infections, haemorrhage or viscera puncture. CONCLUSION: Ward-based ultrasound for pleural procedures is safe and accurate when performed by appropriately trained and supported junior medical officers. Our findings support this model of pleural service care in the Australian healthcare system.

Not all individuals who smoke cannabis report psychotic-like experiences. Given that risk factors for psychotic disorders are multifaceted, precipitating factors to psychotic-like experiences after cannabis are likely to be equally complex. Reduced neurocognitive performance is associated with both psychosis risk and cannabis use. Therefore, it is possible cognitive performance may differentiate those who report psychotic-like experiences after cannabis from those who do not. We determined whether those reporting psychotic/dysphoric experiences after cannabis had reduced neurocognitive performance compared to those reporting primarily euphoric experiences. METHODS: Participants were recruited on the basis of responses to the cannabis high captured by the Psychosis-Dysphoric and Euphoric experiences subscales from the Cannabis Experiences Questionnaire (CEQ). RESULTS: Compared to participants reporting primarily euphoric cannabis experiences (n = 36; 44% male; mean age (SD) = 28 (9) years), those who reported psychotic/dysphoric experiences (n = 40; 45% male; mean age (SD) = 26 (5) years) demonstrated significantly faster responses to a trial and error learning task. In the presence of distracters, those with psychotic/dysphoric experiences after cannabis made more errors on a Continuous Performance Task. CONCLUSIONS: Those who report psychotic/dysphoric experiences after cannabis have subtle inefficiencies in their cognitive processes. The multiple factors which predict vulnerability to psychotic-like experiences after cannabis require further investigation.

OBJECTIVE: Fracture risk is a serious comorbidity in epilepsy and may relate to the use of antiepileptic drugs (AEDs). Many AEDs inhibit ion channel function, and the expression of these channels in osteoblasts raises the question of whether altered bone signaling increases bone fragility. We aimed to confirm the expression of voltage-gated sodium (NaV ) channels in mouse osteoblasts, and to investigate the action of carbamazepine and phenytoin on NaV channels. METHODS: Immunocytochemistry was performed on primary calvarial osteoblasts extracted from neonatal C57BL/6J mice and additional RNA sequencing (RNASeq) was included to confirm expression of NaV . Whole-cell patch-clamp recordings were made to identify the native currents expressed and to assess the actions of carbamazepine (50 μm) or phenytoin (50 μm). RESULTS: NaV expression was demonstrated with immunocytochemistry, RNA sequencing, and functionally, with demonstration of robust tetrodotoxin-sensitive and voltage-activated inward currents. Application of carbamazepine or phenytoin resulted in significant inhibition of current amplitude for carbamazepine (31.6 ± 5.9%, n = 9; p < 0.001), and for phenytoin (35.5 ± 6.9%, n = 7; p < 0.001). SIGNIFICANCE: Mouse osteoblasts express NaV , and native NaV currents are blocked by carbamazepine and phenytoin, supporting our hypothesis that AEDs can directly influence osteoblast function and potentially affect bone strength.

The Australasian Psoriasis Collaboration reviewed methotrexate (MTX) in the management of psoriasis in the Australian and New Zealand setting. The following comments are based on expert opinion and a literature review. Low-dose MTX (< 0.4 mg/kg per week) has a slow onset of action and has moderate to good efficacy, together with an acceptable safety profile. The mechanism of action is anti-inflammatory, rather than immunosuppressive. For pretreatment, consider testing full blood count (FBC), liver and renal function, non-fasting lipids, hepatitis serology, HbA1c and glucose. Body mass index and abdominal circumference should also be measured. Optional investigations in at-risk groups include an HIV test, a QuantiFERON-TB Gold test and a chest X-ray. In patients without complications, repeat the FBC at 2-4 weeks, then every 3-6 months and the liver/renal function test at 3 months and then every 6 months. There is little evidence that a MTX test dose is of value. Low-dose MTX rarely causes clinically significant hepatotoxicity in psoriasis. Most treatment-emergent liver toxicity is related to underlying metabolic syndrome and non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. Alcohol itself is not contraindicated, but should be limited to < 20 gm/day. [Correction added on 6 January 2017, after first online publication: '20 mg/day' has been corrected to '20 gm/day'.] Although MTX is a potential teratogen post-conception, there is little evidence for this pre-conception. MTX does not affect the quality of sperm. There is no evidence that MTX reduces healing, so there is no specific need to stop MTX peri-surgery. MTX may be used in combination with cyclosporine, acitretin, prednisone and anti-tumour necrosis factor biologics.

INTRODUCTION: The integration of patient and caregiver input into guideline development can help to ensure that clinical care addresses patient expectations, priorities, and needs. We aimed to identify topics and outcomes salient to patients and caregivers for inclusion in the Kidney Health Australia Caring for Australasians with Renal Impairment (KHA-CARI) clinical practice guideline on the screening and management of infectious microorganisms in hemodialysis units. METHODS: A facilitated workshop was conducted with 11 participants (patients [n = 8], caregivers [n = 3]). Participants identified and discussed potential topics for inclusion in the guidelines, which were compared to those developed by the guideline working group. The workshop transcript was thematically analyzed to identify and describe the reasons underpinning their priorities. FINDINGS: Patients and caregivers identified a range of topics already covered by the scope of the proposed guidelines and also suggested additional topics: privacy and confidentiality, psychosocial care during/after disease notification, quality of transportation, psychosocial treatment of patients in isolation, patient/caregiver education and engagement, and patient advocacy. Five themes characterized discussion and underpinned their choices: shock and vulnerability, burden of isolation, fear of infection, respect for privacy and confidentiality, and confusion over procedural inconsistencies. DISCUSSION: Patients and caregivers emphasized the need for guidelines to address patient education and engagement, and the psychosocial implications of communication and provision of care in the context of infectious microorganisms in hemodialysis units. Integrating patient and caregiver perspectives can help to improve the relevance of guidelines to enhance quality of care, patient experiences, and health and psychosocial outcomes.

WHAT IS KNOWN AND OBJECTIVE: Human herpesvirus-8 (HHV-8)-positive, HIV-negative multicentric Castleman's disease is a rare lymphoproliferative disorder with no standardized treatment. Concurrent Kaposi's sarcoma, another HHV-8-related disease, is uncommon in HIV-negative patients. The role of antiviral therapy and rituximab in HIV-negative patients is not well established. CASE DESCRIPTION: We report a case of a 5-year, durable remission of HHV-8-positive, HIV-negative comorbid multicentric Castleman's disease and Kaposi's sarcoma treated with long-term valganciclovir, following initial rituximab and liposomal doxorubicin. WHAT IS NEW AND CONCLUSION: Currently, there is no defined role for antiviral therapy in the treatment of HIV-negative HHV-8-positive multicentric Castleman's disease and Kaposi's sarcoma. Ganciclovir followed by indefinite, continuous valganciclovir is thought to have contributed significantly to the durable response in this case.

BACKGROUND: Thyroid nodules are a common presenting complaint for endocrine surgeons; many require ultrasound-guided fine-needle aspiration cytology (US-FNAC). In an attempt to streamline our service, we introduced same-day surgeon-performed US-FNAC in 2014. METHODS: Three groups were defined: (A) retrospective group with FNAC performed in radiology prior to August 2014; (B) prospective radiology FNAC group; and (C) prospective surgeon-performed group. Demographics, nodule characteristics, pathology and management plans were recorded. The number and dates of hospital attendances were extracted from the patient information system. RESULTS: Over 4 years, 635 patients underwent 757 FNACs. There were 438 patients in group A, 78 in group B and 119 in group C. Patient demographics and nodule size were similar between groups. Those patients undergoing FNAC in endocrine surgery clinic required two visits prior to receiving a diagnosis and management plan, compared with three visits for those performed in radiology. Non-diagnostic rates between three groups were 6.5%, 7.4% and 5.4% (P = 0.842) whilst malignant FNAC results occurred in 3%, 4% and 8% (P = 0.015) respectively. Median time from US-FNAC to definitive management plan was 42, 41 and 14 days (P < 0.001). The introduction of the one-stop clinic resulted in a 41% reduction of patients attending the radiology department for FNAC. CONCLUSION: Surgeon-performed US-FNAC decreases the time from fine-needle aspiration request to definitive plan and reduces the number of patient visits, providing more efficient care. Patients referred to the endocrine surgery clinic with thyroid nodules have thyroid cancer more frequently than patients referred to radiology.

INTRODUCTION: Gemistocytic astrocytoma is the second most common subtype of World Health Organization grade 2 astrocytoma, but has a worse prognosis than other grade 2 lesions. We aim to describe the MR imaging features of histopathologically proven gemistocytic tumours. METHODS: Ethics approval was obtained from both institutions. Patient consent was not required for this retrospective study. We reviewed MR imaging findings of 16 consecutive cases of histopathologically proven gemistocytic astrocytoma and anaplastic astrocytoma with gemistocytic features. RESULTS: Average patient age was 48 years, with a 3:1 male to female ratio. Based on our series, the typical appearance of a gemistocytic astrocytoma is a large, heterogeneous mass most commonly supratentorial and lobar. Regions of cyst formation, partial signal suppression on FLAIR images and contrast enhancement are all common features. Additionally, contrary to previous literature that describes gemistocytic astrocytoma as a purely supratentorial lesion, we present two cases of gemistocytic astrocytoma involving the brainstem. CONCLUSIONS: The possibility of gemistocytic astrocytoma should be considered in patients presenting with large heterogeneous tumours that have regions of cyst formation, partial FLAIR suppression and contrast enhancement. This may be especially useful in reconciling a lesion with high-grade MR imaging features with low-grade histopathology. An infratentorial location does not preclude the diagnosis of gemistocytic astrocytoma.

BACKGROUND: Bloodstream infections (BSIs) are a significant complication of treatment for multiple myeloma (MM). The objective of this study was to define the epidemiology of BSI with current era MM treatment regimens, including immunomodulatory drugs, proteasome inhibitors and autologous haematopoietic stem cell transplantation (ASCT). METHODS: Clinical and microbiology records of patients with MM diagnosed between 2008 and 2012 were reviewed using a standardised tool to capture patient demographics, myeloma characteristics and BSI characteristics (type, severity, outcomes). Conditional risk set modelling was used to determine clinical predictors of BSI. RESULTS: Of 199 studied patients, 71 (35.6%) had confirmed BSI (98 infection episodes). Peak incidence was 65.1 infections/100 patient-years at 4-6 months following MM diagnosis with a late peak at 64-66 months. Gram-positive pathogens were responsible for the majority (54.5%) of infections during induction, whilst gram-negative pathogens were responsible for the majority (57.7%) of infections during disease progression. Overall, Escherichia coli was the most frequently identified pathogen. Streptococcus pneumoniae comprised 6.1% of all BSIs at a median of 7.5 months following MM diagnosis. Highest rates of ICU admission (23.1%) and mortality (11.5%) were seen with BSIs in patients with progressive disease. Recent ASCT was independently associated with increased BSI risk (HR 3.09, P = 0.05). CONCLUSIONS: Treatment of progressive disease is a high-risk period for infection, evidenced by high proportions of BSI due to gram-negative pathogens and S. pneumoniae. Targeted evaluation of preventative strategies (prophylaxis, vaccination) to reduce morbidity and mortality during this period is required.

BACKGROUND: Studies have suggested a benefit from extended venous thromboprophylaxis post-operatively in colorectal cancer with an assumed base rate of zero venous thromboembolic events prior to treatment. We aim to establish the incidence of pulmonary embolism in patients with newly diagnosed stage III or IV colorectal cancer prior to any treatment. METHOD: Consecutive patients presenting to a single health service with a new diagnosis of stage III or IV colorectal cancer were identified from a prospective database, for the period between January 2011 and September 2014. Contemporaneous clinical data was reviewed. Included patients had a computerized tomography (CT) chest scan for pre-operative staging for cancer. The diagnosis of pulmonary emboli was made on chest CT. RESULTS: Of 330 patients identified, 224 had baseline CT chest imaging available for review, of which 107 (47.8%) were technically adequate scans. Pulmonary emboli were identified on five (4.7%) of these 107, including one of five patients (1.7%) with stage III and four of five patients (8.3%) with stage IV disease. None of the 107 patients with adequate scans had post-operative pulmonary emboli or deep vein thrombosis. CONCLUSION: There is a clinically significant baseline rate of asymptomatic pulmonary emboli in patients with stage III and IV colorectal cancer that can be demonstrated on the staging chest CT scan. Pulmonary emboli described as a post-operative event in previous series may have been present prior to surgery.

AIM: There are no published data to demonstrate the efficacy of bolus dose vitamin D in newborn infants. The study sought to evaluate this alternative approach of supplementation. METHODS: This single centre, open randomised controlled trial was conducted from August 2013 to May 2014. It compared the efficacy and safety of daily (400 IU) versus a bolus dose (50 000 IU) of cholecalciferol in newborn infants of vitamin D deficient mothers. The primary outcome measure was the rate of 25 hydroxyvitamin D (25OHD) repletion-defined as 25OHD greater than 50 nmol/L. The secondary objective was determining safety using adjusted total serum calcium. RESULTS: Of 70 eligible infants, 36 received a daily dose and 34 received a single high-dose cholecalciferol. Mean 25OHD in the bolus group (154 nmol/L, 95% confidence interval (CI) 131-177) was higher than the daily group (48 nmol/L, 95% CI 42-54) at 1-2 weeks of age. This was reversed at 3-4 months, (65 nmol/L, 95% CI 59-71) compared with the daily group (81 nmol/L, 95% CI 77-85). More infants in the single bolus group achieved vitamin D repletion (100 vs. 31%) at 1-2 weeks. By 3-4 months, both groups achieved similar vitamin D repletion rates (91 vs. 89%). Mean adjusted total serum calcium in the bolus group were normal at 1-2 weeks (2.73 mmol/L) and 3-4 months (2.55 mmol/L). CONCLUSION: Single bolus dosing of 50 000 IU cholecalciferol achieves higher 25OHD repletion rates at 1-2 weeks of age compared with daily dosing, but repletion rates were similar by 3-4 months. There was no hypercalcaemia documented with single bolus dosing in this study.

CONTEXT: Longitudinal integrated clerkships (LICs) represent a model of the structural redesign of clinical education that is growing in the USA, Canada, Australia and South Africa. By contrast with time-limited traditional block rotations, medical students in LICs provide comprehensive care of patients and populations in continuing learning relationships over time and across disciplines and venues. The evidence base for LICs reveals transformational professional and workforce outcomes derived from a number of small institution-specific studies. OBJECTIVES: This study is the first from an international collaborative formed to study the processes and outcomes of LICs across multiple institutions in different countries. It aims to establish a baseline reference typology to inform further research in this field. METHODS: Data on all LIC and LIC-like programmes known to the members of the international Consortium of Longitudinal Integrated Clerkships were collected using a survey tool developed through a Delphi process and subsequently analysed. Data were collected from 54 programmes, 44 medical schools, seven countries and over 15 000 student-years of LIC-like curricula. RESULTS: Wide variation in programme length, student numbers, health care settings and principal supervision was found. Three distinct typological programme clusters were identified and named according to programme length and discipline coverage: Comprehensive LICs; Blended LICs, and LIC-like Amalgamative Clerkships. Two major approaches emerged in terms of the sizes of communities and types of clinical supervision. These referred to programmes based in smaller communities with mainly family physicians or general practitioners as clinical supervisors, and those in more urban settings in which subspecialists were more prevalent. CONCLUSIONS: Three distinct LIC clusters are classified. These provide a foundational reference point for future studies on the processes and outcomes of LICs. The study also exemplifies a collaborative approach to medical education research that focuses on typology rather than on individual programme or context.

OBJECTIVE: There is considerable difficulty in diagnosing hippocampal malrotation (HIMAL), with different criteria of variable reliability. Here we assess qualitative and quantitative criteria in HIMAL diagnosis and explore the role of HIMAL in magnetic resonance imaging (MRI)-negative temporal lobe epilepsy (TLE). METHODS: We studied the MRI of 155 adult patients with MRI-negative TLE and 103 healthy volunteers, and we asked (1) what are the qualitative and quantitative features that allow a reliable diagnosis of HIMAL, (2) how common is HIMAL in a normal control population, and (3) is HIMAL congruent with the epileptogenic side in MRI-negative TLE. RESULTS: We found that the features that are most correlated with the expert diagnosis of HIMAL are hippocampal shape change with hippocampal diameter ratio > 0.8, lack of normal lateral convex margin, and a deep dominant inferior temporal sulcus (DITS) with DITS height ratio > 0.6. In a blinded analysis, a consensus diagnosis of unilateral or bilateral HIMAL was made in 25 of 103 controls (24.3% of people, 14.6% of hippocampi-14 left, six right, 10 bilateral) that did not differ from 155 lesion-negative TLE patients where 25 had HIMAL (16.1% of patients, 11.6% of hippocampi-12 left, two right, 11 bilateral). Of the 12 with left HIMAL only, 9 had seizures arising from the left temporal lobe, whereas 3 had right-sided seizures. Of the two with right HIMAL only, both had seizures arising from the left temporal lobe. SIGNIFICANCE: HIMAL is an anatomic variant commonly found in controls. HIMAL is also an incidental nonpathologic finding in adult MRI-negative TLE and should not influence surgical decision making.

INTRODUCTION: Higher calcium dialysate is recommended for quotidian nocturnal hemodialysis (NHD) (≥6 nights/week) to maintain bone health. It is unclear what the optimal calcium dialysate concentration should be for alternate night NHD. We aimed to determine the effect of low calcium (LC) versus high calcium (HC) dialysate on cardiovascular and bone parameters in this population. METHODS: A randomized controlled trial where participants were randomized to LC (1.3 mmol/L, n = 24) or HC dialysate (1.6 or 1.75 mmol/L, n = 26). Primary outcome was change in mineral metabolism markers. Secondary outcomes included change in vascular calcification (VC) scores [CT abdominal aorta (AA) and superficial femoral arteries (SFA)), pulse wave velocity (PWV), bone mineral density (BMD) and left ventricular mass index (LVMI) over 12 months. FINDINGS: In the LC group, pre-dialysis ionised calcium decreased -0.12 mmol/L (-0.18-0.06, P = 0.0001) and PTH increased 16 pmol/L (3.5-28.5, p = 0.01) from baseline to 12 months with no significant change in the HC group. In both groups, there was no progression of VC in AA or SFA and no change in PWV, LVMI or BMD. At 12 months, calcimimetics were prescribed in a higher percentage in the LC vs. HC groups (45.5% vs. 10.5%) with a lower proportion of the HC group being prescribed calcitriol (31.5% vs. 72%). DISCUSSION: Although dialysate calcium prescription influenced biochemical parameters it was not associated with difference in progression of VC between HC and LC groups. An important finding was the potential impact of alternate night NHD in attenuating progression of VC and inducing stabilisation of LVMI and PWV.

INTRODUCTION: Magnetic resonance diffusion-weighted imaging (DWI) is the most accurate technique available for demonstrating acute infarction; however, false-negative DWI is higher in the infratentorium due to the limited spatial resolution with conventional 5 mm DWI. The aim of this study was to compare 5 mm DWI with 3 mm DWI in the detection of acute infratentorial infarction. METHODS: A 3 mm DWI sequence of the infratentorium was incorporated into the conventional MRI stroke protocol for the evaluation of patients with vertebrobasilar stroke-like deficits. The 5 mm and 3 mm DWI sequences were assessed by two neuroradiologists who were blinded to the clinical findings. Sensitivity and specificity analysis was then performed against the final clinical diagnosis. RESULTS: The sensitivity for detection of infratentorial infarction was 81.1% for 5 mm DWI and 94.6% for 3 mm DWI and the specificity was 100% for 5 mm DWI and 97.7% for 3-mm DWI. The false-negative rate in detection of infratentorial infarcts was 5.6% for the 5-mm sequence and 1.6% for the 3-mm sequence. The six 5-mm DWI false-negative cases (4.8%) were less than 9 mm in diameter (3-8 mm, average 4.67 mm) and located in the brainstem. This supports the hypothesis that small lesions may not be detected on 5 mm DWI due to partial volume averaging. CONCLUSION: Where there is clinical suspicion of infratentorial infarction, 3 mm DWI of the infratentorium adds sensitivity compared to 5 mm DWI with only a small reduction in specificity.

INTRODUCTION: The accuracy of Acoustic Radiation Force Impulse (ARFI) imaging has been validated in the setting of hepatitis C, however, the accuracy in the setting of fatty liver disease (FLD) has been less well-established. The aim of this study was to assess the accuracy of ARFI in the setting of hepatic steatosis. METHODS: Patients with biopsy proven or sonographically diagnosed liver steatosis were assessed for ARFI trends including: inter-operator concordance, interquartile range, ARFI failure rate, relationship between ARFI velocity and steatosis severity, and concordance between biopsy and ARFI fibrosis scores. RESULTS: Three hundred and forty-nine patients were assessed (53 'biopsy' cohort and 296 'ultrasound' cohort), with 28 patients having biopsy on the same day as ARFI. Low stages of fibrosis (F0/1) were over-estimated by ARFI in 62% of cases with biopsy correlation (n = 16, P < 0.001), with ARFI offering increased accuracy in regard to higher-stage fibrosis (14/15 cases, 93%). In both the biopsy and ultrasound cohorts the failure rate and median inter-quartile range increased with increasing steatosis, and the inter-operator concordance remained good across all liver steatosis severities. CONCLUSION: In the setting of steatosis, ARFI is very sensitive in detecting, and accurate in diagnosing, higher stages of fibrosis regardless of steatosis severity. It tends to overestimate the fibrosis category in lower stages of fibrosis. The present study does not show conclusively if the presence of steatosis or its severity independently alters ARFI measurements.

OBJECTIVE: To determine whether the presence of magnetic resonance imaging (MRI) osteoarthritis (OA) features in the patellofemoral or tibiofemoral joint (i.e., bone marrow lesions, cartilage lesions, and osteophytes) and/or functional impairments, 1 year following anterior cruciate ligament reconstruction (ACLR), can predict Knee Injury and Osteoarthritis Outcome Score (KOOS) at 3 years. METHODS: A total of 93 participants (56 [60%] men, mean ± SD age 29 ± 9 years) who had undergone MRI examination and functional testing at 1-year post-ACLR, completed the KOOS at 3 years postsurgery. Multivariate regression models evaluated the prognostic capacity of compartment-specific osteochondral OA features, scored using the MRI Osteoarthritis Knee Score, and functional performance (hop for distance, 1-leg rise), to predict outcome on 4 KOOS subscales (pain, symptoms, sport/recreation, and quality of life [QOL]). RESULTS: Presence of patellofemoral cartilage lesions 1-year post-ACLR predicted worse score on all KOOS subscales at 3 years (P ≤ 0.01). Regression coefficients (B) were -5.1 (95% confidence interval [95% CI] -9.1, -1.2) for symptoms, -4.0 (95% CI -6.7, -1.4) for pain, -6.7 (95% CI -11.0, -2.4) for sport/recreation, and -8.6 (95% CI -15.1, -2.1) for QOL. No significant associations were found between tibiofemoral MRI features and knee symptoms. Poorer performance on the 1-leg-rise test predicted worse KOOS-QOL (B -6.5 [95% CI -12.4, -0.5], P = 0.03). CONCLUSION: The presence of a patellofemoral articular cartilage lesion and lower 1-leg-rise performance at 1 year postsurgery are prognostic for poorer 3-year outcome following ACLR. Particular attention to patellofemoral compartment lesions and functional capacity is warranted during postoperative rehabilitation programs, as these features represent potential targets for therapy aimed at minimizing symptomatic disease progression in these young adults.

AIM: Prisoners exhibit high rates of substance use and mental health problems. In the present study, we sought to gain a detailed understanding of substance use amongst young prisoners to inform early detection and early intervention strategies in a prison setting. METHODS: This is a cross-sectional study of 2102 prisoners who were screened by the London Early Detection and Prevention in Prison Team (LEAP). Data on the use of substances were collected including age of first use, recent use, duration of use and poly-drug use. The Prodromal Questionnaire - Brief Version was used to screen for the at-risk mental state. RESULTS: We found high rates of lifetime and recent use and low age of first use of a number of substances. We also found strong associations between substance use and screening positive for an at-risk mental state. Logistic regression analysis confirmed that use of any drug in the last year, poly-drug and early use, as well as heavy alcohol use, were related to an increased risk of screening positive. CONCLUSIONS: Substance use in the prison population is not only widespread and heavy but is also strongly linked with a higher risk of developing mental health problems. The need for early detection and early intervention in prison is discussed.

To examine practice patterns for breast cancer patients with limited sentinel node (SN) disease in light of the ACOSOG Z0011 results. Retrospective analysis of patients with T1-2 breast cancer and positive sentinel lymph node biopsy (SLNB) admitted between January 2009 and December 2012. Patient demographics, tumor characteristics, and treatments were recorded. Eight hundred positive SLNBs were identified. A total of 452 (56.5%) proceeded to completion axillary lymph node dissection (cALND). cALND rate decreased from 65.1% to 49.7% from 2009-2010 to 2011-2012. cALND was performed for micrometastasis or isolated tumor cells in 39.3% in 2009-2010 and 22.2% in 2011-2012, whereas for macrometastases the rates were 83.1% and 68.6%, respectively. cALND rates diminished for both Z0011-eligible and -ineligible patients. The ACOSOG Z0011 trial presentation and publication coincided with a reduction in cALND for breast cancer with limited nodal disease. There appears equipoise regarding management of macrometastatic SN disease.

OBJECTIVE: To indicate levels of monitoring of type 2 diabetes in rural and regional Australia by examining patterns of glycated haemoglobin (HbA1c) and blood lipid testing. DESIGN AND SETTING: Retrospective analysis of pathology services data from twenty regional and rural towns in eastern Australia over 24 months. PARTICIPANTS: Of 13 105 individuals who had either a single HbA1c result ≥7.0% (53 mmol mol-1 ); or two or more HbA1c tests within the study period. MAIN OUTCOME MEASURES: Frequency of testing of HbA1c and blood lipids (cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides) were compared with guideline recommendations. RESULTS: About 58.3% of patients did not have the recommended 6-monthly HbA1c tests and 30.6% did not have annual lipid testing. For those who did not receive tests at the recommended interval, the mean between-test interval was 10.5 months (95% CI = 7.5-13.5) rather than 6 months for HbA1c testing; and 15.7 (95% CI = 13.3-18.1) months rather than annually for blood lipids. For those with at least one out-of-range test result, 77% of patients failed to receive a follow-up HbA1c test and 86.5% failed to receive a follow-up blood lipid test within the recommended 3 months. Patients less than 50 years of age, living in a more remote area and with poor diabetes control were less likely to have testing at the recommended intervals (P < 0.0001). CONCLUSIONS: Although poor diabetes testing is not limited to rural areas, more intensive diabetes monitoring is likely to be needed for patients living in non-metropolitan areas, particularly for some subgroups.

OBJECTIVE: EDs have long been considered a potential source of eye and tissue donors, but no specific evidence to support this was identified in the Australian setting. The present study aims to bridge that knowledge gap, by analysing medical and social histories of those who have died over a 5 year period so as to determine donation eligibility in this population. METHODS: A retrospective audit was undertaken of all patients who died within the Royal Melbourne Hospital ED between 2010 and 2014. ED records, pharmacy records and electronic medical histories were audited for the presence of eye and tissue donation exclusion criteria and the distribution of these criteria within the target population. RESULTS: Over the 5 year period, of 326 deaths that occurred in the ED, one third was suitable for eye donation (n = 106) and one in seven (n = 45) for tissue donation. Of the age appropriate patients, five criteria were identified that excluded up to 85% of the population not eligible to donate. These were: haematological malignancies, neurodegenerative conditions, non-haematological malignancies, chronic renal failure and eye disease. CONCLUSION: The present study has identified a large pool of potential eye and tissue donors; a pool mostly unrecognised by emergency clinicians. An extensive list of exclusion criteria restricts donor potential. However, the present study has identified that only five fundamentally limit donation in the ED population. Utilisation of this knowledge will allow for the development of clinical triggers that will improve identification, and increase realisation, of potential donors.

INTRODUCTION: Protocol deviations in Randomised Controlled Trials have been found to result in a significant decrease in survival and local control. In some cases, the magnitude of the detrimental effect can be larger than the anticipated benefits of the interventions involved. The implementation of appropriate quality assurance of radiotherapy measures for clinical trials has been found to result in fewer deviations from protocol. This paper reports on a benchmarking study conducted in preparation for the PORTEC-3 trial in Australasia. METHODS: A benchmarking CT dataset was sent to each of the Australasian investigators, it was requested they contour and plan the case according to trial protocol using local treatment planning systems. These data was then sent back to Trans-Tasman Oncology Group for collation and analysis. RESULTS: Thirty three investigators from eighteen institutions across Australia and New Zealand took part in the study. The mean clinical target volume (CTV) volume was 383.4 (228.5-497.8) cm(3) and the mean dose to a reference gold standard CTV was 48.8 (46.4-50.3) Gy. CONCLUSIONS: Although there were some large differences in the contouring of the CTV and its constituent parts, these did not translate into large variations in dosimetry. Where individual investigators had deviations from the trial contouring protocol, feedback was provided. The results of this study will be used to compare with the international study QA for the PORTEC-3 trial.

OBJECTIVE: To examine the feasibility of active surveillance for low volume Gleason sum (GS) 3 + 4 disease compared to GS 3 + 3 disease. PATIENTS AND METHODS: Retrospective review of 929 patients, with biopsy proven GS 3 + 3 and 3 + 4 PCa, undergoing upfront radical prostatectomy (RP) was performed. Suitability for AS was adapted from protocols by Royal Marsden Hospital, University of Toronto, and PRIAS by allowing Gleason 3 + 4 disease. The outcomes assessed were adverse pathology at RP (upgrading ≥GS 4 + 3 and/or upstaging ≥pT3) and biochemical recurrence (BCR) after RP. RESULTS: Adverse pathology at RP was compared between GS 3 + 3 vs 3 + 4 groups. When selecting patients using Royal Marsden (n = 714) or University of Toronto (n = 699) protocols, there was statistically significantly more adverse pathology at RP in GS 3 + 4 group (21% vs 31%, P = 0.0028 and 19% vs 33%, P=<0.001 respectively). Using the more stringent PRIAS protocol (n = 198), there was no statistical significant difference in groups. There was no difference in BCR survival between biopsy GS 3 + 3 and 3 + 4 groups, regardless of which AS protocol assessed. Pre-operative PSA and clinical staging were the predictors for BCR. CONCLUSION: Presence of Gleason 3 + 4 at biopsy, when compared to 3 + 3, increases the risk of adverse pathology being present at radical prostatectomy for less stringent selection criteria. When considering AS, a stricter protocol such as PRIAS, limiting PSA density and number of positive cores to ≤2, appears to decrease the risk of adverse pathology. No differences in BCR were seen between biopsy 3 + 3 and 3 + 4 disease, regardless of AS selection criteria.

AIMS: Many studies show that migrants have a higher incidence of psychosis compared to natives, but the influence of migration on psychosis outcomes is little investigated. We aimed to evaluate the occupational outcomes of a first episode psychosis (FEP) sample in Bologna (Northern Italy). METHODS: An incidence cohort of FEP patients presenting at the Bologna West Community Mental Health Centers between 2002 and 2009 was assessed at the baseline and at 12th month follow-up. Return to school or work was used as occupational outcome. RESULTS: Most of the patients (82.8%) were still in contact at 12 months. Migrants showed significantly higher rate of return to work compared to natives (adjusted OR 4.45, 95% CI 1.55-12.76). CONCLUSIONS: First generation migrants had better occupational outcomes. Further cross-cultural studies are needed to further explain these findings.

OBJECTIVE: Biomarkers are a critical component in the investigation of patients with potential ischaemic heart disease. The proposed benefits of a high-sensitivity troponin (hs-Tn) assay include earlier diagnosis of myocardial infarction. However, the decreased specificity may adversely affect clinical practice. The present study aims to investigate the impact that the introduction of a hs-Tn assay had on patients presenting to the ED. METHODS: A pre- and post-interventional analysis was performed on all patients presenting to the Royal Melbourne Hospital ED, and had a troponin, in the 12 months before and after the introduction of the hs-Tn assay. The main outcome measures were ED length of stay, admission rates, proportion of patients undergoing interventional cardiac procedures and proportion diagnosed with myocardial infarction. RESULTS: There were 6557 patients who had a conventional assay and 7335 patients who had a hs-Tn assay. The introduction of a hs-Tn assay was associated with an increased abnormal troponin rate (23.4% vs 28.1%, P < 0.001). The median length of ED stay decreased by 9.1% (P < 0.001). The proportion admitted to hospital increased (60.9% vs 65.9%, P < 0.001); however, there was no difference in the proportion undergoing revascularisation or the proportion diagnosed with myocardial infarction. CONCLUSIONS: Although the introduction of a hs-Tn assay led to an increase in hospital admissions, the unchanged rate of cardiac procedures or final diagnoses of acute myocardial infarction and ischaemic heart disease suggests that the hs-Tn did not improve the detection of these conditions. It remains unclear whether there was a benefit admitting the additional cohort of patients.

BACKGROUND: Peer-assisted learning (PAL) is increasingly used in medical education, and the benefits of this approach have been reported. Previous reviews have focused on the benefits of peer tutoring of junior students by senior students. Forms of PAL such as discussion groups and role-playing have been neglected, as have alternative teacher-learner configurations (e.g. same-level PAL) and the effects on other stakeholders, including clinician educators and patients. This review examines the benefits of same-level PAL for students, clinician educators and patients in pre-registration clinical medical education. METHODS: Medline, PsycINFO, CINAHL and ERIC were searched in March 2014. A total of 1228 abstracts were retrieved for review; 64 full-text papers were assessed. Data were extracted from empirical studies describing a same-level PAL initiative in a clinical setting, focusing on effects beyond academic performance and student satisfaction. Qualitative thematic analysis was employed to identify types of PAL and to cluster the reported PAL effects. RESULTS: Forty-three studies were included in the review. PAL activities were categorised into role-play, discussion, teaching and assessment. Only 50% of studies reported information beyond self-report and satisfaction with the PAL intervention. Benefits for students (including development of communication and professional skills) and clinician educators (developing less-used facilitation skills) were reported. Direct patient outcomes were not identified. Caveats to the use of PAL emerged, and guidelines for the use of PAL were perceived as useful. CONCLUSION: Many student-related benefits of PAL were identified. PAL contributes to the development of crucial skills required for a doctor in the workplace. Vertical integration of learning and teaching skills across the curriculum and tools such as feedback checklists may be required for successful PAL in the clinical environment. Benefits for patients and educators were poorly characterised within the included studies. Future work should evaluate the use of PAL with regards to student, clinician educator and patient outcomes.

INTRODUCTION: Non-sustained ventricular tachycardia (NSVT) is a risk factor for sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM). We aimed to assess whether diffuse ventricular fibrosis on cardiac magnetic resonance (CMR) imaging could be a surrogate marker for ventricular arrhythmias in patients with HCM. METHODS: A total of 100 patients with HCM (mean age 51 ± 13 years, septal wall thickness 20 ± 5 mm) underwent CMR with a 1.5 T scanner to determine the presence of ventricular late gadolinium enhancement (LGE) for focal fibrosis, and post-contrast T1 mapping for diffuse ventricular fibrosis. The presence of NSVT was determined by Holter monitoring and a subset of high risk patients received an implantable cardioverter-defibrillator (ICD). RESULTS: NSVT was detected in 23 of 100 patients with HCM. Focal ventricular fibrosis (by LGE) was observed in 87%, with no significant difference between patients with (96%) or without NSVT (86%, P = 0.19). However, LGE mass was greater in patients with (16.5 ± 19.1 g) versus without NSVT (7.6 ± 10.2 g, P < 0.01). NSVT was associated with a significant reduction in ventricular T1 relaxation time (422 ± 54 milliseconds) versus patients without NSVT (512 ± 115 milliseconds; P < 0.001). There was significant reduction in ventricular T1 relaxation time in patients with (430 ± 48 milliseconds) versus without aborted SCD (495 ± 113 milliseconds; P = 0.01) over a mean follow-up of 40 ± 10 months. On multivariate analysis post-contrast ventricular T1 relaxation time and septal wall thickness were the only predictors of NSVT. CONCLUSION: Post-contrast T1 relaxation time on CMR is associated with ventricular arrhythmias in patients with HCM. Diffuse ventricular fibrosis may be an important marker of arrhythmic risk in patients with HCM.

BACKGROUND AND AIM: Both sarcopenia and low serum testosterone have been associated with increased mortality in men with cirrhosis. It is not known how these variables interact. METHODS: We conducted a retrospective longitudinal cohort study of 145 men referred for liver transplant evaluation between 2005 and 2012. Baseline demographics included hormone profile and model of end-stage liver disease (MELD) score. Baseline computerized tomography was reformatted to calculate skeletal muscle area at L4 using validated, Tomovision software-based methodology. The primary outcome was time to death or liver transplantation. RESULTS: Median testosterone was low at 6.2 nmol/L (ref. 10-27.6 nmol/L) as was muscle mass at 48.0 cm(2)/m(2) (ref. > 52.4 cm(2)/m(2)). Muscle mass correlated with both serum testosterone (tau = 0.132, P = 0.019) and MELD score (tau = -0.155, P = 0.007). In separate multivariable models, both sarcopenia (hazard ratio [HR] 1.05, P = 0.04) and low testosterone (HR 1.08, P = 0.01) were significantly associated with mortality independent of MELD score. When the variables MELD score, muscle area, and testosterone were entered into a single model, low testosterone but not sarcopenia remained significantly predictive of mortality (HR 1.07, P = 0.02, and HR 1.04, P = 0.09, respectively). CONCLUSION: Low testosterone and sarcopenia are both associated with increased mortality in men with advanced liver disease and may identify patients at high risk of mortality that would be missed by the MELD score alone. Low testosterone appears to be a better predictor of mortality than sarcopenia and is a simpler test to improve the prognostic value of the MELD score. Interventional trials are required to determine whether low testosterone and sarcopenia are markers or mediators of mortality in this population.

BACKGROUND: Thiopurine use in inflammatory bowel disease (IBD) is limited by drug toxicity and lack of therapeutic efficacy. We assessed the utility of thiopurine metabolite testing and the relationship between disease activity, dose, and metabolite levels in a real world setting. METHODS: Patients identified from pathology databases (2007-2012) at two tertiary IBD centers were included if they had thiopurines for at least four weeks. Demographics, dose, test indication, clinical status, action taken, and outcome were obtained by retrospective medical record review. RESULTS: A total of 169 patients were included. 6-Thioguanine (TGN) levels were sub-therapeutic in 52%, therapeutic in 34%, and supratherapeutic in 14%. Test indication was active disease (79%), adverse effect (11%), or adherence assessment (7%). TGN trended lower in the active disease group compared to those with adverse effects (273 (+/- 23.2) versus 447 (+/- 117.7) pmol/8 × 10(8) RBC, P = 0.05). Weight-based dosing did not improve rates of therapeutic TGN levels (under-dosed 31.5% vs standard dose 35.4%), but was significantly associated with shunting toward 6-MMP (23.1% vs 6.8%, P = 0.008, OR = 4.1). Testing resulted in a change in patient treatment in 86% of patients with active disease and subtherapeutic levels and in 68% of tested patients overall. CONCLUSIONS: Metabolite testing resulted in a change in management in most patients not responding to thiopurines or experiencing adverse events. Weight-based dosing did not increase rates of therapeutic levels but was associated with increased 6MMP shunting.

OBJECTIVE: To investigate in a prospective, observational study whether transperineal prostate biopsy (TPbx) results in patient-reported quality-of-life (QoL) changes from baseline in the first 3-months after TPbx. PATIENTS AND METHODS: Consenting patients completed the 26-item Expanded Prostate cancer Index Composite (EPIC-26), the Sexual Health Inventory for Men, the International Prostate Symptom Score, the Generalised Anxiety Disorder seven-item scale, the Patient Health Questionnaire nine-item scale, and a global question about willingness to have a repeat TPbx in a years' time. The instruments were scored using published scoring methods. Wilcoxon signed-rank tests and Mann-Whitney U-tests were used to investigate statistically significant differences. Clinically significant differences were also investigated defined by published minimal important differences for the EPIC-26 and changes in established categorical groups for the other instruments. RESULTS: In all, 53 patients consented to participate and completed the baseline questionnaire, in addition to at least one of the 1- or 3-month follow-up questionnaires. We found that most patients having a TPbx had no clinically significant change in QoL in the first 3 months after TPbx. However, 24% had clinically worse urinary function and 18% had worse sexual function at 1 month. At 3 months, 3% of patients had clinically worse urinary function and 25% continued to have worse sexual function compared with baseline. Patients who were subsequently diagnosed with cancer based on the results of the TPbx, had statistically significantly reduced QoL for the EPIC-26 urinary scales and reduced improvements in scores on the psychological scales at the 1-month follow-up compared with those who were not diagnosed with cancer. CONCLUSIONS: Most patients having a TPbx had no clinically significant change in QoL in the first 3 months after TPbx. However, patients should be advised that a quarter may have clinically worse urinary function and nearly 20% have clinically worse sexual function in the first month, and that sexual function deficits may continue up to 3 months. The results of this study provide a resource that the clinician can use when discussing TPbx with patients.

UNLABELLED: Hepatocellular carcinoma (HCC) incidence is rising rapidly in many developed countries. Primary epidemiological data have invariably been derived from cancer registries that are heterogeneous in data quality and registration methodology; many registries have not adopted current clinical diagnostic criteria for HCC and still rely on histology for classification. We performed the first population-based study in Australia using current diagnostic criteria, hypothesizing that HCC incidence may be higher than reported. Incident cases of HCC (defined by American Association for the Study of Liver Diseases diagnostic criteria or histology) were prospectively identified over a 12-month period (2012-2013) from the population of Melbourne, Australia. Cases were captured from multiple sources: admissions to any of Melbourne's seven tertiary hospitals; attendances at outpatients; and radiology, pathology, and pharmacy services. Our cohort was compared to the Victorian Cancer Registry (VCR) cohort (mandatory notified cases) for the same population and period, and incidence rates were compared for both cohorts. There were 272 incident cases (79% male; median age: 65 years) identified. Cirrhosis was present in 83% of patients, with hepatitis C virus infection (41%), alcohol (39%), and hepatitis B virus infection (22%) the commonest etiologies present. Age-standardized HCC incidence (per 100,000, Australian Standard Population) was 10.3 (95% confidence interval [CI]: 9.0-11.7) for males and 2.3 (95% CI: 1.8 to 3.0) for females. The VCR reported significantly lower rates of HCC: 5.3 (95% CI: 4.4 to 6.4) and 1.0 (95% CI: 0.7 to 1.5) per 100,000 males and females respectively (P < 0.0001). CONCLUSIONS: HCC incidence in Melbourne is 2-fold higher than reported by cancer registry data owing to under-reporting of clinical diagnoses. Adoption of current diagnostic criteria and additional capture sources will improve registry completeness. Chronic viral hepatitis and alcohol remain leading causes of cirrhosis and HCC.

BACKGROUND: Indigenous people in Australia experience higher rates of preterm birth and low birthweight than their nonindigenous counterparts. There is currently no data on these rates from Victoria, with the data coming from states with higher indigenous proportions. MATERIALS AND METHODS: Five years (1st January 2010-31st December 2014) of retrospective data from The Northern Hospital's (Melbourne, Victoria) database were analysed. Mothers and babies were split according to self-reported indigenous status: 13800 nonindigenous mothers, 185 indigenous mothers, 301 indigenous babies and 13843 nonindigenous babies. Primary outcomes measured were low birthweight (LBW) and preterm birth. RESULTS: There was a higher incidence of indigenous babies born preterm (8.8% vs 5.9%, P = 0.034), but the adjusted odds ratios for preterm birth were not significant (indigenous babies OR 1.19, 95% CI: 0.77-1.87, indigenous mothers OR 0.97, CI: 0.52-1.80). There was a similar incidence of LBW among indigenous and nonindigenous babies (6.5% vs 5.4%, P = 0.416). The rate of indigenous women smoking was 29.3% compared to 12.3% of nonindigenous women (P < 0.001), and 40.3% were obese compared to 28.7% (P = 0.001). Indigenous women had lower rates of diabetes (pre-existing or gestational diabetes, 6.1% vs 13.5% P = 0.003). CONCLUSION: Heterogeneity of indigenous people and geography means that inferences about indigenous health are difficult to make. It appears that Victorian urban indigenous women have similar rates of preterm birth and LBW to nonindigenous women. While there were pleasing results concerning LBW, antenatal care, diabetes and preterm birth, the rates of smoking and obesity remain a challenge in the indigenous population.

OBJECTIVE: The leading cause of epilepsy-related premature mortality is sudden unexpected death in epilepsy (SUDEP). The cause of SUDEP remains unknown. To search for genetic risk factors in SUDEP cases, we performed an exome-based analysis of rare variants. METHODS: Demographic and clinical information of 61 SUDEP cases were collected. Exome sequencing and rare variant collapsing analysis with 2,936 control exomes were performed to test for genes enriched with damaging variants. Additionally, cardiac arrhythmia, respiratory control, and epilepsy genes were screened for variants with frequency of <0.1% and predicted to be pathogenic with multiple in silico tools. RESULTS: The 61 SUDEP cases were categorized as definite SUDEP (n = 54), probable SUDEP (n = 5), and definite SUDEP plus (n = 2). We identified de novo mutations, previously reported pathogenic mutations, or candidate pathogenic variants in 28 of 61 (46%) cases. Four SUDEP cases (7%) had mutations in common genes responsible for the cardiac arrhythmia disease, long QT syndrome (LQTS). Nine cases (15%) had candidate pathogenic variants in dominant cardiac arrhythmia genes. Fifteen cases (25%) had mutations or candidate pathogenic variants in dominant epilepsy genes. No gene reached genome-wide significance with rare variant collapsing analysis; however, DEPDC5 (p = 0.00015) and KCNH2 (p = 0.0037) were among the top 30 genes, genome-wide. INTERPRETATION: A sizeable proportion of SUDEP cases have clinically relevant mutations in cardiac arrhythmia and epilepsy genes. In cases with an LQTS gene mutation, SUDEP may occur as a result of a predictable and preventable cause. Understanding the genetic basis of SUDEP may inform cascade testing of at-risk family members.

OBJECTIVE: The objective of the study was to compare QT intervals measured on the original bedside electrocardiographs (ECG), facsimile, iPhone, iPad and 17 inch computer monitor. METHODS: This was a prospective, observational study conducted within a tertiary referral metropolitan ED. Thirteen doctors measured the QT intervals of 15 non-identifiable, routinely recorded ECGs using randomly allocated modalities over five sessions. The QT intervals of lead I, II, V2, V4, V6 and one other were measured. Variations between modalities and between doctors were examined (χ(2) and Kruskal-Wallis tests). RESULTS: QT intervals measured on the iPad were significantly lower than the other modalities (P = 0.02). For each lead, there were no differences in QT interval measurement between the modalities (P > 0.05). However, there were significant differences between the QT interval measurements of the participating doctors (range of median QT intervals 480-530 msec, P < 0.001). There were also significant differences between the QT intervals measurement of the leads examined (range of median QT intervals 480-520 msec, P < 0.001). Lead V2 was the most consistent lead (smallest interquartile range), and lead I was the least (QT interval consistently under-estimated). CONCLUSION: The QT interval can be reliably measured using facsimile, iPhone and computer, but not the iPad. However, it varies between doctors. Lead V2 is recommended for QT interval measurement if only a single lead is to be used for clinical purposes.

AIMS: It is not known whether concomitant use of aspirin might attenuate the beneficial effects of mineralocorticoid receptor antagonists (MRAs). The purpose of this subgroup analysis was to explore the interaction between baseline aspirin treatment and the effect of eplerenone on the primary efficacy outcomes (composite of hospitalization for heart failure or cardiovascular mortality), its components, and safety markers [estimated glomerular filtration rate (eGFR), systolic blood pressure (SBP), and serum potassium >5.5 mmol/L] in the Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure trial (EMPHASIS-HF). METHODS AND RESULTS: Patients with chronic heart failure, reduced ejection fraction (HFREF), and mild symptoms were enrolled in EMPHASIS-HF. We evaluated baseline characteristics according to aspirin use. We explored the interaction between aspirin and eplerenone, using Cox proportional hazards models providing adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) and P-values for interaction. Of the 2737 patients randomized, 1605 patients (58.6%) were taking aspirin. The beneficial effects of eplerenone on the primary endpoint were similar in patients not treated (adjusted HR 0.59, 95% CI 0.46-0.75) or treated (adjusted HR 0.71, 95% CI 0.59-0.87) with aspirin at baseline (interaction P-value = 0.19). We did not observe any significant modification of the safety markers by aspirin that was clinically meaningful. CONCLUSION: Aspirin use in patients with chronic systolic heart failure and mild symptoms did not substantially reduce the overall beneficial effects of the MRA eplerenone contrary to what has been described in some studies with ACE inhibitors.

BACKGROUND AND AIM: The glycoprotein CD147 has a role in tumor progression, is readily detectable in the circulation, and is abundantly expressed in hepatocellular carcinoma (HCC). Advanced HCC patients are a heterogeneous group with some individuals having dismal survival. The aim of this study was to examine circulating soluble CD147 levels as a prognostic marker in HCC patients. METHODS: CD147 was measured in 277 patients (110 HCC, 115 chronic liver disease, and 52 non-liver disease). Clinical data included etiology, tumor progression, Barcelona Clinic Liver Cancer (BCLC) stage, and treatment response. Patients with HCC were stratified into two groups based upon the 75th percentile of CD147 levels (24 ng/mL). RESULTS: CD147 in HCC correlated inversely with poor survival (P = 0.031). Increased CD147 predicted poor survival in BCLC stages C and D (P = 0.045), and CD147 levels >24 ng/mL predicted a significantly diminished 90-day and 180-day survival time (hazard ratio [HR] = 6.1; 95% confidence interval [CI]: 2.1-63.2; P = 0.0045 and HR = 2.8; 95% CI: 1.2-12.6; P = 0.028, respectively). In BCLC stage C, CD147 predicted prognosis; levels >24 ng/mL were associated with a median survival of 1.5 months compared with 6.5 months with CD147 levels ≤24 ng/mL (P = 0.03). CD147 also identified patients with a poor prognosis independent from treatment frequency, modality, and tumor size. CONCLUSIONS: Circulating CD147 is an independent marker of survival in advanced HCC. CD147 requires further evaluation as a potential new prognostic measure in HCC to identify patients with advanced disease who have a poor prognosis.

OBJECTIVE: To provide recommendations for reviewing and reporting clinical in-hospital cardiopulmonary resuscitation (CPR) events in dogs and cats and to establish nonambiguous operational definitions for CPR terminology. DESIGN: Consensus guidelines. SETTING: International, academia, referral practice, general practice, and human medicine. METHODS: An international veterinary Utstein task force was convened in April 2013 in San Francisco to determine the scope of the project, the variables to be reported, their definitions, and a reporting template. Factors that were essential for meaningful data reporting and were amenable to accurate collection (ie, core variables) and additional variables useful for research projects and hypothesis generation (ie, supplemental variables) were defined. Consensus on each item was either achieved during that meeting or during the subsequent online modified Delphi process and dialogue between task force members. RESULTS: Variables were defined and categorized as hospital, animal, event (arrest), and outcome variables. This report recommends a template for standardized reporting of veterinary in-hospital CPR studies involving dogs or cats. Core elements include the suspected cause(s) and location of arrest, first rhythm identified, the occurrence of return of spontaneous circulation (ROSC) of more than 30 seconds (any ROSC) or more than 20 minutes (sustained ROSC), survival to discharge, and functional capacity at discharge. If CPR is discontinued or the patient is euthanized by owner request, a reason is reported. The task force suggests a case report form to be used for individual resuscitation events. CONCLUSIONS: The availability of these veterinary small animal CPR reporting guidelines will encourage and facilitate high-quality veterinary CPR research, improve data comparison between studies and across study sites, and serve as the foundation for veterinary CPR registries.

Moral distress occurs when individuals are unable to act in accordance with what they believe to be ethically correct or just. It results from a discrepancy between a clinician's perception of "the right thing to do" and what is actually happening and is perpetuated by perceived constraints that limit the individual from speaking up or enacting change. Moral distress is reported by many clinicians in caring for patients with serious illness, including chronic kidney disease and kidney failure. If left unidentified, unexpressed, or unaddressed, moral distress may cause burnout, exhaustion, detachment, and ineffectiveness. At an extreme, moral distress may lead to a desire to abandon the speciality entirely. This article offers an international perspective on moral distress in nephrology in diverse contexts and health care systems. We examine and discuss the sociocultural factors that contribute to moral distress in nephrology and offer suggestions for interventions from individual provider, facility, and health care systems perspectives to reduce the impact of moral distress on nephrology providers.

BACKGROUND: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. METHODS: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. RESULTS: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. CONCLUSIONS: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.

BACKGROUND: Expression of genes regulating fatty acid metabolism is reduced in tubular epithelial cells from kidneys with tubulointerstitial fibrosis (TIF), thus decreasing the energy produced by fatty acid oxidation (FAO). Acetyl-CoA carboxylase (ACC), a target for the energy-sensing AMP-activating protein kinase (AMPK), is the major controller of the rate of FAO within cells. Metformin has a well described antifibrotic effect, and increases phosphorylation of ACC by AMPK, thereby increasing FAO. METHODS: We evaluated phosphorylation of ACC in cell and mouse nephropathy models, as well as the effects of metformin administration in mice with and without mutations that reduce ACC phosphorylation. RESULTS: Reduced phosphorylation of ACC on the AMPK site Ser79 occurred in both tubular epithelial cells treated with folate to mimic cellular injury and in wild-type (WT) mice after induction of the folic acid nephropathy model. When this effect was exaggerated in mice with knock-in (KI) Ser to Ala mutations of the phosphorylation sites in ACC, lipid accumulation and fibrosis increased significantly compared with WT. The effect of ACC phosphorylation on fibrosis was confirmed in the unilateral ureteric obstruction model, which showed significantly increased lipid accumulation and fibrosis in the KI mice. Metformin use was associated with significantly reduced fibrosis and lipid accumulation in WT mice. In contrast, in the KI mice, the drug was associated with worsened fibrosis. CONCLUSIONS: These data indicate that reduced phosphorylation of ACC after renal injury contributes to the development of TIF, and that phosphorylation of ACC is required for metformin's antifibrotic action in the kidney.

Introduction: Use of complementary and alternative medicine (CAM) is popular in the general population and medical practitioners may not be fully equipped in their knowledge of CAM to advise patients appropriately. The aim of this paper was to perform a scoping review of current literature describing undergraduate medical student use, attitudes, and knowledge of CAM as a means of better understanding the educational needs of these students. Methods: A systematic search of Medline, PubMed and the Education Resources Information Center (ERIC) databases with keywords related to “complementary and alternative medicine” and “undergraduate medical students” for relevant articles published until August 2020. Results: Of 131 papers identified, 38 underwent full review. It was found 13-80% of medical students use CAM, and overall have a positive attitude towards CAM therapies. Female medical students and those with religiosity had more positive attitudes towards CAM than their male colleagues and those without a religion. Knowledge of CAM is lacking with approximately only half of students feeling they were knowledgeable about CAM therapies. Popular information resources are the Internet and social media, but students expressed they want more teaching of CAM in the undergraduate medical curriculum. Conclusion: Evidence suggests high usage of CAM amongst undergraduate medical students, and positive attitudes towards CAM therapies; however, knowledge of CAM is poor, and students want more CAM teaching to upskill them in counselling patients interested in CAM therapies. Further areas for research include a better understanding of resources medical students use for their knowledge and how gender and religiosity influence attitudes towards CAM.

The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia. As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment for CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (³ 1 of neutropenia, thrombocytopenia, anemia) lasting ³4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (tMNs). tMNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with tMNs. Single cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.