Fiona Stanley Hospital

BACKGROUND: Evidence from a recent trial has shown that the antiinflammatory effects of colchicine reduce the risk of cardiovascular events in patients with recent myocardial infarction, but evidence of such a risk reduction in patients with chronic coronary disease is limited. METHODS: In a randomized, controlled, double-blind trial, we assigned patients with chronic coronary disease to receive 0.5 mg of colchicine once daily or matching placebo. The primary end point was a composite of cardiovascular death, spontaneous (nonprocedural) myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization. The key secondary end point was a composite of cardiovascular death, spontaneous myocardial infarction, or ischemic stroke. RESULTS: A total of 5522 patients underwent randomization; 2762 were assigned to the colchicine group and 2760 to the placebo group. The median duration of follow-up was 28.6 months. A primary end-point event occurred in 187 patients (6.8%) in the colchicine group and in 264 patients (9.6%) in the placebo group (incidence, 2.5 vs. 3.6 events per 100 person-years; hazard ratio, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P<0.001). A key secondary end-point event occurred in 115 patients (4.2%) in the colchicine group and in 157 patients (5.7%) in the placebo group (incidence, 1.5 vs. 2.1 events per 100 person-years; hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.007). The incidence rates of spontaneous myocardial infarction or ischemia-driven coronary revascularization (composite end point), cardiovascular death or spontaneous myocardial infarction (composite end point), ischemia-driven coronary revascularization, and spontaneous myocardial infarction were also significantly lower with colchicine than with placebo. The incidence of death from noncardiovascular causes was higher in the colchicine group than in the placebo group (incidence, 0.7 vs. 0.5 events per 100 person-years; hazard ratio, 1.51; 95% CI, 0.99 to 2.31). CONCLUSIONS: In a randomized trial involving patients with chronic coronary disease, the risk of cardiovascular events was significantly lower among those who received 0.5 mg of colchicine once daily than among those who received placebo. (Funded by the National Health Medical Research Council of Australia and others; LoDoCo2 Australian New Zealand Clinical Trials Registry number, ACTRN12614000093684.).

BACKGROUND: The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma. METHODS: Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated. RESULTS: At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group. CONCLUSIONS: As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies. FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

OBJECTIVES: To identify common recommendations for high-quality care for the most common musculoskeletal (MSK) pain sites encountered by clinicians in emergency and primary care (spinal (lumbar, thoracic and cervical), hip/knee (including osteoarthritis [OA] and shoulder) from contemporary, high-quality clinical practice guidelines (CPGs). DESIGN: Systematic review, critical appraisal and narrative synthesis of MSK pain CPG recommendations. ELIGIBILITY CRITERIA: Included MSK pain CPGs were written in English, rated as high quality, published from 2011, focused on adults and described development processes. Excluded CPGs were for: traumatic MSK pain, single modalities (eg, surgery), traditional healing/medicine, specific disease processes (eg, inflammatory arthropathies) or those that required payment. DATA SOURCES: Four scientific databases (MEDLINE, Embase, CINAHL and Physiotherapy Evidence Database) and four guideline repositories. RESULTS: 6232 records were identified, 44 CPGs were appraised and 11 were rated as high quality (low back pain: 4, OA: 4, neck: 2 and shoulder: 1). We identified 11 recommendations for MSK pain care: ensure care is patient centred, screen for red flag conditions, assess psychosocial factors, use imaging selectively, undertake a physical examination, monitor patient progress, provide education/information, address physical activity/exercise, use manual therapy only as an adjunct to other treatments, offer high-quality non-surgical care prior to surgery and try to keep patients at work. CONCLUSION: These 11 recommendations guide healthcare consumers, clinicians, researchers and policy makers to manage MSK pain. This should improve the quality of care of MSK pain.

Importance: High-intensity, aerobically prepared fecal microbiota transplantation (FMT) has demonstrated efficacy in treating active ulcerative colitis (UC). FMT protocols involving anaerobic stool processing methods may enhance microbial viability and allow efficacy with a lower treatment intensity. Objective: To assess the efficacy of a short duration of FMT therapy to induce remission in UC using anaerobically prepared stool. Design, Setting, and Participants: A total of 73 adults with mild to moderately active UC were enrolled in a multicenter, randomized, double-blind clinical trial in 3 Australian tertiary referral centers between June 2013 and June 2016, with 12-month follow-up until June 2017. Interventions: Patients were randomized to receive either anaerobically prepared pooled donor FMT (n = 38) or autologous FMT (n = 35) via colonoscopy followed by 2 enemas over 7 days. Open-label therapy was offered to autologous FMT participants at 8 weeks and they were followed up for 12 months. Main Outcomes and Measures: The primary outcome was steroid-free remission of UC, defined as a total Mayo score of ≤2 with an endoscopic Mayo score of 1 or less at week 8. Total Mayo score ranges from 0 to 12 (0 = no disease and 12 = most severe disease). Steroid-free remission of UC was reassessed at 12 months. Secondary clinical outcomes included adverse events. Results: Among 73 patients who were randomized (mean age, 39 years; women, 33 [45%]), 69 (95%) completed the trial. The primary outcome was achieved in 12 of the 38 participants (32%) receiving pooled donor FMT compared with 3 of the 35 (9%) receiving autologous FMT (difference, 23% [95% CI, 4%-42%]; odds ratio, 5.0 [95% CI, 1.2-20.1]; P = .03). Five of the 12 participants (42%) who achieved the primary end point at week 8 following donor FMT maintained remission at 12 months. There were 3 serious adverse events in the donor FMT group and 2 in the autologous FMT group. Conclusions and Relevance: In this preliminary study of adults with mild to moderate UC, 1-week treatment with anaerobically prepared donor FMT compared with autologous FMT resulted in a higher likelihood of remission at 8 weeks. Further research is needed to assess longer-term maintenance of remission and safety. Trial Registration: anzctr.org.au Identifier: ACTRN12613000236796.

Importance: Extended-spectrum β-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective "carbapenem-sparing" option to treat extended-spectrum β-lactamase producers. Objectives: To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae. Design, Setting, and Participants: Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study. Interventions: Patients were randomly assigned 1:1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician. Main Outcomes and Measures: The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used. Results: Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6% [1-sided 97.5% CI, -∞ to 14.5%]; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group. Conclusions and relevance: Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting. Trial Registration: anzctr.org.au Identifiers: ACTRN12613000532707 and ACTRN12615000403538 and ClinicalTrials.gov Identifier: NCT02176122.

This document outlines recommendations for physiotherapy management for COVID-19 in the acute hospital setting. It includes: recommendations for physiotherapy workforce planning and preparation; a screening tool for determining requirement for physiotherapy; and recommendations for the selection of physiotherapy treatments and personal protective equipment. It is intended for use by physiotherapists and other relevant stakeholders in the acute care setting caring for adult patients with confirmed or suspected COVID-19.

Cancer-associated thrombosis is a major cause of mortality in cancer patients, the most common type being venous thromboembolism (VTE). Several risk factors for developing VTE also coexist with cancer patients, such as chemotherapy and immobilisation, contributing to the increased risk cancer patients have of developing VTE compared with non-cancer patients. Cancer cells are capable of activating the coagulation cascade and other prothrombotic properties of host cells, and many anticancer treatments themselves are being described as additional mechanisms for promoting VTE. This review will give an overview of the main thrombotic complications in cancer patients and outline the risk factors for cancer patients developing cancer-associated thrombosis, focusing on VTE as it is the most common complication observed in cancer patients. The multiple mechanisms involved in cancer-associated thrombosis, including the role of anticancer drugs, and a brief outline of the current treatment for cancer-associated thrombosis will also be discussed.

Texture modification has become one of the most common forms of intervention for dysphagia, and is widely considered important for promoting safe and efficient swallowing. However, to date, there is no single convention with respect to the terminology used to describe levels of liquid thickening or food texture modification for clinical use. As a first step toward building a common taxonomy, a systematic review was undertaken to identify empirical evidence describing the impact of liquid consistency and food texture on swallowing behavior. A multi-engine search yielded 10,147 non-duplicate articles, which were screened for relevance. A team of ten international researchers collaborated to conduct full-text reviews for 488 of these articles, which met the study inclusion criteria. Of these, 36 articles were found to contain specific information comparing oral processing or swallowing behaviors for at least two liquid consistencies or food textures. Qualitative synthesis revealed two key trends with respect to the impact of thickening liquids on swallowing: thicker liquids reduce the risk of penetration-aspiration, but also increase the risk of post-swallow residue in the pharynx. The literature was insufficient to support the delineation of specific viscosity boundaries or other quantifiable material properties related to these clinical outcomes. With respect to food texture, the literature pointed to properties of hardness, cohesiveness, and slipperiness as being relevant both for physiological behaviors and bolus flow patterns. The literature suggests a need to classify food and fluid behavior in the context of the physiological processes involved in oral transport and flow initiation.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

Public health measures targeting coronavirus disease 2019 have potential to impact transmission of other respiratory viruses. We found 98.0% and 99.4% reductions in respiratory syncytial virus and influenza detections, respectively, in Western Australian children through winter 2020 despite schools reopening. Border closures have likely been important in limiting external introductions.

In less than a decade, C. auris has emerged in health care settings worldwide; this species is capable of colonizing skin and causing outbreaks of invasive candidiasis. In contrast to other Candida species, C. auris is unique in its ability to spread via nosocomial transmission and its high rates of drug resistance. As part of the public health response, whole-genome sequencing has played a major role in characterizing transmission dynamics and detecting new C. auris introductions. Through a global collaboration, we assessed genome evolution of isolates of C. auris from 19 countries. Here, we described estimated timing of the expansion of each C. auris clade and of fluconazole resistance, characterized discrete phylogeographic population structure of each clade, and compared genome data to sensitivity measurements to describe how antifungal resistance mechanisms vary across the population. These efforts are critical for a sustained, robust public health response that effectively utilizes molecular epidemiology.

BACKGROUND: Patient blood management (PBM) programs are associated with improved patient outcomes, reduced transfusions and costs. In 2008, the Western Australia Department of Health initiated a comprehensive health-system-wide PBM program. This study assesses program outcomes. STUDY DESIGN AND METHODS: This was a retrospective study of 605,046 patients admitted to four major adult tertiary-care hospitals between July 2008 and June 2014. Outcome measures were red blood cell (RBC), fresh-frozen plasma (FFP), and platelet units transfused; single-unit RBC transfusions; pretransfusion hemoglobin levels; elective surgery patients anemic at admission; product and activity-based costs of transfusion; in-hospital mortality; length of stay; 28-day all-cause emergency readmissions; and hospital-acquired complications. RESULTS: Comparing final year with baseline, units of RBCs, FFP, and platelets transfused per admission decreased 41% (p < 0.001), representing a saving of AU$18,507,092 (US$18,078,258) and between AU$80 million and AU$100 million (US$78 million and US$97 million) estimated activity-based savings. Mean pretransfusion hemoglobin levels decreased 7.9 g/dL to 7.3 g/dL (p < 0.001), and anemic elective surgery admissions decreased 20.8% to 14.4% (p = 0.001). Single-unit RBC transfusions increased from 33.3% to 63.7% (p < 0.001). There were risk-adjusted reductions in hospital mortality (odds ratio [OR], 0.72; 95% confidence interval [CI], 0.67-0.77; p < 0.001), length of stay (incidence rate ratio, 0.85; 95% CI, 0.84-0.87; p < 0.001), hospital-acquired infections (OR, 0.79; 95% CI, 0.73-0.86; p < 0.001), and acute myocardial infarction-stroke (OR, 0.69; 95% CI, 0.58-0.82; p < 0.001). All-cause emergency readmissions increased (OR, 1.06; 95% CI, 1.02-1.10; p = 0.001). CONCLUSION: Implementation of a unique, jurisdiction-wide PBM program was associated with improved patient outcomes, reduced blood product utilization, and product-related cost savings.

Importance: Whether immune-related adverse events (irAEs) indicate drug activity in patients treated with immune checkpoint inhibitors remains unknown. Objective: To investigate the association between irAEs and recurrence-free survival (RFS) in the double-blind EORTC 1325/KEYNOTE-054 clinical trial comparing pembrolizumab therapy and placebo for the treatment of patients with high-risk stage III melanoma. Design, Setting, and Participants: A total of 1019 adults with stage III melanoma were randomly assigned on a 1:1 ratio to receive treatment with pembrolizumab therapy or placebo. Eligible patients were adults 18 years and older with complete resection of cutaneous melanoma metastatic to lymph nodes, classified with stage IIIA (at least 1 micrometastasis measuring >1 mm in greatest diameter), IIIB, or IIIC (without in-transit metastasis) cancer. Patients were randomized from August 26, 2015, to November 14, 2016. The clinical cutoff for the data set was October 2, 2017. Analyses were then performed on the database, which was locked on November 28, 2017. Interventions: Participants were scheduled to receive 200 mg of pembrolizumab or placebo every 3 weeks for a total of 18 doses for approximately 1 year or until disease recurrence, unacceptable toxic effects, major protocol violation, or withdrawal of consent. Main Outcomes and Measures: The association between irAEs and RFS was estimated using a Cox model adjusted for sex, age, and AJCC-7 stage, with a time-varying covariate that had a value of 0 before irAE onset and 1 after irAE onset. Results: Of 1011 patients who began treatment with pembrolizumab therapy or placebo, 622 (61.5%) were men and 389 (38.5%) were women; 386 patients (38.2%) were aged 50 to 64 years, 377 (37.3%) were younger than 50 years, and 248 (24.5%) were 65 years and older. Consistent with the reported main analysis in the intent-to-treat population, RFS was longer in the pembrolizumab arm compared with the placebo arm (hazard ratio [HR], 0.56; 98.4% CI, 0.43-0.74) among patients who started treatment. The incidence of irAEs was 190 (37.4%) in the pembrolizumab arm (n = 509) and 45 (9.0%) in the placebo arm (n = 502); in each treatment group, the incidence was similar for men and women. The occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm (HR, 0.61; 95% CI, 0.39-0.95; P = .03) in both men and women. However, in the placebo arm, this association was not significant. Compared with the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater after the onset of an irAE than without or before an irAE (HR, 0.37; 95% CI, 0.24-0.57 vs HR, 0.61; 95% CI, 0.49-0.77, respectively; P = .03). Conclusions and Relevance: In this study, the occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm. Trial Registrations: ClinicalTrials.gov identifier: NCT02362594; EudraCT identifier: 2014-004944-37.

To the Editor—Yeoh et al reported the dramatic impact of public health measures introduced during the coronavirus disease 2019 (COVID-19) pandemic on influenza and respiratory syncytial virus (RSV) detections in Western Australian (WA) children [1]. Here, we present data from ongoing local prospective surveillance. Following the end of winter, there has been a persistent absence of severe acute respiratory syndrome coronavirus 2 community transmission and no increase in influenza detections. Limited physical distancing measures have remained in place, with largely no restrictions on gathering sizes and no mandate for wearing masks [2]. Schools have remained open. Strict quarantine for overseas arrivals has been maintained, with a persistent marked decrease in visitor numbers compared with previous numbers [3]. Border restrictions for travelers from other states within Australia have been reduced as of 14 November 2020, with quarantine not required for travelers from states with no community severe acute respiratory syndrome coronavirus 2 transmission [4]. Similar to the previous report laboratory data prospectively collected as part of routine regional public health surveillance were collated per week from January 2012 to 13 December 2020. Cases were defined as detections of RSV by validated nucleic acid amplification test or antigen detection kits in children (<16 years of age) in the metropolitan area. Laboratory results were provided by PathWest Laboratory Medicine, the only public pathology provider to the state. Samples were drawn from all public hospitals and emergency departments. Average epidemic curves for the period 2012 to 2019 were calculated using a World Health Organization–described method [5]. Median age was compared using 2-sample Wilcoxon test. As demonstrated in Figure 1, RSV activity increased from late September, in the setting of relaxed physical distancing recommendations, ahead of the opening of interstate borders. Case numbers have further increased, exceeding the median seasonal peak from 2012 to 2019. This has been observed without any significant change in testing practices. The median patient age this year was 18.4 months, significantly higher than the upper range between 2012 and 2019 (7.3–12.5 months) (P < .001). Respiratory syncytial virus detection in children from metropolitan Western Australian up to week 50 of 2020, in the context of COVID-19 restrictions, compared to average epidemic curve (2012–2019). Borders closed – week 12 – international borders closed to all nonresidents; 14-day quarantine required for all arrivals. Period 1 (weeks 14–17): statewide stay-at-home restrictions in place with school holidays extended; borders closed to inter-state travelers (week 14). Period 2 (weeks 18–26): restrictions sequentially lifted, allowing gatherings of 10 (week 18), 20 (week 21), and 100 (week 24) people; schools reopened with increased cleaning and some physical distancing measures. Period 3 (weeks 27–47): majority of local restrictions removed, except the limitation of major sport and entertainment venues to 50% capacity; schools returned to all normal activities. Period 4 (weeks 47–50) relaxation of state border restrictions. Average epidemic curve: 2012–2019. Abbreviation: EYTD, end of year to date. These data demonstrate the fragility of RSV control and the critical impact of physical distancing and respiratory hygiene practices. The rise in numbers and change in median age suggest that the expanded cohort of RSV-naïve patients, including an increased number of older children coupled with waning population immunity [6], may have contributed to this marked resurgence. Notably, RSV activity was first observed in mid-late August in regional centers before emergence in the metropolitan area, with transmission potentially facilitated by increased travel within the state [7]. Conversely, the initial rise in RSV cases in WA preceded the opening of interstate borders, suggesting this pathway was not the primary mechanism. Our findings raise concerns for RSV control in the Northern Hemisphere, where a shortened season was experienced last winter [8]. The eventual reduction of COVID-19–related public health measures may herald a significant rise in RSV [9]. Depending on the timing, the accompanying morbidity and mortality, especially in older adults [6], may overburden already strained healthcare systems. To delineate the relative contribution of an increasingly susceptible population and the reduction in border restrictions, further surveillance, transmission studies, and assessment of relatedness of RSV strains is progressing. Financial support. This was an investigator-initiated project supported by a clinician-scientist partnership grant from the Wesfarmers Centre for Vaccines and Infectious Diseases (2020). D. K. Y. is supported by an Australian Government Research Training Program Postgraduate Scholarship. A. O. M. is supported by an NHMRC Postgraduate Scholarship (1191465) and an Australian Government Research Training Program Fees Offset. A. C. M. is supported by a Raine Clinician Research Fellowship. C. C. B. is supported by an NHMRC Career Development Fellowship (GNT1111596). H. C. M. is supported by a Telethon Kids Institute Emerging Research Leader Fellowship. Potential conflicts of interest. A. O. M. reports grants from Australian Government (Research Training Program Fees Offset) and grants from NHMRC (Postgraduate Scholarship 1191465), outside the submitted work. A. C. M. reports grants from Raine Medical Research Foundation (Raine Clinician Research Fellowship), outside the submitted work. C. C. B. reports grants from NHMRC (Career Development Fellowship (GNT1111596)), outside the submitted work. D. K. Y. reports grants from Australian Government (Research Training Program Postgraduate Scholarship), outside the submitted work. H. C. M. reports from Telethon Kids Institute (Emerging Research Leader Fellowship) and grants (clinician-scientist partnership grant) and nonfinancial support from Wesfarmers Centre for Vaccines and Infectious Diseases, during the conduct of the study. All other authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Importance: Penicillin allergy is a significant public health issue for patients, antimicrobial stewardship programs, and health services. Validated clinical decision rules are urgently needed to identify low-risk penicillin allergies that potentially do not require penicillin skin testing by a specialist. Objective: To develop and validate a penicillin allergy clinical decision rule that enables point-of-care risk assessment of patient-reported penicillin allergies. Design, Setting, and Participants: In this diagnostic study, a multicenter prospective antibiotic allergy-tested cohort of 622 patients from 2 tertiary care sites in Melbourne, Australia (Austin Health and Peter MacCallum Cancer Centre) was used for derivation and internal validation of a penicillin allergy decision rule. Backward stepwise logistic regression was used to derive the model, including clinical variables predictive of a positive penicillin allergy test result. Internal validation of the final model used bootstrapped samples and the model scoring derived from the coefficients. External validation was performed in retrospective penicillin allergy-tested cohorts consisting of 945 patients from Sydney and Perth, Australia, and Nashville, Tennessee. Patients who reported a penicillin allergy underwent penicillin allergy testing using skin prick, intradermal, or patch testing and/or oral challenge (direct or after skin testing). Data were collected from June 26, 2008, to June 3, 2019, and analyzed from January 9 to 12, 2019. Main Outcomes and Measures: The primary outcome for the model was any positive result of penicillin allergy testing performed during outpatient or inpatient assessment. Results: From an internal derivation and validation cohort of 622 patients (367 female [59.0%]; median age, 60 [interquartile range{IQR}, 48-71] years) and an external validation cohort of 945 patients (662 female [70.1%]; median age, 55 [IQR, 38-68] years), the 4 features associated with a positive penicillin allergy test result on multivariable analysis were summarized in the mnemonic PEN-FAST: penicillin allergy, five or fewer years ago, anaphylaxis/angioedema, severe cutaneous adverse reaction (SCAR), and treatment required for allergy episode. The major criteria included an allergy event occurring 5 or fewer years ago (2 points) and anaphylaxis/angioedema or SCAR (2 points); the minor criterion (1 point), treatment required for an allergy episode. Internal validation showed minimal mean optimism of 0.003 with internally validated area under the curve of 0.805. A cutoff of less than 3 points for PEN-FAST was chosen to classify a low risk of penicillin allergy, for which only 17 of 460 patients (3.7%) had positive results of allergy testing, with a negative predictive value of 96.3% (95% CI, 94.1%-97.8%). External validation resulted in similar findings. Conclusions and Relevance: In this study, PEN-FAST was found to be a simple rule that accurately identified low-risk penicillin allergies that do not require formal allergy testing. The results suggest that a PEN-FAST score of less than 3, associated with a high negative predictive value, could be used by clinicians and antimicrobial stewardship programs to identify low-risk penicillin allergies at the point of care.

⁶⁸Ga-PSMA PET/CT scanning has been shown to be more sensitive than conventional imaging techniques in patients with prostate cancer. This prospective Australian multicenter study assessed whether ⁶⁸Ga-PSMA PET/CT imaging affects management intent in patients with primary or recurrent prostate cancer. <b>Methods:</b> Before undertaking ⁶⁸Ga-PSMA PET imaging, referring medical specialists completed a questionnaire detailing relevant demographic and clinical data as well as their proposed management plan. A separate follow-up questionnaire was completed after the ⁶⁸Ga-PSMA PET/CT scan results were available to determine whether the management plan would change. <b>Results:</b> A total of 431 patients with prostate cancer from 4 Australian centers had pre– and post–⁶⁸Ga-PSMA management plans completed. Scans were obtained for primary staging of intermediate- and high-risk disease in 25% of patients and for restaging/biochemical recurrence in 75% of patients. Overall, ⁶⁸Ga-PSMA PET/CT scanning led to a change in planned management in 51% of patients. The impact was greater in the group of patients with biochemical failure after definitive surgery or radiation treatment (62% change in management intent) than in patients undergoing primary staging (21% change). Imaging with ⁶⁸Ga-PSMA PET/CT revealed unsuspected disease in the prostate bed in 27% of patients, locoregional lymph nodes in 39%, and distant metastatic disease in 16%. <b>Conclusion:</b>⁶⁸Ga-PSMA PET/CT scans detect previously unsuspected disease and may influence planned clinical management in a high proportion of patients with prostate cancer. The impact was greater in patients with biochemical recurrence. These results demonstrate the potential clinical value of ⁶⁸Ga-PSMA PET/CT in management of prostate cancer.

BACKGROUND: Preoperative anaemia affects a high proportion of patients undergoing major elective surgery and is associated with poor outcomes. We aimed to test the hypothesis that intravenous iron given to anaemic patients before major open elective abdominal surgery would correct anaemia, reduce the need for blood transfusions, and improve patient outcomes. METHODS: In a double-blind, parallel-group randomised trial, we recruited adult participants identified with anaemia at preoperative hospital visits before elective major open abdominal surgery at 46 UK tertiary care centres. Anaemia was defined as haemoglobin less than 130 g/L for men and 120 g/L for women. We randomly allocated participants (1:1) via a secure web-based service to receive intravenous iron or placebo 10-42 days before surgery. Intravenous iron was administered as a single 1000 mg dose of ferric carboxymaltose in 100 mL normal saline, and placebo was 100 mL normal saline, both given as an infusion over 15 min. Unblinded study personnel prepared and administered the study drug; participants and other clinical and research staff were blinded to treatment allocation. Coprimary endpoints were risk of the composite outcome of blood transfusion or death, and number of blood transfusions from randomisation to 30 days postoperatively. The primary analysis included all randomly assigned patients with data available for the primary endpoints; safety analysis included all randomly assigned patients according to the treatment received. This study is registered, ISRCTN67322816, and is closed to new participants. FINDINGS: Of 487 participants randomly assigned to placebo (n=243) or intravenous iron (n=244) between Jan 6, 2014, and Sept 28, 2018, complete data for the primary endpoints were available for 474 (97%) individuals. Death or blood transfusion occurred in 67 (28%) of the 237 patients in the placebo group and 69 (29%) of the 237 patients in the intravenous iron group (risk ratio 1·03, 95% CI 0·78-1·37; p=0·84). There were 111 blood transfusions in the placebo group and 105 in the intravenous iron group (rate ratio 0·98, 95% CI 0·68-1·43; p=0·93). There were no significant differences between the two groups for any of the prespecified safety endpoints. INTERPRETATION: Preoperative intravenous iron was not superior to placebo to reduce need for blood transfusion when administered to patients with anaemia 10-42 days before elective major abdominal surgery. FUNDING: UK National Institute of Health Research Health Technology Assessment Program.

// Elin S. Gray 1 , Helen Rizos 2,8 , Anna L. Reid 1 , Suzanah C. Boyd 2,8 , Michelle R. Pereira 1 , Johnny Lo 3 , Varsha Tembe 4 , James Freeman 1 , Jenny H.J. Lee 4,5 , Richard A. Scolyer 6,8 , Kelvin Siew 9 , Chris Lomma 9 , Adam Cooper 5 , Muhammad A. Khattak 10,11 , Tarek M. Meniawy 9,11 , Georgina V. Long 7,8 , Matteo S. Carlino 5,8 , Michael Millward 9,11 and Melanie Ziman 1,12 1 School of Medical Sciences, Edith Cowan University, Joondalup, Western Australia, Australia 2 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia 3 School of Engineering, Edith Cowan University, Joondalup, Western Australia, Australia 4 Centre for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales, Australia 5 Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales, Australia 6 Disciplines of Pathology, The University of Sydney, Sydney,&nbsp;New South Wales, Australia 7 Medicine, Sydney Medical School, The University of Sydney, Sydney,&nbsp;New South Wales, Australia 8 Melanoma Institute Australia, Sydney, New South Wales, Australia 9 Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia 10 Department of Medical Oncology, Fiona Stanley Hospital, Murdoch, Western Australia, Australia 11 School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia 12 School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Western Australia, Australia Correspondence to: Elin Gray, email: // Keywords : melanoma, ctDNA, acquired resistance, MAPK inhibition, immunotherapy Received : August 03, 2015 Accepted : August 31, 2015 Published : September 22, 2015 Abstract Repeat tumor biopsies to study genomic changes during therapy are difficult, invasive and data are confounded by tumoral heterogeneity. The analysis of circulating tumor DNA (ctDNA) can provide a non-invasive approach to assess prognosis and the genetic evolution of tumors in response to therapy. Mutation-specific droplet digital PCR was used to measure plasma concentrations of oncogenic BRAF and NRAS variants in 48 patients with advanced metastatic melanoma prior to treatment with targeted therapies (vemurafenib, dabrafenib or dabrafenib/trametinib combination) or immunotherapies (ipilimumab, nivolumab or pembrolizumab). Baseline ctDNA levels were evaluated relative to treatment response and progression-free survival (PFS). Tumor-associated ctDNA was detected in the plasma of 35/48 (73%) patients prior to treatment and lower ctDNA levels at this time point were significantly associated with response to treatment and prolonged PFS, irrespective of therapy type. Levels of ctDNA decreased significantly in patients treated with MAPK inhibitors ( p &lt; 0.001) in accordance with response to therapy, but this was not apparent in patients receiving immunotherapies. We show that circulating NRAS mutations, known to confer resistance to BRAF inhibitors, were detected in 3 of 7 (43%) patients progressing on kinase inhibitor therapy. Significantly, ctDNA rebound and circulating mutant NRAS preceded radiological detection of progressive disease. Our data demonstrate that ctDNA is a useful biomarker of response to kinase inhibitor therapy and can be used to monitor tumor evolution and detect the early appearance of resistance effectors.