Multi-cancer early detection test in symptomatic patients referred for cancer investigation in England and Wales (SYMPLIFY): a large-scale, observational cohort study.

BACKGROUND: Analysis of circulating tumour DNA could stratify cancer risk in symptomatic patients. We aimed to evaluate the performance of a methylation-based multicancer early detection (MCED) diagnostic test in symptomatic patients referred from primary care. METHODS: We did a multicentre, prospective, observational study at National Health Service (NHS) hospital sites in England and Wales. Participants aged 18 or older referred with non-specific symptoms or symptoms potentially due to gynaecological, lung, or upper or lower gastrointestinal cancers were included and gave a blood sample when they attended for urgent investigation. Participants were excluded if they had a history of or had received treatment for an invasive or haematological malignancy diagnosed within the preceding 3 years, were taking cytotoxic or demethylating agents that might interfere with the test, or had participated in another study of a GRAIL MCED test. Patients were followed until diagnostic resolution or up to 9 months. Cell-free DNA was isolated and the MCED test performed blinded to the clinical outcome. MCED predictions were compared with the diagnosis obtained by standard care to establish the primary outcomes of overall positive and negative predictive value, sensitivity, and specificity. Outcomes were assessed in participants with a valid MCED test result and diagnostic resolution. SYMPLIFY is registered with ISRCTN (ISRCTN10226380) and has completed follow-up at all sites. FINDINGS: 6238 participants were recruited between July 7 and Nov 30, 2021, across 44 hospital sites. 387 were excluded due to staff being unable to draw blood, sample errors, participant withdrawal, or identification of ineligibility after enrolment. Of 5851 clinically evaluable participants, 376 had no MCED test result and 14 had no information as to final diagnosis, resulting in 5461 included in the final cohort for analysis with an evaluable MCED test result and diagnostic outcome (368 [6·7%] with a cancer diagnosis and 5093 [93·3%] without a cancer diagnosis). The median age of participants was 61·9 years (IQR 53·4-73·0), 3609 (66·1%) were female and 1852 (33·9%) were male. The MCED test detected a cancer signal in 323 cases, in whom 244 cancer was diagnosed, yielding a positive predictive value of 75·5% (95% CI 70·5-80·1), negative predictive value of 97·6% (97·1-98·0), sensitivity of 66·3% (61·2-71·1), and specificity of 98·4% (98·1-98·8). Sensitivity increased with increasing age and cancer stage, from 24·2% (95% CI 16·0-34·1) in stage I to 95·3% (88·5-98·7) in stage IV. For cases in which a cancer signal was detected among patients with cancer, the MCED test's prediction of the site of origin was accurate in 85·2% (95% CI 79·8-89·3) of cases. Sensitivity 80·4% (95% CI 66·1-90·6) and negative predictive value 99·1% (98·2-99·6) were highest for patients with symptoms mandating investigation for upper gastrointestinal cancer. INTERPRETATION: This first large-scale prospective evaluation of an MCED diagnostic test in a symptomatic population demonstrates the feasibility of using an MCED test to assist clinicians with decisions regarding urgency and route of referral from primary care. Our data provide the basis for a prospective, interventional study in patients presenting to primary care with non-specific signs and symptoms. FUNDING: GRAIL Bio UK.

LID study: Plasma lidocaine levels following airway topicalisation for paediatric microlaryngobronchoscopy (MLB).

OBJECTIVES: A dose of 5 mg/kg lidocaine is considered appropriate for paediatric airway topicalisation. Existing literature suggests that younger children are susceptible to toxic lidocaine plasma levels and achieve this at a faster rate. MAIN OUTCOME MEASURES: The primary outcome of this study was to ascertain peak plasma lidocaine levels after topicalisation for airway endoscopy. Secondary endpoints included: time to peak lidocaine plasma levels, signs of lidocaine toxicity (restricted to ECG changes or seizures when under anaesthesia) and clinical adverse events of laryngospasm, coughing or desaturation during the procedure. SETTING: Data were collected prospectively over 18 months at Royal Manchester Children's Hospital. PARTICIPANTS: Children aged 0-8 years undergoing elective diagnostic or therapeutic airway endoscopy were included within the study. DESIGN: Standardised 2% lidocaine was used for airway topicalisation. Dose varied depending upon the practitioner's usual practice. Venous bloodsampling occurred at 5, 10, 15 and 20 min post-administration and plasma lidocaine levels (ng/ml) were analysed. RESULTS: A significant relationship exists between higher peak plasma levels and ages <18 months (p = .00973). Strong linear correlation exists between body weight and age for our cohort (r = .88). Higher peak plasma lidocaine levels occur with total dose volumes between 2 and 3 mls of 2% lidocaine local anaesthetic (p = .03) compared with <2 ml total dose volumes. Data suggest a potential relationship of lower body weights achieving higher peak plasma levels (p = .0516). Reduced interquartile variation of peak plasma lidocaine levels exists when lidocaine dosing is <5 mg/kg. CONCLUSIONS: Age and total dose volume of topicalised lidocaine have a significant relationship with plasma lidocaine levels. A dose of 5 mg/kg topicalised lidocaine for paediatric airway endoscopy is safe and provides good operating conditions. Lower patient body weights trend towards higher peak lidocaine plasma concentrations and require further investigation.

Surgical Emphysema in a Pediatric Tertiary Referral Center.

BACKGROUND: Laryngeal trauma in pediatrics is extremely rare; however, because of the smaller pediatric larynx, it can have catastrophic consequences. Following laryngeal trauma, surgical emphysema is a relatively common presentation. In pediatrics, it can be a life-threatening condition. Here we describe 2 cases of laryngeal trauma resulting in extensive surgical emphysema. CASES: The first case described involves bilateral pneumothoraces, airway compromise, and respiratory arrest and was managed with bilateral chest drains, intubation, and tracheostomy. The second case resulted in widespread surgical emphysema in a stable patient and was managed conservatively. Both cases were monitored closely for a period of time to ensure there were no further sequelae. DISCUSSION: Patients with laryngeal trauma resulting in surgical emphysema have the potential to deteriorate rapidly. Furthermore, surgical emphysema degrades the quality of ultrasound images, which may delay the diagnosis. If there are any concerns about the safety of the airway, then it should be secured definitively with either endotracheal intubation or emergency tracheostomy depending on clinical judgment. It is acceptable to monitor patients closely in a high-dependency unit setting if they are stable and do not show any evidence of laryngeal edema. CONCLUSIONS: We present 2 cases of laryngeal trauma that were dealt with effectively so that both patients made a full recovery. It is important to act quickly to secure the airway if there are any concerns about its patency. Stable patients with no evidence of laryngeal edema can be managed conservatively. Close monitoring is essential to prevent any potential airway compromise.

An International Interprofessional Study of Mental Models and Factors Delaying Neuroimaging of Critically Head-Injured Children Presenting to Emergency Departments.

OBJECTIVES: Thousands of head-injured children are cared for by interprofessional teams in emergency departments every day. Teams must balance performing time-consuming interventions with safe transport for neuroimaging. This study aims to describe and compare providers' perspectives on the transfer of head-injured children to neuroimaging and factors contributing to delays. METHODS: Participants were interprofessional health care providers involved in the care of head-injured children at sites in the United Kingdom, the United States, and New Zealand. They first viewed a 3-minute video of a child with a severe head injury presenting to their resuscitation bay. Next, they were presented with 5 physiologically different simulated scenarios and asked to report whether interventions were required before transporting each patient to neuroimaging. Then, they reported team and system factors contributing to delays in neuroimaging. RESULTS: Two hundred forty of 296 providers completed the intervention. The percentage of providers reporting that they would directly transport to neuroimaging without intervention was 89% for "stable," 49% for "Cushing's triad," 26% for "hypoxic," 25% for "tachycardic," and 5% for "extremis." There were differences noted in responses by profession for the hypoxia and tachycardia cases. No differences were noted between trainees and attending physicians for any cases. The most frequent factors reported as delaying neuroimaging were team decision making and waiting for equipment, medications, and scanner availability. CONCLUSIONS: There is variability in providers' perspectives on the interventions required before transporting severely head-injured patients for imaging. Diverse team and system factors contribute to delays in imaging.

Genetic polymorphism of CYP1A2 but not total or free teriflunomide concentrations is associated with leflunomide cessation in rheumatoid arthritis.

AIM: Leflunomide, via its active metabolite teriflunomide, is used in rheumatoid arthritis (RA) treatment, yet approximately 20 to 40% of patients cease due to toxicity. The aim was to develop a time-to-event model describing leflunomide cessation due to toxicity within a clinical cohort and to investigate potential predictors of cessation such as total and free teriflunomide exposure and pharmacogenetic influences. METHODS: This study included individuals enrolled in the Early Arthritis inception cohort at the Royal Adelaide Hospital between 2000 and 2013 who received leflunomide. A time-to-event model in nonmem was used to describe the time until leflunomide cessation and the influence of teriflunomide exposure and pharmacogenetic variants. Random censoring of individuals was simultaneously described. The clinical relevance of significant covariates was visualized via simulation. RESULTS: Data from 105 patients were analyzed, with 34 ceasing due to toxicity. The baseline dropout hazard and baseline random censoring hazard were best described by step functions changing over discrete time intervals. No statistically significant associations with teriflunomide exposure metrics were identified. Of the screened covariates, carriers of the C allele of CYP1A2 rs762551 had a 2.29 fold increase in cessation hazard compared with non-carriers (95% CI 2.24, 2.34, P = 0.016). CONCLUSIONS: A time-to-event model described the time between leflunomide initiation and cessation due to side effects. The C allele of CYP1A2 rs762551 was linked to increased leflunomide toxicity, while no association with teriflunomide exposure was identified. Future research should continue to investigate exposure-toxicity relationships, as well as potentially toxic metabolites.

Beverage- and Brand-Specific Binge Alcohol Consumption among Underage Youth in the U.S.

BACKGROUND AND OBJECTIVES: Binge drinking is a common and risky pattern of alcohol consumption among youth; beverage and brand-specific consumption during binge drinking is poorly understood. The objective was to characterize beverage- and brand-specific consumption associated with binge drinking among underage youth in the U.S. METHODS: An internet panel was used to obtain a sample of 1,032 underage youth aged 13-20, who drank alcohol in the past 30 days. For each brand consumed, youth reported drinking quantity and frequency, and whether they engaged in binge drinking with that brand (≥5 drinks for males, ≥4 for females). Each youth reporting binge drinking with a brand constituted a binge drinking report. RESULTS: Overall, 50.9% of youth binge drank with ≥1 brand, and 36.5% of youth who consumed any particular brand reported binge drinking with it. Spirits accounted for 43.8% of binge drinking reports. Twenty-five brands accounted for 46.2% of binge drinking reports. Many of these brands were disproportionately associated with binge drinking relative to their youth market share. CONCLUSIONS: Binge drinking among youth is most commonly involves spirits, and binge drinking is concentrated within a relatively small number of brands. Understanding factors underlying beverage and brand preference among binge drinking youth could assist prevention efforts.

Immersive virtual reality and psychological well-being in adult chronic physical illness: systematic review.

INTRODUCTION: Individuals with chronic physical illness are at increased risk of negative psychological sequelae. Immersive virtual reality (VR) is an emerging treatment that might reduce these negative effects and increase quality of life in individuals with chronic physical illness. OBJECTIVE: To systematically review literature examining the use of immersive VR in adult populations with chronic physical illness to understand: (1) how immersive VR is used to improve psychological well-being of adults with chronic physical illness (2) what effect this immersive VR has on the psychological well-being of adults with chronic physical illness. DESIGN: Systematic literature review and meta-analysis. Searches of Ovid Medline/PubMed, PsycINFO, Embase, Web of Science and Scopus between July 1993 and March 2023 inclusive. RESULTS: 12 811 texts were identified; 31 met the inclusion criteria. Relaxing and engaging immersive VR interventions were shown to be acceptable and feasible among adults with cancer, dementia, cardiovascular disease, kidney disease and multiple sclerosis. Many of the studies reviewed were feasibility or pilot studies and so the evidence about effectiveness is more limited. The evidence, mostly from studies of people with cancer, suggests that immersive VR can have a positive effects on anticipatory anxiety symptoms and pain. CONCLUSIONS: Environment-based and game-based relaxing immersive VR offer novel interventions, with beneficial effects among people with cancer and, potentially, beneficial effects in those with other long-term physical illness.

A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis.

RATIONALE: Bronchiectasis is a chronic debilitating disease with few evidence-based long-term treatments. OBJECTIVES: A randomized controlled trial assessing the efficacy of nebulized gentamicin therapy over 1 year in patients with non-cystic fibrosis bronchiectasis. METHODS: Sixty-five patients were randomized to either twice-daily nebulized gentamicin, 80 mg, or nebulized 0.9% saline, for 12 months. All were reviewed at three-monthly intervals during treatment and at 3 months' follow-up. MEASUREMENTS AND MAIN RESULTS: At each review the following were assessed: quantitative and qualitative sputum bacteriology; sputum purulence and 24-hour volume; FEV(1), FVC, and forced expiratory flow, midexpiratory phase; exercise capacity; Leicester Cough Questionnaire and St. George's Respiratory Questionnaire; and exacerbation frequency. Fifty-seven patients completed the study. At the end of 12 months' treatment, compared with the saline group, in the gentamicin group there was reduced sputum bacterial density with 30.8% eradication in those infected with Pseudomonas aeruginosa and 92.8% eradication in those infected with other pathogens; less sputum purulence (8.7% vs. 38.5%; P < 0.0001); greater exercise capacity (510 [350-690] m vs. 415 [267.5-530] m; P = 0.03); and fewer exacerbations (0 [0-1] vs. 1.5 [1-2]; P < 0.0001) with increased time to first exacerbation (120 [87-161.5] d vs. 61.5 [20.7-122.7] d; P = 0.02). The gentamicin group had greater improvements in Leicester Cough Questionnaire (81.4% vs. 20%; P < 0.01) and St. George's Respiratory Questionnaire (87.5% vs. 19.2%; P < 0.004) score. No differences were seen in 24-hour sputum volume, FEV(1), FVC, or forced expiratory flow, midexpiratory phase. No P. aeruginosa isolates developed resistance to gentamicin. At follow-up, all outcome measures were similar to baseline. CONCLUSIONS: Regular, long-term nebulized gentamicin is of significant benefit in non-cystic fibrosis bronchiectasis but treatment needs to be continuous for its ongoing efficacy. Clinical trial registered with www.clinicaltrials.gov (NCT 00749866).

Pediatric cardiac anesthesia in the developing world.

More children die of congenital heart disease (CHD) in low-income countries and acquired cardiac disease is more frequent. Advances in diagnosis, surgery, perfusion and anesthesia in the developed world have had dramatic results on children's lives, and many forms of CHD can now be safely corrected or palliated. However, in developing countries, for the children who receive cardiac surgery, perioperative mortality and morbidity remain high. Pediatric cardiac anesthesia is a specialty in its infancy worldwide, and in developing countries, it is often nonexistent. Visiting 'specialists' as part of medical mission teams often provides anesthesia, but the hope for the future is that local staff will be trained in pediatric cardiac anesthesia and collaborative regional cardiac centers will be the mainstay of care, offering safer surgery to more children.

Pharmacogenomics of Type I interferon therapy: a survey of response-modifying genes.

Interferon-beta (IFN-beta) is routinely prescribed as an immunomodulatory treatment for multiple sclerosis (MS), but is associated with variable clinical efficacy. Ideally an early predictor of response status would allow more rational provision of this therapy. Both pharmacogenomic and expression analysis have highlighted IFN-beta regulated genes which may influence treatment efficacy. In this review we have summarized and discussed the main genes identified by these studies in MS patients, and supplemented this with data from similar studies of Type I IFN treatment in hepatitis.

The changing epidemiology of Burkholderia species infection at an adult cystic fibrosis centre.

BACKGROUND: This study reviews the impact of changing infection control practices at the Manchester Adult Cystic Fibrosis Centre (MACFC) upon the epidemiology of Burkholderia species infections. METHODS: We reviewed strain and genomovar typing of all available Burkholderia isolates at our centre between 1983-2006. RESULTS: The incidence/prevalence of infection with Burkholderia species between 1983-1990 was below 5%/9% each year. There was a rise in incidence/prevalence of Burkholderia species between 1991 and 1994 with a peak of 16.3%/31.2% in 1992. Following complete cohort segregation, the incidence has fallen to below 3% for all but one year and the prevalence has gradually reduced to 9.3% in 2005. Currently, there is an increase in the prevalence to 10.6% for the first time since 1994, predominantly due to patients with unique infections transferring into the unit from referring centres. The presence of unique strains now exceeds transmissible strains for the first time since 1991. CONCLUSIONS: Infection control measures including patient segregation have controlled spread of transmissible B. cenocepacia strains, but not the acquisition of unique strains. Unique strains of Burkholderia species now account for the majority of new infections at the Manchester Adult Cystic Fibrosis Centre.

The neuropeptide genes TAC1, TAC3, TAC4, VIP and PACAP(ADCYAP1), and susceptibility to multiple sclerosis.

The related immunomodulatory neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase activating peptide (PACAP; gene symbol ADCYAP1) have recently been proposed as novel therapeutics for the treatment of multiple sclerosis (MS). These neuropeptides, as well as those belonging to the tachykinin family exert pleiotropic effects, many of which are of relevance to central nervous system inflammation. In the present study, we have analysed 14 single nucleotide polymorphisms (SNPs) and 4 microsatellite markers in the VIP, ADCYAP1, TAC3 and TAC4 genes for susceptibility to MS in a case-control collection from Northern Ireland. Following correction for multiple comparisons, we did not find any significant associations between single polymorphic markers or multiple-marker haplotypes and susceptibility to MS. Furthermore, we analysed 2 SNPs in the TAC1 gene in a set of Sardinian trio MS families, based on our previous observation of association of these SNPs with MS in the Northern Irish (Genes Immun. 2005, 6, 265-270). Analysis of these SNPs in the Sardinians was not significant though a similar trend to that originally observed in the Northern Irish was present. Meta-analysis of the Sardinian and Northern Irish TAC1 SNP genotype data revealed a Mantel-Haenszel Common OR Estimate for the TAC1 intron 1 SNP rs2072100 of 0.76 (95% CI 0.63-0.92; P=0.005; A allele) and for the TAC1 promoter SNP rs7793277 of 0.76 (95% CI 0.615-0.95; P=0.014; C allele). Our data advocate a need for further exploration of the TAC1 gene region in MS.

ITGA4 polymorphisms and susceptibility to multiple sclerosis.

In multiple sclerosis (MS), alpha(4)beta(1) integrin, also known as Very Late Antigen 4 (VLA4), facilitates migration of leukocytes across the blood brain barrier. Several studies suggest that expression of alpha(4) integrin may be increased in MS patients compared to controls, and down-regulation or antagonism of alpha(4) integrin may be associated with immunomodulatory treatment success. We analysed association of 13 single nucleotide polymorphisms (SNPs) in the gene encoding alpha(4) integrin (ITGA4) with susceptibility to MS in two distinct populations comprising cases and controls from the Basque Country in northern Spain (352 patients; 235 controls) and Nordic countries (1119 patients; 1235 controls). Carriage of the C allele of the ITGA4 promoter SNP rs1449263 was independently and weakly increased in MS patients from each population compared to respective controls (P = 0.037 in Basque; and P = 0.042 in Nordic cohorts), though these associations were lost upon application of permutation correction. Meta-analysis of rs1449263*C carriage revealed a Mantel-Haenszel common OR of 1.26 (95% CI 1.06-1.49; P = 0.0069). Though our data only modestly argue for a role of ITGA4 in determining susceptibility to MS, we suggest that further examination of this gene, particularly the promoter region, is warranted.

CTLA4 gene polymorphisms and multiple sclerosis in Northern Ireland.

Four CTLA4 polymorphisms were investigated in a Northern Irish collection of relapsing-remitting (RR) and primary-progressive (PP) multiple sclerosis (MS) patients. The CTLA4 promoter (-318 C/T), exon 1 (+49 A/G) and intergenic CT60 SNPs, as well as a microsatellite found in the 3' UTR (AT(n)) were analysed in 246 RRMS, 84 PPMS and 158 healthy controls. The A allele of the exon 1 +49 A/G SNP (OR=1.36; 95% CI=1.11-1.81; P=0.038), and more so the AA genotype (OR=1.70; 95% CI=1.11-2.60; P=0.015) were associated with RR, but not PPMS. In the PPMS population, overall allele distribution of the AT(n) microsatellite was significantly different from that in the healthy controls. We did not find any association with the promoter (-318 C/T) or intergenic CT60 SNPs in either of the disease cohorts. In concordance with several recent studies, we detected a trend toward higher carriage rates of the +49 G allele in PP vs RR MS patients (66.7% vs 58.9%), though this was not significant. Our data highlight the CTLA4 +49 A/G and 3'UTR polymorphisms as potential modifiers of disease course in MS.

A Randomized Controlled Trial of Atorvastatin in Patients With Bronchiectasis Infected With Pseudomonas Aeruginosa: A Proof of Concept Study.

BACKGROUND: There are no randomized controlled trials of statin therapy in patients with severe bronchiectasis who are chronically infected with Pseudomonas aeruginosa. METHODS: Thirty-two patients chronically infected with P aeruginosa were recruited in this double-blind cross-over randomized controlled trial. Sixteen patients were recruited in each arm, were given atorvastatin 80 mg or placebo for 3 months followed by a washout period for 6 weeks, and then crossed over and administered the alternative therapy for 3 months. RESULTS: Twenty-seven patients completed the study. Atorvastatin did not significantly improve the primary end point of cough as measured by the Leicester Cough Questionnaire (mean difference, 1.92; 95% CI for difference, -0.57-4.41; P = .12). However, atorvastatin treatment resulted in an improved St. Georges Respiratory Questionnaire (-5.62 points; P = .016) and reduced serum levels of CXCL8 (P = .04), tumor necrosis factor (P = .01), and intercellular adhesion molecule 1 (P = .04). There was a trend toward improvement in serum C-reactive protein and serum neutrophil counts (P = .07 and P = .06, respectively). We demonstrated in vitro that atorvastatin 10 µM reduced formyl-methionyl-leucyl phenylalanine-induced upregulation of CD11b expression and changes in calcium flux, reflecting an ability to decrease neutrophil activation. CONCLUSIONS: We demonstrated that atorvastatin reduced systemic inflammation and improved quality of life in patients with bronchiectasis who were infected with P aeruginosa. These effects may be due to an ability of atorvastatin to modulate neutrophil activation. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01299194; URL: www.clinicaltrials.gov.

Pseudomonas expression of an oxygen sensing prolyl hydroxylase homologue regulates neutrophil host responses in vitro and in vivo.

Background: Pseudomonas species are adapted to evade innate immune responses and can persist at sites of relative tissue hypoxia, including the mucus-plugged airways of patients with cystic fibrosis and bronchiectasis.  The ability of these bacteria to directly sense and respond to changes in local oxygen availability is in part consequent upon expression of the 2-oxoglutarate oxygenase, Pseudomonas prolyl hydroxylase (PPHD), which acts on elongation factor Tu (EF-Tu), and is homologous with the human hypoxia inducible factor (HIF) prolyl hydroxylases. We report that PPHD expression regulates the neutrophil response to acute pseudomonal infection. Methods:In vitro co-culture experiments were performed with human neutrophils and PPHD-deficient and wild-type bacteria and supernatants, with viable neutrophil counts determined by flow cytometry. In vivo consequences of infection with PPHD deficient P. aeruginosa were determined in an acute pneumonia mouse model following intra-tracheal challenge. Results: Supernatants of PPHD-deficient bacterial cultures contained higher concentrations of the phenazine exotoxin pyocyanin and induced greater acceleration of neutrophil apoptosis than wild-type PAO1 supernatants in vitro.  In vivo infection with PPHD mutants compared to wild-type PAO1 controls resulted in increased levels of neutrophil apoptosis and impaired control of infection, with higher numbers of P. aeruginosa recovered from the lungs of mice infected with the PPHD-deficient strain.  This resulted in an overall increase in mortality in mice infected with the PPHD-deficient strain. Conclusions: Our data show that Pseudomonas expression of its prolyl hydroxylase influences the outcome of host-pathogen interactions in vitro and in vivo, demonstrating the importance of considering how both host and pathogen adaptations to hypoxia together define outcomes of infection. Given that inhibitors for the HIF prolyl hydroxylases are in late stage trials for the treatment of anaemia and that the active sites of PPHD and human HIF prolyl hydroxylases are closely related, the results are of current clinical interest.

Putting recommendations into practice: Australian rheumatologists' opinions on leflunomide use in rheumatoid arthritis.

Leflunomide is the most recently introduced conventional disease-modifying anti-rheumatic drugs in Australia. It has several unique methods for initiation, unique monitoring recommendations and a distinctive cessation protocol in the event of serious toxicity. The aim of this study was to evaluate initiation and monitoring practices of Australian rheumatologists using leflunomide. A survey was emailed twice, approximately 3 months apart to 332 rheumatologist members of the Australian Rheumatology Association. Wave analysis was used to assess evidence of non-response bias. The response rate to the survey was 20% and there was no difference between the responses of waves 1 and 2. Fifty percent of the respondents indicated that 20 mg once daily was the initial dose of leflunomide that they most commonly prescribed, 45% indicated 10 mg once daily, whilst only 3% preferred to initiate leflunomide at 100 mg daily for 2-3 days followed by 10 mg once a day as recommended when first marketed. Of the responders, 12% had used doses above 20 mg daily and 70% had used alternate daily dosing with leflunomide. In a patient taking leflunomide with an ALT or AST >3 times the ULN on two or more blood tests, 75% of responders indicated they would stop leflunomide immediately and 20% would follow cessation by administering a cholestyramine washout. The choice of initial leflunomide dose among responding Australian rheumatologists varied considerably, although most preferred not to use the loading dose. Despite the recommendation of clinical guidelines, the use of a cholestyramine washout procedure for hepatic toxicity is not universal.