Ten years of external quality assessment (EQA) of Neisseria gonorrhoeae antimicrobial susceptibility testing in Europe elucidate high reliability of data.

BACKGROUND: Confidence in any diagnostic and antimicrobial susceptibility testing data is provided by appropriate and regular quality assurance (QA) procedures. In Europe, the European Gonococcal Antimicrobial Susceptibility Programme (Euro-GASP) has been monitoring the antimicrobial susceptibility in Neisseria gonorrhoeae since 2004. Euro-GASP includes an external quality assessment (EQA) scheme as an essential component for a quality-assured laboratory-based surveillance programme. Participation in the EQA scheme enables any problems with the performed antimicrobial susceptibility testing to be identified and addressed, feeds into the curricula of laboratory training organised by the Euro-GASP network, and assesses the capacity of individual laboratories to detect emerging new, rare and increasing antimicrobial resistance phenotypes. Participant performance in the Euro-GASP EQA scheme over a 10 year period (2007 to 2016, no EQA in 2013) was evaluated. METHODS: Antimicrobial susceptibility category and MIC results from the first 5 years (2007-2011) of the Euro-GASP EQA were compared with the latter 5 years (2012-2016). These time periods were selected to assess the impact of the 2012 European Union case definitions for the reporting of antimicrobial susceptibility. RESULTS: Antimicrobial susceptibility category agreement in each year was ≥91%. Discrepancies in susceptibility categories were generally because the MICs for EQA panel isolates were on or very close to the susceptibility or resistance breakpoints. A high proportion of isolates tested over the 10 years were within one (≥90%) or two (≥97%) MIC log2 dilutions of the modal MIC, respectively. The most common method used was Etest on GC agar base. There was a shift to using breakpoints published by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) in the latter 5 years, however overall impact on the validity of results was limited, as the percentage categorical agreement and MIC concordance changed very little between the two five-year periods. CONCLUSIONS: The high level of comparability of results in this EQA scheme indicates that high quality data are produced by the Euro-GASP participants and gives confidence in susceptibility and resistance data generated by laboratories performing decentralised testing.

A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.

BACKGROUND: In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients. METHODS: In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis. RESULTS: In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P=0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P=0.16) or in rates of death from any cause (P=0.10) or from idiopathic pulmonary fibrosis (P=0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P=0.01) and from idiopathic pulmonary fibrosis (P=0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation. CONCLUSIONS: Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side-effect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.).

Effect of continued treatment with pirfenidone following clinically meaningful declines in forced vital capacity: analysis of data from three phase 3 trials in patients with idiopathic pulmonary fibrosis.

BACKGROUND: The assessment of treatment response in idiopathic pulmonary fibrosis (IPF) is complicated by the variable clinical course. We examined the variability in the rate of disease progression and evaluated the effect of continued treatment with pirfenidone in patients who experienced meaningful progression during treatment. METHODS: The source population included patients enrolled in the ASCEND and CAPACITY trials (N=1247). Pearson's correlation coefficients were used to characterise the relationship between changes in FVC during consecutive 6-month intervals in the placebo population. Outcomes following a ≥10% decline in FVC were evaluated by comparing the proportion of patients in the pirfenidone and placebo groups who experienced a ≥10% decline in FVC or death during the subsequent 6 months. RESULTS: A weak negative correlation was observed between FVC changes during consecutive intervals in the placebo population (coefficient, -0.146, p<0.001), indicating substantial variability. Thirty-four (5.5%) and 68 (10.9%) patients in the pirfenidone and placebo groups, respectively, experienced a ≥10% decline in FVC by month 6. During the subsequent 6 months, fewer patients in the pirfenidone group compared with placebo experienced a ≥10% decline in FVC or death (5.9% vs 27.9%; relative difference, 78.9%). There was one (2.9%) death in the pirfenidone group and 14 (20.6%) deaths in the placebo group (relative difference, 85.7%). CONCLUSIONS: Longitudinal FVC data from patients with IPF showed substantial intrasubject variability, underscoring the inability to reliably assess therapeutic response using serial FVC trends. In patients who progressed during treatment, continued treatment with pirfenidone resulted in a lower risk of subsequent FVC decline or death. TRIAL REGISTRATION NUMBERS: NCT01366209, NCT00287729, NCT00287716.

Efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis with more preserved lung function.

This post hoc analysis examined the differences in idiopathic pulmonary fibrosis disease progression and the effects of pirfenidone in patients stratified by more preserved versus less preserved baseline lung function status using forced vital capacity (FVC) or GAP (gender, age and physiology) index stage.Efficacy outcomes, i.e. FVC, 6-min walking distance (6MWD) and dyspnoea (University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ)), were analysed at 12 months in patients randomised to pirfenidone 2403 mg·day(-1) or placebo in the pooled phase 3 CAPACITY/ASCEND population (n=1247), with subgroups stratified by baseline FVC ≥80% versus <80% or GAP stage I versus II-III. Treatment-by-subgroup interaction was tested based on a rank ANCOVA model; factors in the model included study, region, treatment, subgroup and treatment-by-subgroup interaction term.Patients with both more preserved (FVC ≥80% or GAP stage I) and less preserved (FVC <80% or GAP stage II-III) lung function at baseline demonstrated clinically significant disease progression at 12 months in terms of categorical decline in FVC, 6MWD and UCSD SOBQ. The magnitude of pirfenidone treatment effect was comparable between subgroups, regardless of whether lung function was classified using FVC or GAP index stage.These findings support the initiation of treatment with pirfenidone, irrespective of stage of baseline lung function in this patient population.

Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials.

Pirfenidone is an antifibrotic agent that has been evaluated in three multinational phase 3 trials in patients with idiopathic pulmonary fibrosis (IPF). We analysed pooled data from the multinational trials to obtain the most precise estimates of the magnitude of treatment effect on measures of disease progression.All patients randomised to pirfenidone 2403 mg·day(-1) or placebo in the CAPACITY or ASCEND studies were included in the analysis. Pooled analyses of outcomes at 1 year were based on the pre-specified end-points and analytic methods described in the ASCEND study protocol.A total of 1247 patients were included in the analysis. At 1 year, pirfenidone reduced the proportion of patients with a ≥10% decline in per cent predicted forced vital capacity or death by 43.8% (95% CI 29.3-55.4%) and increased the proportion of patients with no decline by 59.3% (95% CI 29.0-96.8%). A treatment benefit was also observed for progression-free survival, 6-min walk distance and dyspnoea. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group, but rarely led to discontinuation.Analysis of data from three phase 3 trials demonstrated that treatment with pirfenidone for 1 year resulted in clinically meaningful reductions in disease progression in patients with IPF.

Evaluation of the World Health Organization Global Invasive Bacterial Vaccine-Preventable Disease (IB-VPD) Surveillance Network's Laboratory External Quality Assessment Programme, 2014-2019.

Introduction. In 2009, the World Health Organization (WHO) established the Global Invasive Bacterial Vaccine Preventable Disease (IB-VPD) Surveillance Network (GISN) to monitor the global burden and aetiology of bacterial meningitis, pneumonia and sepsis caused by Haemophilus influenzae (Hi), Neisseria meningitidis (Nm) and Streptococcus pneumoniae (Sp).Hypothesis/Gap Statement. The GISN established an external quality assessment (EQA) programme for the characterization of Hi, Nm and Sp by culture and diagnostic PCR.Aim. To assess the performance of sentinel site laboratories (SSLs), national laboratories (NLs) and regional reference laboratories (RRLs) between 2014 and 2019 in the EQA programme.Methodology. Test samples consisted of bacterial smears for Gram-staining, viable isolates for identification and serotyping or serogrouping (ST/SG), plus simulated cerebrospinal fluid (CSF) samples for species detection and ST/SG by PCR. SSLs and NLs were only required to analyse the slides for Gram staining and identify the species of the live isolates. RRLs, and any SLs and NLs that had the additional laboratory capacity, were also required to ST/SG the viable isolates and analyse the simulated CSF samples.Results. Across the period, 69-112 SS/NL labs and eight or nine RRLs participated in the EQA exercise. Most participants correctly identified Nm and Sp in Gram-stained smears but were less successful with Hi and other species. SSLs/NLs identified the Hi, Nm and Sp cultures well and also submitted up to 56 % of Hi, 62 % of Nm and 33 % of Sp optional ST/SG results each year. There was an increasing trend in the proportion of correct results submitted over the 6 years for Nm and Sp. Some SSLs/NLs also performed the optional detection and ST/SG of the three organisms by PCR in simulated CSF from 2015 onwards; 89-100 % of the CSF samples were correctly identified and 76-93 % of Hi-, 90-100 % of Nm- and 75-100 % of Sp-positive samples were also correctly ST/SG across the distributions. The RRLs performed all parts of the EQA to a very high standard, with very few errors across all aspects of the EQA.Conclusion. The EQA has been an important tool in maintaining high standards of laboratory testing and building of laboratory capacity in the GISN.

Hepatitis B virus and human immunodeficiency virus drugs in pregnancy: findings from the Antiretroviral Pregnancy Registry.

BACKGROUND & AIMS: Fetal safety of antiviral therapies is important given the long-term treatment of women with chronic hepatitis B (CHB) infection who may become pregnant. We analyzed neonatal safety data from the Antiretroviral Pregnancy Registry (APR), the largest safety database in pregnancy for antivirals used for HIV and CHB. METHODS: Data were extracted from APR cases prospectively enrolled between 1989 and 2011. Primary outcomes were major birth defects rates with exposure to all antivirals, individual classes, and drugs compared to population-based controls. Relevant to CHB, only lamivudine (LAM) and tenofovir disoproxil fumarate (TDF) had sufficient individual data for review (≥200 cases). RESULTS: Of 13,711 cases analyzed, the overall birth defect prevalence (2.8%, 95% CI 2.6-3.1%) was comparable to Centers for Disease Control population-based data (2.72%, 2.68-2.76%, p=0.87) and two prospective antiretroviral exposed newborn cohorts (2.8%, 2.5-3.2%, p=0.90 and 1.5%, 1.1-2.0%, p<0.001). The birth defects prevalence between first and second/third trimesters exposure was similar (3.0% vs. 2.7%). No increased risk of major birth defects with LAM or TDF exposure compared to population-based controls was observed. No specific pattern of major birth defects was observed for individual antivirals or overall. CONCLUSIONS: No increased risk of major birth defects including in non-live births was observed for pregnant women exposed to antivirals relevant to CHB treatment overall or to LAM or TDF compared to population-based controls. Continued safety and efficacy reporting on antivirals in pregnancy are essential to inform patients on their risks and benefits during pregnancy.

Functional subdivisions in the left angular gyrus where the semantic system meets and diverges from the default network.

The left angular gyrus (AG) is reliably activated across a wide range of semantic tasks, and is also a consistently reported component of the so-called default network that it is deactivated during all goal-directed tasks. We show here that there is only partial overlap between the semantic system and the default network in left AG and the overlap defines a reliable functional landmark that can be used to segregate functional subdivisions within AG. In 94 healthy human subjects, we collected functional magnetic resonance imaging (fMRI) data during fixation and eight goal directed tasks that involved semantic matching, perceptual matching or speech production in response to familiar or unfamiliar stimuli presented in either verbal (letters) or nonverbal (pictures) formats. Our results segregated three different left AG regions that were all activated by semantic relative to perceptual matching: (1) a midregion (mAG) that overlapped with the default network because it was deactivated during all tasks relative to fixation; (2) a dorsomesial region (dAG) that was more activated by all tasks relative to fixation; and (3) a ventrolateral region (vAG) that was only activated above fixation during semantic matching. By examining the effects of task and stimuli in each AG subdivision, we propose that mAG is involved in semantic associations regardless of the presence or absence of a stimulus; dAG is involved in searching for semantics in all visual stimuli, and vAG is involved in the conceptual identification of visual inputs. Our findings provide a framework for reporting and interpreting AG activations with greater definition.

Variation in timely surgery for hip fracture by day and time of presentation: a nationwide prospective cohort study from the National Hip Fracture Database for England, Wales and Northern Ireland.

BACKGROUND AND OBJECTIVE: Several studies report poorer quality healthcare for patients presenting at weekends. Our objective was to examine how timely surgery for patients with hip fracture varies with day and time of their presentation. METHODS: This population-based cohort study used 2017 data from the National Hip Fracture Database, which recorded all patients aged 60 years and over who presented with a hip fracture at a hospital in England, Wales and Northern Ireland. Provision of prompt surgery (surgery within 36 hours of presentation) was examined, using multivariable logistic regression with generalised estimating equations to derive adjusted risk ratios (RRs). Time was categorised into three 8-hour intervals (day: 08:00-15:59, evening: 16:00-23:59 and night: 00:00-07:59) for each day of the week. The model accounted for clustering by hospital and was adjusted by sex, age, fracture type, operation type, American Society of Anesthesiologists grade, preinjury mobility and location. RESULTS: We studied 68 977 patients from 177 hospitals. The average patient presenting during the day on Friday or Saturday was significantly less likely to undergo prompt surgery (Friday during 08:00-15:59, RR=0.93, 95% CI 0.91 to 0.96; Saturday during 08:00-15:59, RR=0.91, 95% CI 0.88 to 0.94) than patients in the comparative category (Thursday, during the day). Patients presenting during the evening (16:00-23:59) were consistently significantly less likely to undergo prompt surgery, and the effect was more marked on Fridays and Saturdays (Friday during 16:00-23:59, RR=0.83, 95% CI 0.80 to 0.85; Saturday during 16:00-23:59, RR=0.81, 95% CI 0.78 to 0.85). Patients presenting overnight (00:00-07:59), except on Saturdays, were significantly more likely to undergo surgery within 36 hours (RR>1.07). CONCLUSION: The provision of prompt hip fracture surgery was complex, with evidence of both an 'evening' and a 'night' effect. Investigation of weekly variation in hip fracture care is required to help implement strategies to reduce the variation in timely surgery throughout the entire week.

Histologic evidence of active liver injury in chronic hepatitis B patients with normal range or minimally elevated alanine aminotransferase levels.

GOALS: To evaluate the proportion of patients with histologic evidence of active liver disease (HEALD) who have chronic hepatitis B (CHB) and normal/minimally elevated serum alanine aminotransferase (ALT). Sub-analysis was performed to determine whether HEALD based upon liver biopsy better correlates with ALT using modified ALT (30 men/19 women) upper limit of normal (ULN) criteria compared with local conventional laboratory. BACKGROUND: There are limited data on CHB with normal range ALT (NRALT). We designed a study to evaluate histologic damage in this cohort of patients. STUDY: A retrospective, multicenter study evaluated CHB patients with normal/minimally elevated ALT [< or = 1.2 x ULN (hepatitis B e antigen positive) or < or = 1.5 x ULN (hepatitis B e antigen negative)]. Liver biopsy specimens were reviewed by an independent histopathologist. HEALD was defined as Knodell necroinflammatory score greater than 5 and Ishak fibrosis stage greater than 1. RESULTS: Forty-five patients met criteria: median age of 40 years; 51% males; 73% Asian; and 67% hepatitis B e antigen negative. Median hepatitis B virus DNA was 6.04 log10 copies/mL, aspartate aminotransferase (AST) 30 IU/L, and ALT 42 IU/L; and 40% of the patients had ALT greater than ULN. Overall, 20% had HEALD and among patients with NRALT, 4 of 27 (15%) and 0 of 5 (0%) had HEALD through conventional or modified ALT ULN, respectively. CONCLUSIONS: One fifth of patients with CHB and normal/minimally elevated ALT had HEALD. Among the subset of patients with NRALT, 15% (4 of 27) had HEALD when using conventional laboratory compared with 0% (0 of 5) patients by modified ALT ULN criteria. Use of the modified ALT ULN will likely improve accuracy in identifying patients who may have HEALD compared with conventional laboratory ULN.

Cerebrospinal fluid neopterin in paediatric neurology: a marker of active central nervous system inflammation.

AIM: Cerebrospinal fluid (CSF) neopterin production is increased by interferon-gamma stimulation and appears to act as a marker of intrathecal immune activation. We aimed to test the usefulness of elevated CSF neopterin as a biological marker of central nervous system (CNS) inflammation. METHOD: We retrospectively reviewed CSF neopterin in 158 children (89 males, 69 females, mean age 4y 1mo, SD 3y 11mo, range 1mo-15y). RESULTS: CSF neopterin levels in children with chronic static CNS disorders (n=105) were predominantly low, suggesting that inflammation is rare in these patients. We created an upper value of normal (chronic static group 95th centile 27.4 nmol/l). CSF neopterin was elevated in all 10 patients with acute encephalitis and in 10 of 12 patients with other acute inflammatory CNS disorders (demyelination, post-infectious ataxia, myelitis). CSF neopterin was also significantly elevated in patients with chronic progressive disorders of inflammatory origin. Interestingly, CSF neopterin was elevated in four of six patients with chronic static disorders who were tested during a febrile exacerbation of seizures or dystonia, suggesting that intrathecal immune activation may be important in this setting. INTERPRETATION: Neopterin has a short half-life and was useful for monitoring inflammation activity in a patient with relapsing-remitting encephalitis. CSF neopterin is a useful marker of inflammation in a broad range of acute and chronic CNS disorders, and is a significantly more sensitive marker of inflammation than CSF pleocytosis.

The pharmacological management of acute behavioural disturbance: Data from a clinical audit conducted in UK mental health services.

BACKGROUND: A quality improvement programme addressing prescribing practice for acutely disturbed behaviour was initiated by the Prescribing Observatory for Mental Health. METHOD: This study analysed data from a baseline clinical audit conducted in inpatient mental health services in member trusts. RESULTS: Fifty-eight mental health services submitted data on 2172 episodes of acutely disturbed behaviour. A benzodiazepine alone was administered in 60% of the 1091 episodes where oral medication only was used and in 39% of the 1081 episodes where parenteral medication (rapid tranquillisation) was used. Haloperidol was combined with lorazepam in 22% of rapid tranquillisation episodes and with promethazine in 3%. Physical violence towards others was strongly associated with receiving rapid tranquillisation in men (odds ratio 1.74, 1.25-2.44; p<0.001) as was actual or attempted self-harm in women (odds ratio 1.87, 1.19-2.94; p=0.007). Where physical violence towards others was exhibited, a benzodiazepine and antipsychotic was more likely to be prescribed than a benzodiazepine alone (odds ratio 1.39, 1.00-1.92; p=0.05). The data suggested that 25% of patients were at least 'extremely or continuously active' in the hour after rapid tranquillisation was administered. CONCLUSION: The current management of acutely disturbed behaviour with parenteral medication may fail to achieve a calming effect in up to a quarter of episodes. The most common rapid tranquillisation combination used was lorazepam and haloperidol, for which the randomised controlled trial evidence is very limited. Rapid tranquillisation prescribing practice was not wholly consistent with the relevant National Institute for Health and Care Excellence guideline, which recommends intramuscular lorazepam on its own or intramuscular haloperidol combined with intramuscular promethazine. Clinical factors prompting the use of rapid tranquillisation rather than oral medication may differ between the genders.

A UK clinical audit addressing the quality of prescribing of sodium valproate for bipolar disorder in women of childbearing age.

OBJECTIVES: To review prescribing practice concerning valproate, an established human teratogen, for the management of bipolar disorder in women of childbearing age. DESIGN: The Prescribing Observatory for Mental Health conducted a baseline clinical audit in the UK, as part of a quality improvement programme. PARTICIPANTS: Six hundred and forty-eight clinical teams from 55 mental health Trusts submitted retrospective treatment data relating to patients with a diagnosis of bipolar disorder. RESULTS: Of the audit sample of 6705 patients, 3854 were 50 years of age or younger. Valproate was prescribed for 24% of women and 43% men in this age group, and the mean dose of valproate was lower in women (1196 mg) than in men (1391 mg). For only half of such women was there documented evidence that information had been provided on the risks for the unborn child and the need for adequate contraception. Valproate was more often used in men to treat mania and aggression, while the most common treatment targets in women were hypomania and relapse prevention. CONCLUSIONS: Despite explicit recommendations in national treatment guidelines and published safety alerts and warnings regarding the use of valproate in women of childbearing age, current prescribing of this medication to such women in the context of the treatment of bipolar disorder falls short of best practice, particularly with regard to provision of information regarding the risks associated with exposure to valproate during pregnancy. While women younger than 50 years of age were less likely to be prescribed valproate than men in the same age group, and at a lower dosage, it is unclear to what extent this reflects clinicians' concerns about teratogenicity or is driven by perceptions of the indication for valproate, and the dosage required, for the treatment of different phases of the disorder in men and women.

Overcrowding and Its Association With Patient Outcomes in a Median-Low Volume Emergency Department.

BACKGROUND: Crowding occurs commonly in high volume emergency departments (ED) and has been associated with negative patient care outcomes. We aim to assess ED crowding in a median-low volume setting and evaluate associations with patient care outcomes. METHODS: This was a prospective single-center study from November 14, 2016 until December 14, 2016. ED crowding was measured every 2 h by three different estimation tools: National Emergency Department Overcrowding Score (NEDOCS); Community Emergency Department Overcrowding Score (CEDOCS); and Severely-overcrowding Overcrowding and Not-overcrowding Estimation Tool (SONET) categorized under six different levels of crowding (not busy, busy, extremely busy, overcrowded, severely overcrowded, and dangerously overcrowded). Crowding scores were assigned to each patient upon ED arrival. We evaluated the distributions of crowding and patient ED length of stay (ED LOS) across estimation tools. Accelerated failure time models were utilized to estimate time ratios and their corresponding 95% confidence intervals comparing median LOS across levels of crowding within each estimation tool. RESULTS: This study comprised 2,557 patients whose median ED LOS was 150 min. Approximately 2% of patients arrived during 2 h time intervals deemed overcrowded regardless of the crowding tool used. Median ED LOS increased with the increased level of ED crowding and prolonged median ED LOS (> 150 min) occurred at ED of extremely busy status. Time ratios ranged from 1.09 to 1.48 for NEDOCS, 1.25 - 1.56 for CEDOCS, and 1.26 - 1.72 for SONET. CONCLUSION: Overcrowding rarely occurred in study ED with median-low annual volume and might not be a valuable marker for ED crowding report. Though similar patterns of prolonged ED LOS occurred with increased levels of ED crowding, it seems crowding alerts should be initiated during extremely busy status in this ED setting.

Safety of pirfenidone in patients with idiopathic pulmonary fibrosis: integrated analysis of cumulative data from 5 clinical trials.

BACKGROUND: Pirfenidone is an oral antifibrotic agent that has been shown to reduce the decline in lung function in patients with idiopathic pulmonary fibrosis (IPF). We performed an integrated analysis of safety data from five clinical trials evaluating pirfenidone in patients with IPF. METHODS: All patients treated with pirfenidone in the three multinational Phase 3 studies (CAPACITY (studies 004 and 006), ASCEND (study 016)) and two ongoing open-label studies (study 002 and study 012 (RECAP)) were included in the analysis. Safety outcomes were assessed during the period from the first dose until 28 days after the last dose of study drug. RESULTS: A total of 1299 patients were included in the analysis. The cumulative total exposure to pirfenidone was 3160 person exposure years (PEY). The median duration of exposure was 1.7 years (range 1 week to 9.9 years), and the mean (±SD) daily dose was 2053.8 (±484.9) mg. Gastrointestinal events (nausea (37.6%), diarrhoea (28.1%), dyspepsia (18.4%), vomiting (15.9%)) and rash (25.0%) were the most common adverse events; these were generally mild to moderate in severity and without significant clinical consequence. Elevations in alanine aminotransferase or aspartate aminotransferase greater than three times the upper limit of normal occurred in 40/1299 (3.1%) patients (adjusted incidence, 2.3 per 100 PEY). Elevations were generally transient and reversible with dose modification or discontinuation. CONCLUSIONS: A comprehensive analysis of safety outcomes in a large and well-defined cohort of 1299 patients with IPF who were followed prospectively for up to 9.9 years demonstrated that long-term treatment with pirfenidone is safe and generally well tolerated. TRIAL REGISTRATION NUMBERS: NCT00287716, NCT00287729, NCT00662038, NCT01366209.

Sensitivity Analyses of the Change in FVC in a Phase 3 Trial of Pirfenidone for Idiopathic Pulmonary Fibrosis.

BACKGROUND: FVC outcomes in clinical trials on idiopathic pulmonary fibrosis (IPF) can be substantially influenced by the analytic methodology and the handling of missing data. We conducted a series of sensitivity analyses to assess the robustness of the statistical finding and the stability of the estimate of the magnitude of treatment effect on the primary end point of FVC change in a phase 3 trial evaluating pirfenidone in adults with IPF. METHODS: Source data included all 555 study participants randomized to treatment with pirfenidone or placebo in the Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) study. Sensitivity analyses were conducted to assess whether alternative statistical tests and methods for handling missing data influenced the observed magnitude of treatment effect on the primary end point of change from baseline to week 52 in FVC. RESULTS: The distribution of FVC change at week 52 was systematically different between the two treatment groups and favored pirfenidone in each analysis. The method used to impute missing data due to death had a marked effect on the magnitude of change in FVC in both treatment groups; however, the magnitude of treatment benefit was generally consistent on a relative basis, with an approximate 50% reduction in FVC decline observed in the pirfenidone group in each analysis. CONCLUSIONS: Our results confirm the robustness of the statistical finding on the primary end point of change in FVC in the ASCEND trial and corroborate the estimated magnitude of the pirfenidone treatment effect in patients with IPF. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01366209; URL: www.clinicaltrials.gov.

Assaying the effect of levodopa on the evaluation of risk in healthy humans.

In humans, dopamine is implicated in reward and risk-based decision-making. However, the specific effects of dopamine augmentation on risk evaluation are unclear. Here we sought to measure the effect of 100 mg oral levodopa, which enhances synaptic release of dopamine, on choice behaviour in healthy humans. We use a paradigm without feedback or learning, which solely isolates effects on risk evaluation. We present two studies (n = 20; n = 20) employing a randomised, placebo-controlled, within-subjects design. We manipulated different dimensions of risk in a controlled economic paradigm. We test effects on risk-reward tradeoffs, assaying both aversion to variance (the spread of possible outcomes) and preference for relative losses and gains (asymmetry of outcomes--skewness), dissociating this from potential non-specific effects on choice randomness using behavioural modelling. There were no systematic effects of levodopa on risk attitudes, either for variance or skewness. However, there was a drift towards more risk-averse behaviour over time, indicating that this paradigm was sensitive to detect changes in risk-preferences. These findings suggest that levodopa administration does not change the evaluation of risk. One possible reason is that dopaminergic influences on decision making may be due to changing the response to reward feedback.

Hepatitis B screening and vaccination practices in asian american primary care.

BACKGROUND/AIMS: Screening for hepatitis B virus (HBV) is recommended in populations with anticipated prevalence ≥2%. This study surveyed HBV screening and vaccination practices of Asian American primary care providers (PCPs). METHODS: Approximately 15,000 PCPs with Asian surnames in the New York, Los Angeles, San Francisco, Houston, and Chicago areas were invited to participate in a web-based survey. Asian American PCPs with ≥25% Asian patients in their practice were eligible. RESULTS: Of 430 (2.9%) survey respondents, 217 completed the survey. Greater than 50% followed ≥200 Asian patients. Although 95% of PCPs claimed to have screened patients for HBV, 41% estimated that ≤25% of their adult Asian patients had ever been screened, and 50% did not routinely screen all Asian patients. In a multivariable analysis, the proportion of Asian patients in the practice, provider geographic origin and the number of liver cancers diagnosed in the preceding 12 months were significantly associated with a higher likelihood of screening for HBV. Over 80% of respondents reported that ≤50% of their adult Asian patients had received the HBV vaccine. CONCLUSIONS: Screening and vaccination for HBV in Asian American patients is inadequate. Measures to improve HBV knowledge and care by primary-care physicians are critically needed.