Magnetically localized and wash-free fluorescent immuno-assay: From a research platform (MLFIA) to a multiplexed POC system (MagIA).

Sexually transmitted infections (STI) remain one of the world's public health priorities: Nearly 400 million people are infected not only in emerging, but also in western countries. HIV, HBV and HCV share common infection pathways; thus these 3 diseases are recommended to be tested at the same time. However, this combined approach is currently mainly available in laboratories, and seldomly at the Point-of-care (POC). Consequently, there is a need for a STI screening POC platform with laboratory-like performance. Such a platform should be autonomous and portable and enable multiplexed screening from capillary blood. The previously developed and introduced MLFIA (Magnetically Localized and wash-free Fluorescent Immuno-Assay) technology has the potential to address these needs, as the MLFIA 18-chamber microfluidic cartridge and the MLFIA Analyzer were previously characterized and evaluated with plasma and serum from patients infected with HIV, Hepatitis B (Hep B) or C (Hep C). Here, we present the efforts to transfer this research platform (MLFIA) to a fully integrated multi-analysis solution (MagIA). First, we present the design changes of the consumable enabling to perform multiple assays in parallel, a fast filling of the cartridge with patient samples, and a homogeneous reagent/sample incubation. Second, we describe the development a piezoelectric actuator integrated into the Analyzer: this mixing module allows for an automated, fully integrated and portable workflow, with homogeneous in-situ mixing capabilities. The obtained MagIA platform was further characterized and validated for immunoassays (LOD, cartridge stability over time), using various biological models including OVA and IgG. We discuss the performances of the MLFIA and MagIA platforms for the detection of HIV / Hep B / Hep C using results from 102 patient plasma samples. Lastly, we assessed the compatibility of the MagIA platform with veinous and capillary blood samples as a final step towards its POC validation.

Magnetically localized and wash-free fluorescence immunoassay (MLFIA): proof of concept and clinical applications.

Immunoassays are used for many applications in various markets, from clinical diagnostics to the food industry, generally relying on gold-standard ELISAs that are sensitive, robust, and cheap but also time-consuming and labour intensive. As an alternative, we propose here the magnetically localized and wash-free fluorescence immunoassay (MLFIA): a no-wash assay to directly measure a biomolecule concentration, without mixing nor washing steps. To do so, a fluorescence no-wash measurement is performed to generate a detectable signal. It consists of a differential measurement between the fluorescence of fluorophores bound to magnetic nanoparticles specifically captured by micro-magnets against the residual background fluorescence of unbound fluorophores. Targeted biomolecules (antibodies or antigens) are locally concentrated on micro-magnet lines, with the number of captured biomolecules quantitatively measured without any washing step. The performance of the MLFIA platform is assessed and its use is demonstrated with several biological models as well as clinical blood samples for HIV, HCV and HBV detection, with benchmarking to standard analyzers of healthcare laboratories. Thus, we demonstrated for the first time the versatility of the innovative MLFIA platform. We highlighted promising performances with the successful quantitative detection of various targets (antigens and antibodies), in different biological samples (serum and plasma), for different clinical tests (HCV, HBV, HIV).

Excellent results of large-diameter ceramic-on-ceramic bearings in total hip arthroplasty: Is Squeaking Related to Head Size.

AIMS: This study reports the mid-term results of total hip arthroplasty (THA) performed using a monoblock acetabular component with a large-diameter head (LDH) ceramic-on-ceramic (CoC) bearing. PATIENTS AND METHODS: Of the 276 hips (246 patients) included in this study, 264 (96%) were reviewed at a mean of 67 months (48 to 79) postoperatively. Procedures were performed with a mini posterior approach. Clinical and radiological outcomes were recorded at regular intervals. A noise assessment questionnaire was completed at last follow-up. RESULTS: There were four re-operations (1%) including one early revision for insufficient primary fixation (0.4%). No hip dislocation was reported. The mean University of California, Los Angeles (UCLA) activity score, 12-Item Short-Form Health Survey (SF-12) Mental Component Summary (MCS) score, SF-12 Physical Component Summary (PCS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and Forgotten Joint Score (FJS) were 6.6 (2 to 10), 52.8 (25.5 to 65.7), 53.0 (27.2 to 66.5), 7.7 (0 to 63), and 88.5 (23 to 100), respectively. No signs of loosening or osteolysis were observed on radiological review. The incidence of squeaking was 23% (n = 51/225). Squeaking was significantly associated with larger head diameter (p < 0.001), younger age (p < 0.001), higher SF-12 PCS (p < 0.001), and UCLA scores (p < 0.001). Squeaking did not affect patient satisfaction, with 100% of the squeaking hips satisfied with the surgery. CONCLUSION: LDH CoC THAs have demonstrated excellent functional outcomes at medium-term follow-up, with very low revision rate and no dislocations. The high incidence of squeaking did not affect patient satisfaction or function. LDH CoC with a monoblock acetabular component has the potential to provide long term implant survivorship with unrestricted activity, while avoiding implant impingement, liner fracture at insertion, and hip instability. Cite this article: Bone Joint J 2018;100-B:1434-41.

Kinematic TKA using navigation: Surgical technique and initial results.

BACKGROUND: Kinematic alignment for total knee arthroplasty (TKA) may be one way of improving outcomes. Previous studies have either used patient-specific instrumentation, which adds cost, or standard instrumentation, which provides no intraoperative feedback on resection alignment. HYPOTHESIS: To determine if computer navigation could reproduce native patient anatomy and simplify ligament balance during TKA whilst giving satisfactory improvements in functional scores at early follow-up. MATERIALS AND METHODS: Computer navigation was used for kinematic distal femoral and proximal tibial cuts in 100 consecutive and unselected TKAs. Resections were modified only if measured angles fell outside a pre-defined safe range of combined coronal orientation within±3 degrees of neutral and/or independent femoral or tibial cuts within±5 degrees. Pre- and postoperative measurements of the hip-knee-ankle (HKA) angle, the lateral distal femoral angle (LDFA) and the medial proximal tibial angle (MPTA) were taken using long-leg standing radiographs. Clinical evaluation was with the WOMAC and KOOS scales. RESULTS: Mean follow-up was 2.4 years (range 1.0-3.7, SD 0.8). The mean pre-op LDFA was 2.1 degrees valgus (9.2 valgus to 3.7 varus, SD 2.5) and 1.8 degrees valgus post-op (5.7 valgus to 4.2 varus, SD 2.0) (P=0.41). The mean pre-op MPTA was 3.0 degrees varus (10.6 valgus to 10.2 varus, SD 3.2) and 2.4 degrees varus post-op (4.0 valgus to 6.8 varus, SD 2.2) (P=0.03). The mean WOMAC score improved from 49.4 (29-85, SD 12.8) to 24.7 (0-73, SD 16.5) (P<0.001) and the mean KOOS score from 37.1 (7.2-77.2, SD 13.0) to 65.1 (26.8-100, SD 16) (P<0.001). Five knees (5%) required additional ligament release, four with valgus OA and one with varus OA. Two knees (2%) required lateral retinacular release for patellar tracking. DISCUSSION: Computer navigation for kinematic TKA provides the operating surgeon with full control and feedback at each step, whilst also allowing partial correction of more extreme anatomy that might be unsuitable for recreation during TKA. This technique helps to preserve ligament isometry and produces satisfactory improvements in functional scores. LEVEL OF EVIDENCE: IV (retrospective case series review).

A randomised trial of all-polyethylene and metal-backed tibial components in unicompartmental arthroplasty of the knee.

This randomised trial evaluated the outcome of a single design of unicompartmental arthroplasty of the knee (UKA) with either a cemented all-polyethylene or a metal-backed modular tibial component. A total of 63 knees in 45 patients (17 male, 28 female) were included, 27 in the all-polyethylene group and 36 in the metal-backed group. The mean age was 57.9 years (39.6 to 76.9). At a mean follow-up of 6.4 years (5 to 9.9), 11 all-polyethylene components (41%) were revised (at a mean of 5.8 years; 1.4 to 8.0) post-operatively and two metal-backed components were revised (at one and five years). One revision in both groups was for unexplained pain, one in the metal-backed group was for progression of osteoarthritis. The others in the all-polyethylene group were for aseptic loosening. The survivorship at seven years calculated by the Kaplan-Meier method for the all-polyethylene group was 56.5% (95% CI 31.9 to 75.2, number at risk 7) and for the metal-backed group was 93.8% (95% CI 77.3 to 98.4, number at risk 16) This difference was statistically significant (p < 0.001). At the most recent follow-up, significantly better mean Western Ontario and McMaster Universities Arthritis Index Scores were found in the all-polyethylene group (13.4 vs 23.0, p = 0.03) but there was no difference in the mean Knee injury and Osteoarthritis Outcome scores (68.8; 41.4 to 99.0 vs 62.6; 24.0 to 100.0), p = 0.36). There were no significant differences for range of movement (p = 0.36) or satisfaction (p = 0.23). This randomised study demonstrates that all-polyethylene components in this design of fixed bearing UKA had unsatisfactory results with significantly higher rates of failure before ten years compared with the metal-back components.

Symptomatic cytomegalovirus gastrointestinal infection with positive quantitative real-time PCR findings in apparently immunocompetent patients: a case series.

Cytomegalovirus (CMV) gastrointestinal disease rarely occurs in immunocompetent patients, and is mainly diagnosed on the basis of histopathological findings. Real-time PCR for CMV DNA quantification is considered to be a useful diagnostic tool, but its place in the diagnostic strategy is not clearly defined. The goal of the study was to describe the clinical and paraclinical features of apparently immunocompetent patients with CMV gastrointestinal disease diagnosed according to quantitative PCR results. In this retrospective study conducted in a 1500-bed tertiary-care centre, we reviewed the case records of apparently immunocompetent patients with positive findings of CMV DNA in gastrointestinal biopsies with compatible symptoms and endoscopic findings. A total of 13 patients were included between January 2007 and December 2010. The median age was 81 years, and 54% of patients had underlying immune-modulating conditions. Diarrhoea, haematochezia and dysphagia were the main reported symptoms, and ulcers were the main endoscopic findings. The mean value of CMV DNA load in gastrointestinal biopsies was 3845 copies/µg total DNA (range, 15-15 500 copies/µg total DNA). The highest values were found in two patients who were diagnosed with adenocarcinoma in the subsequent course of CMV infection. Clinical features were similar to those in previous series in which diagnosis was based on histopathological analysis. Elderly people are more commonly affected, and a link with immune senescence is possible. Quantification of CMV DNA seems to be a useful tool for diagnosis when combined with clinical and endoscopic findings, but further studies are necessary to interpret quantitative values.

Is hand-rub consumption correlated with hand hygiene and rate of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE)-acquired infections?

A retrospective investigation was conducted to determine whether the consumption of alcohol-based hand rub (ABHR) used was correlated with the incidence of acquired nosocomial infection due to meticillin-resistant Staphylococcus aureus or to extended-spectrum beta lactamase (ESBL)-producing strains. Between 2005 and 2008, the use of ABHRs increased significantly by 8 L per 1000 patient-days of hospitalization per year. During the same period, adherence to hand hygiene increased significantly from 55.6% to 70.9% (P < 0.0001). Despite these improvements there was a steady increase in the incidence of ESBL-producing strains in the past three years and no correlation was found between ABHR consumption and either nosocomially acquired ESBL or adherence to hand hygiene.

Normal serum concentrations of anti-Mullerian hormone in a population of fertile women in their first trimester of pregnancy.

BACKGROUND: Anti-Müllerian hormone (AMH) levels are used to evaluate the ovarian reserve. AMH serum concentrations have recently been studied among women attending fertility centers, and among women with regular menstrual cycles but normative values have not been established among fertile women: the objective of this study was to establish those values. METHODS: This prospective cross-sectional study included 340 healthy fertile women attending a single centre, aged between 15 and 50 years. The women were all in the first trimester of pregnancy, had no serious medical history and attended the abortion service of the University Hospital of Nice, France. Serum AMH was measured using a second-generation AMH enzyme-linked immunosorbent assay. RESULTS: Median AMH concentration was 2.42 ng/ml (25-75 percentiles 1.19-4.12). The relationship between AMH concentration and age was best fitted by a polynomial function. Serum AMH values rose until age 29 years and then showed a significant decline (R(2)= 0.289, P < 0.001). Normative values for serum AMH were established in different age groups between 15 and 50 years. CONCLUSIONS: We established the normative values for serum AMH in a population of French fertile women in their first trimester of pregnancy.

[Epidemiology of patients harboring extended-spectrum beta-lactamase-producing enterobacteriaceae (ESBLE), on admission]. / Épidémiologie des patients porteurs d'entérobactéries sécrétrices de bêtalactamase à spectre élargi (EBLSE), à l'admission.

OBJECTIVE: The incidence of extended-spectrum beta-lactamase-producing enterobacteria (ESBLE) has regularly increased over the last few years. However, little is known about epidemiology of ESBLE carriers in France. The objective of this study was to determine the ESBLE carriers or infected patients profile, identified within 48 hours following hospital admission. DESIGN: This retrospective study included all patients admitted in 2006 and 2007 at the Necker-Enfants-Malades (NEM) teaching hospital, carrying or infected with ESBLE isolated within 48 hours following admission. The pediatric and adult populations were compared. RESULTS: There was no significant difference between pediatric and adult populations. Escherichia coli and Klebsiella pneumoniae were the two main species isolated, accounting respectively for 59.6 and 21.1 % of the 114 isolated strains. Among the 114 analyzed files, 24 patients (21 %) were known to be EBLSE carriers, 37 (32 %) were transferred from another hospital, including 16 from another country. Concerning the 54 (47 %) other patients, five (4 %) came from a country with high prevalence, and 44 (39 %) were treated for a chronic illness. Only five patients (4 %) carrying ESBLE did not have any usual risk factor for multidrug resistance (MDR) bacterial carriage. CONCLUSIONS: In our study, 4 % of patients carrying ESBLE admitted had no usual risk factor for MDR bacteria. Targeted screening of previous carriers, patients with chronic illness, transferred patients, or patients coming from country with high prevalence, would help to limit the spread of ESBLE.

Keyhole sign: how specific is it for the diagnosis of posterior urethral valves?

OBJECTIVES: Posterior urethral valves (PUV) are the most common cause of renal impairment in boys during early childhood. Although antenatal suspicion of this pathology has become quite common in recent years, prenatal diagnosis remains challenging. The aim of this study was to evaluate the predictive value of different ultrasound criteria currently used to diagnose PUV. METHODS: We reviewed the antenatal and postnatal files of 54 male patients referred to our center from 2000 to 2006 after detection of fetal bilateral hydronephrosis. The following ultrasound criteria were evaluated in relation to the postnatal diagnosis of PUV: amniotic fluid volume, bladder wall thickness, bladder dilatation and the presence of the 'keyhole sign'. RESULTS: Forty-two fetuses (77.8%) were suspected to have PUV on prenatal examination. Out of these, 29 (69.0%) had PUV confirmed postnatally. The sensitivity and specificity of the antenatal diagnosis of PUV were 94% and 43%, respectively. Increased bladder wall thickness and bladder dilatation were highly associated with the diagnosis of PUV (P < 0.001). However, a thick-walled bladder was observed in 39.1% and a dilated bladder in 47.8% of the infants with a postnatal diagnosis other than PUV. The presence of the keyhole sign was not found to predict a diagnosis of PUV (P = 0.27). CONCLUSION: In this series the use of classical prenatal ultrasound signs to diagnose PUV showed high sensitivity but low specificity. The best diagnostic indicators were increased bladder wall thickness and dilatation of the bladder. The keyhole sign was not found to be a reliable predictor of PUV.

[Return to sport after hip resurfacing or total hip arthroplasty: a randomized study]. / Activités sportives après resurfaçage et prothèse totale de hanche : une étude prospective randomisée.

PURPOSE OF THE STUDY: Since component wear of the prosthetic metal-polyethylene bearing is directly related to the level of patient activity, it would be logical, for patients with a total hip arthroplasty, to advise against long-term participation in activities with repeated movements The purpose of this prospective randomized study was to compare the type, intensity and frequency of sports activities performed after resurfacing hip arthroplasty (RH) or total hip arthroplasty (THA) using a metal-on-metal bearing. MATERIAL AND METHODS: This study concerned 205 hips, including 152 with a unilateral hip arthroplasty (71 THA and 81 RH). Three clinical scores were used: an overall activity score, the University of California, Los Angeles (UCLA) score and the Western Ontario McMaster Osteoarthritis Index (WOMAC) score, as well as patient satisfaction, return to sports activities (using a visual analog scale [VAS]) and frequency of factors limiting activity. Patients completed a questionnaire to determine the type, intensity and frequency of sports activities practiced pre- and postoperatively. RESULTS: The mean overall activity score immediately before surgery was not statistically different between the two groups (p=0.111). One year after surgery, the score was 17.9 in the RH group and 12.4 in the THA group (p=0.001). At last follow-up, the mean WOMAC score was 8.1 (range 0-73, S.D. 13.1) in the RH group and 9.8 (range 0-41, S.D. 10.9) in the THA group (p=0.409). The mean UCLA score was 7.17 in the RH group (range 2-10, S.D. 1.90) and 6.75 in the THA group (range 2-10, S.D. 1.71) (p=0.174). The mean satisfaction with return to sports activities as assessed on the VAS was 7.78 in the RH group and 7.43 in the THA group (p=0.313). DISCUSSION: The results of this study demonstrate that the degree and intensity of postoperative sports activities are greater in the RH group than in the THA group, although this difference was less pronounced than expected. The excellent joint stability after RH (big head effect) could be one of the main factors favoring a high activity level compared to conventional THA, by limiting the episodes of dislocation and increasing the suction effect between the joint components. It is nevertheless difficult to ascertain the long-term effect of intense sports activity on the fixation of osteo-integrated implants (cups) and cemented components (femoral stem).

Long-acting beta2-agonists versus placebo in addition to inhaled corticosteroids in children and adults with chronic asthma.

BACKGROUND: Long-acting inhaled beta2-adrenergic agonists are recommended as 'add-on' medication to inhaled corticosteroids in the maintenance therapy of asthmatic adults and children aged two years and above. OBJECTIVES: To quantify in asthmatic patients the safety and efficacy of the addition of long-acting beta2-agonists to inhaled corticosteroids on the incidence of asthma exacerbations, pulmonary function and other measures of asthma control. SEARCH STRATEGY: We identified randomised controlled trials (RCTs) through electronic database searches (the Cochrane Airways Group Specialised Register, MEDLINE, EMBASE and CINAHL), bibliographies of RCTs and correspondence with manufacturers, until April 2004. SELECTION CRITERIA: RCTs were included that compared the addition of inhaled long-acting beta2-agonists to corticosteroids with inhaled corticosteroids alone for asthma therapy in children aged two years and above and in adults. DATA COLLECTION AND ANALYSIS: Studies were assessed independently by two review authors for methodological quality and data extraction. Confirmation was obtained from the trialists when possible. The primary endpoint was rate of asthma exacerbations requiring systemic corticosteroids. Secondary endpoints included pulmonary function tests (PFTs), symptom scores, adverse events and withdrawal rates. MAIN RESULTS: Of 594 identified citations, 49 trials met the inclusion criteria: 27 full-text publications, one unpublished full-text report and 21 abstracts. Twenty-three citations (21 abstracts and two full-text publications) provided data in insufficient detail, 26 trials contributed to this systematic review. All but three trials were of high methodological quality. Most interventions (N = 26) were of four-month duration or less. Eight trials focused on children and 18 on adults, with participants generally symptomatic with moderate airway obstruction despite their current inhaled steroid regimen. If a trial had more than one intervention or control group, additional control to intervention comparisons were considered separately. Formoterol (N = 17) or salmeterol (N = 14) were most frequently added to low-dose inhaled corticosteroids (200 to 400 microg/day of beclomethasone (BDP) or equivalent). The addition of a daily long-acting beta2-agonist (LABA) reduced the risk of exacerbations requiring systemic steroids by 19% (relative risk (RR) 0.81, 95% CI 0.73 to 0.90). The number needed to treat for one extra patient to be free from exacerbation for one year was 18 (95% CI 13 to 33). The addition of LABA significantly improved FEV1 (weighted mean difference (WMD) 170 mL, 95% CI 110 to 240) using a random-effects model, increased the proportion of symptom-free days (WMD 17%, 95% CI 12 to 22, N = 6 trials) and rescue-free days (WMD 19%, 95% CI 12 to 26, N = 2 trials). The group treated with LABA plus inhaled corticosteroid showed a reduction in the use of rescue short-acting beta2-agonists (WMD -0.7 puffs/day, 95% CI -1.2 to -0.2), experienced less withdrawals due to poor asthma control (RR 0.5, 95% CI 0.4 to 0.7) and less withdrawals due to any reason (RR 0.9, 95% CI 0.8 to 0.98), using a random-effects model. There was no group difference in risk of overall adverse effects (RR 0.98, 95% CI 0.92 to 1.05), withdrawals due to adverse health events (RR 1.29, 95% CI 0.96 to 1.75) or specific adverse health events. AUTHORS' CONCLUSIONS: In patients who are symptomatic on low to high doses of inhaled corticosteroids, the addition of a long-acting beta2-agonist reduces the rate of exacerbations requiring systemic steroids, improves lung function, symptoms and use of rescue short-acting beta2-agonists. The similar number of serious adverse events and withdrawal rates in both groups provides some indirect evidence of the safety of long-acting beta2-agonists as add-on therapy to inhaled corticosteroids.

Combination of inhaled long-acting beta2-agonists and inhaled steroids versus higher dose of inhaled steroids in children and adults with persistent asthma.

BACKGROUND: In asthmatic patients inadequately controlled on inhaled corticosteroids and/or those with moderate persistent asthma, two main options are recommended: the combination of a long-acting inhaled beta2 agonist (LABA) with inhaled corticosteroids (ICS) or use of a higher dose of inhaled corticosteroids. OBJECTIVES: To determine, in asthmatic patients, the effect of the combination of long-acting beta2 agonists and inhaled corticosteroids compared to a higher dose of inhaled corticosteroids on the incidence of asthma exacerbations, on pulmonary function and on other measures of asthma control and to look for characteristics associated with greater benefit for either treatment option. SEARCH STRATEGY: We identified randomized controlled trials (RCTs) through electronic database searches (MEDLINE, EMBASE and CINAHL), bibliographies of RCTs and correspondence with manufacturers until April 2004. SELECTION CRITERIA: RCTs were included that compared the combination of inhaled LABA and ICS to a higher dose of inhaled corticosteroids, in children aged 2 years and older, and in adults with asthma. DATA COLLECTION AND ANALYSIS: Studies were assessed independently by two authors for methodological quality and data extraction. Confirmation was obtained from the trialists when possible. The primary endpoint was rate of patients experiencing one or more asthma exacerbations requiring oral corticosteroids. Secondary endpoints included pulmonary function tests (PFTs), symptoms, use of rescue beta2 agonists, adverse events and withdrawal rates. The meta-analysis was done with RevMan Analyses and the meta-regression, with Stata. MAIN RESULTS: Of 593 citations identified, 30 (three pediatric; 27 adult) trials were analysed recruiting 9509 participants, including one study providing two control-intervention comparisons. Only one trial included corticosteroid-naive patients. Participants were symptomatic, generally (N=20 trials) presenting with moderate (FEV1 60-79% of predicted) rather than mild airway obstruction. Trials tested the combination of salmeterol (N=22) or formoterol (N=8) with a median of 400 mcg of beclomethasone or equivalent (BDP-eq) compared to a median of 800 to 1000 mcg/day of BDP-eq. Trial duration was 24 weeks or less in all but four trials. There was no significant group difference in the rate of patients with exacerbations requiring systemic corticosteroids [N=15, RR=0.88 (95% CI: 0.77, 1.02)]. The combination of LABA and ICS resulted in greater improvement from baseline in FEV1 [N=7, WMD=0.10 L (95% CI: 0.07, 0.12)], in symptom-free days [N=8 , WMD=11.90% (95% CI:7.37, 16.44), random effects model], and in the daytime use of rescue beta2 agonists than a higher dose of ICS [N=4, WMD= -0.99 puffs/day (95% CI: -1.41, -0.58), random effects model]. There was no significant group difference in the rate of overall adverse events [N=15, RR=0.93 (95% CI: 0.84, 1.03), random effects model], or specific side effects, with the exception of a three-fold increase rate of tremor in the LABA group [N= 10, RR=2.96 (95%CI: 1.60, 5.45)]. The rate of withdrawals due to poor asthma control favoured the combination of LABA and ICS [N=20, RR=0.69 (95%CI: 0.52, 0.93)]. AUTHORS' CONCLUSIONS: In adult asthmatics, there was no significant difference between the combination of LABA and ICS and a higher dose of ICS for the prevention of exacerbations requiring systemic corticosteroids. Overall, the combination therapy led to greater improvement in lung function, symptoms and use of rescue beta2 agonists, (although most of the results are from trials of up to 24 weeks duration). There were less withdrawals due to poor asthma control in this group than when using a higher dose of inhaled corticosteroids. Apart from an increased rate of tremor, the two options appear safe although adverse effects associated with long-term ICS treatment were seldom monitored.