Outcomes, Prognostic Factors and Salvage Treatment for Recurrent Chordoma After Pencil Beam Scanning Proton Therapy at the Paul Scherrer Institute.

AIMS: The outcome of chordoma patients with local or distant failure after proton therapy is not well established. We assessed the disease-specific (DSS) and overall survival of patients recurring after proton therapy and evaluated the prognostic factors affecting DSS. MATERIALS AND METHODS: A retrospective analysis was carried out of 71 recurring skull base (n = 36) and extracranial (n = 35) chordoma patients who received adjuvant proton therapy at initial presentation (n = 42; 59%) or after post-surgical recurrence (n = 29; 41%). The median proton therapy dose delivered was 74 GyRBE (range 62-76). The mean age was 55 ± 14.2 years and the male/female ratio was about one. RESULTS: The median time to first failure after proton therapy was 30.8 months (range 3-152). Most patients (n = 59; 83%) presented with locoregional failure only. There were only 12 (17%) distant failures, either with (n = 5) or without (n = 7) synchronous local failure. Eight patients (11%) received no salvage therapy for their treatment failure after proton therapy. Salvage treatments after proton therapy failure included surgery, systemic therapy and additional radiotherapy in 45 (63%), 20 (28%) and eight (11%) patients, respectively. Fifty-three patients (75%) died, most often from disease progression (47 of 53 patients; 89%). The median DSS and overall survival after failure was 3.9 (95% confidence interval 3.1-5.1) and 3.4 (95% confidence interval 2.5-4.4) years, respectively. On multivariate analysis, extracranial location and late failure (≥31 months after proton therapy) were independent favourable prognostic factors for DSS. CONCLUSION: The survival of chordoma patients after a treatment failure following proton therapy is poor, particularly for patients who relapse early or recur in the skull base. Although salvage treatment is administered to most patients with uncontrolled disease, they will ultimately die as a result of disease progression in most cases.

Younger age and in situ duration of peripheral intravenous catheters were risk factors for extravasation in a retrospective paediatric study.

AIM: Epidemiological data on the incidence and risk factors of extravasation of peripheral intravenous catheters (PIVC) in neonates and children are scarce and that is what this study explored. METHODS: This was a one-year retrospective study of all neonates and paediatric intensive care patients with at least one recorded PIVC at the Geneva University Hospitals, Switzerland, in 2013. The extravasation rate was determined for all patients, including neonates below 28 days, and for all PIVCs. Multivariate analysis of the associated risk factors was performed. RESULTS: We analysed 1300 PIVC in 695 paediatric patients with a median age of 1.5 years. The overall extravasation incidence was 17.6% for all patients and 11.7% for PIVC. The overall incidence rate of PIVC extravasation was 4.5 per 100 catheters days, and the risk was highest in the 201 neonates, at 28.4%. The incidence rate four days after insertion of the PIVC was around three times higher than on day one. Neonates and the in situ duration of PIVCs were associated risk factors (p < 0.001). CONCLUSION: Extravasation was frequent and neonates were particularly at risk. Younger age and longer in situ PIVC duration were independent risk factors for extravasation.

Hypertension, haematuria and renal functioning in haemophilia - a cross-sectional study in Europe.

BACKGROUND AND OBJECTIVES: This cross-sectional, epidemiological study sought to assess the prevalence and extent of potential risk factors for hypertension, particularly renal function related to haematuria and their associations in people with haemophilia. METHODOLOGY: Demographic and medical data were collected at a single time-point in patients with haemophilia over 40 years of age from 16 European centres. Associations with diagnosis of hypertension were tested in univariate and multivariate analyses. RESULTS: We enrolled 532 patients (median age 52 years, range 40-98) with haemophilia A (n = 467) or haemophilia B (n = 65). Haemophilia was severe (<0.01 IU mL-1 ) in 313 patients (59%). Hypertension was diagnosed in 239 patients (45%). In multivariate analyses, age and body mass index (BMI) were significantly and independently associated with hypertension (adjusted odds ratio (OR) 18.1, P < 0.001, in elderly patients and OR = 25.1, P < 0.001, in patients with BMI >30 kg m-2 ). Estimated glomerular filtration rate (eGFR) <70 mL min-1 (OR = 2.7, P = 0.047) was significantly associated with hypertension, but mean eGFR was significantly higher for severe than mild haemophilia. Further variables with OR > 2.8 were diabetes (OR = 2.8, P = 0.04), coronary artery disease (OR = 3.3, P = 0.052) and family history of hypertension (OR = 4.4, P < 0.001). Neither severity of haemophilia nor history of haematuria was significantly associated with hypertension in univariate or multivariate analyses. CONCLUSION: As in the general population, age and BMI were major risk factors for hypertension in people with haemophilia. Renal dysfunction was associated with hypertension, but the prevalence of renal dysfunction was not extensive and furthermore not significantly correlated with haematuria. The associations of other variables with hypertension require further studies to confirm causal relationships over time.

How to compare cardiovascular disease and risk factors in elderly patients with haemophilia with the general population.

INTRODUCTION: Studies on the prevalence of cardiovascular disease (CVD) and risk factors in patients with haemophilia (PWH) in comparison to the general population have generated inconsistent results. The ADVANCE Working Group collected data on CV comorbidities in PWH aged ≥40 years (H(3) Study). AIM: Identification of German epidemiological data on CVD for the general population, evaluation for appropriateness, and execution of comparisons with PWH. METHODS: Identification of data sources by structured literature (EMBASE, MEDLINE) searches. INCLUSION CRITERIA: German general population, CVD and risk factors, gender/age stratification, sample size >500 male persons, age groups ≥40 years, current data collection, language English/German. Comparison of data on CVD and risk factors in PWH (H(3)  Study) with published German general population data. RESULTS: Criteria for data source appropriateness were defined. Of five national and three international epidemiological studies, the DEGS1 Study (German Health Interview and Examination Survey for Adults) was identified as the most suitable comparator. Compared with men from DEGS1, hypertension was significantly more prevalent in PWH aged 50-59 years (41.7% [95% CI: 37.3-46.2] vs. 52.0% [95% CI: 43.7-60.1], P = 0.03). Coronary artery/heart disease (CHD) was significantly less prevalent in PWH aged ≥60 years (60-69 years: 19.5% [95% CI: 15.9-23.7] vs. 8.1% [95% CI: 3.3-16.1], P = 0.02; 70-79 years: 30.5% [95% CI: 25.9-35.5] vs. 11.8% [95% CI: 5.2-21.9], P = 0.002). No statistically significant difference for ischaemic cerebrovascular disease/stroke was detected. CONCLUSION: Increased prevalence of hypertension in PWH should trigger regular screening. CHD does occur in PWH aged ≥60 years though apparently with lower prevalence. Given the growing population of elderly PWH, guidelines for prevention and treatment of CVD should be developed.

Urinary incontinence as a predictor of death after new-onset stroke: a meta-analysis.

BACKGROUND AND PURPOSE: Urinary incontinence (UI) could be an indicator of increased mortality after new-onset stroke. The aim of the present meta-analysis was to characterize this association. METHODS: A systematic search retrieved all studies exploring the post-stroke period and comparing death among patients suffering from UI with those without UI. Hazard ratios (HRs) were extracted or estimated from the published proportion of deaths. Various meta-analyses pooled unadjusted HRs, HRs adjusted for confounders and HRs stratified by subgroups of strokes (ischaemic or haemorrhagic), using models with random effects. Heterogeneity was explored through stratification of studies and meta-regression of predefined parameters. RESULTS: The meta-analysis included 24 studies. UI increased the mortality among the general stroke patients in pooled unadjusted (HR, 5.1; 95% CI, 3.9-6.7) and adjusted (HR, 2.2; 95% CI, 1.8-2.7) analyses. This association was also found among ischaemic (HR, 8.5; 95% CI, 4.6-15.7) and haemorrhagic (HR, 3.9; 95% CI, 1.4-11.3) subgroups of strokes. Studies including indwelling catheters, published more than 10 years ago or with the highest quality on the selection criteria of the Newcastle-Ottawa Quality Assessment scale were associated with a greater effect of UI on mortality. Funnel plots showed a clear asymmetry for adjusted associations. After correcting for this potential publication bias, the pooled HRs still demonstrated a positive association between UI and mortality. CONCLUSIONS: Urinary incontinence indicates high risk of death after a new-onset stroke. Validity of the analyses on adjusted models is limited by an obvious publication bias.

Diagnostic characteristics of lower limb venous compression ultrasonography in suspected pulmonary embolism: a meta-analysis.

UNLABELLED: Essentials Lower limb ultrasonography (CUS) could be useful in suspected pulmonary embolism (PE). We performed a metaanalysis on the diagnostic characteristics of CUS in suspected PE. With a sensitivity of 41%, proximal CUS would be positive in one of every 7.3 patients. Complete CUS has a higher sensitivity but specificity for PE is too low to use it in suspected PE. SUMMARY: Background Diagnosis of pulmonary embolism (PE) is commonly based on D-dimer measurement and computed tomography (CT) angiography. Lower limb vein compression ultrasonography (CUS) for diagnosing deep vein thrombosis may be of interest in patients with suspected PE. Objectives We aimed to summarize the data on the diagnostic characteristics of CUS in suspected PE patients. Patients/Methods We conducted a literature review by using PUBMED and EMBASE and included 15 prospective studies in which CUS was performed in consecutive patients with suspected PE. Results Of the 6991 included patients, 2001 (30%) had pulmonary embolism. Eight of the 15 studies included only outpatients, two included hospitalized patients and five involved both in- and outpatients. In 13 studies, only proximal CUS was performed. Two studies analyzed the added value of distal CUS including the calf veins (whole-leg CUS). Pooled estimate of proximal CUS sensitivity was 41% (95% confidence interval [CI], 36-46%) with strong heterogeneity (I square, 79%). Specificity of proximal CUS was 96% (95% CI, 94-98%). The overall positive likelihood ratio for proximal CUS was 11.9 (95% CI, 7.1-19.8), whereas the overall negative likelihood ratio was 0.6 (95% CI, 0.5-0.7). The sensitivity of whole-leg CUS was 79% (95% CI, 24-98%) and specificity was 84% (95% CI, 76-90%). Conclusions Proximal CUS has low sensitivity and cannot be used to rule out PE. Nevertheless, its high specificity allows confirming PE, which may be useful in patients with contraindications to CT angiography. Whole-leg CUS has a higher sensitivity but low specificity for PE and can therefore not be recommended.

Drug information leaflets improve parental knowledge of their child's treatment at paediatric emergency department discharge.

BACKGROUND: Hospital discharge is a complex multidisciplinary process that can lead to non-compliance and drugs-related problems. Crucial issue for children is parental knowledge of discharge treatments, especially in the time-limited and stressful environment of an emergency department (ED). OBJECTIVE: To compare parental correct knowledge of treatment with and without supply of customised drug information leaflets for the 10 most commonly prescribed drugs. METHOD: Inclusion criteria: paediatric patients (0-16 years) with French-speaking parents discharged from ED of the paediatric department of Geneva University Hospitals before (phase A) and after (phase B) intervention. INTERVENTION: Supply and brief comment of drug information leaflets focusing on specific information not available in official drugs information documents. Follow-up Semi-structured phone interview within 72 h after discharge to evaluate the percentage of parents with correct knowledge of dose, frequency, duration and indication of drugs. Multivariate analysis to identify factors associated with correct knowledge (phases A/B, drugs collection at usual pharmacy, drugs categories). RESULTS: 125 patients were included (phase A: 56; phase B: 69). Drug information leaflets were given to 63/69 ED patients (91%), covering 96/138 prescribed drugs (70%). Parental knowledge was significantly improved in phase B (dose: 62.3% to 89.1%; frequency: 57.9% to 85.5%; duration: 34.2% to 66.7%; indication: 70.2% to 94.9%; p<0.0001). Phase B and collection of drugs at usual pharmacy were significant factors associated with correct knowledge. CONCLUSIONS: Drug information leaflets significantly improved treatment knowledge of French-speaking parents after paediatric ED discharge. Leaflets are now available online for general population.

A literature-based approach to evaluate the predictive capacity of a marker using time-dependent summary receiver operating characteristics.

Meta-analyses are popular tools to summarize the results of publications. Prognostic performances of a marker are usually summarized by meta-analyses of survival curves or hazard ratios. These approaches may detect a difference in survival according to the marker but do not allow evaluation of its prognostic capacity. Time-dependent receiver operating characteristic curves evaluate the ability of a marker to predict time-to-event. In this article, we describe an adaptation of time-dependent summary receiver operating characteristic curves from published survival curves. To achieve this goal, we modeled the marker and the time-to-event distributions using non-linear mixed models. First, we applied this methodology to individual data in kidney transplantation presented as aggregated data, in order to validate the method. Second, we re-analyzed a published meta-analysis, which focused on the capacity of KI-67 to predict the overall survival of patients with breast cancer.

Meta-analysis of two-arm studies: Modeling the intervention effect from survival probabilities.

Pooling the hazard ratios is not always feasible in meta-analyses of two-arm survival studies, because the measure of the intervention effect is not systematically reported. An alternative approach proposed by Moodie et al. is to use the survival probabilities of the included studies, all collected at a single point in time: the intervention effect is then summarised as the pooled ratio of the logarithm of survival probabilities (which is an estimator of the hazard ratios when hazards are proportional). In this article, we propose a generalization of this method. By using survival probabilities at several points in time, this generalization allows a flexible modeling of the intervention over time. The method is applicable to partially proportional hazards models, with the advantage of not requiring the specification of the baseline survival. As in Moodie et al.'s method, the study-level factors modifying the survival functions can be ignored as long as they do not modify the intervention effect. The procedures of estimation are presented for fixed and random effects models. Two illustrative examples are presented.

Effects of impaired renal function on levels and performance of D-dimer in patients with suspected pulmonary embolism.

Clinical probability and D-dimer measurement play an essential role in the non-invasive diagnostic strategies for pulmonary embolism (PE). PE can be ruled out without further imaging in patients with non-high clinical probability and negative D-dimer. D-dimer level is increased in patients with renal impairment. Whether its diagnostic usefulness is maintained in these patients is not well determined. We aimed to evaluate the effects of renal impairment on diagnostic performances of D-dimer in patients with suspected PE. A retrospective analysis of 1,625 patients with suspected PE included in a multicentre prospective study was performed. D-dimer levels and percentages of patients with a negative D-dimer were compared between three subgroups according to glomerular filtration rate (GFR) estimated by the MDRD formula: ≥90 ml/min (normal renal function), 60-89 ml/min (mild renal impairment), 30-59 ml/min (moderate renal impairment). D-dimer levels increased and the proportion of negative D-dimer decreased significantly according to renal status: 46% negative D-dimer in patients with normal GFR, 31% in patients with mild renal impairment, 11% in those with moderate renal impairment, corresponding to number of patients needed to test to obtain one negative test of 2.2, 3.2 and 9, respectively. In conclusion, the clinical usefulness of D-dimer decreases with renal impairment. However, PE can still be ruled out by negative D-dimer in a substantial proportion of patients with non-high clinical probability, avoiding exposure to contrast media.

Rituximab in systemic lupus erythematosus: an updated systematic review and meta-analysis.

The wide spectrum of clinical manifestations and high relapse rate represent a therapeutic challenge in systemic lupus erythematosus (SLE). Observational studies suggested efficacy of rituximab (RTX), a B-cell-targeting antibody, to control the activity of SLE. Two randomized trials controlled by placebo did not prove the superiority of RTX when used in addition to conventional treatment in nonrenal (EXPLORER) and renal (LUNAR) lupus. A systematic review of studies exploring the efficacy of RTX in SLE patients was conducted. The pooled percentages of response were assessed. Thirty studies with 1243 patients were analyzed. In studies using the British Isles Lupus Assessment Group (BILAG), the complete response (CR) rate was 46.7% (95% CI 36.8%-56.8%) and the partial response (PR) was 37.9% (95% CI 30.6%-45.8%). With the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), the CR was 56.6% (95% CI 32.4%-78.1%) and the PR was 30.9% (95% CI 8.9%-46%). In renal lupus the CR was 36.1% (95% CI 25.2%-48.6%); PR was 37.4% (95% CI 28.5%-47.3%). In EXPLORER, CR was 12.4% and PR was 17.2%; in LUNAR CR was 26.4% and PR was 30.6%, in both cases not different from controls. Assessment and standardization of SLE response to treatment remain a challenge. The discrepancy in the perceived efficacy of RTX between controlled and observational studies reflects the heterogeneity of lupus and stringency in criteria of response. Further randomized trials focusing on selected SLE manifestations and using composite response indices are warranted.

Accuracy of vertical height measurements on direct digital panoramic radiographs using posterior mandibular implants and metal balls as reference objects.

OBJECTIVES: Conventional panoramic radiography, a widely used radiographic examination tool in implant treatment planning, allows evaluation of the available bone height before inserting posterior mandibular implants. Image distortion and vertical magnification due to projection geometry is well described for rotational panoramic radiographs. To assess the accuracy of vertical height measurements on direct digital panoramic radiographs, implants and metal balls positioned in the posterior mandible were used as radio-opaque reference objects. The reproducibility of the measuring method was assessed by the inter- and intraobserver agreements. METHODS: Direct digital panoramic radiographs, performed using a Kodak 8000C (Eastman Kodak Company, Rochester, NY), of 17 partially edentulous patients (10 females, 7 males, mean age 65 years) were selected from an X-ray database gathered during routine clinical evaluation of implant sites. Proprietary software and a mouse-driven calliper were used to measure the radiological length of 25 implants and 18 metal reference balls, positioned in mandibular posterior segments. The distortion ratio (DR) was calculated by dividing the radiological implant length by the implant's real length and the radiological ball height by the ball's real height. RESULTS: Mean vertical DR was 0.99 for implants and 0.97 for balls, and was unrelated to mandibular sites, side, age, gender or observer. Inter- and intraobserver agreements were acceptable for both reference objects. CONCLUSIONS: Vertical measurements had acceptable accuracy and reproducibility when a software-based calibrated measurement tool was used, confirming that digital panoramic radiography can be reliably utilized to determine the pre-operative implant length in premolar and molar mandibular segments.

Embryonic stem cell-based screen for small molecules: cluster analysis reveals four response patterns in developing neural cells.

Neural differentiation of embryonic stem cells (ESC) is considered a promising model to perform in vitro testing for neuroactive and neurotoxic compounds. We studied the potential of a dual reporter murine ESC line to identify bioactive and/or toxic compounds. This line expressed firefly luciferase under the control of the neural cell-specific tubulin alpha promoter (TUBA1A), and renilla luciferase under the control of the ubiquitous translation elongation factor 1-alpha-1 (EEF1A1) promoter. During neural differentiation, TUBA1A activity increased, while EEF1A1 activity decreased. We first validated our test system using the known neurotoxin methyl mercury. This compound altered expression of both reporter genes, with ESC-derived neural precursors being affected at markedly lower concentrations than undifferentiated ESCs. Analysis of a library of 1040 bioactive compounds picked up 127 compounds with altered EEF1A1 and/or TUBA1A promoter activity, which were classified in 4 clusters. Cluster 1 (low EEF1A1 and TUBA1A) was the largest cluster, containing many cytostatic drugs, as well as known neurodevelopmental toxicants, psychotropic drugs and endocrine disruptors. Cluster 2 (high EEF1A1, stable TUBA1A) was limited to three sulfonamides. Cluster 3 (high EEF1A1 and TUBA1A) was small, but markedly enriched in neuroactive and neurotoxic compounds. Cluster 4 (stable EEF1A1, high TUBA1A) was heterogeneous, containing endocrine disruptors, neurotoxic and cytostatic drugs. The dual reporter gene assay described here might be a useful addition to in vitro drug testing panels. Our two-dimensional testing strategy provides information on complex response patterns, which could not be achieved by a single marker approach.

Clinical presentation and diagnostic delay in bullous pemphigoid: a prospective nationwide cohort.

BACKGROUND: Prospective systematic analyses of the clinical presentation of bullous pemphigoid (BP) are lacking. Little is known about the time required for its diagnosis. Knowledge of the disease spectrum is important for diagnosis, management and inclusion of patients in therapeutic trials. OBJECTIVES: The primary aims of the study were: (i) to characterize the clinical features of BP at time of diagnosis; and (ii) to assess the diagnostic delay in BP and its impact on prognosis METHODS: All new cases of BP diagnosed in Switzerland between 1 January 2001 and 31 December 2002 were prospectively registered by means of a standardized data collection form. RESULTS: One hundred-seventeen patients with BP were included in the study. 97cases (82.9%) had typical features with vesicles, blisters and/or erosions at time of diagnosis, while in the remaining cases (17.1%) only excoriations, eczematous and/or urticarial infiltrated lesions were observed. Head/neck as well as palmo-plantar involvement were found in up to 20% of patients, while mucosal lesions were present in 14.5% of the cases. Diagnosis was made after a mean of 6.1 months after the first symptoms. In patients, in whom the diagnostic delay was 4 months or more (defined as late diagnosis group), lesions were more often limited to one body area. The type of lesions did not affect the diagnostic delay. Diagnosis was made more rapidly in patients with limb involvement compared to those without. The calculated mortality rate in the early and late diagnosis group was 18.9% and 17.9%, respectively, without significant difference. CONCLUSION: BP often presents with bullous lesions at time of diagnosis after a mean diagnostic delay of 6 months. Nevertheless, up to 20% of patients lack obvious blistering and postbullous erosions, mimicking thus a variety of inflammatory dermatoses. Localized disease is associated with an increased diagnostic delay, which has however no impact on prognosis.

Association between early preterm birth and periodontitis according to USA and European consensus definitions.

OBJECTIVE: Prospective case-control study assessing the association between maternal periodontitis according to the recently issued USA and European consensus definitions and early preterm delivery (<35 weeks gestation). Cases were women delivering between 22 and 34(6/7) weeks of gestation (n = 84) and controls were women delivering at term (≥ 37 weeks) (n = 345). METHODS: Periodontal examination at the immediate postpartum period identified periodontitis according to both consensus definitions. A multivariate logistic model was used to assess the association between early preterm delivery and the presence of periodontitis adjusted for confounders. RESULTS: All women had periodontitis by the European consensus definitions. When using the USA definitions, more cases had severe periodontitis than controls (34.5% vs. 17.72%); p = 0.003. After adjustment for main confounders, the association between severe (OR: 2.38; 95% CI: 1.36-4.14) periodontitis and early preterm delivery persisted. The only other independent factor associated with early preterm delivery was vaginal bleeding during pregnancy. CONCLUSIONS: Early preterm delivery is associated with periodontitis when the USA consensus definitions are used. The European definitions revealed inadequate for the study population because of the lack of discrimination power.

Influence of the paraoxonase-1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: a systematic review and meta-analysis.

BACKGROUND: A poor biological response to clopidogrel is associated with an increased risk of major cardiovascular ischemic events (MACE). Paraoxonase 1 (PON1) enzyme activity is modulated by the PON1-Q192R variant (rs662) and was recently suggested to be strongly involved in clopidogrel bioactivation, but the influence of the PON1-Q192R variant on the risk of MACE in clopidogrel-treated patients is controversial. OBJECTIVES: To determine whether the PON1-Q192R variant influences clopidogrel biological responsiveness and the risk of MACE in patients treated with clopidogrel. METHODS: Systematic review and meta-analysis of studies of the association between the PON1-Q192R polymorphism and the biological response to clopidogrel and/or the risk of MACE during clopidogrel administration. RESULTS: Seventeen studies were included. In the 12 studies of the biological response to clopidogrel (n = 5302 patients), there was no significant difference between 192QQ and 192QR + 192RR subjects, whatever the laboratory method used (global mean standardized difference = 0.10 [-0.06; 0.25], P = 0.22). Eleven studies assessed the risk of MACE, four using a case-control design (n = 2739 patients) and seven a prospective design (n = 5353 patients). Overall, MACE occurred in 19% of patients in case-control studies and in 6% of patients in prospective cohort studies, with no significant difference between 192QQ and 192QR + 192RR patients (OR = 1.28 [0.97; 1.68], P = 0.08). Similar results were obtained when study design was taken into account. Heterogeneity was mainly driven by one publication. CONCLUSIONS: This meta-analysis suggests that the PON1-Q192R polymorphism has no major impact on the risk of MACE and does not alter the biological response to clopidogrel in clopidogrel-treated patients.

Strong serological responses and HIV RNA increase following AS03-adjuvanted pandemic immunization in HIV-infected patients.

INTRODUCTION: We aimed to determine the antibody responses and effect on viral load of the AS03-adjuvanted pandemic H1N1 vaccine in HIV-infected patients. METHOD: A total of 121 HIV-infected patients and 138 healthy subjects were enrolled in a prospective, open-label study. Healthy subjects received one dose and HIV-infected patients two doses of the AS03-adjuvanted split influenza A/09/H1N1 vaccine (Pandemrix®; GlaxoSmithKline, Brentford, United Kingdom.) at an interval of 3-4 weeks. The study was extended in 2010/2011 for 66 patients. Geometric mean titres (GMTs), seroprotection rates (post-vaccination titre ≥ 1:40) and HIV-1 RNA levels were measured before and 4 weeks after immunization. RESULTS: After two immunizations, the seroprotection rate (94.2 vs. 87%, respectively) and GMT (376 vs. 340, respectively) in HIV-infected patients were as high as in healthy subjects after one dose, regardless of CD4 cell count. Four weeks after immunization, HIV RNA was detected in plasma samples from 40 of 68 (58.0%) previously aviraemic patients [median 152 HIV-1 RNA copies/mL; interquartile range (IQR) 87-509 copies/mL]. Subsequent measures indicated that HIV RNA levels had again declined to <20 copies/mL in most patients (27 of 34; 79.4%). Following (nonadjuvanted) influenza immunization in 2010/2011, HIV RNA levels only slightly increased (median final level 28 copies/mL) in three of 66 (4.5%) previously aviraemic patients, including two of 25 (8%) patients in whom an increase had been elicited by AS03-adjuvanted vaccine the year before. CONCLUSION: Most HIV-infected patients developed seroprotection after two doses of AS03-adjuvanted pandemic vaccine. A transient effect on HIV RNA levels was observed in previously aviraemic patients. A booster dose of the nonadjuvanted influenza vaccine containing the A/09/H1N1 strain the following year did not reproduce this finding, indicating a non-antigen-specific adjuvant effect.

Neonatal bleeding in haemophilia: a European cohort study.

Birth is the first haemostatic challenge for a child with haemophilia. Our aim was to examine the association between perinatal risk factors and major neonatal bleeding in infants with haemophilia. This observational cohort study in 12 European haemophilia treatment centres (HTC) incorporated 508 children with haemophilia A or B, born between 1990 and 2008. Risk factors for bleeding were analysed by univariate analysis. Head bleeds occurred in 18 (3·5%) children within the first 28 d of life, including three intraparenchymal bleeds, one subdural haematoma and 14 cephalohaematomas. Intra-cranial bleeds were associated with long-term neurological sequelae in two (0·4%) cases; no deaths occurred. Assisted delivery (forceps/vacuum) was the only risk factor for neonatal head bleeding [Odds Ratio (OR) 8·84: 95% confidence interval (CI) 3·05-25·61]. Mild haemophilia and maternal awareness of her haemophilia carrier status seemed to be protective (OR 0·24; 95%CI 0·05-1·05 and OR 0·34; 95%CI 0·10-1·21, respectively), but due to the low number of events this was not statistically significant. We found no association between neonatal head bleeding and country, maternal age, parity, gestational age or presence of HTC. Maternal awareness of carrier status protected against assisted delivery (unadjusted OR 0·37; 95%CI 0·15-0·90; adjusted OR 0·47 (95%CI 0·18-1·21).

Mortality of bullous pemphigoid in Switzerland: a prospective study.

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease of the skin and has been associated with a significant morbidity and an increased mortality rate. OBJECTIVES: Our aims were: (i) to evaluate the mortality rate of BP in Swiss patients during the first 3 years after the diagnosis of BP, as the primary endpoint; and (ii) to compare this mortality rate with that of the general Swiss population and determine prognostics factors, as secondary endpoints. METHODS: All new cases of BP diagnosed in Switzerland between 1 January 2001 and 31 December 2002 were collected prospectively by means of a standardized data collection form. After collection of the data, the treating physicians were asked to specify the course and evolution of the disease. In total, 115 patients were included in our study. RESULTS: The 1-, 2- and 3-year probability of death were 20·9%, 28·0% and 38·8%, respectively. The mortality rate of patients with BP was three times higher than that of age- and sex-matched members of the general Swiss population. Besides age, the presence of neurological diseases at diagnosis was associated with increased mortality in multivariate analysis. CONCLUSION: This is the first prospective study analysing the mortality rate of BP in an entire country. The calculated mortalities are in the lower range of those reported in previous European studies. However, in line with the latter, our findings confirm a high case-fatality rate for BP, with an increased 1-year mortality rate compared with the expected mortality rate for age- and sex-adjusted general population.