Safety and patient-reported outcomes of atezolizumab, carboplatin, and etoposide in extensive-stage small-cell lung cancer (IMpower133): a randomized phase I/III trial.

BACKGROUND: The addition of atezolizumab to carboplatin and etoposide (CP/ET) significantly improved progression-free and overall survival for patients with extensive-stage small-cell lung cancer (ES-SCLC) in the IMpower133 study (NCT02763579). We have evaluated adverse events (AEs) and patient-reported outcomes in IMpower133 to assess the benefit-risk profile of this regimen. PATIENTS AND METHODS: Patients received four 21-day cycles of CP/ET plus intravenous atezolizumab 1200 mg or placebo (induction phase), followed by atezolizumab or placebo (maintenance phase) until progression or loss of benefit. AEs were assessed and patient-reported outcomes were evaluated every 3 weeks during treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (QLQ-C30) and QLQ-LC13. RESULTS: Overall, 394 patients were assessable for safety in the induction phase and 318 in the maintenance phase. The frequency of AEs, grade 3-4 AEs, and serious AEs was similar between arms in both phases. Immune-related AEs were more frequent in the atezolizumab arm during both induction (28% versus 17%; leading to atezolizumab/placebo interruption 9% versus 5%, leading to withdrawal 4% versus 0%) and maintenance (26% versus 15%; leading to atezolizumab/placebo interruption, 3% versus 2%, leading to withdrawal 1% versus 1%), most commonly rash (induction 11% versus 9%, maintenance 14% versus 4%), and hypothyroidism (induction 4.0% versus 0%, maintenance 10% versus 1%). Changes in patient-reported treatment-related symptoms commonly associated with quality of life impairment were generally similar during induction and most of the maintenance phase. Patient-reported function and health-related quality of life (HRQoL) improved in both arms after initiating treatment, with more pronounced and persistent HRQoL improvements in the atezolizumab arm. CONCLUSIONS: In patients with ES-SCLC, atezolizumab plus CP/ET has a comparable safety profile to placebo plus CP/ET, and the addition of atezolizumab did not adversely impact patient-reported HRQoL. These data demonstrate the positive benefit-risk profile of first-line atezolizumab plus CP/ET in ES-SCLC and further support this regimen as a new standard of care in this setting. CLINICAL TRIALS NUMBER: NCT02763579.

Safety and effectiveness of neuraminidase inhibitors for influenza treatment, prophylaxis, and outbreak control: a systematic review of systematic reviews and/or meta-analyses.

OBJECTIVES: To review evidence from systematic reviews and/or meta-analyses (SR/MAs) regarding neuraminidase inhibitor (NI) safety and effectiveness. METHODS: We conducted an SR of SR/MAs of randomized control and/or observational studies. We searched eight electronic databases for SR/MAs that examined the effectiveness or safety of NIs administered for influenza (i.e. influenza-like illness or lab-confirmed) treatment or prophylaxis. RESULTS: We identified 27 (0.7%) eligible SR/MAs of 3723 articles reviewed. NI (n = 2) or oseltamivir (n = 1) versus no treatment were consistently associated with a decrease in mortality odds among the hospitalized, general population (OR range 0.2 - 0.8). Oseltamivir versus no treatment was associated with a decrease in hospitalization and pneumonia risk/odds in 2/4 SR/MAs. Oseltamivir (n = 4) and zanamivir (n = 3) were consistently associated with a 0.5 - 1 day decrease in symptom duration. Oseltamivir (n = 4) or zanamivir (n = 4) versus no prophylaxis were consistently associated with a decrease in the odds/risk of symptomatic secondary transmission (OR/RR range 0.1 - 0.5). Oseltamivir versus no treatment was consistently associated with a 1.5- to 2.5-fold increase in the odds/risk of nausea (n = 4) and vomiting (n = 5). CONCLUSIONS: NI treatment is likely to be effective at reducing mortality among hospitalized patients, and symptom duration by up to 1 day in the general population. Oseltamivir or zanamivir prophylaxis are likely to be effective at reducing secondary symptomatic influenza transmission. Increased nausea and vomiting are likely associated with oseltamivir use. We recommend that decisions regarding NI use are made in consideration of potential adverse events, particularly for the general population at low risk of complications. Among hospitalized patients, NI administration seems warranted to reduce mortality risk.

Comparative effectiveness of linezolid versus vancomycin as definitive antibiotic therapy for heterogeneously resistant vancomycin-intermediate coagulase-negative staphylococcal central-line-associated bloodstream infections in a neonatal intensive care unit.

Objectives: Heterogeneously resistant vancomycin-intermediate coagulase-negative staphylococci (hVICoNS) are emerging pathogens causing central-line-associated bloodstream infections (CLABSIs) in neonatal intensive care unit (NICU) patients. Given the burden of disease associated with CLABSI and the current lack of therapeutic guidelines, we aimed to compare the effectiveness of linezolid versus vancomycin used as the definitive antibiotic therapy for hVICoNS CLABSI. Methods: We performed a retrospective cohort study of infants with hVICoNS CLABSI from a single NICU between 2009 and 2014, treated with either linezolid or vancomycin as definitive antibiotic therapy. CLABSI duration, early and late recurrence and in-hospital mortality were compared using propensity score-adjusted proportional hazards and logistic regression models. Results: Of 89 infants with hVICoNS CLABSI, 33 (37.1%) treated with linezolid were compared with 56 (62.9%) treated with vancomycin. The median duration of CLABSI was 5 (range 1-12) versus 4 days (range 0-14) ( P = 0.11), early recurrences were 3.0% versus 7.1% ( P = 0.42), late recurrences 0% versus 14.3% ( P = 0.02) and mortality 27.3% versus 28.6% ( P = 0.90), when treated with linezolid versus vancomycin, respectively. When adjusting using a continuous propensity score, linezolid had an HR of 0.78 (95% CI 0.48-1.27) for CLABSI duration, an OR of 0.23 (95% CI 0.02-2.56) for early recurrence and an OR of 0.9 (95% CI 0.3-2.67) for mortality, relative to vancomycin. Conclusions: There was no statistically significant difference between linezolid and vancomycin when used as definitive treatment for hVICoNS CLABSI in NICU patients, in terms of CLABSI duration, recurrence or all-cause mortality.

Safety and effectiveness of neuraminidase inhibitors in situations of pandemic and/or novel/variant influenza: a systematic review of the literature, 2009-15.

Objectives: To review systematically the published literature evaluating neuraminidase inhibitor (NI) safety and effectiveness in situations of pandemic and novel/variant influenza. Methods: We searched six online databases using comprehensive search criteria for observational studies and randomized controlled trials investigating the effects of NI treatment, prophylaxis or outbreak control in patients of all ages. Results: Overall, 165 studies were included (95% observational), which were generally of low methodological quality due to lack of adjustment for confounding variables. In studies reporting adjusted estimates in general populations, NI treatment appeared likely to be effective against mortality (primarily if administered within 48 h of symptom onset) and potentially effective in reducing pneumonia. NIs appeared effective in reducing secondary transmission when indicated for prophylaxis. Limited, low-quality data suggest NIs are likely safe in general populations and may be safe in pregnant women and children. Data are scarce regarding safety of NIs in adults and high-risk individuals. Conclusions: Most included studies were observational, statistically underpowered and at high risk of reporting biased and/or confounded effect estimates. NI treatment appeared likely effective in reducing mortality (cause unspecified) and pneumonia in general populations, with increasing benefit when administered with 48 h of symptom onset. NI pre- or post-exposure prophylaxis is likely effective in reducing secondary transmission of influenza in a general population. Our evidence suggests NIs are likely safe to use in the general population; however, data for children and pregnant women are limited. Knowledge gaps persist in specific populations such as Aboriginals, high-risk individuals and the elderly.

Measuring antimicrobial use in hospitalized patients: a systematic review of available measures applicable to paediatrics.

OBJECTIVES: The optimal measure to use for surveillance of antimicrobial usage in hospital settings, especially when including paediatric populations, is unknown. This systematic review of literature aims to list, define and compare existing measures of antimicrobial use that have been applied in settings that included paediatric inpatients, to complement surveillance of resistance. METHODS: We identified cohort studies and repeated point-prevalence studies presenting data on antimicrobial use in populations of inpatients or validations/comparisons of antimicrobial measures through a systematic search of literature using MEDLINE, EMBASE, CINAHL and LILACS (1975-2011) and citation tracking. Study populations needed to include hospitalized paediatric patients. Two reviewers independently extracted data on study characteristics and results. RESULTS: Overall, 3878 records were screened and 79 studies met selection criteria. Twenty-six distinct measures were found, the most frequently used being defined daily doses (DDD)/patient-days and exposed patients/patients. Only two studies compared different measures quantitatively, showing (i) a positive correlation between proportion of exposed patients and antimicrobial-days/patient-days and (ii) a strong correlation between doses/patient-days and agent-days/patient-days (r = 0.98), with doses/patient-days correlating more with resistance rates (r = 0.80 versus 0.55). CONCLUSIONS: The measure of antimicrobial use that best predicts antimicrobial resistance prevalence and rates, for surveillance purposes, has still not been identified; additional evidence on this topic is a necessity.

Hand hygiene compliance in the prevention of hospital-acquired infections: a systematic review.

BACKGROUND: The hands of healthcare workers (HCWs) are known to be a primary source of transmission of hospital-acquired infections (HAIs). Thus, both practising hand hygiene (HH) and adhering to HH guidelines are expected to decrease the risk of transmission. However, there is no consensus on the optimal hand hygiene compliance (HHC) rate for HCWs. AIM: To systematically review the published literature to determine an optimal threshold for the HCW HHC rate associated with the lowest HAI incidence rate. METHODS: This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Online databases were searched using comprehensive search criteria for randomized controlled trials and non-randomized controlled studies, investigating the impact of the HCW HHC rate on HAI incidence rates in patients of all ages within healthcare facilities in high-income countries. FINDINGS: Of the 8093 article titles and abstracts screened, 35 articles were included in the review. Most studies reported overall HAIs per 1000 patient-days and device-associated HAIs per 1000 device-days. Most studies reported HHC rates between 60% and 70%. Lower HAI incidence rates seemed to be achieved with HHC rates of approximately 60%. The studies included in this review were not originally designed to assess the impact of HHC on HAI incidence rates, but risk of bias was assessed in accordance with the predetermined exposure and outcome criteria. Eleven (31%) studies were deemed to have low risk of bias. CONCLUSIONS: Although HHC is part of the HCW code of conduct, very high HHC rates are difficult to reach. In observational studies, HHC and HAIs had a negative relationship up to approximately 60% HHC. Due to flaws in the study design, causality could not be inferred; only general trends could be discussed. Given the limitations, there is a need for high-quality evidence to support the implementation of specified targets for HHC rates.

Enteropathogens in paediatric gastroenteritis: comparison of routine diagnostic and molecular methods.

OBJECTIVES: Studies of acute gastroenteritis (AGE) are hampered by the lack of routine diagnostic methods with good sensitivity and specificity. Molecular methods are increasingly used for clinical purposes, but the clinical significance of a positive result remains a challenge. In this study we aimed to compare results of routine diagnostic methods and molecular methods in symptomatic children and asymptomatic controls. METHODS: Patients presenting to the pediatric emergency departments of two university hospitals in Brussels with AGE were recruited prospectively from May 2015 to October 2016; asymptomatic controls were recruited from the same hospitals. Stool analyses were performed for all participants for common pathogenic bacteria (culture), virus (immunochromatography) and parasites (microscopy). Stools were also analysed with the Luminex Gastrointestinal Pathogen Panel, a multiplex-PCR for common enteropathogens. RESULTS: Stools from 178 patients and 165 controls were analysed. An enteropathogen was detected in 62.4% (111/178) of cases when combining the two methods (56.2% (100/178) by Luminex, 42.7% (76/178) with routine methods) and 29.1% (48/165) of controls (24.2% (40/165) by Luminex and 10.3% (17/165) by routine methods). Some pathogens were detected more often with Luminex than with routine methods, such as Salmonella (16.3% (29/178) with Luminex and 3.9% (7/178) with routine method, p < 0.05), whereas others identified by culture methods, such as Campylobacter, Shigella, Yersinia, were missed by Luminex. CONCLUSIONS: Molecular tools seem attractive methods, providing high positivity and a rapid turn-around time for the diagnosis of AGE. However, high rates of positivity in both cases and controls highlight the difficulty in interpreting results. Pathogens missed by Luminex but detected by culture methods raise more questions about the true clinical interest of the technique for our patients.

Epidemiology of Clostridioides difficile infection in Canada: A six-year review to support vaccine decision-making.

BACKGROUND: Two vaccines against Clostridioides difficile infections (CDI) are currently in phase III trials. To enable decision-making on their use in public health programs, national disease epidemiology is necessary. OBJECTIVES: To determine the epidemiology of hospital-acquired CDI (HA-CDI) and community-associated CDI (CA-CDI) in Canada using provincial surveillance data and document discrepancies in CDI-related definitions among provincial surveillance programs. METHODS: Publicly-available CDI provincial surveillance data from 2011 to 2016 that distinguished between HA-CDI and CA-CDI were included and the most common surveillance definitions for each province were used. The HA-, CA-CDI incidence rates and CA-CDI proportions (%) were calculated for each province. Both HA- and CA-CDI incidence rates were examined for trends. Types of disparities were summarized and detailed discrepancies were documented. RESULTS: Canadian data were analyzed from nine provinces. The HA-CDI rates ranged from 2.1/10,000 to 6.5/10,000 inpatient-days, with a decreasing trend over time. Available data on CA-CDI showed that both rates and proportions have been increasing over time. Discrepancies among provincial surveillance definitions were documented in CDI case classifications, surveillance populations and rate calculations. CONCLUSION: In Canada overall, the rate of HA-CDI has been decreasing and the rate of CA-CDI has been increasing, although this calculation was impeded by discrepancies in CDI-related definitions among provincial surveillance programs. Nationally-adopted common definitions for CDI would enable better comparisons of CDI rates between provinces and a calculation of the pan-Canadian burden of illness to support vaccine decision-making.

Clinical characteristics of pediatric pertussis cases, Quebec 2015-2017.

BACKGROUND: The introduction of the acellular pertussis vaccine may have changed the epidemiological and clinical features of pertussis in Canadian children. OBJECTIVE: To describe the demographics, clinical presentation and outcomes of children and adolescents with pertussis presenting to a tertiary care hospital. METHODS: Retrospective cohort of consecutive patients evaluated at the Centre Hospitalier Universitaire Sainte-Justine (CHUSJ) and tested with a bacterial multiplex real-time polymerase chain reaction (PCR) for Bordetella pertussis or B. parapertussis between June 2015 and March 2017. Demographics, clinical presentations and outcomes were described for positive test results. The Modified Preziosi Scale was used to assess disease severity; severe disease was defined as a score ≥7. RESULTS: The age distribution of the 144 positive patients with a clinical encounter at CHUSJ was as follows: less than three months (n=25/144, 17.4%), four months to nine years (n=63/144, 43.8%) and 10 to 18 years (n=56/144, 38.9%). The most common symptoms at presentation were paroxysmal cough (70.1%), post-tussive emesis (47.2%) and coryza (33.3%). Over 84.0% of cases in infants less than three months of age had severe pertussis (92.0% required hospitalization and 28.0% intensive care admission). In children four months to nine years of age, 22.2% had severe pertussis and 11.1% required hospitalization. Only two (3.6%) children greater than 10 years had severe disease. CONCLUSION: Pertussis still affects children of all ages in Quebec. In older children, it tends to be a milder disease. When it affects infants, who do not yet have full protection from pertussis vaccination, it often causes severe disease, especially in those less than three months of age. This evidence further supports the implementation of a pertussis vaccination program in pregnant women.

Should equivocal Bordetella pertussis PCR results in children be reported to public health?

INTRODUCTION: Real-time polymerase chain reaction (PCR) is the preferred method for the diagnosis of pertussis. In Quebec, positive and equivocal results are reportable to public health; in contrast, in Ontario equivocal results are not reportable. OBJECTIVE: To determine the clinical significance of equivocal, compared with positive results, in children with suspected pertussis. METHODS: Retrospective cohort of consecutive patients seen at the Centre Hospitalier Universitaire Sainte-Justine in Montréal, Quebec, with suspected pertussis and tested with a bacterial multiplex PCR (including Bordetella pertussis) between 2015 and 2017. Medical records were reviewed using a standardized form. Univariate analyses (Student's t-test and chi-square test) and multivariable logistic regression were used to compare cases of positive and equivocal results. RESULTS: Of the 1,526 multiplex PCR performed, 109 were positive and 24 equivocal. Both groups were similar in terms of demographics and disease severity assessments, but patients in the equivocal group had less paroxysmal cough (33.3% vs 79.8%, adjusted odds ratio [aOR] 0.11, 95% confidence interval [CI] 0.04-0.29) and whoop (0% vs 18.3%, p<0.001), lower lymphocyte counts (6.6 vs 11.9 x109/L, p=0.008), were more likely to be diagnosed with a viral co-infection (16.7% vs 3.7%, aOR 5.62, 95% CI 1.17-27.54) and were less likely to receive a macrolide (25% vs 89%, aOR 0.04, 95% CI 0.01-0.11). When admitted, patients with equivocal results had a shorter average length of stay (3.3 vs 12.2 days, p=0.001). CONCLUSION: Although there were similarities in disease severity, children with suspected pertussis who had equivocal PCR results had significantly different clinical presentations compared with those with positive results. In the context of limited public health resources, these results may inform the decision whether or not equivocal results need to be reported to public health by laboratories.

Summary of NACI Statement: Interim Recommendations on the Use of Pneumococcal Vaccines in Immunocompetent Adults 65 Years of Age and Older.

BACKGROUND: Since 2015, pneumococcal 13-valent conjugate vaccine (PNEU-C-13) has been authorized for the prevention of invasive pneumococcal disease (IPD) and pneumococcal community-acquired pneumonia (CAP) in adults. Adults with immunocompromising conditions are still recommended to receive PNEU-C-13 followed by the pneumococcal 23-valent polysaccharide vaccine (PNEU-P-23). NACI guidance has been requested on the use of PNEU-C-13 vaccine in immunocompetent adults 65 years of age and older. OBJECTIVES: To make recommendations, at the individual level, for the use of PNEU-C-13 in immunocompetent adults 65 years of age and over. METHODS: The NACI Pneumococcal Working Group (PWG) reviewed key questions and performed an evidence review and synthesis. In consideration of the burden of illness to be prevented, the target population, safety, immunogenicity, efficacy and effectiveness of the vaccine, the PWG proposed recommendations for vaccine use to NACI. All evidence was rated and reported in evidence tables. NACI approved specific evidence-based recommendations and elucidated the rationale and relevant considerations in the statement update. RESULTS: NACI identified and reviewed evidence from one randomized controlled trial investigating the efficacy of PNEU-C-13 to prevent IPD and CAP in adults who were immunocompetent at enrollment and three clinical trials assessing the immunogenicity in immunocompetent and immunocompromised adults. CONCLUSIONS: Based on reviewed evidence, NACI issued new recommendations for the use of pneumococcal vaccines in immunocompetent adults 65 years of age and older.

Summary of the National Advisory Committee on Immunization's Statement on the re-immunization with polysaccharide 23-valent pneumococcal vaccine.

BACKGROUND: Individuals who are 2 years of age and over and at high risk for invasive pneumococcal disease (IPD) (defined as those with functional or anatomic asplenia or sickle cell disease; hepatic cirrhosis; chronic renal failure or nephrotic syndrome; HIV infection; and immunosuppression related to disease or therapy) are recommended to receive one lifetime booster dose of polysaccharide 23-valent pneumococcal vaccine (Pneu-P-23) vaccine, in addition to age- and risk-specific recommendations for the conjugate 13-valent pneumococcal vaccine (Pneu-C-13). Adults aged 65 years and over are also considered at high risk for invasive pneumococcal disease (IPD). OBJECTIVE: To determine the optimal time between initial vaccination with Pneu-P-23 and subsequent booster doses to protect against IPD in those at high risk for IPD. METHODS: The National Advisory Committee on Immunization (NACI) conducted a systematic review of the literature on booster doses of pneumococcal vaccine for individuals at high risk for IPD disease. NACI reviewed the evidence considering the target population, safety, immunogenicity, efficacy, effectiveness of the vaccines, vaccine schedules, and other aspects of the overall immunization strategy, and then approved three specific recommendations. RESULTS: For all individuals aged 2 years and over who are at high risk for IPD and who have received a dose of Pneu-P-23, re-vaccination with a second dose of Pneu-P-23 should be provided five years after the initial dose of Pneu-P-23. They should also have previously received age-appropriate doses of 13-valent conjugate pneumococcal vaccine. There is currently insufficient evidence to determine the optimal timing and number of Pneu-P-23 boosters in high-risk adults. One lifetime booster of Pneu-P-23 is currently recommended for individuals at high risk for IPD, five years after the previous dose. Given the increased risk of IPD in adults aged 65 years and older and the rapid decline in antibodies following Pneu-P-23, all individuals should receive one dose of Pneu-P-23 at age 65 years-as long as five years have passed since the previous Pneu-P-23 dose. No additional booster dose is currently recommended for this age group, if they have no medical conditions that put them at high risk for IPD. CONCLUSION: The new and complete set of current recommendations for pneumococcal vaccines will be published in the updated "Pneumococcal" chapter in the Canadian Immunization Guide in the near future.

Updates to the Canadian Immunization Guide: March 2014 to March 2015.

The National Advisory Committee on Immunization (NACI) develops recommendations for the use of vaccines for Canadians, which are summarized in the Canadian Immunization Guide (the Guide) and which is updated on a regular basis. Between March 2014 and February 2015 recommendations on five vaccines have been issued. Updates to the Guide include recommendations made for the alternative dosing administration of the human papillomavirus (HPV) vaccine in adolescents, timing of varicella zoster immune globulin (VarIg) following exposure to varicella, and the meningococcal and quadrivalent influenza vaccines, recently authorized for use in Canada. A change in recommendations for the use of pneumococcal vaccines in adults and individuals with asthma has also been made. The chapter on tick-borne encephalitis vaccine has now been removed from the Guide as this vaccine is no longer available in Canada.

Effects of pharmacologically facilitating glutamatergic transmission in the trisynaptic intrahippocampal circuit.

The effects of a recently synthesized benzoyl-piperidine drug that enhances currents mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptors were tested on monosynaptic and polysynaptic responses in hippocampal slices of the rat. Stimulation of perforant path inputs to the dentate gyrus evoked extracellular responses in field CA1 that had latencies and laminar profiles indicating that they were relayed through the trisynaptic intrahippocampal circuit. Under control conditions, trisynaptic field excitatory postsynaptic potentials did not show larger paired-pulse facilitation than monosynaptic responses and failed to exhibit frequency facilitation. Low concentrations of picrotoxin greatly enhanced trisynaptic responses and, under these conditions, frequency facilitation was obtained. Benzoyl-piperidine-12 (250 microM) had a three-fold greater effect on the amplitude of trisynaptic responses than on monosynaptic field excitatory postsynaptic potentials, indicating that the drug's effect is amplified across the successive stages of a polysynaptic circuit. The AMPA receptor modulator did not change the frequency characteristics of monosynaptic potentials and had only a modest influence on those of the trisynaptic response. The effect of benzoyl-piperidine-12 on trisynaptic responses was significantly greater when GABAergic inhibition was partially blocked with picrotoxin; the GABA blocker did not alter the effects of benzoyl-piperidine-12 on monosynaptic responses. These results indicate that centrally active AMPA receptor modulators are likely to have a greater influence on brain operations involving long chains of connections than on those mediated by simple reflex-like circuits, and will vary markedly in their effects depending upon the excitability of local interneurons.

Effects of an AMPA receptor modulator on methamphetamine-induced hyperactivity in rats.

The present study tested if a positive modulator of AMPA-type glutamate receptors would counteract the behavioral effects of a drug that enhances the release of dopamine. BDP-29, a compound shown to increase AMPA receptor-mediated synaptic responses in hippocampal slices, markedly attenuated the amount of stereotypic rearings seen in rats after methamphetamine injections. These results suggest that AMPA receptor modulators ameliorate certain aberrant, dopamine-related behaviors and hence may be of interest with regard to schizophrenia.

Early-onset dementias: Specific etiologies and contribution of MRI.

Early-onset dementias are defined by onset of first symptoms before the age of 65. They have specific diagnostic features which differ from those of elderly patients in terms of their many causes and atypical clinical presentations. MRI is an essential procedure for identifying the underlying cause of the dementia (degenerative, vascular, infectious, inflammatory, metabolic or toxic). Clinical clues and MRI signs are described, and their defining features are related to the young age of the patients concerned. Diagnostic algorithms are proposed from signs which can be seen on the different MRI sequences (T1-weighted volume acquisition, T2-weighted FLAIR sequences, T2-weighted gradient-echo, diffusion-weighted imaging). Once obvious causes have been excluded, MRI can point towards the rarer causes of dementia which are characteristic in young people (particularly metabolic and autoimmune) and which require specific management and genetic counseling.

Determinants Of Oral corticosteroid Responsiveness in Wheezing Asthmatic Youth (DOORWAY): protocol for a prospective multicentre cohort study of children with acute moderate-to-severe asthma exacerbations.

INTRODUCTION: Oral corticosteroids are the cornerstone of acute asthma management in the emergency department. Recent evidence has raised doubts about the efficacy of this treatment in preschool-aged children with viral-induced wheezing and in smoking adults. The aims of the study were to: (1) document the magnitude of response to oral corticosteroids in children presenting to the emergency department with moderate or severe asthma; (2) quantify potential determinants of response to corticosteroids and (3) explore the role of gene polymorphisms associated with the responsiveness to corticosteroids. METHODS AND ANALYSIS: The design is a prospective cohort study of 1008 children aged 1-17 years meeting a strict definition of asthma and presenting with a clinical score of ≥4 on the validated Pediatric Respiratory Assessment Measure. All children will receive standardised severity-specific treatment with prednisone/prednisolone and cointerventions (salbutamol with/without ipratropium bromide). Determinants, namely viral aetiology, environmental tobacco smoke and single nucleotide polymorphism, will be objectively documented. The primary efficacy endpoint is the failure of emergency department (ED) management within 72 h of the ED visit. Secondary endpoints include other measures of asthma severity and time to recovery within 7 days of the index visit. The study has 80% power for detecting a risk difference of 7.5% associated with each determinant from a baseline risk of 21%, at an α of 0.05. ETHICS AND DISSEMINATION: Ethical approval has been obtained from all participating institutions. An impaired response to systemic steroids in certain subgroups will challenge the current standard of practice and call for the immediate search for better approaches. A potential host-environment interaction will broaden our understanding of corticosteroid responsiveness in children. Documentation of similar effectiveness of corticosteroids across determinants will provide the needed reassurance regarding current treatment recommendations. RESULTS: Results will be disseminated at international conferences and manuscripts targeted at emergency physicians, paediatricians, geneticists and respirologists. TRIAL REGISTRATION NUMBER: This study is registered at Clinicaltrials.gov (NCT02013076).

Nosocomial rotavirus gastroenteritis in a Canadian paediatric hospital: incidence, disease burden and patients affected.

Rotavirus is a well-recognised nosocomial pathogen in paediatric settings. Although rotavirus gastroenteritis is a vaccine-preventable disease, there is currently no publicly funded programme in Canada. The objective of this study was to inform rotavirus vaccination strategy by determining the incidence of nosocomial rotavirus gastroenteritis (NRVGE), estimating the burden of disease and characterising the patients affected. We performed a retrospective cohort study of all NRVGE cases over a period of 10 years in a Canadian tertiary-care paediatric hospital. Cases (N = 214) were identified by the hospital's prospective surveillance programme for nosocomial infections. The incidence was 0.5 per 1,000 patient-days (95% confidence interval: 0.43-0.57) with no significant decline over the 10-year period. The infection rate per hospital day was highest among patients with a hospital stay of > 5 days. A chronic underlying medical condition was present in 126 patients (59%), was often associated with previous hospitalisation, and was identifiable early in life for 95 patients (44%). Rehydration was required for 132 (62%) patients and was intravenous in 98 (46%). Twenty-six patients (12%) required readmission, for a median of four days, for NRVGE that occurred after discharge. Nosocomial rotavirus infection continues to be an important problem in paediatric hospitals, predominantly for children with underlying medical conditions requiring recurrent and prolonged hospitalisation. A rotavirus immunisation programme targeted at vulnerable patients, such as infants with congenital pathology and low birth weight, requires assessment in Canada and other countries that have not introduced universal rotavirus immunisation.