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1.  Populations at Risk for Severe or Complicated Avian Influenza H5N1: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(3):e89697.
Background
Little is known about risk factors for severe outcomes in patients infected with H5N1 and no systematic review has been conducted. Understanding risk factors is an important step for prioritizing prophylaxis or treatment in the event of a pandemic.
Objectives
To systematically evaluate risk factors for severe outcomes in patients with avian influenza H5N1 infection.
Data sources
MEDLINE, EMBASE, CINAHL, GlobalHealth, and CENTRAL through March 2011
Eligibility criteria for selecting studies
Observational studies of any design published in English, French, Spanish, German or Korean that reported on risk factor-outcome combinations of interest in participants with confirmed H5N1 infections. Outcomes considered included death, ventilator support, hospital and ICU admission, pneumonia, and composite outcomes.
Study appraisal
Risk of bias was assessed using the Newcastle-Ottawa scale (NOS).
Results
We identified 20 studies reporting on 999 patients infected with H5N1. The majority of studies (n = 14, 70%) were at intermediate risk of bias, i.e. 4–6 points on the NOS. Females were at increased risk of death (OR 1.75, 95% CI 1.27–2.44), while young age, in particular <5 years of age (OR 0.44, 95% CI 0.25–0.79 for death), was protective. Data on traditional risk factors was scarce and requires further studies. Another major limitation in the published literature was lack of adjustment for confounders.
Interpretation
Females were at increased risk for complications following H5N1 infection while young age protected against severe outcomes. Research on traditional risk factors was limited and is required.
doi:10.1371/journal.pone.0089697
PMCID: PMC3948335  PMID: 24603885
2.  DO IT Trial: vitamin D Outcomes and Interventions in Toddlers – a TARGet Kids! randomized controlled trial 
BMC Pediatrics  2014;14:37.
Background
Vitamin D levels are alarmingly low (<75 nmol/L) in 65-70% of North American children older than 1 year. An increased risk of viral upper respiratory tract infections (URTI), asthma-related hospitalizations and use of anti-inflammatory medication have all been linked with low vitamin D. No study has determined whether wintertime vitamin D supplementation can reduce the risk of URTI and asthma exacerbations, two of the most common and costly illnesses of early childhood. The objectives of this study are: 1) to compare the effect of ‘high dose’ (2000 IU/day) vs. ‘standard dose’ (400 IU/day) vitamin D supplementation in achieving reductions in laboratory confirmed URTI and asthma exacerbations during the winter in preschool-aged Canadian children; and 2) to assess the effect of ‘high dose’ vitamin D supplementation on vitamin D serum levels and specific viruses that cause URTI.
Methods/Design
This study is a pragmatic randomized controlled trial. Over 4 successive winters we will recruit 750 healthy children 1–5 years of age. Participating physicians are part of a primary healthcare research network called TARGet Kids!. Children will be randomized to the ‘standard dose’ or ‘high dose’ oral supplemental vitamin D for a minimum of 4 months (200 children per group). Parents will obtain a nasal swab from their child with each URTI, report the number of asthma exacerbations and complete symptom checklists. Unscheduled physician visits for URTIs and asthma exacerbations will be recorded. By May, a blood sample will be drawn to determine vitamin D serum levels. The primary analysis will be a comparison of URTI rate between study groups using a Poisson regression model. Secondary analyses will compare vitamin D serum levels, asthma exacerbations and the frequency of specific viral agents between groups.
Discussion
Identifying whether vitamin D supplementation of preschoolers can reduce wintertime viral URTIs and asthma exacerbations and what dose is optimal may reduce population wide morbidity and associated health care and societal costs. This information will assist in determining practice and health policy recommendations related to vitamin D supplementation in healthy Canadian preschoolers.
doi:10.1186/1471-2431-14-37
PMCID: PMC3942179  PMID: 24506910
Vitamin D deficiency; Vitamin D supplementation; Infant; Toddler
3.  Serum 25-Hydroxyvitamin D Level and Influenza Vaccine Immunogenicity in Children and Adolescents 
PLoS ONE  2014;9(1):e83553.
Background
Vaccination is an important strategy in the prevention of influenza, but immunologic response to vaccination can vary widely. Recent studies have shown an association between serum 25-hydroxyvitamin D (25[OH]D) levels and immune function. The purpose of this study was to determine if serum 25(OH)D level correlates with influenza vaccine immunogenicity in children and adolescents.
Methods
We conducted a prospective cohort study of children age 3 to 15 years of age vaccinated with trivalent influenza vaccine (A/Brisbane/59/2007[H1N1]-like virus, A/Brisbane/10/2007 [H3N2]-like virus and B/Florida/4/2006-like virus) in Hutterite communities in Alberta, Saskatchewan and Manitoba. Serum 25(OH)D levels were measured at baseline and immunogenicity was assessed using hemagluttination inhibition (HAI) titers done at baseline and 3–5 weeks post vaccination. Logistic regression was used to assess the relationship between serum 25(OH)D level as both a continuous and dichotomous variable and seroprotection, seroconversion, fold increase in geometric mean titer (GMT) and post vaccination titer.
Results
A total of 391 children and adolescents were included in the study and 221 (57% had post-vaccination HAI titers. The median serum 25(OH)D level was 61.0 nmol/L (Interquartile range [IQR] 50.0, 71.0). No relationship was found between serum 25(OH)D level and seroprotection (post-vaccination titer ≥40 and ≥320) or seroconversion (post-vaccination titer ≥40 for participants with pre-vaccine titer <10 or four-fold rise in post-vaccination titer for those with a pre-vaccine titer ≥10).
Conclusion
Serum 25(OH)D level was not associated with influenza vaccine immunogenicity in otherwise healthy children and adolescents. Other strategies to enhance influenza vaccine response should continue to be evaluated in this population.
The role of serum 25(OH)D level in vaccine responsiveness in other populations, especially those hyporesponsive to influenza vaccination, requires further study.
doi:10.1371/journal.pone.0083553
PMCID: PMC3888395  PMID: 24427274
4.  Challenges Assessing Nursing Home Residents with Advanced Dementia for Suspected Urinary Tract Infections 
Background
Urinary tract infections (UTI) are often misdiagnosed in nursing home (NH) residents leading to unnecessary antimicrobial exposure. The diagnosis is particularly challenging among residents with advanced dementia who have minimal verbal ability to communicate symptoms.
Design
twelve-month prospective study
Setting
25 NHs
Participants
Two-hundred and sixty-six residents with advanced dementia.
Measurements
Charts were abstracted monthly for documentation of suspected UTI episodes to determine whether episodes met minimum criteria to initiate antimicrobials according to consensus guidelines.
Results
Seventy-two residents experienced 131 suspected UTI episodes. Presenting signs and symptoms for these episodes were: mental status change, 44.3%; fever, 20.6%; hematuria, 6.9%; dysuria, 3.8%; costovertebral tenderness, 2.3%; frequency, 1.5%; rigors, 1.5; urgency; 0% and suprapubic pain, 0%. Only 21 (16.0%) episodes met minimal criteria to initiate antimicrobials based on signs and symptoms. Among the 110 episodes that lacked minimum criteria to justify antimicrobial initiation, 82 (74.5%) were treated with antimicrobials. Urinalyses and urine culture results were available for 101 episodes, of which 80 (79.2%) had positive results on both tests. The proportion of episodes with a positive urinalysis and culture was similar for those that met or did not meet minimum criteria (83.3% versus 78.3% p = 0.06).
Conclusion
The symptoms and signs necessary to meet minimum criteria to support antimicrobial initiation for UTIs are frequently absent among NH residents with advanced dementia. Antimicrobials are prescribed for the majority of suspected UTIs that do not meet these minimum criteria. Urine specimens are frequently positive regardless of symptoms. These observations underscore the need to reconsider the diagnosis and the initiation of treatment for suspected UTIs in advanced dementia.
doi:10.1111/jgs.12070
PMCID: PMC3545416  PMID: 23311553
advanced dementia; urinary tract infection; antimicrobials; criteria
5.  A novel computer algorithm improves antibody epitope prediction using affinity-selected mimotopes: A case study using monoclonal antibodies against the West Nile virus E protein 
Molecular immunology  2008;46(1):10.1016/j.molimm.2008.07.020.
Understanding antibody function is often enhanced by knowledge of the specific binding epitope. Here, we describe a computer algorithm that permits epitope prediction based on a collection of random peptide epitopes (mimotopes) isolated by antibody affinity purification. We applied this methodology to the prediction of epitopes for five monoclonal antibodies against the West Nile virus (WNV) E protein, two of which exhibit therapeutic activity in vivo. This strategy was validated by comparison of our results with existing F(ab)-E protein crystal structures and mutational analysis by yeast surface display. We demonstrate that by combining the results of the mimotope method with our data from mutational analysis, epitopes could be predicted with greater certainty. The two methods displayed great complementarity as the mutational analysis facilitated epitope prediction when the results with the mimotope method were equivocal and the mimotope method revealed a broader number of residues within the epitope than the mutational analysis. Our results demonstrate that the combination of these two prediction strategies provides a robust platform for epitope characterization.
doi:10.1016/j.molimm.2008.07.020
PMCID: PMC3856767  PMID: 18760481
Epitope mapping; Monoclonal antibody; Phage display; Neutralization; Flavivirus
6.  Meta-analysis of genetic association studies under heterogeneity 
European Journal of Human Genetics  2012;20(11):1174-1181.
In multi-cohort genetic association studies or meta-analysis, associations of genetic variants with complex traits across cohorts may be heterogeneous because of genuine genetic diversity or differential biases or errors. To detect the associations of genes with heterogeneous associations across cohorts, new global fixed-effect (FE) and random-effects (RE) meta-analytic methods have been recently proposed. These global methods had improved power over both traditional FE and RE methods under heterogeneity in limited simulation scenarios and data application, but their usefulness in a wide range of practical situations is not clear. We assessed the performance of these methods for both binary and quantitative traits in extensive simulations and applied them to a multi-cohort association study. We found that these new approaches have higher power to detect mostly the very small to small associations of common genetic variants when associations are highly heterogeneous across cohorts. They worked well when both the underlying and assumed genetic models are either multiplicative or dominant. But, they offered no clear advantage for less common variants unless heterogeneity was substantial. In conclusion, these new meta-analytic methods can be used to detect the association of genetic variants with high heterogeneity, which can then be subjected to further exploration, in multi-cohort association studies and meta-analyses.
doi:10.1038/ejhg.2012.75
PMCID: PMC3476718  PMID: 22643179
genome-wide and genetic association studies; single-nucleotide polymorphism; meta-analysis; study heterogeneity; statistical power; type I error rates
7.  Populations at risk for severe or complicated influenza illness: systematic review and meta-analysis 
Objective To evaluate risk factors for severe outcomes in patients with seasonal and pandemic influenza.
Design Systematic review.
Study selection Observational studies reporting on risk factor-outcome combinations of interest in participants with influenza. Outcomes included death, ventilator support, admission to hospital, admission to an intensive care unit, pneumonia, and composite outcomes.
Data sources Medline, Embase, CINAHL, Global Health, and the Cochrane Central Register of Controlled Trials to March 2011.
Risk of bias assessment Newcastle-Ottawa scale to assess the risk of bias. GRADE framework to evaluate the quality of evidence.
Results 63 537 articles were identified of which 234 with a total of 610 782 participants met the inclusion criteria. The evidence supporting risk factors for severe outcomes of influenza ranged from being limited to absent. This was particularly relevant for the relative lack of data for non-2009 H1N1 pandemics and for seasonal influenza studies. Limitations in the published literature included lack of power and lack of adjustment for confounders was widespread: adjusted risk estimates were provided for only 5% of risk factor-outcome comparisons in 39 of 260 (15%) studies. The level of evidence was low for “any risk factor” (odds ratio for mortality 2.77, 95% confidence interval 1.90 to 4.05 for pandemic influenza and 2.04, 1.74 to 2.39 for seasonal influenza), obesity (2.74, 1.56 to 4.80 and 30.1, 1.74 to 2.39), cardiovascular diseases (2.92, 1.76 to 4.86 and 1.97, 1.06 to 3.67), and neuromuscular disease (2.68, 1.91 to 3.75 and 3.21, 1.84 to 5.58). The level of evidence was very low for all other risk factors. Some well accepted risk factors such as pregnancy and belonging to an ethnic minority group could not be identified as risk factors. In contrast, women who were less than four weeks post partum had a significantly increased risk of death from pandemic influenza (4.43, 1.24 to 15.81).
Conclusion The level of evidence to support risk factors for influenza related complications is low and some well accepted risk factors, including pregnancy and ethnicity, could not be confirmed as risks. Rigorous and adequately powered studies are needed.
doi:10.1136/bmj.f5061
PMCID: PMC3805492  PMID: 23974637
8.  Surveillance Definitions of Infections in Long-Term Care Facilities: Revisiting the McGeer Criteria 
(See the commentary by Moro, on pages 978–980.)
Infection surveillance definitions for long-term care facilities (ie, the McGeer Criteria) have not been updated since 1991. An expert consensus panel modified these definitions on the basis of a structured review of the literature. Significant changes were made to the criteria defining urinary tract and respiratory tract infections. New definitions were added for norovirus gastroenteritis and Clostridum difficile infections.
doi:10.1086/667743
PMCID: PMC3538836  PMID: 22961014
9.  Host Genomics in Infectious Diseases 
Infection & Chemotherapy  2013;45(3):253-259.
Understanding mechanisms by which genetic variants predispose to complications of infectious diseases can lead to important benefits including the development of biomarkers to prioritize vaccination or prophylactic therapy. Family studies, candidate genes in animal models, and the absence of well-defined risks where the complications are rare all can point to genetic predisposition. The most common approach to assessing genetic risk is to conduct an association study, which is a case control study using either a candidate gene approach or a genome wide approach. Although candidate gene variants may focus on potentially causal variants, because other variants across the genome are not tested these studies frequently cannot be replicated. Genome wide association studies need a sizable sample and usually do not identify causal variants but variants which may be in linkage disequilibrium to the actual causal variant. There are many pitfalls that can lead to bias in such studies, including misclassification of cases and controls, use of improper phenotypes, and genotyping errors. These studies have been limited to common genes and rare variants may not be detected. As the use of next generation sequencing becomes more common, it can be anticipated that more variants will be confirmed. The purpose of this review article is to address the issue of genomics in infectious diseases with an emphasis on the host. Although there are a plentitude of studies that focus on the molecular characteristics of pathogens, there are far fewer studies that address the role of human genetics in the predisposition to infection or more commonly its complications. This paper will review both the approaches used to study host genetics in humans and the pitfalls associated with some of these methods. The focus will be on human disease and therefore discussion of the use of animal models will be limited to those where there are genes that have been replicated in humans. The paper will focus on common genetic variants that account for complex traits such as infectious diseases using examples from flaviviruses.
doi:10.3947/ic.2013.45.3.253
PMCID: PMC3848513  PMID: 24396626
West Nile virus; Genomics; Association study; Epidemiology; Encephalitis
10.  Comparing influenza vaccine efficacy against mismatched and matched strains: a systematic review and meta-analysis 
BMC Medicine  2013;11:153.
Background
Influenza vaccines are most effective when the antigens in the vaccine match those of circulating strains. However, antigens contained in the vaccines do not always match circulating strains. In the present work we aimed to examine the vaccine efficacy (VE) afforded by influenza vaccines when they are not well matched to circulating strains.
Methods
We identified randomized clinical trials (RCTs) through MEDLINE, EMBASE, the Cochrane Library, and references of included RCTs. RCTs reporting laboratory-confirmed influenza among healthy participants vaccinated with antigens of matching and non-matching influenza strains were included. Two independent reviewers screened citations/full-text articles, abstracted data, and appraised risk of bias. Conflicts were resolved by discussion. A random effects meta-analysis was conducted. VE was calculated using the following formula: (1 - relative risk × 100%).
Results
We included 34 RCTs, providing data on 47 influenza seasons and 94,821 participants. The live-attenuated influenza vaccine (LAIV) showed significant protection against mismatched (six RCTs, VE 54%, 95% confidence interval (CI) 28% to 71%) and matched (seven RCTs, VE 83%, 95% CI 75% to 88%) influenza strains among children aged 6 to 36 months. Differences were observed between the point estimates for mismatched influenza A (five RCTs, VE 75%, 95% CI 41% to 90%) and mismatched influenza B (five RCTs, VE 42%, 95% CI 22% to 56%) estimates among children aged 6 to 36 months. The trivalent inactivated vaccine (TIV) also afforded significant protection against mismatched (nine RCTs, VE 52%, 95% CI 37% to 63%) and matched (eight RCTs, VE 65%, 95% CI 54% to 73%) influenza strains among adults. Numerical differences were observed between the point estimates for mismatched influenza A (five RCTs, VE 64%, 95% CI 23% to 82%) and mismatched influenza B (eight RCTs, VE 52%, 95% CI 19% to 72%) estimates among adults. Statistical heterogeneity was low (I2 <50%) across all meta-analyses, except for the LAIV meta-analyses among children (I2 = 79%).
Conclusions
The TIV and LAIV vaccines can provide cross protection against non-matching circulating strains. The point estimates for VE were different for matching versus non-matching strains, with overlapping CIs.
doi:10.1186/1741-7015-11-153
PMCID: PMC3706345  PMID: 23800265
Antigenic variation; Cross protection; Influenza A virus; Influenza B virus; Meta-analysis; Systematic review; Vaccines
11.  Risk Factors for Influenza among Health Care Workers during 2009 Pandemic, Toronto, Ontario, Canada 
Emerging Infectious Diseases  2013;19(4):606-615.
Influenza was associated with household exposure, aerosol-generating procedures, and lower adherence to hand hygiene recommendations.
doi:10.3201/eid1904.111812
PMCID: PMC3647716  PMID: 23631831
Influenza; virus; viruses; pandemic; health care worker; risk; hand hygiene; transmission; respiratory; ventilation; aerosol; Canada
12.  Blood CD33(+)HLA-DR(−) myeloid-derived suppressor cells are increased with age and a history of cancer 
Journal of Leukocyte Biology  2013;93(4):633-637.
Myeloid-derived suppressor cells are increased with age and elevated in donors with a history of cancer; an age-related effect has never been shown in humans.
As we age, the composition of our peripheral leukocytes changes dramatically. Many of these alterations contribute to the general immune dysfunction that burdens the elderly, which in turn, contributes to increased susceptibility to disease. MDSCs represent a heterogeneous population of immunosuppressive leukocytes that are elevated in the peripheral blood of cancer patients. Given the relation between cancer incidence and age, this study examined the frequency of peripheral blood CD33(+)HLA-DR(−) MDSCs across three cohorts: healthy adults (19–59 years old), community-dwelling seniors (61–76 years old), and frail elderly (67–99 years old). This analysis is the first to demonstrate that MDSCs and specifically the CD11b(+)CD15(+) MDSC subset are increased with age. Proinflammatory cytokines that are required for the differentiation of MDSCs (e.g., TNF-α, IL-6, and IL-1β) were similarly found to be increased in the serum of the frail elderly. Furthermore, the proportion of MDSCs and the CD11b(+)CD15(+) subset were found to be elevated significantly in elderly donors with a history of cancer. This age-related elevation in the frequency of MDSCs may contribute to the increased cancer incidence that occurs with age. Further investigation into the functional consequences of elevated MDSCs will provide valuable insight into the progression of age-related pathologies.
doi:10.1189/jlb.0912461
PMCID: PMC3701116  PMID: 23341539
aging; elderly; inflammaging; mortality
13.  The Polyfunctionality of Human Memory CD8+ T Cells Elicited by Acute and Chronic Virus Infections Is Not Influenced by Age 
PLoS Pathogens  2012;8(12):e1003076.
As humans age, they experience a progressive loss of thymic function and a corresponding shift in the makeup of the circulating CD8+ T cell population from naïve to memory phenotype. These alterations are believed to result in impaired CD8+ T cell responses in older individuals; however, evidence that these global changes impact virus-specific CD8+ T cell immunity in the elderly is lacking. To gain further insight into the functionality of virus-specific CD8+ T cells in older individuals, we interrogated a cohort of individuals who were acutely infected with West Nile virus (WNV) and chronically infected with Epstein Barr virus (EBV) and Cytomegalovirus (CMV). The cohort was stratified into young (<40 yrs), middle-aged (41–59 yrs) and aged (>60 yrs) groups. In the aged cohort, the CD8+ T cell compartment displayed a marked reduction in the frequency of naïve CD8+ T cells and increased frequencies of CD8+ T cells that expressed CD57 and lacked CD28, as previously described. However, we did not observe an influence of age on either the frequency of virus-specific CD8+ T cells within the circulating pool nor their functionality (based on the production of IFNγ, TNFα, IL2, Granzyme B, Perforin and mobilization of CD107a). We did note that CD8+ T cells specific for WNV, CMV or EBV displayed distinct functional profiles, but these differences were unrelated to age. Collectively, these data fail to support the hypothesis that immunosenescence leads to defective CD8+ T cell immunity and suggest that it should be possible to develop CD8+ T cell vaccines to protect aged individuals from infections with novel emerging viruses.
Author Summary
The prevalence and severity of viral infections increases with advanced age, a phenomenon associated with a defective immune system. The thymic output of naïve T cells declines as we age and it is this lack of naïve T cells that is believed to contribute to the inability of the aged to respond to novel infections and develop subsequent memory T cell responses. Here we show that individuals aged 60+ are capable of developing memory CD8+ T cells to West Nile virus, novel pathogen, indistinguishable in terms of polyfunctionality to those of subjects <60 years of age. Furthermore, we show that chronic and life-long infections with CMV and EBV result in similar polyfunctional virus-specific memory CD8+ T cell responses in subjects of all age groups. Our work demonstrates that aged individuals can elicit functional memory CD8+ T cell responses to a new pathogen while maintaining polyfunctional CD8+ T cells against recurrent chronic virus infections. Current vaccine platforms, which rely upon inactivated pathogens or recombinant subunits, are poorly effective in the aged. Our data suggest that live viruses may be more effective vaccine platforms in older humans.
doi:10.1371/journal.ppat.1003076
PMCID: PMC3521721  PMID: 23271970
14.  Serological Response to Influenza Vaccination among Children Vaccinated for Multiple Influenza Seasons 
PLoS ONE  2012;7(12):e51498.
Background
To evaluate if, among children aged 3 to 15 years, influenza vaccination for multiple seasons affects the proportion sero-protected.
Methodology/Principal Findings
Participants were 131 healthy children aged 3–15 years. Participants were vaccinated with trivalent inactivated seasonal influenza vaccine (TIV) over the 2005–06, 2006–07 and 2007–8 seasons. Number of seasons vaccinated were categorized as one (2007–08); two (2007–08 and 2006–07 or 2007–08 and 2005–06) or three (2005–06, 2006–07, and 2007–08). Pre- and post-vaccination sera were collected four weeks apart. Antibody titres were determined by hemagglutination inhibition (HAI) assay using antigens to A/Solomon Islands/03/06 (H1N1), A/Wisconsin/67/05 (H3N2) and B/Malaysia/2506/04. The proportions sero-protected were compared by number of seasons vaccinated using cut-points for seroprotection of 1∶40 vs. 1∶320. The proportions of children sero-protected against H1N1 and H3N2 was high (>85%) regardless of number of seasons vaccinated and regardless of cut-point for seroprotection. For B Malaysia there was no change in proportions sero-protected by number of seasons vaccinated; however the proportions protected were lower than for H1N1 and H3N2, and there was a lower proportion sero-protected when the higher, compared to lower, cut-point was used for sero-protection.
Conclusion/Significance
The proportion of children sero-protected is not affected by number of seasons vaccinated.
doi:10.1371/journal.pone.0051498
PMCID: PMC3519855  PMID: 23240030
15.  Genetic Variants and Susceptibility to Neurological Complications Following West Nile Virus Infection 
The Journal of Infectious Diseases  2011;204(7):1031-1037.
To determine genetic factors predisposing to neurological complications following West Nile virus infection, we analyzed a cohort of 560 neuroinvasive case patients and 950 control patients for 13 371 mostly nonsynonymous single-nucleotide polymorphisms (SNPs). The top 3 SNPs on the basis of statistical significance were also in genes of biological plausibility: rs2066786 in RFC1 (replication factor C1) (P = 1.88 × 10−5; odds ratio [OR], 0.68 [95% confidence interval {CI}, .56–.81]); rs2298771 in SCN1A (sodium channel, neuronal type I α subunit) (P = 5.87 × 10−5; OR, 1.47 [95% CI, 1.21–1.77]); and rs25651 in ANPEP (ananyl aminopeptidase) (P = 1.44 × 10−4; OR, 0.69 [95% CI, .56–.83]). Additional genotyping of these SNPs in a separate sample of 264 case patients and 296 control patients resulted in a lack of significance in the replication cohort; joint significance was as follows: rs2066786, P = .0022; rs2298771, P = .005; rs25651, P = .042. Using mostly nonsynonymous variants, we therefore did not identify genetic variants associated with neuroinvasive disease.
doi:10.1093/infdis/jir493
PMCID: PMC3203390  PMID: 21881118
16.  Community-acquired pneumonia 
Clinical Evidence  2010;2010:1503.
Introduction
In the northern hemisphere about 12/1000 people a year (on average) contract pneumonia while living in the community, with most cases caused by Streptococcus pneumoniae. Mortality ranges from about 5% to 35% depending on severity of disease, with a worse prognosis in older people, men, and people with chronic diseases.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent community-acquired pneumonia? What are the effects of treatments for community-acquired pneumonia in outpatient settings, in people admitted to hospital, and in people receiving intensive care? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 15 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics (oral, intravenous), different combinations, and prompt administration of antibiotics in intensive-care settings, early mobilisation, influenza vaccine, and pneumococcal vaccine.
Key Points
In the northern hemisphere about 12/1000 people a year (on average) contract pneumonia while living in the community, with most cases caused by Streptococcus pneumoniae. People at greatest risk include those at the extremes of age, smokers, alcohol-dependent people, and people with lung or heart disease or immunosuppression.Mortality ranges from about 5% to 35% depending on severity of disease, with a worse prognosis in older people, men, and people with chronic diseases.
Deaths from influenza are usually caused by pneumonia. Influenza vaccine reduces the risk of clinical influenza, and may reduce the risk of pneumonia and mortality in older people. Pneumococcal vaccine is unlikely to reduce all-cause pneumonia or mortality in immunocompetent adults, but may reduce pneumococcal pneumonia in this group.
Antibiotics lead to clinical cure in at least 80% of people with pneumonia being treated in the community or in hospital, although no one regimen has been shown to be superior to the others in either setting. Early mobilisation may reduce hospital stay compared with usual care in people being treated with antibiotics. Intravenous antibiotics have not been shown to improve clinical cure rates or survival compared with oral antibiotics in people treated in hospital for non-severe community-acquired pneumonia.
Prompt administration of antibiotics may improve survival compared with delayed treatment in people receiving intensive care for community-acquired pneumonia, although we found few studies. We don't know which is the optimum antibiotic regimen to use in these people.
PMCID: PMC3275325  PMID: 21418681
17.  Effect of influenza vaccines against mismatched strains: a systematic review protocol 
Systematic Reviews  2012;1:35.
Background
Influenza vaccines are most effective when the antigens in the vaccine match those of circulating influenza strains. The extent to which the vaccine is protective when circulating strains differ from vaccine antigens, or are mismatched, is uncertain. We propose to systematically review the cross-protection offered by influenza vaccines against circulating influenza A or B viruses that are not antigenically well-matched to vaccine strains.
Methods/Design
This is a protocol for a systematic review and meta-analysis. Placebo-controlled randomized clinical trials (RCTs) reporting laboratory-confirmed influenza among healthy participants vaccinated with antigens of influenza strains that differed from those circulating will be included. The primary outcome is the incidence of laboratory-confirmed influenza (polymerase chain reaction (PCR) or viral culture). The secondary outcome is the incidence of laboratory-confirmed influenza through antibody assay (a less sensitive test than PCR or viral culture) alone or combined with PCR, and/ or viral culture. The review will be limited to RCTs written in English.
We will search MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, previous influenza reviews, and the reference lists of included studies to identify potentially relevant RCTs. Two independent reviewers will conduct all levels of screening, data abstraction, and quality appraisal (using the Cochrane risk of bias tool).
If appropriate, random effects meta-analysis of vaccine efficacy will be conducted in SAS (version 9.2) by calculating the relative risk. Vaccine efficacy will be calculated using the following formula: (1 - relative risk × 100). The results will be analyzed by type of vaccine (live attenuated, trivalent inactivated, or other). Subgroup analysis will include the effects of age (children, adults, older participants), and influenza A versus influenza B on the results. For influenza B we will also consider variable degrees of antigenic mismatch (lineage and drift mismatch).
Discussion
Our results can be used by researchers and policy-makers to help predict the efficacy of influenza vaccines during mismatched influenza seasons. Furthermore, the review will be of interest to patients and clinicians to determine whether to get immunized or support immunization for a particular influenza season.
doi:10.1186/2046-4053-1-35
PMCID: PMC3488466  PMID: 22846340
Antigenic variation; Cross protection; Influenza A virus; Influenza B virus; Protocol; Systematic review; Vaccines
18.  Zinc for the treatment of the common cold: a systematic review and meta-analysis of randomized controlled trials 
Background:
Results of randomized controlled trials evaluating zinc for the treatment of the common cold are conflicting. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of zinc for such use.
Methods:
We searched electronic databases and other sources for studies published through to Sept. 30, 2011. We included all randomized controlled trials comparing orally administered zinc with placebo or no treatment. Assessment for study inclusion, data extraction and risk-of-bias analyses were performed in duplicate. We conducted meta-analyses using a random-effects model.
Results:
We included 17 trials involving a total of 2121 participants. Compared with patients given placebo, those receiving zinc had a shorter duration of cold symptoms (mean difference −1.65 days, 95% confidence interval [CI] −2.50 to −0.81); however, heterogeneity was high (I2 = 95%). Zinc shortened the duration of cold symptoms in adults (mean difference −2.63, 95% CI −3.69 to −1.58), but no significant effect was seen among children (mean difference −0.26, 95% CI −0.78 to 0.25). Heterogeneity remained high in all subgroup analyses, including by age, dose of ionized zinc and zinc formulation. The occurrence of any adverse event (risk ratio [RR] 1.24, 95% CI 1.05 to 1.46), bad taste (RR 1.65, 95% CI 1.27 to 2.16) and nausea (RR 1.64, 95% CI 1.19 to 2.27) were more common in the zinc group than in the placebo group.
Interpretation:
The results of our meta-analysis showed that oral zinc formulations may shorten the duration of symptoms of the common cold. However, large high-quality trials are needed before definitive recommendations for clinical practice can be made. Adverse effects were common and should be the point of future study, because a good safety and tolerance profile is essential when treating this generally mild illness.
doi:10.1503/cmaj.111990
PMCID: PMC3394849  PMID: 22566526
19.  The Role of Host Genetics in Susceptibility to Influenza: A Systematic Review 
PLoS ONE  2012;7(3):e33180.
Background
The World Health Organization has identified studies of the role of host genetics on susceptibility to severe influenza as a priority. A systematic review was conducted to summarize the current state of evidence on the role of host genetics in susceptibility to influenza (PROSPERO registration number: CRD42011001380).
Methods and Findings
PubMed, Web of Science, the Cochrane Library, and OpenSIGLE were searched using a pre-defined strategy for all entries up to the date of the search. Two reviewers independently screened the title and abstract of 1,371 unique articles, and 72 full text publications were selected for inclusion. Mouse models clearly demonstrate that host genetics plays a critical role in susceptibility to a range of human and avian influenza viruses. The Mx genes encoding interferon inducible proteins are the best studied but their relevance to susceptibility in humans is unknown. Although the MxA gene should be considered a candidate gene for further study in humans, over 100 other candidate genes have been proposed. There are however no data associating any of these candidate genes to susceptibility in humans, with the only published study in humans being under-powered. One genealogy study presents moderate evidence of a heritable component to the risk of influenza-associated death, and while the marked familial aggregation of H5N1 cases is suggestive of host genetic factors, this remains unproven.
Conclusion
The fundamental question “Is susceptibility to severe influenza in humans heritable?” remains unanswered. Not because of a lack of genotyping or analytic tools, nor because of insufficient severe influenza cases, but because of the absence of a coordinated effort to define and assemble cohorts of cases. The recent pandemic and the ongoing epizootic of H5N1 both represent rapidly closing windows of opportunity to increase understanding of the pathogenesis of severe influenza through multi-national host genetic studies.
doi:10.1371/journal.pone.0033180
PMCID: PMC3305291  PMID: 22438897
20.  Swine Outbreak of Pandemic Influenza A Virus on a Canadian Research Farm Supports Human-to-Swine Transmission 
Background. Swine outbreaks of pandemic influenza A (pH1N1) suggest human introduction of the virus into herds. This study investigates a pH1N1 outbreak occurring on a swine research farm with 37 humans and 1300 swine in Alberta, Canada, from 12 June through 4 July 2009.
Methods. The staff was surveyed about symptoms, vaccinations, and livestock exposures. Clinical findings were recorded, and viral testing and molecular characterization of isolates from humans and swine were performed. Human serological testing and performance of the human influenza-like illness (ILI) case definition were also studied.
Results. Humans were infected before swine. Seven of 37 humans developed ILI, and 2 (including the index case) were positive for pH1N1 by reverse-transcriptase polymerase chain reaction (RT-PCR). Swine were positive for pH1N1 by RT-PCR 6 days after contact with the human index case and developed symptoms within 24 h of their positive viral test results. Molecular characterization of the entire viral genomes from both species showed minor nucleotide heterogeneity, with 1 amino acid change each in the hemagglutinin and nucleoprotein genes. Sixty-seven percent of humans with positive serological test results and 94% of swine with positive swab specimens had few or no symptoms. Compared with serological testing, the human ILI case definition had a specificity of 100% and sensitivity of 33.3%. The only factor associated with seropositivity was working in the swine nursery.
Conclusions. Epidemiologic data support human-to-swine transmission, and molecular characterization confirms that virtually identical viruses infected humans and swine in this outbreak. Both species had mild illness and recovered without sequelae.
doi:10.1093/cid/ciq030
PMCID: PMC3106227  PMID: 21148514
21.  Prognosis of West Nile virus associated acute flaccid paralysis: a case series 
Introduction
Little is known about the long-term health related quality of life outcomes in patients with West Nile virus associated acute flaccid paralysis. We describe the quality of life scores of seven patients with acute flaccid paralysis who presented to hospital between 2003 and 2006, and were followed for up to two years.
Case presentations
Between 2003 and 2006, 157 symptomatic patients with West Nile virus were enrolled in a longitudinal cohort study of West Nile virus in Canada. Seven patients (4%) had acute flaccid paralysis. The first patient was a 55-year-old man who presented with left upper extremity weakness. The second patient was a 54-year-old man who presented with bilateral upper extremity weakness. The third patient was a 66-year-old woman who developed bilateral upper and lower extremity weakness. The fourth patient was a 67-year-old man who presented with right lower extremity weakness. The fifth patient was a 60-year-old woman who developed bilateral lower extremity weakness. The sixth patient was a 71-year-old man with a history of Parkinson's disease and acute onset bilateral lower extremity weakness. The seventh patient was a 52-year-old man who presented with right lower extremity weakness. All were Caucasian. Patients were followed for a mean of 1.1 years. At the end of follow-up the mean score on the Physical Component Summary of the Short-Form 36 scale had only slightly increased to 39. In contrast, mean score on the Mental Component Summary of the Short-Form 36 scale at the end of follow-up had normalized to 50.
Conclusion
Despite the poor physical prognosis for patients with acute flaccid paralysis, the mental health outcomes are generally favorable.
doi:10.1186/1752-1947-5-395
PMCID: PMC3177918  PMID: 21854567
22.  Association between HLA Class I and Class II Alleles and the Outcome of West Nile Virus Infection: An Exploratory Study 
PLoS ONE  2011;6(8):e22948.
Background
West Nile virus (WNV) infection is asymptomatic in most individuals, with a minority developing symptoms ranging from WNV fever to serious neuroinvasive disease. This study investigated the impact of host HLA on the outcome of WNV disease.
Methods
A cohort of 210 non-Hispanic mostly white WNV+ subjects from Canada and the U.S. were typed for HLA-A, B, C, DP, DQ, and DR. The study subjects were divided into three WNV infection outcome groups: asymptomatic (AS), symptomatic (S), and neuroinvasive disease (ND). Allele frequency distribution was compared pair-wise between the AS, S, and ND groups using χ2 and Fisher's exact tests and P values were corrected for multiple comparisons (Pc). Allele frequencies were compared between the groups and the North American population (NA) used as a control group. Logistic regression analysis was used to evaluate the potential synergistic effect of age and HLA allele phenotype on disease outcome.
Results
The alleles HLA-A*68, C*08 and DQB*05 were more frequently associated with severe outcomes (ND vs. AS, PA*68 = 0.013/Pc = 0.26, PC*08 = 0.0075/Pc = 0.064, and PDQB1*05 = 0.029/Pc = 0.68), However the apparent DQB1*05 association was driven by age. The alleles HLA-B*40 and C*03 were more frequently associated with asymptomatic outcome (AS vs. S, PB*40 = 0.021/Pc = 0.58 and AS vs. ND PC*03 = 0.039/Pc = 0.64) and their frequencies were lower within WNV+ subjects with neuroinvasive disease than within the North American population (NA vs. S, PB*40 = 0.029 and NA vs. ND, PC*03 = 0.032).
Conclusions
Host HLA may be associated with the outcome of WNV disease; HLA-A*68 and C*08 might function as “susceptible” alleles, whereas HLA-B*40 and C*03 might function as “protective” alleles.
doi:10.1371/journal.pone.0022948
PMCID: PMC3148246  PMID: 21829673
24.  Surface Phenotype and Functionality of WNV Specific T Cells Differ with Age and Disease Severity 
PLoS ONE  2010;5(12):e15343.
West Nile virus (WNV) infection can result in severe neuroinvasive disease, particularly in persons with advanced age. As rodent models demonstrate that T cells play an important role in limiting WNV infection, and strong T cell responses to WNV have been observed in humans, we postulated that inadequate antiviral T cell immunity was involved in neurologic sequelae and the more severe outcomes associated with age. We previously reported the discovery of six HLA-A*0201 restricted WNV peptide epitopes, with the dominant T cell targets in naturally infected individuals being SVG9 (Env) and SLF9 (NS4b). Here, memory phenotype and polyfunctional CD8+ T cell responses to these dominant epitopes were assessed in 40 WNV seropositive patients displaying diverse clinical symptoms. The patients' PBMC were stained with HLA-I multimers loaded with the SVG9 and SLF9 epitopes and analyzed by multicolor flow cytometry. WNV-specific CD8+ T cells were found in peripheral blood several months post infection. The number of WNV-specific T cells in older individuals was the same, if not greater, than in younger members of the cohort. WNV-specific T cells were predominantly monofunctional for CD107a, MIP-1β, TNFα, IL-2, or IFNγ. When CD8+ T cell responses were stratified by disease severity, an increased number of terminally differentiated, memory phenotype (CD45RA+ CD27− CCR7− CD57+) T cells were detected in patients suffering from viral neuroinvasion. In conclusion, T cells of a terminally differentiated/cytolytic profile are associated with neuroinvasion and, regardless of age, monofunctional T cells persist following infection. These data provide the first indication that particular CD8+ T cell phenotypes are associated with disease outcome following WNV infection.
doi:10.1371/journal.pone.0015343
PMCID: PMC3001480  PMID: 21179445
25.  Antimicrobial Susceptibilities of Health Care-Associated and Community-Associated Strains of Methicillin-Resistant Staphylococcus aureus from Hospitalized Patients in Canada, 1995 to 2008▿  
We determined the in vitro antimicrobial susceptibilities of 7,942 methicillin-resistant Staphylococcus aureus (MRSA) isolates obtained from patients hospitalized in 48 Canadian hospitals from 1995 to 2008. Regional variations in susceptibilities were identified. The dissemination of community-associated strains in Canada appears to have contributed to increased susceptibility of MRSA to several non-β-lactam antimicrobial agents in the past decade. Reduced susceptibility to glycopeptides was not identified.
doi:10.1128/AAC.01717-09
PMCID: PMC2863599  PMID: 20231402

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