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1.  Immune Biomarkers Predictive of Respiratory Viral Infection in Elderly Nursing Home Residents 
PLoS ONE  2014;9(10):e108481.
Objective
To determine if immune phenotypes associated with immunosenescence predict risk of respiratory viral infection in elderly nursing home residents.
Methods
Residents ≥65 years from 32 nursing homes in 4 Canadian cities were enrolled in Fall 2009, 2010 and 2011, and followed for one influenza season. Following influenza vaccination, peripheral blood mononuclear cells (PBMCs) were obtained and analysed by flow cytometry for T-regs, CD4+ and CD8+ T-cell subsets (CCR7+CD45RA+, CCR7-CD45RA+ and CD28-CD57+) and CMV-reactive CD4+ and CD8+ T-cells. Nasopharyngeal swabs were obtained and tested for viruses in symptomatic residents. A Cox proportional hazards model adjusted for age, sex and frailty, determined the relationship between immune phenotypes and time to viral infection.
Results
1072 residents were enrolled; median age 86 years and 72% female. 269 swabs were obtained, 87 were positive for virus: influenza (24%), RSV (14%), coronavirus (32%), rhinovirus (17%), human metapneumovirus (9%) and parainfluenza (5%). In multivariable analysis, high T-reg% (HR 0.41, 95% CI 0.20–0.81) and high CMV-reactive CD4+ T-cell% (HR 1.69, 95% CI 1.03–2.78) were predictive of respiratory viral infection.
Conclusions
In elderly nursing home residents, high CMV-reactive CD4+ T-cells were associated with an increased risk and high T-regs were associated with a reduced risk of respiratory viral infection.
doi:10.1371/journal.pone.0108481
PMCID: PMC4183538  PMID: 25275464
2.  Oseltamivir use amongst hospitalized patients infected with influenza 
doi:10.1111/irv.12260
PMCID: PMC4181818  PMID: 24996027
hospitalization; influenza; oseltamivir
3.  Alterations to the Frequency and Function of Peripheral Blood Monocytes and Associations with Chronic Disease in the Advanced-Age, Frail Elderly 
PLoS ONE  2014;9(8):e104522.
Background
Circulating myeloid cells are important mediators of the inflammatory response, acting as a major source of resident tissue antigen presenting cells and serum cytokines. They represent a number of distinct subpopulations whose functional capacity and relative concentrations are known to change with age. Little is known of these changes in the very old and physically frail, a rapidly increasing proportion of the North American population.
Design
In the following study the frequency and receptor expression of blood monocytes and dendritic cells (DCs) were characterized in a sample of advanced-age, frail elderly (81–100 yrs), and compared against that of adults (19–59 yrs), and community-dwelling seniors (61–76 yrs). Cytokine responses following TLR stimulation were also investigated, as well as associations between immunophenotyping parameters and chronic diseases.
Results
The advanced-age, frail elderly had significantly fewer CD14(++) and CD14(+)CD16(+), but not CD14(++)CD16(+) monocytes, fewer plasmacytoid and myeloid DCs, and a lower frequency of monocytes expressing the chemokine receptors CCR2 and CX3CR1. At baseline and following stimulation with TLR-2 and -4 agonists, monocytes from the advanced-age, frail elderly produced more TNF than adults, although the overall induction was significantly lower. Finally, monocyte subset frequency and CX3CR1 expression was positively associated with dementia, while negatively associated with anemia and diabetes in the advanced-age, frail elderly.
Conclusions
These data demonstrate that blood monocyte frequency and phenotype are altered in the advanced-age, frail elderly and that these changes correlate with certain chronic diseases. Whether these changes contribute to or are caused by these conditions warrants further investigation.
doi:10.1371/journal.pone.0104522
PMCID: PMC4126708  PMID: 25105870
4.  Low Serum 25-Hydroxyvitamin D Level and Risk of Upper Respiratory Tract Infection in Children and Adolescents 
Respiratory tract infections (RTIs) are very common worldwide. We prospectively demonstrate an association between low serum 25-hydroxyvitamin D level and increased risk of laboratory-confirmed viral upper RTI in children. Future studies should evaluate the role of supplementation to reduce RTIs.
Background. Vitamin D may be important for immune function. Studies to date have shown an inconsistent association between vitamin D and infection with respiratory viruses. The purpose of this study was to determine if serum 25-hydroxyvitamin D (25(OH)D) was associated with laboratory-confirmed viral respiratory tract infections (RTIs) in children.
Methods. Serum 25(OH)D levels were measured at baseline and children from Canadian Hutterite communities were followed prospectively during the respiratory virus season. Nasopharyngeal specimens were obtained if symptoms developed and infections were confirmed using polymerase chain reaction. The association between serum 25(OH)D and time to laboratory-confirmed viral RTI was evaluated using a Cox proportional hazards model.
Results. Seven hundred forty-three children aged 3–15 years were followed between 22 December 2008 and 23 June 2009. The median serum 25(OH)D level was 62.0 nmol/L (interquartile range, 51.0–74.0). A total of 229 participants (31%) developed at least 1 laboratory-confirmed viral RTI. Younger age and lower serum 25(OH)D levels were associated with increased risk of viral RTI. Serum 25(OH)D levels <75 nmol/L increased the risk of viral RTI by 50% (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.10–2.07, P = .011) and levels <50 nmol/L increased the risk by 70% (HR, 1.67; 95% CI, 1.16–2.40, P = .006).
Conclusions. Lower serum 25(OH)D levels were associated with increased risk of laboratory-confirmed viral RTI in children from Canadian Hutterite communities. Interventional studies evaluating the role of vitamin D supplementation to reduce the burden of viral RTIs are warranted.
doi:10.1093/cid/cit289
PMCID: PMC3888147  PMID: 23677871
vitamin D; serum 25-hydroxyvitamin D; upper respiratory tract infection; cold
5.  Universal Glove and Gown Use and Acquisition of Antibiotic resistant bacteria in the ICU: A Randomized Trial 
Importance
Antibiotic-resistant bacteria are associated with increased patient morbidity and mortality. It is unknown whether wearing gloves and gowns for all patient contact in the intensive care unit (ICU) decreases acquisition of antibiotic-resistant bacteria.
Objective
To assess whether wearing gloves and gowns for all patient contact in the ICU decreases acquisition of methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE) compared with usual care.
Design, Setting, and Participants
Cluster-randomized trial in 20 medical and surgical ICUs in 20 US hospitals from January 4, 2012, to October 4, 2012.
Interventions
In the intervention ICUs, all health care workers were required to wear gloves and gowns for all patient contact and when entering any patient room.
Main Outcomes and Measures
The primary outcome was acquisition of MRSA or VRE based on surveillance cultures collected on admission and discharge from the ICU. Secondary outcomes included individual VRE acquisition, MRSA acquisition, frequency of health care worker visits, hand hygiene compliance, health care–associated infections, and adverse events.
Results
From the 26 180 patients included, 92 241 swabs were collected for the primary outcome. Intervention ICUs had a decrease in the primary outcome of MRSA or VRE from 21.35 acquisitions per 1000 patient-days (95% CI, 17.57 to 25.94) in the baseline period to 16.91 acquisitions per 1000 patient-days (95% CI, 14.09 to 20.28) in the study period, whereas control ICUs had a decrease in MRSA or VRE from 19.02 acquisitions per 1000 patient-days (95% CI, 14.20 to 25.49) in the baseline period to 16.29 acquisitions per 1000 patient-days (95% CI, 13.48 to 19.68) in the study period, a difference in changes that was not statistically significant (difference, −1.71 acquisitions per 1000 person-days, 95% CI, −6.15 to 2.73; P = .57). For key secondary outcomes, there was no difference in VRE acquisition with the intervention (difference, 0.89 acquisitions per 1000 person-days; 95% CI, −4.27 to 6.04, P = .70), whereas for MRSA, there were fewer acquisitions with the intervention (difference, −2.98 acquisitions per 1000 person-days; 95% CI, −5.58 to −0.38; P = .046). Universal glove and gown use also decreased health care worker room entry (4.28 vs 5.24 entries per hour, difference, −0.96; 95% CI, −1.71 to −0.21, P = .02), increased room-exit hand hygiene compliance (78.3% vs 62.9%, difference, 15.4%; 95% CI, 8.99% to 21.8%; P = .02) and had no statistically significant effect on rates of adverse events (58.7 events per 1000 patient days vs 74.4 events per 1000 patient days; difference, −15.7; 95% CI, −40.7 to 9.2, P = .24).
Conclusions and Relevance
The use of gloves and gowns for all patient contact compared with usual care among patients in medical and surgical ICUs did not result in a difference in the primary outcome of acquisition of MRSA or VRE. Although there was a lower risk of MRSA acquisition alone and no difference in adverse events, these secondary outcomes require replication before reaching definitive conclusions.
doi:10.1001/jama.2013.277815
PMCID: PMC4026208  PMID: 24097234
6.  Vitamin D3 and gargling for the prevention of upper respiratory tract infections: a randomized controlled trial 
BMC Infectious Diseases  2014;14:273.
Background
We undertook a 2X2 factorial, randomized controlled trial (RCT) to assess whether vitamin D3 supplementation (10,000 international units per week) versus placebo and gargling versus no gargling could prevent viral, clinical upper respiratory tract infection (URTI) in university students.
Methods
We randomized 600 students into 4 treatment arms: 1) vitamin D3 and gargling, 2) placebo and gargling, 3) vitamin D3 and no gargling, and 4) placebo and no gargling. Students completed weekly electronic surveys and submitted self-collected mid-turbinate nasal flocked swabs during September and October in 2010 or 2011. Symptomatic students also completed an electronic symptom diary. The primary and secondary outcomes were the occurrence of symptomatic clinical URTI and laboratory confirmed URTI respectively.
Results
Of 600 participants, 471 (78.5%) completed all surveys while 43 (7.2%) completed none; 150 (25.0%) reported clinical URTI. Seventy participants (23.3%) randomized to vitamin D3 reported clinical URTI compared to 80 (26.7%) randomized to placebo (RR:0.79, CI95:0.61-1.03, p = 0.09). Eighty-five participants (28.3%) randomized to gargling reported clinical URTI compared to 65 participants (21.7%) randomized to the no gargling arm (RR:1.3, CI95:0.92-1.57, p = 0.19). Laboratory testing identified 70 infections (46.7 per 100 URTIs). Vitamin D3 treatment was associated with a significantly lower risk for laboratory confirmed URTI (RR: 0.54, CI95:0.34-0.84, p = 0.007) and with a significantly lower mean viral load measured as log10 viral copies/mL (mean difference: -0.89, CI95: -1.7, -0.06, p = 0.04). Fewer students assigned to gargling experienced laboratory confirmed URTI, however this was not statistically significant (RR:0.82, CI95:0.53-1.26, p = 0.36).
Conclusions
These results suggest that vitamin D3 is a promising intervention for the prevention of URTI. Vitamin D3 significantly reduced the risk of laboratory confirmed URTI and may reduce the risk of clinical infections.
Trial registration
Clinical Trials Registration: NCT01158560.
doi:10.1186/1471-2334-14-273
PMCID: PMC4041358  PMID: 24885201
Rhinovirus; Vitamin D3; Viral load; Gargling; Randomized controlled trial; Upper respiratory tract infection
7.  Knowledge, attitudes, beliefs and behaviours of older adults about pneumococcal immunization, a Public Health Agency of Canada/Canadian Institutes of Health Research Influenza Research Network (PCIRN) investigation 
BMC Public Health  2014;14:442.
Background
Fewer Canadian seniors are vaccinated against pneumococcal disease than receive the influenza vaccine annually. Improved understanding of factors influencing pneumococcal vaccination among older adults is needed to improve vaccine uptake.
Methods
A self-administered survey measuring knowledge, attitudes, beliefs and behaviours about pneumococcal vaccination was administered to a cohort of seniors participating in a clinical trial of seasonal influenza vaccines at eight centers across Canada. Eligible participants were ambulatory adults 65 years of age or older, in good health or with stable health conditions, previously given influenza vaccine. The primary outcome was self-reported receipt of pneumococcal vaccination. Multi-variable logistic regression was used to determine factors significantly associated with pneumococcal vaccine receipt.
Results
A total of 863 participants completed questionnaires (response rate 92%); 58% indicated they had received the pneumococcal vaccine. Being offered the vaccine by a health care provider had the strongest relationship with vaccine receipt (AOR 23.4 (95% CI 13.4-40.7)). Other variables that remained significantly associated with vaccine receipt in the multivariable model included having heard of the vaccine (AOR 10.1(95% CI 4.7-21.7)), and strongly agreeing that it is important for adults > 65 to be vaccinated against pneumococcus (AOR 3.3 (95% CI 1.2-9.2)). Participants who were < 70 years of age were less likely to be vaccinated.
Conclusions
These results indicate healthcare recommendation significantly influenced vaccine uptake in this population of older adults. Measures to encourage healthcare providers to offer the vaccine may help increase coverage.
doi:10.1186/1471-2458-14-442
PMCID: PMC4046143  PMID: 24884433
Invasive pneumococcal disease; Polysaccharide pneumococcal vaccine; Older adults
8.  Immunosenescence in the nursing home elderly 
BMC Geriatrics  2014;14:50.
Background
To describe T-cell and natural killer (NK) cell phenotypes within nursing home elderly.
Methods
Nursing home elderly were recruited from four nursing homes in Hamilton, Ontario between September 2010 and December 2011. Healthy adults were recruited from McMaster University between September 2011 and December 2011. Nursing home elderly ≥65 years were eligible; those on immunosuppressive medications were excluded. Healthy adults ≥18-64 years were eligible. CD8+ and CD4+ T-cells% and their subsets, T-regs% and NK cell subset% were compared between the nursing home elderly and healthy adults.
Results
262 nursing home elderly were enrolled; median age 87 years and 81% were female. 16 healthy adults were enrolled; median age 31 and 50% were female. There was no significant difference between CD8+ T-cell% in nursing home and healthy adults (median 17.1 versus 18.0, p = 0.56), however there were fewer naïve CD8 + T-cell% (median 0.9 versus 5.2, p < 0.001), more terminally differentiated CD8 + T-cell% (median 7.3 versus 4.1, p = 0.004) and more senescent T-cell% (median 5.3 versus 3.1, p = 0.04) in the nursing home elderly. There were more CD4+ T-cell% in the nursing home elderly compared to healthy adults (median 45.5 versus 37.1, p = 0.001). Nursing home elderly had a higher CD4+/CD8+ ratio than healthy adults (2.6 versus 1.9, p = 0.048), higher T-reg% (median 1.8 versus 0.8, p < 0.001) and increased mature NK cell% (median 12.1 versus 5.4, p = 0.001) compared to healthy adults.
Conclusion
Differences in naïve CD8+ T-cells, terminally differentiated and senescent CD8+ T-cells, T-regs and NK cell subsets were similar to studies involving community dwelling elderly. In contrast, the CD4+/CD8+ ratio was higher in nursing home elderly.
doi:10.1186/1471-2318-14-50
PMCID: PMC4013821  PMID: 24742120
Immunosenescence; Aging; Immune phenotypes; Nursing home elderly
9.  Newcastle-Ottawa Scale: comparing reviewers’ to authors’ assessments 
Background
Lack of appropriate reporting of methodological details has previously been shown to distort risk of bias assessments in randomized controlled trials. The same might be true for observational studies. The goal of this study was to compare the Newcastle-Ottawa Scale (NOS) assessment for risk of bias between reviewers and authors of cohort studies included in a published systematic review on risk factors for severe outcomes in patients infected with influenza.
Methods
Cohort studies included in the systematic review and published between 2008–2011 were included. The corresponding or first authors completed a survey covering all NOS items. Results were compared with the NOS assessment applied by reviewers of the systematic review. Inter-rater reliability was calculated using kappa (K) statistics.
Results
Authors of 65/182 (36%) studies completed the survey. The overall NOS score was significantly higher (p < 0.001) in the reviewers’ assessment (median = 6; interquartile range [IQR] 6–6) compared with those by authors (median = 5, IQR 4–6). Inter-rater reliability by item ranged from slight (K = 0.15, 95% confidence interval [CI] = −0.19, 0.48) to poor (K = −0.06, 95% CI = −0.22, 0.10). Reliability for the overall score was poor (K = −0.004, 95% CI = −0.11, 0.11).
Conclusions
Differences in assessment and low agreement between reviewers and authors suggest the need to contact authors for information not published in studies when applying the NOS in systematic reviews.
doi:10.1186/1471-2288-14-45
PMCID: PMC4021422  PMID: 24690082
Newcastle Ottawa Scale; Inter-rater; Reliability; Validity; Risk of bias; Observational studies
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  Safety, immunogenicity, and tolerability of three influenza vaccines in older adults 
Human Vaccines & Immunotherapeutics  2013;9(11):2460-2473.
To determine if newer influenza vaccines can safely improve seroprotection rates of older adults, we compared three licensed trivalent inactivated vaccines (TIVs) in a randomized, controlled trial with evaluator blinding. Participants were non-frail adults ≥ 65 y old, annually TIV-immunized. Study vaccines included intradermal (IDV), MF59-adjuvanted (ADV) and subunit (TIV) formulations of equal potency and strain composition. Blood was obtained before vaccination (V1) and 21 (V2) and 180 d (V3) afterward and tested by hemagglutination inhibition (HAI) assay. Safety diaries were completed daily by participants and specific tolerability questions were posed regarding injections and symptoms. In total, 911 participants were immunized and 887 (97.4%) completed V3. Groups had similar demographics. General symptom rates post-vaccination were similar among groups. Rates of injection site redness after IDV/ADV/TIV were 75%/13%/13% and rates of pain were 29%/38%/20%, respectively, but each vaccine was well tolerated, with symptoms causing little bother. Baseline antibody titers did not differ significantly among groups but B/Brisbane titers were too high for meaningful response assessments. At V2, seroprotection rates (HAI titer ≥ 40) were highest after ADV, the rate advantage over IDV and TIV being significant at 11.8% and 11.4% for H3N2 and 10.2% and 12.5% for H1N1, respectively. At day 180, seroprotection rates had declined ~25% and no longer differed significantly among groups. While IDV and TIV were also well tolerated, ADV induced modestly higher antibody titers in seniors to influenza A strains at 3 weeks but not 6 months post-vaccination. Immune responses to IDV and TIV were similar in this population.
doi:10.4161/hv.25580
PMCID: PMC3981857  PMID: 23839537
immunization; adults; influenza; adjuvant; vaccine safety
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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