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1.  Comparison of Characteristics between Patients with H7N9 Living in Rural and Urban Areas of Zhejiang Province, China: A Preliminary Report 
PLoS ONE  2014;9(4):e93775.
A total of 134 cases of H7N9 influenza infection were identified in 12 provinces of China between March 25 and September 31, 2013. Of these, 46 cases occurred in Zhejiang Province. We carried out a preliminary comparison of characteristics between rural and urban H7N9 cases from Zhejiang Province, China. Field investigations were conducted for each confirmed H7N9 case. A standardized questionnaire was used to collect information about demographics, exposure history, clinical signs and symptoms, timelines of medical visits and care after onset of illness. Of the 46 H7N9 cases in Zhejiang Province identified between March 25 and September 31, 2013, there were 16 rural cases and 30 urban cases. Compared to urban cases, there was a higher proportion of females among the rural cases [11/16 (69%) vs. 6/30 (20%), P = 0.001]. Among the rural cases, 14/15 (93%) with available data had a history of recent poultry exposure, which was significantly higher than that among urban cases (64%, P = 0.038). More patients from the rural group had a history of breeding poultry compared with those from the urban group [38% (6/16) vs. 10% (3/30), respectively; P = 0.025]. Interestingly, the median number of medical visits of patients from rural areas was higher than that of patients from urban areas (P = 0.046). There was no difference between the two groups in terms of age distribution, fatality rate, incubation period, symptoms, and underlying medical conditions. In conclusion, compared to patients from urban areas, more patients from rural areas were female, had an exposure history, had a history of breeding poultry, and had a higher number of medical visits. These findings indicate that there are different exposure patterns between patients living in rural and urban areas and that more rural cases were infected through backyard poultry breeding.
PMCID: PMC3977906  PMID: 24710171
2.  Suboptimal Herd Performance Amplifies the Spread of Infectious Disease in the Cattle Industry 
PLoS ONE  2014;9(3):e93410.
Farms that purchase replacement breeding cattle are at increased risk of introducing many economically important diseases. The objectives of this analysis were to determine whether the total number of replacement breeding cattle purchased by individual farms could be reduced by improving herd performance and to quantify the effects of such reductions on the industry-level transmission dynamics of infectious cattle diseases. Detailed information on the performance and contact patterns of British cattle herds was extracted from the national cattle movement database as a case example. Approximately 69% of beef herds and 59% of dairy herds with an average of at least 20 recorded calvings per year purchased at least one replacement breeding animal. Results from zero-inflated negative binomial regression models revealed that herds with high average ages at first calving, prolonged calving intervals, abnormally high or low culling rates, and high calf mortality rates were generally more likely to be open herds and to purchase greater numbers of replacement breeding cattle. If all herds achieved the same level of performance as the top 20% of herds, the total number of replacement beef and dairy cattle purchased could be reduced by an estimated 34% and 51%, respectively. Although these purchases accounted for only 13% of between-herd contacts in the industry trade network, they were found to have a disproportionately strong influence on disease transmission dynamics. These findings suggest that targeting extension services at herds with suboptimal performance may be an effective strategy for controlling endemic cattle diseases while simultaneously improving industry productivity.
PMCID: PMC3966883  PMID: 24671129
3.  Estimating the Risk of Parvovirus B19 Infection in Blood Donors and Pregnant Women in Japan 
PLoS ONE  2014;9(3):e92519.
Seroepidemiological study of parvovirus B19 has not taken place for some 20 years in Japan. To estimate the risk of parvovirus B19 infection in Japan among blood donors and pregnant women in this century, a seroepidemiological survey and statistical modeling of the force of infection were conducted.
Methodology/Principal Findings
The time- and age-specific seroprevalence data were suggestive of strong age-dependency in the risk of infection. Employing a piecewise constant model, the highest forces of infection of 0.05 and 0.12 per year were observed among those aged 0–4 and 5–9 years, respectively, while estimates among older individuals were less than 0.01 per year. Analyzing the antigen detection data among blood donors, the age-specific proportion positive was highest among those aged 30–39 years, agreeing with the presence of dip in seroprevalence in this age-group. Among pregnant women, up to 107 fetal deaths and 21 hydrops fetalis were estimated to have occurred annually across Japan.
Seroepidemiological profiles of PVB19 infection in Japan was characterized with particular emphasis on the risk of infection in blood donors and the burden of infection among pregnant women. When a vaccine becomes available in the future, a similar seroepidemiological study is expected to play a key role in planning the appropriate immunization policy.
PMCID: PMC3962423  PMID: 24658180
4.  The Pandemic Influenza A (H1N1) 2009 Vaccine Does Not Increase the Mortality Rate of Idiopathic Interstitial Pneumonia: A Matched Case-Control Study 
PLoS ONE  2014;9(2):e88927.
Evidence regarding the mortality rate after administration of the pandemic influenza A (H1N1) 2009 vaccine on patients with underlying diseases is currently scarce. We conducted a case-control study in Japan to compare the mortality rates of patients with idiopathic interstitial pneumonia after the vaccines were administered and were not administered.
Between October 2009 and March 2010, we collected clinical records in Japan and conducted a 1∶1 matched case-control study. Patients with idiopathic interstitial pneumonia who died during this period were considered case patients, and those who survived were considered control patients. We determined and compared the proportion of each group that received the pandemic influenza A (H1N1) 2009 vaccine and estimated the odds ratio. Finally, we conducted simulations that compensated for the shortcomings of the study associated with adjusted severity of idiopathic interstitial pneumonia.
The case and control groups each comprised of 75 patients with idiopathic interstitial pneumonia. The proportion of patients who received the pandemic influenza A (H1N1) 2009 vaccine was 30.7% and 38.7% for the case and control groups, respectively. During that winter, the crude conditional odds ratio of mortality was 0.63 (95% confidence interval, 0.25–1.47) and the adjusted conditional odds ratio was 1.18 (95% confidence interval, 0.33–4.49); neither was significant. The simulation study showed more accurate conditional odds ratios of 0.63–0.71.
In our study, we detected no evidence that the influenza A (H1N1) 2009 vaccine increased the mortality rate of patients with idiopathic interstitial pneumonia. The results, however, are limited by the small sample size and low statistical power. A larger-scale study is required.
PMCID: PMC3934868  PMID: 24586445
5.  Age-Dependent Prevalence of Nasopharyngeal Carriage of Streptococcus pneumoniae before Conjugate Vaccine Introduction: A Prediction Model Based on a Meta-Analysis 
PLoS ONE  2014;9(1):e86136.
Data on the prevalence of nasopharyngeal carriage of S.pneumoniae in all age groups are important to help predict the impact of introducing pneumococcal conjugate vaccines (PCV) into routine infant immunization, given the important indirect effect of the vaccine. Yet most carriage studies are limited to children under five years of age. We here explore the association between carriage prevalence and serotype distribution in children aged ≥5 years and in adults compared to children.
We conducted a systematic review of studies providing carriage estimates across age groups in healthy populations not previously exposed to PCV, using MEDLINE and Embase. We used Bayesian linear meta-regression models to predict the overall carriage prevalence as well as the prevalence and distribution of vaccine and nonvaccine type (VT and NVT) serotypes in older age groups as a function of that in <5 y olds.
Twenty-nine studies compromising of 20,391 individuals were included in the analysis. In all studies nasopharyngeal carriage decreased with increasing age. We found a strong positive linear association between the carriage prevalence in pre-school childen (<5 y) and both that in school aged children (5–17 y olds) and in adults. The proportion of VT serotypes isolated from carriers was consistently lower in older age groups and on average about 73% that of children <5 y among 5–17 y olds and adults respectively. We provide a prediction model to infer the carriage prevalence and serotype distribution in 5–17 y olds and adults as a function of that in children <5 years of age.
Such predictions are helpful for assessing the potential population-wide effects of vaccination programmes, e.g. via transmission models, and thus assist in the design of future pneumococcal conjugate vaccination strategies.
PMCID: PMC3900487  PMID: 24465920
6.  Estimating the Delay between Host Infection and Disease (Incubation Period) and Assessing Its Significance to the Epidemiology of Plant Diseases 
PLoS ONE  2014;9(1):e86568.
Knowledge of the incubation period of infectious diseases (time between host infection and expression of disease symptoms) is crucial to our epidemiological understanding and the design of appropriate prevention and control policies. Plant diseases cause substantial damage to agricultural and arboricultural systems, but there is still very little information about how the incubation period varies within host populations. In this paper, we focus on the incubation period of soilborne plant pathogens, which are difficult to detect as they spread and infect the hosts underground and above-ground symptoms occur considerably later. We conducted experiments on Rhizoctonia solani in sugar beet, as an example patho-system, and used modelling approaches to estimate the incubation period distribution and demonstrate the impact of differing estimations on our epidemiological understanding of plant diseases. We present measurements of the incubation period obtained in field conditions, fit alternative probability models to the data, and show that the incubation period distribution changes with host age. By simulating spatially-explicit epidemiological models with different incubation-period distributions, we study the conditions for a significant time lag between epidemics of cryptic infection and the associated epidemics of symptomatic disease. We examine the sensitivity of this lag to differing distributional assumptions about the incubation period (i.e. exponential versus Gamma). We demonstrate that accurate information about the incubation period distribution of a pathosystem can be critical in assessing the true scale of pathogen invasion behind early disease symptoms in the field; likewise, it can be central to model-based prediction of epidemic risk and evaluation of disease management strategies. Our results highlight that reliance on observation of disease symptoms can cause significant delay in detection of soil-borne pathogen epidemics and mislead practitioners and epidemiologists about the timing, extent, and viability of disease control measures for limiting economic loss.
PMCID: PMC3899291  PMID: 24466153
7.  Cost-effective length and timing of school closure during an influenza pandemic depend on the severity 
There has been a variation in published opinions toward the effectiveness of school closure which is implemented reactively when substantial influenza transmissions are seen at schools. Parameterizing an age-structured epidemic model using published estimates of the pandemic H1N1-2009 and accounting for the cost effectiveness, we examined if the timing and length of school closure could be optimized.
Age-structured renewal equation was employed to describe the epidemic dynamics of an influenza pandemic. School closure was assumed to take place only once during the course of the pandemic, abruptly reducing child-to-child transmission for a fixed length of time and also influencing the transmission between children and adults. Public health effectiveness was measured by reduction in the cumulative incidence, and cost effectiveness was also examined by calculating the incremental cost effectiveness ratio and adopting a threshold of 1.0 × 107 Japanese Yen/life-year.
School closure at the epidemic peak appeared to yield the largest reduction in the final size, while the time of epidemic peak was shown to depend on the transmissibility. As the length of school closure was extended, we observed larger reduction in the cumulative incidence. Nevertheless, the cost effectiveness analysis showed that the cost of our school closure scenario with the parameters derived from H1N1-2009 was not justifiable. If the risk of death is three times or greater than that of H1N1-2009, the school closure could be regarded as cost effective.
There is no fixed timing and duration of school closure that can be recommended as universal guideline for different types of influenza viruses. The effectiveness of school closure depends on the transmission dynamics of a particular influenza virus strain, especially the virulence (i.e. the infection fatality risk).
PMCID: PMC3901768  PMID: 24447310
8.  Biochemical Phenotypes to Discriminate Microbial Subpopulations and Improve Outbreak Detection 
PLoS ONE  2013;8(12):e84313.
Clinical microbiology laboratories worldwide constitute an invaluable resource for monitoring emerging threats and the spread of antimicrobial resistance. We studied the growing number of biochemical tests routinely performed on clinical isolates to explore their value as epidemiological markers.
Methodology/Principal Findings
Microbiology laboratory results from January 2009 through December 2011 from a 793-bed hospital stored in WHONET were examined. Variables included patient location, collection date, organism, and 47 biochemical and 17 antimicrobial susceptibility test results reported by Vitek 2. To identify biochemical tests that were particularly valuable (stable with repeat testing, but good variability across the species) or problematic (inconsistent results with repeat testing), three types of variance analyses were performed on isolates of K. pneumonia: descriptive analysis of discordant biochemical results in same-day isolates, an average within-patient variance index, and generalized linear mixed model variance component analysis. Results: 4,200 isolates of K. pneumoniae were identified from 2,485 patients, 32% of whom had multiple isolates. The first two variance analyses highlighted SUCT, TyrA, GlyA, and GGT as “nuisance” biochemicals for which discordant within-patient test results impacted a high proportion of patient results, while dTAG had relatively good within-patient stability with good heterogeneity across the species. Variance component analyses confirmed the relative stability of dTAG, and identified additional biochemicals such as PHOS with a large between patient to within patient variance ratio. A reduced subset of biochemicals improved the robustness of strain definition for carbapenem-resistant K. pneumoniae. Surveillance analyses suggest that the reduced biochemical profile could improve the timeliness and specificity of outbreak detection algorithms.
The statistical approaches explored can improve the robust recognition of microbial subpopulations with routinely available biochemical test results, of value in the timely detection of outbreak clones and evolutionarily important genetic events.
PMCID: PMC3877295  PMID: 24391936
9.  Excess Mortality Associated With Influenza A and B Virus in Hong Kong, 1998–2009 
The Journal of Infectious Diseases  2012;206(12):1862-1871.
Background. Although deaths associated with laboratory-confirmed influenza virus infections are rare, the excess mortality burden of influenza estimated from statistical models may more reliably quantify the impact of influenza in a population.
Methods. We applied age-specific multiple linear regression models to all-cause and cause-specific mortality rates in Hong Kong from 1998 through 2009. The differences between estimated mortality rates in the presence or absence of recorded influenza activity were used to estimate influenza-associated excess mortality.
Results. The annual influenza-associated all-cause excess mortality rate was 11.1 (95% confidence interval [CI], 7.2–14.6) per 100 000 person-years. We estimated an average of 751 (95% CI, 488–990) excess deaths associated with influenza annually from 1998 through 2009, with 95% of the excess deaths occurring in persons aged ≥65 years. Most of the influenza-associated excess deaths were from respiratory (53%) and cardiovascular (18%) causes. Influenza A(H3N2) epidemics were associated with more excess deaths than influenza A(H1N1) or B during the study period.
Conclusions. Influenza was associated with a substantial number of excess deaths each year, mainly among the elderly, in Hong Kong in the past decade. The influenza-associated excess mortality rates were generally similar in Hong Kong and the United States.
PMCID: PMC3502382  PMID: 23045622
10.  Estimating Influenza Deaths in Canada, 1992–2009 
PLoS ONE  2013;8(11):e80481.
Poisson regression modelling has been widely used to estimate the disease burden attributable to influenza, though not without concerns that some of the excess burden could be due to other causes. This study aims to provide annual estimates of the mortality and hospitalization burden attributable to both seasonal influenza and the 2009 A/H1N1 pandemic influenza for Canada, and to discuss issues related to the reliability of these estimates.
Weekly time-series for all-cause mortality and regression models were used to estimate the number of deaths in Canada attributable to influenza from September 1992 to December 2009. To assess their robustness, the annual estimates derived from different parameterizations of the regression model for all-cause mortality were compared. In addition, the association between the annual estimates for mortality and hospitalization by age group, underlying cause of death or primary reason for admission and discharge status is discussed.
The crude influenza-attributed mortality rate based on all-cause mortality and averaged over 17 influenza seasons prior to the 2009 A/H1N1 pandemic was 11.3 (95%CI, 10.5 - 12.1) deaths per 100 000 population per year, or an average of 3,500 (95%CI, 3,200 - 3,700) deaths per year attributable to seasonal influenza. The estimated annual rates ranged from undetectable at the ecological level to more than 6000 deaths per year over the three A/Sydney seasons. In comparison, we attributed an estimated 740 deaths (95%CI, 350–1500) to A(H1N1)pdm09. Annual estimates from different model parameterizations were strongly correlated, as were estimates for mortality and morbidity; the higher A(H1N1)pdm09 burden in younger age groups was the most notable exception.
With the exception of some of the Serfling models, differences in the ecological estimates of the disease burden attributable to influenza were small in comparison to the variation in disease burden from one season to another.
PMCID: PMC3842334  PMID: 24312225
11.  A Bayesian Meta-Analysis on Prevalence of Hepatitis B Virus Infection among Chinese Volunteer Blood Donors 
PLoS ONE  2013;8(11):e79203.
Although transfusion-transmitted infection of hepatitis B virus (HBV) threatens the blood safety of China, the nationwide circumstance of HBV infection among blood donors is still unclear.
To comprehensively estimate the prevalence of HBsAg positive and HBV occult infection (OBI) among Chinese volunteer blood donors through bayesian meta-analysis.
We performed an electronic search in Pub-Med, Web of Knowledge, Medline, Wanfang Data and CNKI, complemented by a hand search of relevant reference lists. Two authors independently extracted data from the eligible studies. Then two bayesian random-effect meta-analyses were performed, followed by bayesian meta-regressions.
5957412 and 571227 donors were identified in HBsAg group and OBI group, respectively. The pooled prevalence of HBsAg group and OBI group among donors is 1.085% (95% credible interval [CI] 0.859%∼1.398%) and 0.094% (95% CI 0.0578%∼0.1655%). For HBsAg group, subgroup analysis shows the more developed area has a lower prevalence than the less developed area; meta-regression indicates there is a significant decreasing trend in HBsAg positive prevalence with sampling year (beta = −0.1202, 95% −0.2081∼−0.0312).
Blood safety against HBV infection in China is suffering serious threats and the government should take effective measures to improve this situation.
PMCID: PMC3827339  PMID: 24236110
12.  Detection of Oseltamivir-Resistant Pandemic Influenza A(H1N1)pdm2009 in Brazil: Can Community Transmission Be Ruled Out? 
PLoS ONE  2013;8(11):e80081.
Although surveillance efforts that monitor the emergence of drug-resistant strains of influenza are critical, systematic analysis is overlooked in most developing countries. We report on the occurrence of strains of pandemic influenza A(H1N1)pdm09 with resistance and decreased susceptibility to oseltamivir (OST) in Brazil in 2009, 2011 and 2012. We found 7 mutant viruses, 2 with the mutation S247N and other 5 with the mutation H275Y. Most of these viruses were from samples concentrated in the southern region of Brazil. Some of these resistant viruses were detected prior to the initiation of OST treatment, suggesting that community transmission of mutant viruses may exist. Moreover, we show that one of these OST-resistant (H275Y) strains of A(H1N1)pdm09 was discovered in the tri-border region between Brazil, Argentina and Paraguay, highlighting that this strain could also be found in other Latin American countries. Our findings reinforce the importance of enhanced antiviral resistance surveillance in Brazil and in other Latin American countries to confirm or rule out the community transmission of OST-resistant strains of A(H1N1)pdm09.
PMCID: PMC3823798  PMID: 24244615
13.  Epidemiology and Risk Factors of Cervical Spine Injury during Heating Season in the Patients with Cervical Trauma: A Cross-Sectional Study 
PLoS ONE  2013;8(11):e78358.
The purpose of this study was to describe the epidemiology of cervical spine injury in the patients with cervical trauma and analyze its associated risk factors during the special heating season in North China.
This cross-sectional study investigated predictors for cervical spine injury in cervical trauma patients using retrospectively collected data of Hebei Provincial Orthopaedic Hospital from 11/2011 to 02/2012, and 11/2012 to 02/2013. Binary logistic regression analysis was used to determine risk factors for cervical fractures/dislocations or cord injury.
A total of 106 patients were admitted into this study. Of all, 34 patients (32.1%) were treated from 11/2011 to 02/2012 and 72 patients (67.9%) from 11/2012 to 02/2013. The mean age was 41.9±13.3 years old; 85 patients (80.2%) were male and 82 (77.4%) from rural areas. Eighty patients (75.5%) were caused by fall including 45 (42.5%) by severe fall (>2 m). Sixty-five patients (61.3%) of all suffered injuries to other body regions and 32 (30.2%) got head injury. Thirty-one patients (29.2%) sustained cervical cord injury with cervical fractures/dislocations. Twenty-six (83.9%) of cervical cord injury patients were from rural areas and 24 (77.4%) of those resulted from fall including 15 (48.4%) from severe fall (>2 m). Logistic regression displayed that age (OR, 1.47; 95% CI, 1.05–2.07), head injury (OR, 5.63; 95% CI, 2.23–14.26), were risk factors for cervical cord injury and snowing (OR, 8.25; 95% CI, 2.26–30.15) was a risk factor for cervical spine injury due to severe fall (>2 m).
The elder male patients and patients with head trauma are high-risk population for cervical cord injury. As a seasonal factor, snowing during heating season is of note a risk factor for cervical spine injury resulting from severe fall (>2 m) in the patients with cervical trauma in North China.
PMCID: PMC3817250  PMID: 24223795
14.  Predicting the Long-Term Impact of Antiretroviral Therapy Scale-Up on Population Incidence of Tuberculosis 
PLoS ONE  2013;8(9):e75466.
To investigate the impact of antiretroviral therapy (ART) on long-term population-level tuberculosis disease (TB) incidence in sub-Saharan Africa.
We used a mathematical model to consider the effect of different assumptions about life expectancy and TB risk during long-term ART under alternative scenarios for trends in population HIV incidence and ART coverage.
All the scenarios we explored predicted that the widespread introduction of ART would initially reduce population-level TB incidence. However, many modelled scenarios projected a rebound in population-level TB incidence after around 20 years. This rebound was predicted to exceed the TB incidence present before ART scale-up if decreases in HIV incidence during the same period were not sufficiently rapid or if the protective effect of ART on TB was not sustained. Nevertheless, most scenarios predicted a reduction in the cumulative TB incidence when accompanied by a relative decline in HIV incidence of more than 10% each year.
Despite short-term benefits of ART scale-up on population TB incidence in sub-Saharan Africa, longer-term projections raise the possibility of a rebound in TB incidence. This highlights the importance of sustaining good adherence and immunologic response to ART and, crucially, the need for effective HIV preventive interventions, including early widespread implementation of ART.
PMCID: PMC3775764  PMID: 24069418
15.  A Novel Approach to Accounting for Loss to Follow-Up when Estimating the Relationship between CD4 Count at ART Initiation and Mortality 
PLoS ONE  2013;8(7):e69300.
While CD4 strongly predicts mortality on antiretroviral therapy (ART), estimates from programmatic data suffer from incomplete patient outcomes.
We conducted a pooled analysis of one-year mortality data on ART accounting for lost patients. We identified articles reporting one-year mortality by ART initiation CD4 count. We estimated the average mortality among those lost as the value that maximizes the fit of a regression of the natural log of mortality on the natural log of the imputed mean CD4 count in each band.
We found 20 studies representing 64,426 subjects and 51 CD4 observations. Without correcting for losses, one-year mortality was >4.8% for all CD4 counts <200 cells/mm3. When searching over different values for mortality among those lost, the best fitting model occurs at 60% mortality. In this model, those with a CD4≤200 had a one-year mortality above 8.7, while those with a CD4>500 had a one-year mortality <6.8%. Comparing those starting ART at 500 vs. 50, one-year mortality risk was reduced by 54% (6.8 vs. 12.5%). Regardless of CD4 count, mortality was substantially higher than when assuming no mortality among those lost, ranging from a 23–94% increase.
Our best fitting regression estimates that every 10% increase in CD4 count at initiation is associated with a 2.8% decline in one-year mortality, including those lost. Our study supports the health benefits of higher thresholds for CD4 count initiation and suggests that reports of programmatic ART outcomes can and should adjust results for mortality among those lost.
PMCID: PMC3728360  PMID: 23935977
16.  Theoretical Biology and Medical Modelling: ensuring continued growth and future leadership 
Theoretical biology encompasses a broad range of biological disciplines ranging from mathematical biology and biomathematics to philosophy of biology. Adopting a broad definition of "biology", Theoretical Biology and Medical Modelling, an open access journal, considers original research studies that focus on theoretical ideas and models associated with developments in biology and medicine.
PMCID: PMC3710265  PMID: 23842034
17.  Decreasing Fertility Rate Correlates with the Chronological Increase and Geographical Variation in Incidence of Kawasaki Disease in Japan 
PLoS ONE  2013;8(7):e67934.
Kawasaki disease (KD) is a common cause of acquired paediatric heart disease in developed countries. KD was first identified in the 1960s in Japan, and has been steadily increasing since it was first reported. The aetiology of KD has not been defined, but is assumed to be infection-related. The present study sought to identify the factor(s) that mediate the geographical variation and chronological increase of KD in Japan.
Methods and Findings
Based upon data reported between 1979 and 2010 from all 47 prefectures in Japan, the incidence and mean patient age at the onset of KD were estimated. Using spatial and time-series analyses, incidence and mean age were regressed against climatic/socioeconomic variables. Both incidence and mean age of KD were inversely correlated with the total fertility rate (TFR; i.e., the number of children that would be born to one woman). The extrapolation of a time-series regressive model suggested that KD emerged in the 1960s because of a dramatic decrease in TFR in the 1940s through the 1950s.
Mean patient age is an inverse surrogate for the hazard of contracting the aetiologic agent. Therefore, the observed negative correlation between mean patient age and TFR suggests that a higher TFR is associated with KD transmission. This relationship may be because a higher TFR facilitates sibling-to-sibling transmission. Additionally, the observed inverse correlation between incidence and TFR implies a paradoxical “negative” correlation between the incidence and the hazard of contracting the aetiologic agent. It was hypothesized that a decreasing TFR resulted in a reduced hazard of contracting the agent for KD, thereby increasing KD incidence.
PMCID: PMC3704585  PMID: 23861836
18.  Incidence Survey of Acute Otitis Media in Children in Sado Island, Japan—Sado Otitis Media Study (SADOMS) 
PLoS ONE  2013;8(7):e68711.
Acute otitis media (AOM) is one of the most common forms of bacterial infection and cause for clinic visits in children. The incidence of AOM was 0.9–1.2 episodes per person-year during the first 2 years of life in previous reports conducted before 2000. The aim of this study was to 1) evaluate the latest AOM incidence in pediatric outpatients and 2) identify the bacterial pathogens from these patients and ascertain their serotypes and resistance.
The study was conducted in a closed population, involving all pediatricians and otolaryngologists in Sado Island allowing accurate determination of AOM incidence. In each month, one week was assigned as “surveillance week”, and all outpatients with acute illness aged 0–18 years examined during the surveillance weeks were enrolled. AOM was diagnosed on the basis of otoscopic findings and clinical symptoms were recorded. Specimens were collected from the nasopharynx or middle ear cavity of AOM patients and examined for bacteria. Antimicrobial susceptibilities, serotypes, and molecular typing for resistance were determined among Streptococcus pneumoniae and Haemophilus influenzae.
In total, 8,283 clinic visits were conducted, and 354 episodes (4.3%, 95% CI: 3.9–4.7%) among 312 children were diagnosed as AOM. The incidence of AOM was highest in children of 1 year of age (0.54 episodes/child/year, 95% CI: 0.44–0.64). Serotype coverage of 7- and 13-valent pneumococcal conjugate vaccines in this study were 38.0% (95% CI: 29.3–47.3) and 62.8% (95% CI: 53.6–71.4), respectively. Of 122 H.influenzae isolates available for typing, 120 were nontypeable and 2 were type b. A high proportion of S. pneumoniae isolates (46%) showed resistance to penicillin. Approximately half of H. influenzae isolates had genetic markers for beta-lactamase-negative ampicillin-resistance.
Approximately 4–5% of pediatric outpatients, even without AOM-related symptoms, had AOM in our study. Pediatricians as well as otolaryngologists should check the tympanic membrane findings of all pediatric outpatients.
PMCID: PMC3699511  PMID: 23844235
19.  Household transmission of 2009 pandemic influenza A(H1N1): a systematic review and meta-analysis 
Epidemiology (Cambridge, Mass.)  2012;23(4):531-542.
During the 2009 influenza A(H1N1) pandemic, household transmission studies were implemented to understand better the characteristics of the transmission of the novel virus in a confined setting.
We conducted a systematic review and meta-analysis to assess and summarize the findings of these studies. We identified 27 articles, around half of which reported studies conducted in May and June 2009.
In 13 of the 27 studies (48%) that collected respiratory specimens from household contacts, point estimates of the risk of secondary infection ranged from 3 to 38%, with substantial heterogeneity. Meta-regression analyses revealed that a part of the heterogeneity reflected varying case ascertainment and study designs. The estimates of symptomatic secondary infection risk, based on 20 studies identifying febrile acute respiratory illness among household contacts, also showed substantial variability, with point estimates ranging from 4% to 37%.
Transmission of the 2009 pandemic virus in households appeared to vary in different countries and settings, with differences in estimates of the secondary infection risk also partly due to differences in study designs.
PMCID: PMC3367058  PMID: 22561117
20.  Aerosol transmission is an important mode of influenza A virus spread 
Nature communications  2013;4:1935.
Influenza A viruses are believed to spread between humans through contact, large respiratory droplets and small particle droplet nuclei (aerosols), but the relative importance of each of these modes of transmission is unclear. Volunteer studies suggest that infections via aerosol transmission may have a higher risk of febrile illness. Here we apply a mathematical model to data from randomized controlled trials of hand hygiene and surgical face masks in Hong Kong and Bangkok households. In these particular environments, inferences on the relative importance of modes of transmission are facilitated by information on the timing of secondary infections and apparent differences in clinical presentation of secondary infections resulting from aerosol transmission. We find that aerosol transmission accounts for approximately half of all transmission events. This implies that measures to reduce transmission by contact or large droplets may not be sufficient to control influenza A virus transmission in households.
PMCID: PMC3682679  PMID: 23736803
21.  Increased Risk of Noninfluenza Respiratory Virus Infections Associated With Receipt of Inactivated Influenza Vaccine 
We randomized 115 children to trivalent inactivated influenza vaccine (TIV) or placebo. Over the following 9 months, TIV recipients had an increased risk of virologically-confirmed non-influenza infections (relative risk: 4.40; 95% confidence interval: 1.31-14.8). Being protected against influenza, TIV recipients may lack temporary non-specific immunity that protected against other respiratory viruses.
PMCID: PMC3404712  PMID: 22423139
22.  Occupation and Environmental Heat-Associated Deaths in Maricopa County, Arizona: A Case-Control Study 
PLoS ONE  2013;8(5):e62596.
Prior research shows that work in agriculture and construction/extraction occupations increases the risk of environmental heat-associated death.
To assess the risk of environmental heat-associated death by occupation.
This was a case-control study. Cases were heat-caused and heat-related deaths occurring from May-October during the period 2002–2009 in Maricopa County, Arizona. Controls were selected at random from non-heat-associated deaths during the same period in Maricopa County. Information on occupation, age, sex, and race-ethnicity was obtained from death certificates. Logistic regression analysis was used to estimate odds ratios for heat-associated death.
There were 444 cases of heat-associated deaths in adults (18+ years) and 925 adult controls. Of heat-associated deaths, 332 (75%) occurred in men; a construction/extraction or agriculture occupation was described on the death certificate in 115 (35%) of these men. In men, the age-adjusted odds ratios for heat-associated death were 2.32 (95% confidence interval 1.55, 3.48) in association with construction/extraction and 3.50 (95% confidence interval 1.94, 6.32) in association with agriculture occupations. The odds ratio for heat-associated death was 10.17 (95% confidence interval 5.38, 19.23) in men with unknown occupation. In women, the age-adjusted odds ratio for heat-associated death was 6.32 (95% confidence interval 1.48, 27.08) in association with unknown occupation. Men age 65 years and older in agriculture occupations were at especially high risk of heat-associated death.
The occurrence of environmental heat-associated death in men in agriculture and construction/extraction occupations in a setting with predictable periods of high summer temperatures presents opportunities for prevention.
PMCID: PMC3667080  PMID: 23734174
23.  How to interpret the transmissibility of novel influenza A(H7N9): an analysis of initial epidemiological data of human cases from China 
As the human infections with novel influenza A(H7N9) virus have been reported from several different provinces in China, the pandemic potential of the virus has been questioned. The presence of human-to-human transmission has not been demonstrated, but the absence of demonstration does not guarantee that there is no such transmission.
A mathematical model of cluster size distribution is devised without imposing an assumption of subcriticality of the reproduction number and accounting for right censoring of new clusters. The proportion of cases with a history of bird contact is analytically derived, permitting us to fit the model to the observed data of confirmed cases. Using contact history with bird among confirmed cases (n = 129), we estimate the reproduction number of the novel influenza A(H7N9) from human to human.
Analysing twenty confirmed cases with known exposure, the reproduction number for human-to-human transmission was estimated at 0.28 (95% CI: 0.11, 0.45). Sensitivity analysis indicated that the reproduction number is substantially below unity.
It is unlikely to observe an immediate pandemic of novel influenza A(H7N9) virus with human to human transmission. Continued monitoring of cases and animals would be the key to elucidate additional epidemiological characteristics of the virus.
PMCID: PMC3655037  PMID: 23642092
24.  Sex Bias in Infectious Disease Epidemiology: Patterns and Processes 
PLoS ONE  2013;8(4):e62390.
Infectious disease incidence is often male-biased. Two main hypotheses have been proposed to explain this observation. The physiological hypothesis (PH) emphasizes differences in sex hormones and genetic architecture, while the behavioral hypothesis (BH) stresses gender-related differences in exposure. Surprisingly, the population-level predictions of these hypotheses are yet to be thoroughly tested in humans.
Methods and Findings
For ten major pathogens, we tested PH and BH predictions about incidence and exposure-prevalence patterns. Compulsory-notification records (Brazil, 2006–2009) were used to estimate age-stratified ♂:♀ incidence rate ratios for the general population and across selected sociological contrasts. Exposure-prevalence odds ratios were derived from 82 published surveys. We estimated summary effect-size measures using random-effects models; our analyses encompass ∼0.5 million cases of disease or exposure. We found that, after puberty, disease incidence is male-biased in cutaneous and visceral leishmaniasis, schistosomiasis, pulmonary tuberculosis, leptospirosis, meningococcal meningitis, and hepatitis A. Severe dengue is female-biased, and no clear pattern is evident for typhoid fever. In leprosy, milder tuberculoid forms are female-biased, whereas more severe lepromatous forms are male-biased. For most diseases, male bias emerges also during infancy, when behavior is unbiased but sex steroid levels transiently rise. Behavioral factors likely modulate male–female differences in some diseases (the leishmaniases, tuberculosis, leptospirosis, or schistosomiasis) and age classes; however, average exposure-prevalence is significantly sex-biased only for Schistosoma and Leptospira.
Our results closely match some key PH predictions and contradict some crucial BH predictions, suggesting that gender-specific behavior plays an overall secondary role in generating sex bias. Physiological differences, including the crosstalk between sex hormones and immune effectors, thus emerge as the main candidate drivers of gender differences in infectious disease susceptibility.
PMCID: PMC3634762  PMID: 23638062
25.  The Impact of Model Building on the Transmission Dynamics under Vaccination: Observable (Symptom-Based) versus Unobservable (Contagiousness-Dependent) Approaches 
PLoS ONE  2013;8(4):e62062.
The way we formulate a mathematical model of an infectious disease to capture symptomatic and asymptomatic transmission can greatly influence the likely effectiveness of vaccination in the presence of vaccine effect for preventing clinical illness. The present study aims to assess the impact of model building strategy on the epidemic threshold under vaccination.
Methodology/Principal Findings
We consider two different types of mathematical models, one based on observable variables including symptom onset and recovery from clinical illness (hereafter, the “observable model”) and the other based on unobservable information of infection event and infectiousness (the “unobservable model”). By imposing a number of modifying assumptions to the observable model, we let it mimic the unobservable model, identifying that the two models are fully consistent only when the incubation period is identical to the latent period and when there is no pre-symptomatic transmission. We also computed the reproduction numbers with and without vaccination, demonstrating that the data generating process of vaccine-induced reduction in symptomatic illness is consistent with the observable model only and examining how the effective reproduction number is differently calculated by two models.
To explicitly incorporate the vaccine effect in reducing the risk of symptomatic illness into the model, it is fruitful to employ a model that directly accounts for disease progression. More modeling studies based on observable epidemiological information are called for.
PMCID: PMC3625221  PMID: 23593507

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