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1.  Hygiene, atopy and wheeze–eczema–rhinitis symptoms in schoolchildren from urban and rural Ecuador 
Thorax  2013;69(3):232-239.
Background
Rural residence is protective against atopy and wheeze–rhinitis–eczema symptoms in developed countries, an effect attributed to farming and poor hygiene exposures. There are few data from developing countries addressing this question. We compared atopy and wheeze–rhinitis–eczema symptoms between urban and rural Ecuador, and explored the effects of farming and poor hygiene exposures.
Methods
We performed cross sectional studies of schoolchildren living in rural and urban Ecuador. Data on symptoms and farming/hygiene exposures were collected by parental questionnaire, atopy by allergen skin prick test reactivity and geohelminth infections by stool examinations.
Results
Among 2526 urban and 4295 rural schoolchildren, prevalence was: atopy (10.0% vs 12.5%, p=0.06), wheeze (9.4% vs 10.1%, p=0.05), rhinitis (8.1% vs 6.4%, p=0.02) and eczema (5.9% vs 4.7%, p=0.06). A small proportion of symptoms were attributable to atopy (range 3.9–10.7%) with greater attributable fractions for respiratory symptoms observed in urban schoolchildren. Respiratory symptoms were associated with poor hygiene/farming exposures: wheeze with lack of access to potable water; and rhinitis with household pets, no bathroom facilities and contact with large farm animals. Birth order was inversely associated with respiratory symptoms. Area of residence and atopy had few effects on these associations.
Conclusions
Urban schoolchildren living in Ecuador have a similar prevalence of atopy, eczema and wheeze but a higher prevalence of rhinitis compared with rural children. Some farming and poor hygiene exposures were associated with an increase in the prevalence of wheeze or rhinitis while birth order was inversely associated with these symptoms.
doi:10.1136/thoraxjnl-2013-203818
PMCID: PMC3932750  PMID: 24105783
Wheeze-Rhinitis-Eczema; Atopy; Hygiene; Farming; Urban-Rural
2.  The second study of infectious intestinal disease (IID2): increased rates of recurrent diarrhoea in individuals aged 65 years and above 
BMC Public Health  2013;13:739.
Background
Infectious intestinal disease (IID) is a major health and economic burden in high-income countries. In the UK, there are an estimated 17 million IID cases annually, of which 6 million are caused by the 12 most common pathogens. Host factors that influence risk of IID are not well understood.
Methods
We analyzed data from the IID2 Study, a UK cohort that measured IID incidence, to investigate factors associated with recurrent IID. We calculated rates of IID by age group, sex, previous episodes experienced, and socioecomic indicators. We used Cox models to investigate factors associated with recurrent illness.
Results
The rate of IID was five times higher among infants than those aged 65 years and above (hazard ratio, HR = 5.0, 95% CI: 3.1 – 8.0). However, the association between previous IID and a subsequent IID episode was stronger in the elderly. Among those aged 65 years and above, each additional IID episode increased the rate of subsequent IID three-fold (HR = 3.1, 95% CI: 2.5 – 3.7). Among infants, the corresponding increase was 1.7-fold (HR = 1.7, 95% CI: 1.3 – 2.3).
Conclusions
Elderly populations have a high propensity for recurrent IID. More detailed studies are needed to identify vulnerable subgroups and susceptibility factors, and inform adequate control policies among the elderly.
doi:10.1186/1471-2458-13-739
PMCID: PMC3750603  PMID: 24219653
Diarrhoea; Diarrhoeal diseases; Infectious intestinal disease; Enteric pathogens; Elderly populations; Cohort studies
3.  BCG vaccination in England since 2005: a survey of policy and practice 
BMJ Open  2012;2(5):e001303.
Objective
Assess the current BCG vaccination policies and delivery pathways for immunisation in Primary Care Trusts (PCTs) in England since the 2005 change in recommendations.
Design
A survey of key informants across PCTs using a standardised, structured questionnaire.
Setting
152 PCTs in England.
Results
Complete questionnaires were returned from 127 (84%) PCTs. Sixteen (27%) PCTs reported universal infant vaccination and 111 (73%) had selective infant vaccination. Selective vaccination outside infancy was also reported from 94 (74%) PCTs. PCTs with selective infant policy most frequently vaccinated on postnatal wards (51/102, 50%), whereas PCTs with universal infant vaccination most frequently vaccinated in community clinics (9/13, 69%; p=0.011). To identify and flag up eligible infants in PCTs with targeted infant immunisation, those who mostly vaccinate on postnatal wards depend on midwives and maternity records, whereas those who vaccinate primarily in the community rely more often on various healthcare professionals.
Conclusions
Targeted infant vaccination has been implemented in most PCTs across the UK. PCTs with selective infant vaccination provide BCG vaccine via a greater variety of healthcare professionals than those with universal infant vaccination policies. Data on vaccine coverage would help evaluate the effectiveness of delivery. Interruptions of delivery noted here emphasise the importance of not just an agreed, standardised, local pathway, but also a named person in charge.
doi:10.1136/bmjopen-2012-001303
PMCID: PMC3467615  PMID: 22964115
4.  Behavior problems and prevalence of asthma symptoms among Brazilian children 
Journal of Psychosomatic Research  2011;71(3):160-165.
Objective
Asthma is the most common chronic disease in childhood and has been designated a public health problem due to the increase in its prevalence in recent decades, the amount of health service expenditure it absorbs and an absence of consensus about its etiology. The relationships among psychosocial factors and the occurrence, symptomatology, and severity of asthma have recently been considered. There is still controversy about the association between asthma and a child's mental health, since the pathways through which this relationship is established are complex and not well researched. This study aims to investigate whether behavior problems are associated with the prevalence of asthma symptoms in a large urban center in Latin America.
Methods
It is a cross-section study of 869 children between 6 and 12 years old, residents of Salvador, Brazil. The International Study of Allergy and Asthma in Childhood (ISAAC) instrument was used to evaluate prevalence of asthma symptoms. The Child Behavior Checklist (CBCL) was employed to evaluate behavioral problems.
Results
19.26% (n = 212) of the children presented symptoms of asthma. 35% were classified as having clinical behavioral problems. Poisson's robust regression model demonstrated a statistically significant association between the presence of behavioral problems and asthma symptoms occurrence (PR: 1.43; 95% CI: 1.10–1.85).
Conclusion
These results suggest an association between behavioral problems and pediatric asthma, and support the inclusion of mental health care in the provision of services for asthma morbidity.
doi:10.1016/j.jpsychores.2011.02.004
PMCID: PMC3160547  PMID: 21843751
SCAALA, Social Changes, Asthma and Allergy in Latin America; ISAAC, International Study of Asthma and Allergies in Childhood; CBCL, Child Behavior Checklist; ICC, Intraclass correlation coefficient; Childhood asthma; Behavior problems; SCAALA Programme
5.  Urbanisation is associated with prevalence of childhood asthma in diverse, small rural communities in Ecuador 
Thorax  2011;66(12):1043-1050.
Background
Studies conducted in transitional communities from Africa and Asia have pointed to the process of urbanisation as being responsible for the increase in asthma prevalence in developing regions. In Latin America, there are few published data available on the potential impact of urbanisation on asthma prevalence. The aim of the present study was to explore how the process of urbanisation may explain differences in asthma prevalence in transitional communities in north-eastern Ecuador.
Methodology/principal findings
An ecological study was conducted in 59 communities in Esmeraldas Province, Ecuador. Indicators of urbanisation were grouped into three indices representing the processes associated with urbanisation: socioeconomic, lifestyle and urban infrastructure. Categorical principal components analysis was used to generate scores for each index and a fourth index—a summary urbanisation index—was derived from the most representative variables in each of the three indices. The authors analysed the associations between community asthma prevalence and the indices, as well as with each indicator variable of every group. The overall prevalence of asthma was 10.1% (range 0–31.4% between communities). Three of the four indices presented significant associations with community asthma prevalence: socioeconomic (r=0.295, p=0.023), lifestyle (r=0.342, p=0.008) and summary urbanisation index (r=0.355, p=0.006). Variables reflecting better socioeconomic status and a more urban lifestyle were associated with greater asthma prevalence.
Conclusions
These data provide evidence that the prevalence of asthma increases with increasing levels of urbanisation in transitional communities, and factors associated with greater socioeconomic level and changes towards a more urban lifestyle may be particularly important.
doi:10.1136/thoraxjnl-2011-200225
PMCID: PMC3221322  PMID: 21825085
Asthma; urbanisation; transitional communities; childhood; urban lifestyle; asthma epidemiology; asthma in primary care; bacterial infection; cytokine biology; eosinophil biology; exercise; immunodeficiency; lymphocyte biology; neutrophil biology; allergic lung disease; respiratory infection; tuberculosis; asthma guidelines; cystic fibrosis; exhaled airway markers; lung physiology; paediatric asthma; paediatric lung disease
6.  Pattern of asthma medication use among children from a large urban center in Brazil 
Purpose
Despite the advances in asthma therapeutics, there are few data on the use and determinants of anti-asthmatic drugs in the general population of children. This study describes the use of asthma medications among children in the general population and in children with current asthma, living in a large urban center in Brazil.
Methods
A population-based cross-sectional survey, aimed at analyzing asthma determinants, was conducted with 1,382 children aged 4–11 years, between February and May 2006, in Salvador, Brazil. At baseline, an extensive questionnaire was applied, including questions about the use of asthma medications in the last 12 months.
Results
In all studied children (n = 1,382) aged 4–11 years, oral beta2-agonists were the drugs most frequently used (9.8%), followed by short-acting inhaled beta2-agonists (4.3%) and systemic corticosteroids (1.6%). Anti-asthmatic drug use was higher among males than females, and it significantly decreased with age in both genders. A total of 312 children (22.6%) reported current asthma, and 62% of them were not being treated with any anti-asthmatic drugs. Of all those who reported following a certain type of treatment, 20% used oral beta2-agonists alone; 6.1%, short-acting inhaled beta2-agonists alone; and 4.8%, a combination of both drugs. Anti-asthmatic drug use did not differ according to socioeconomic status, except for the use of inhaled beta2-agonists and systemic corticosteroids.
Conclusions
An overwhelming majority of asthmatic children were not using long-term medications for asthma, in particular inhaled corticosteroids, regardless of the severity of their disease. This result points to the deficiencies of the Brazilian public health system in recognizing this important pharmacological need for child care and thereby limiting the access of these children to a group of efficacious, available, and low risk therapeutic medications.
doi:10.1007/s00228-011-1092-6
PMCID: PMC3414696  PMID: 21717145
Asthma; Pharmacoepidemiology; Asthma; Therapy; Children; Prevalence; Cross-sectional studies; Brazil
7.  Longitudinal study of infectious intestinal disease in the UK (IID2 study): incidence in the community and presenting to general practice 
Gut  2011;61(1):69-77.
Objectives
To estimate, overall and by organism, the incidence of infectious intestinal disease (IID) in the community, presenting to general practice (GP) and reported to national surveillance.
Design
Prospective, community cohort study and prospective study of GP presentation conducted between April 2008 and August 2009.
Setting
Eighty-eight GPs across the UK recruited from the Medical Research Council General Practice Research Framework and the Primary Care Research Networks.
Participants
6836 participants registered with the 88 participating practices in the community study; 991 patients with UK-acquired IID presenting to one of 37 practices taking part in the GP presentation study.
Main outcome measures
IID rates in the community, presenting to GP and reported to national surveillance, overall and by organism; annual IID cases and GP consultations by organism.
Results
The overall rate of IID in the community was 274 cases per 1000 person-years (95% CI 254 to 296); the rate of GP consultations was 17.7 per 1000 person-years (95% CI 14.4 to 21.8). There were 147 community cases and 10 GP consultations for every case reported to national surveillance. Norovirus was the most common organism, with incidence rates of 47 community cases per 1000 person-years and 2.1 GP consultations per 1000 person-years. Campylobacter was the most common bacterial pathogen, with a rate of 9.3 cases per 1000 person-years in the community, and 1.3 GP consultations per 1000 person-years. We estimate that there are up to 17 million sporadic, community cases of IID and 1 million GP consultations annually in the UK. Of these, norovirus accounts for 3 million cases and 130 000 GP consultations, and Campylobacter is responsible for 500 000 cases and 80 000 GP consultations.
Conclusions
IID poses a substantial community and healthcare burden in the UK. Control efforts must focus particularly on reducing the burden due to Campylobacter and enteric viruses.
doi:10.1136/gut.2011.238386
PMCID: PMC3230829  PMID: 21708822
Campylobacter; diarrhoeal disease; epidemiology; infectious diarrhoea; salmonella
8.  Chronic virus infections supress atopy but not asthma in a set of children from a large latin american city: a cross-section study 
Background
The prevalence of allergic diseases has increased over recent decades in affluent countries, but remains low in rural populations and some non-affluent countries. An explanation for these trends is that increased exposure to infections may provide protection against the development of allergy. In this work we investigated the association between exposure to viral infections in children living in urban Brazil and the prevalence of atopy and asthma.
Methods
School age children living in poor neighborhoods in the city of Salvador were studied. Data on asthma symptoms and relevant risk factors were obtained by questionnaire. Skin prick tests (SPTs) were performed to seven aeroallergens, and specific IgE was measured to four of these. Viral infections were determined by the presence of specific IgG in serum to Herpes simplex (HSV), Herpes zoster (HZV), Epstein-Barr (EBV), and Hepatitis A (HAV) viruses.
Results
A total of 644 (49.7%) children had at least one allergen-specific IgE> 0.35 kU/L and 489 (37.7%) had specific IgE> 0.70 kU/L. A total of 391 (30.2%) children were skin test positive (SPT+), and 295 (22.8%) children were asthmatic. The seroprevalence of viral infections was 88.9% for EBV, 55.4% for HSV, 45.5% for VZV and 17.5% for HAV. Negative associations were observed between SPT+ and HSV (OR = 0.64, CI = 0.51, 0.82) and EBV (OR = 0.63, CI = 0.44, 0.89) infections, but no associations were seen between viral infections and the presence of allergen-specific IgE or asthma.
Conclusion
These data do not support previous data showing a protective effect of HAV against atopy, but did show inverse associations between SPT+ (but not specific IgE+) and infections with HSV and EBV. These findings suggest that different viral infections may protect against SPT+ in different settings and may indicate an immunoregulatory role of such infections on immediate hypersensitivity responses. The data provide no support for a protective effect of viral infections against asthma in this population.
doi:10.1186/1471-2466-11-24
PMCID: PMC3125392  PMID: 21569568
9.  Selection and quantification of infection endpoints for trials of vaccines against intestinal helminths 
Vaccine  2011;29(20):3686-3694.
Vaccines against human helminths are being developed but the choice of optimal parasitological endpoints and effect measures to assess their efficacy has received little attention. Assuming negative binomial distributions for the parasite counts, we rank the statistical power of three measures of efficacy: ratio of mean parasite intensity at the end of the trial, the odds ratio of infection at the end of the trial, and the rate ratio of incidence of infection during the trial. We also use a modelling approach to estimate the likely impact of trial interventions on the force of infection, and hence statistical power. We conclude that (1) final mean parasite intensity is a suitable endpoint for later phase vaccine trials, and (2) mass effects of trial interventions are unlikely to appreciably reduce the force of infection in the community – and hence statistical power – unless there is a combination of high vaccine efficacy and a large proportion of the population enrolled.
doi:10.1016/j.vaccine.2011.03.026
PMCID: PMC3093614  PMID: 21435404
Helminth vaccines; Parasitological endpoints; Mathematical model
10.  Evidence for a modulatory effect of IL-10 on both Th1 and Th2 cytokine production: The role of the environment 
Clinical Immunology (Orlando, Fla.)  2011;139(1-3):57-64.
Allergic and other immune-mediated diseases are complex disease states determined by interplay between host genetics and environmental factors. Environmental changes such as fewer infections and reduced exposure to microbial products have been suggested to have led to insufficient regulation of Th1 and Th2 immune responses, causing an increased incidence of inflammatory diseases. The objective of the present study was to investigate the effect of poor living environmental conditions on mitogen-induced production of cytokines (Th1 and Th2) by peripheral blood leukocytes in children living in urban Brazil and investigate the role of IL-10 in modifying this effect. Our data showed that the proportion of children producing Th1 and Th2 cytokines was lower among those with poor living conditions and that this finding was stronger in children producing IL-10. These results provide a possible biologic explanation for the temporal trends of increasing risk of inflammatory diseases observed in populations living in affluent countries.
doi:10.1016/j.clim.2010.12.019
PMCID: PMC3070800  PMID: 21285005
BMI, Body mass index; CpG-DNA, bacterial DNA; DC, dendritic cell; IFN, Interferon; LB, B lymphocyte; LPS, lipopolysaccharide; MΦ, macrophage; MHC, major histocompatibility complex; Neu, neutrophil; NO, nitric oxide; OR, odds ratio; PBLs, peripheral blood leukocytes; SCAALA, Social Changes Asthma and Allergy in Latin America; TGF-β, transforming growth factor β; Th1, T helper 1; Th17, T helper 17; Th2, T helper 2; TLR, toll like receptors; Treg, T regulatory; WBC, whole blood cells culture; IL-10; Th1/Th2; Environment; Sewage system; Street paving; Immune regulation
11.  Effect of reminders on mitigating participation bias in a case-control study 
Background
Researchers commonly employ strategies to increase participation in health studies. These include use of incentives and intensive reminders. There is, however, little evidence regarding the quantitative effect that such strategies have on study results. We present an analysis of data from a case-control study of Campylobacter enteritis in England to assess the usefulness of a two-reminder strategy for control recruitment.
Methods
We compared sociodemographic characteristics of participants and non-participants, and calculated odds ratio estimates for a wide range of risk factors by mailing wave.
Results
Non-participants were more often male, younger and from more deprived areas. Among participants, early responders were more likely to be female, older and live in less deprived areas, but despite these differences, we found little evidence of a systematic bias in the results when using data from early reponders only.
Conclusions
We conclude that the main benefit of using reminders in our study was the gain in statistical power from a larger sample size.
doi:10.1186/1471-2288-11-33
PMCID: PMC3079699  PMID: 21453477
bias; case-control studies; epidemiologic methods; survey methods; data collection; nonrespondents; respondents; community surveys
12.  Validation of epidemiological tools for eczema diagnosis in brazilian children: the isaac's and uk working party's criteria 
BMC Dermatology  2010;10:11.
Background
Instruments for field diagnosis of eczema are increasingly used, and it is essential to understand specific limitations to make best use of their strengths. Our objective was to assess the validity of ISAAC and UK Working Party criteria for field diagnosis of eczema in children.
Methods
We performed a cohort study in urban Brazil. Parents/guardians of 1,419 children answered ISAAC phase II questionnaire. Children were examined for skin lesions (UKWP protocol). Two dermatologists examined most cases of eczema (according to ISAAC or UKWP), and a sample without eczema.
Results
Agreement between repeat questionnaires on the filter question was poor (kappa = 0.4). Agreement between the 2 dermatologists was fair (kappa = 0.6). False positive reports included scabies in 39% of ISAAC cases and 33% of UKWP cases. Sensitivity and PPV were low (ISAAC: 37.1% and 16.1%; UKWP: 28.6% and 23.8%). Specificity and NPV were high (ISAAC: 90.0% and 96.6%; UKWP: 95.3% and 96.2%). One-year prevalence of eczema was 11.3% (ISAAC), 5.9% (UKWP) and 4.9% (adjusted dermatologist diagnosis). Point prevalence of scabies (alone or not) was 43%, 33% and 18%, in eczemas according to ISAAC, to UKWP and to dermatologists. The reasons why children with eczema were not identified by ISAAC or UKWP were wrongly denying dry skin, itchy rash or personal history of atopic diseases. A limitation is that questionnaire was already validated in Brazil, but not field tested in this specific setting.
Conclusions
Studies using UKWP or ISAAC criteria should include a validation arm, to contribute to the understanding of potential limitations of their use in different contexts and to explore solutions. We list specific recommendations.
doi:10.1186/1471-5945-10-11
PMCID: PMC2992474  PMID: 21062476
13.  Is it better to be rich in a poor area or poor in a rich area? A multilevel analysis of a case–control study of social determinants of tuberculosis 
Background Tuberculosis is known to have socio-economic determinants at individual and at area levels, but it is not known whether they are independent, whether they interact and their relative contributions to the burden of tuberculosis.
Methods A case–control study was conducted in Recife, Brazil, to investigate individual and area social determinants of tuberculosis, to explore the relationship between determinants at the two levels and to calculate their relative contribution to the burden of tuberculosis. It included 1452 cases of tuberculosis diagnosed by the tuberculosis services and 5808 controls selected at random from questionnaires completed for the demographic census. Exhaustive information on social factors was collected from cases, using the questionnaire used in the census. Socio-economic information for areas was downloaded from the census. Multilevel logistic regression investigated individual and area effects.
Results There was a marked and independent influence of social variables on the risk of tuberculosis, both at individual and area levels. At individual level, being aged ≥20, being male, being illiterate, not working in the previous 7 days and possessing few goods, all increased the risk of tuberculosis. At area level, living in an area with many illiterate people and where few households own a computer also increased this risk; individual and area levels did not appear to interact. Twice as many cases were attributable to social variables at individual level than at area level.
Conclusions Although individual characteristics are the main contributor to the risk of tuberculosis, contextual characteristics make a substantial independent contribution.
doi:10.1093/ije/dyp224
PMCID: PMC2755128  PMID: 19656772
Tuberculosis; social determinants; multilevel; Brazil; poverty
14.  Allergies and Diabetes as Risk Factors for Dengue Hemorrhagic Fever: Results of a Case Control Study 
Background
The physiopathology of dengue hemorrhagic fever (DHF), a severe form of Dengue Fever, is poorly understood. We are unable to identify patients likely to progress to DHF for closer monitoring and early intervention during epidemics, so most cases are sent home. This study explored whether patients with selected co-morbidities are at higher risk of developing DHF.
Methods
A matched case-control study was conducted in a dengue sero-positive population in two Brazilian cities. For each case of DHF, 7 sero-positive controls were selected. Cases and controls were interviewed and information collected on demographic and socio-economic status, reported co-morbidities (diabetes, hypertension, allergy) and use of medication. Conditional logistic regression was used to calculate the strength of the association between the co-morbidities and occurrence of DHF.
Results
170 cases of DHF and 1,175 controls were included. Significant associations were found between DHF and white ethnicity (OR = 4.70; 2.17–10.20), high income (OR = 6.84; 4.09–11.43), high education (OR = 4.67; 2.35–9.27), reported diabetes (OR = 2.75; 1.12–6.73) and reported allergy treated with steroids (OR = 2.94; 1.01–8.54). Black individuals who reported being treated for hypertension had 13 times higher risk of DHF then black individuals reporting no hypertension.
Conclusions
This is the first study to find an association between DHF and diabetes, allergy and hypertension. Given the high case fatality rate of DHF (1–5%), we believe that the evidence produced in this study, when confirmed in other studies, suggests that screening criteria might be used to identify adult patients at a greater risk of developing DHF with a recommendation that they remain under observation and monitoring in hospital.
Author Summary
Dengue is an arboviral disease that affects large areas of countries in tropical and subtropical regions of the world. Around 500,000 cases and 22,000 deaths of dengue hemorrhagic fever (DHF)/Dengue Shock Syndrome (DSS), the most severe presentations of this disease, occur annually. It is unclear why some cases of dengue fever (0.5% to 4%) progress to DHF/DSS. There is weak evidence that some diseases could have a role in this process, such as diabetes, hypertension, and allergies. In epidemics most dengue fever cases are sent home as there are too many to be kept in observation, but if it were possible to identify those with a higher risk of progression to DHF, they could be kept for observation, for early detection of signs, symptoms and alterations in laboratory tests suggestive of DHF, to enable timely and effective clinical management and early intervention. We study this issue and we believe that the evidence produced in this study, when confirmed in other studies, suggests that screening criteria might be used to identify adult patients at a greater risk of developing DHF with a recommendation that they remain under observation and monitoring in a hospital.
doi:10.1371/journal.pntd.0000699
PMCID: PMC2879373  PMID: 20532230
15.  Chronic Intestinal Helminth Infections Are Associated with Immune Hyporesponsiveness and Induction of a Regulatory Network▿ † ‡  
Infection and Immunity  2010;78(7):3160-3167.
Helminth infections have been associated with protection against allergy and autoimmune diseases. We investigated the effects of chronic infections with Ascaris lumbricoides and Trichuris trichiura (measured twice over a 5-year period) on cytokine and antibody responses. We collected blood from 1,060 children aged 4 to 11 years living in a poor urban area of Brazil and measured Th1 (gamma interferon [IFN-γ]) and Th2 (interleukin-5 [IL-5] and IL-13) cytokines and the regulatory cytokine IL-10 in unstimulated and stimulated (with mitogen or A. lumbricoides antigens) cultures of peripheral blood leukocytes and levels of total IgE and anti-A. lumbricoides IgG4 and IgE in serum. Intestinal helminth infections were associated with an increased proportion of children producing IL-5 in response to A. lumbricoides and producing IL-10 spontaneously, especially among coinfected and chronically infected children. Helminth infections were associated with a generalized suppression of cytokine responses to mitogen. Levels of total IgE and anti-A. lumbricoides IgG4 and IgE were especially elevated in chronically infected children. In conclusion, intestinal helminth infections were associated with a typical Th2 immune response profile and with the induction of immune hyporesponsiveness that was associated with greater frequencies of the production of spontaneous IL-10.
doi:10.1128/IAI.01228-09
PMCID: PMC2897394  PMID: 20404082
16.  Determinants of the Relationship between Cytokine Production in Pregnant Women and Their Infants 
PLoS ONE  2009;4(11):e7711.
Exposure to environmental factors during fetal life and infancy is thought to play an important role in the early development of innate and adaptive immunity. The immunological relationship between mother and infant and the effect that environmental exposures have during pregnancy and early childhood have not been studied extensively. Here the production of cytokines was measured in 146 pairs of mothers and their 2- month-old infants. The effect of place of residence, socio-economic variables, parasitic infections as well as maternal and child characteristics on measured cytokine production was determined. Mothers producing high levels of IL-10, IFN-γ and IL-5 were more likely to have infants who also produced high levels of these cytokines either spontaneously (OR 2.6(95%CI 1.2–5.4), OR 2.9(CI 1.3–6.6), OR 11.2(CI 4.6–27.2), respectively) or in response to PHA (IL-10: OR 3.0(CI 1.4–6.6), IFN-γ: OR 2.0(CI 1.0–4.2), respectively) even after adjustment for potential confounding variables. This was not the case for TNF-α. In response to LPS, place of residence was a strong determinant of infant IL-10 (OR 0.2(CI 0.1–0.9)) and TNF-α (OR 0.3(CI 0.1–0.9)) production. Maternal protozoan infections was independently associated with reduced infant IL10 in response to PHA and to LPS as well as reduced TNF-α and IFN-γ in response to PHA. These results indicate strong relationship between maternal and infant's cellular immune responses even after taking into account many environmental influences that could affect infant's response directly or indirectly through uterine microenvironment. However, place of residence and intestinal infections may still directly affect the immune responses of the infant. Taken together, the study provides evidence for imprinted cytokine responses of an infant which may have implications for their reaction to incoming antigens, warranting further investigation into the role that genetics or epigenetics play in shaping the cytokine response by an infant to self or external antigens.
doi:10.1371/journal.pone.0007711
PMCID: PMC2768784  PMID: 19898617
17.  Chicken Consumption and Use of Acid-Suppressing Medications as Risk Factors for Campylobacter Enteritis, England 
Emerging Infectious Diseases  2009;15(9):1402-1408.
Each of these factors increases risk for Campylobacter enteritis.
In a case–control study of Campylobacter spp. risk factors in England during 2005–2006, we identified recent consumption of commercially prepared chicken as an important risk factor. The risk for illness associated with recent chicken consumption was much lower for persons who regularly ate chicken than in those who did not, which suggests that partial immunologic protection may follow regular chicken preparation or consumption. Chicken-related risk factors accounted for 41% of cases; acid-suppressing medication, for 10%; self-reported past Campylobacter enteritis, 2%; and recent acquisition of a pet dog, 1%. Understanding the risks associated with chicken from different sources will benefit strategies to reduce Campylobacter infections. Better characterization of immune correlates for Campylobacter infection is necessary to assess the relative importance of immunity and behavioral factors in determining risk.
doi:10.3201/eid1509.080773
PMCID: PMC2819848  PMID: 19788807
Campylobacter; infectious intestinal disease; food poisoning; bacteria; gastrointestinal infections; enteric diseases; diarrhea; England; risk factors; research
18.  Risk factors for falls with severe fracture in elderly people living in a middle-income country: a case control study 
BMC Geriatrics  2008;8:21.
Background
Fracture after falling has been identified as an important problem in public health. Most studies of risk factors for fractures due to falls have been carried out in developed countries, although the size of the elderly population is increasing fast in middle income countries. The objective of this paper is to identify risk factors for fall related to severe fractures in those aged 60 or more in a middle-income country.
Methods
A case-control study was carried out in Rio de Janeiro-Brazil based general hospitals between 2002–2003. Two hundred-fifty hospitalised cases of fracture were matched with 250 community controls by sex, age group and living area. Data were collected for socio-demographic variables, health status and drugs used before the fall. A conditional logistic regression model was fitted to identify variables associated with the risk of fall related severe fracture.
Results
Low body mass index, cognitive impairment, stroke and lack of urine control were associated with increased risk of severe fall related fractures. Benzodiazepines and muscle relaxants were also related to an increased risk of severe fractures while moderate use of alcohol was associated with reduced risk.
Conclusion
Although the association between benzodiazepines and fractures due to fall has been consistently demonstrated for old people, this has not been the case for muscle relaxant drugs. The decision to prescribe muscle relaxants for elderly people should take into account the risk of severe fracture associated with these drugs.
doi:10.1186/1471-2318-8-21
PMCID: PMC2532993  PMID: 18727832
19.  Skin prick test reactivity to common allergens among women in Entebbe, Uganda 
Summary
The objectives of this study were to estimate the prevalence of atopic sensitization, and to identify common aeroallergens associated with atopic sensitization among women in Entebbe, Uganda, and to determine risk factors for atopic sensitization among those with and without a history of asthma or eczema. A case–control study was conducted within a trial of deworming in pregnancy, approximately 2 years after the intervention. Skin prick test reactivity was assessed among 20 women with a history of asthma, 25 with history of eczema and 95 controls. Overall prevalence of reactivity was estimated by adjusting for the prevalence of asthma in the whole cohort. Overall skin prick test prevalence was: any allergen 30.7%, Blomia tropicalis 10.9%, Dermatophagoides mix 16.8%, cockroach 15.8%. The prevalence of a positive skin prick test was significantly associated with a history of asthma (70% to any allergen vs. 32%, P = 0.002) but not with a history of eczema (44% vs. 36%, P = 0.49). Women with Mansonella perstans had significantly reduced odds for atopic sensitization (adjusted odds ratio 0.14, 95% CI 0.03–0.69); women with a history of asthma were less likely to have hookworm (adjusted odds ratio 0.24, 95% CI 0.07–0.81) but this association was weaker for women with a history of eczema. [Clinical Trial No. ISRCTN32849447]
doi:10.1016/j.trstmh.2008.01.017
PMCID: PMC2628422  PMID: 18321545
Worms; Allergy; Atopy; Skin prick test; Mansonella perstans; Uganda
20.  BCG Revaccination Does Not Protect Against Leprosy in the Brazilian Amazon: A Cluster Randomised Trial 
Background
Although BCG has been found to impart protection against leprosy in many populations, the utility of repeat or booster BCG vaccinations is still unclear. When a policy of giving a second BCG dose to school children in Brazil was introduced, a trial was conducted to assess its impact against tuberculosis, and a leprosy component was then undertaken in parallel. Objective: to estimate the protection against leprosy imparted by a second dose of BCG given to schoolchildren.
Methods and Findings
This is a cluster randomised community trial, with 6 years and 8 months of follow-up. Study site: City of Manaus, Amazon region, a leprosy-endemic area in Brazil. Participants: 99,770 school children with neonatal BCG (aged 7–14 years at baseline), of whom 42,662 were in the intervention arm (revaccination). Intervention: BCG given by intradermal injection. Main outcome: Leprosy (all clinical forms). Results: The incidence rate ratio of leprosy in the intervention over the control arm within the follow-up, in schoolchildren with neonatal BCG, controlled for potential confounders and adjusted for clustering, was 0.99 (95% confidence interval: 0.68 to 1.45).
Conclusions/Significance
There was no evidence of protection conferred by the second dose of BCG vaccination in school children against leprosy during the trial follow-up. These results point to a need to consider the effectiveness of the current policy of BCG vaccination of contacts of leprosy cases in Brazilian Amazon region.
Author Summary
BCG is a vaccine developed and used to protect against tuberculosis, but it can also protect against leprosy. In Brazil, children receive BCG at birth, and since 1996 a trial has been conducted to find out if a second dose of BCG administered to schoolchildren gives additional protection against tuberculosis. We use this trial to find out if such vaccination protects against leprosy. The trial was conducted in the Brazilian Amazon, involving almost 100,000 children aged 7–14 years who had received neonatal BCG. Half of them received a second dose of BCG at school, and the other half did not. We followed the children for 6 years and observed that there were as many new cases of leprosy in the vaccinated children as in the unvaccinated children. Therefore, we concluded that a second dose of BCG given at school age in the Brazilian Amazon offers no additional protection against leprosy.
doi:10.1371/journal.pntd.0000167
PMCID: PMC2238709  PMID: 18270542
21.  A guide to modern statistical analysis of immunological data 
BMC Immunology  2007;8:27.
Background
The number of subjects that can be recruited in immunological studies and the number of immunological parameters that can be measured has increased rapidly over the past decade and is likely to continue to expand. Large and complex immunological datasets can now be used to investigate complex scientific questions, but to make the most of the potential in such data and to get the right answers sophisticated statistical approaches are necessary. Such approaches are used in many other scientific disciplines, but immunological studies on the whole still use simple statistical techniques for data analysis.
Results
The paper provides an overview of the range of statistical methods that can be used to answer different immunological study questions. We discuss specific aspects of immunological studies and give examples of typical scientific questions related to immunological data. We review classical bivariate and multivariate statistical techniques (factor analysis, cluster analysis, discriminant analysis) and more advanced methods aimed to explore causal relationships (path analysis/structural equation modelling) and illustrate their application to immunological data. We show the main features of each method, the type of study question they can answer, the type of data they can be applied to, the assumptions required for each method and the software that can be used.
Conclusion
This paper will help the immunologist to choose the correct statistical approach for a particular research question.
doi:10.1186/1471-2172-8-27
PMCID: PMC2234437  PMID: 17963513
22.  The association between drinking water turbidity and gastrointestinal illness: a systematic review 
BMC Public Health  2007;7:256.
Background
Studies suggest that routine variations in public drinking water turbidity may be associated with endemic gastrointestinal illness. We systematically reviewed the literature on this topic.
Methods
We searched databases and websites for relevant studies in industrialized countries. Studies investigating the association between temporal variations in drinking water turbidity and incidence of acute gastrointestinal illness were assessed for quality. We reviewed good quality studies for evidence of an association between increased turbidity and gastrointestinal illness.
Results
We found six relevant good quality studies. Of five studies investigating effluent water turbidity, two found no association. Two studies from Philadelphia reported increased paediatric and elderly hospital use on specific days after increased turbidity. A fifth study reported more telephone health service calls on specific days after peak turbidity. There were differences between studies affecting their comparability, including baseline turbidity and adjustment for seasonal confounders.
Conclusion
It is likely that an association between turbidity and GI illness exists in some settings or over a certain range of turbidity. A pooled analysis of available data using standard methods would facilitate interpretation.
doi:10.1186/1471-2458-7-256
PMCID: PMC2174477  PMID: 17888154
23.  Ecological study of socio-economic indicators and prevalence of asthma in schoolchildren in urban Brazil 
BMC Public Health  2007;7:205.
Background
There is evidence of higher prevalence of asthma in populations of lower socio-economic status in affluent societies, and the prevalence of asthma is also very high in some Latin American countries, where societies are characterized by a marked inequality in wealth. This study aimed to examine the relationship between estimates of asthma prevalence based on surveys conducted in children in Brazilian cities and health and socioeconomic indicators measured at the population level in the same cities.
Methods
We searched the literature in the medical databases and in the annals of scientific meeting, retrieving population-based surveys of asthma that were conducted in Brazil using the methodology defined by the International Study of Asthma and Allergies in Childhood. We performed separate analyses for the age groups 6–7 years and 13–14 years. We examined the association between asthma prevalence rates and eleven health and socio-economic indicators by visual inspection and using linear regression models weighed by the inverse of the variance of each survey.
Results
Six health and socioeconomic variables showed a clear pattern of association with asthma. The prevalence of asthma increased with poorer sanitation and with higher infant mortality at birth and at survey year, GINI index and external mortality. In contrast, asthma prevalence decreased with higher illiteracy rates.
Conclusion
The prevalence of asthma in urban areas of Brazil, a middle income country, appears to be higher in cities with more marked poverty or inequality.
doi:10.1186/1471-2458-7-205
PMCID: PMC1988821  PMID: 17697314
24.  Children with pertussis inform the investigation of other pertussis cases among contacts 
BMC Pediatrics  2007;7:21.
Background
The number of reported pertussis has increased in the last two decades. However, many cases of pertussis may be underreported or not diagnosed. The World Health Organization estimates that pertussis causes 200.000 – 400.000 deaths each year, most deaths are in infants and in developing countries. Infants with pertussis can indicate an undetected source cases in the community.
Methods
At a University Hospital in Brazil individuals that had frequent contacts with a child with confirmed pertussis (the index case) and had recent history of cough were enrolled into the study. Nasopharyngeal swabs were collected from every contact that had cough within the last 21 days. Cases confirmation followed the guidelines of the Center for Disease Control and Prevention – Atlanta, U.S.A.
Results
Pertussis diagnosis was confirmed in 51 children, (considered the index cases). Among the index cases, 72.5% (37/51) were under 6 months of age; culture for Bordetella pertussis was positive in 78.4% (40/51). Pertussis was confirmed in 39% (107/276) of the contacts of 51 index cases. Among these contacts identified as a pertussis case, 40.2% (43/107) were between 6 months and 111/2 years of age and 59.8% (64/107) were older than 111/2 years of age. Pertussis was confirmed by culture in 11.2% (12/107) of them and by epidemiologic linkage in 88.8% (95/107). Each index case allowed identifying two new cases of pertussis.
Conclusion
Public health authorities should consider implementing early recognition of pertussis index cases and searching for pertussis cases among the contacts. Treatment of the cases and prophylaxis of the contacts is fundamental to control outbreaks in the community.
doi:10.1186/1471-2431-7-21
PMCID: PMC1894795  PMID: 17518997
25.  Influenza, Campylobacter and Mycoplasma Infections, and Hospital Admissions for Guillain-Barré Syndrome, England 
Emerging Infectious Diseases  2006;12(12):1880-1887.
TOC Summary line: Campylobacter, Mycoplasma pneumoniae, and influenza (or influenza vaccination) act as infectious triggers for Guillain-Barré syndrome.
Guillain-Barré syndrome (GBS) is the most common cause of acute flaccid paralysis in polio-free regions. Considerable evidence links Campylobacter infection with GBS, but evidence that implicates other pathogens as triggers remains scarce. We conducted a time-series analysis to investigate short-term correlations between weekly laboratory-confirmed reports of putative triggering pathogens and weekly hospitalizations for GBS in England from 1993 through 2002. We found a positive association between the numbers of reports of laboratory-confirmed influenza A in any given week and GBS hospitalizations in the same week. Different pathogens may trigger GBS in persons of different ages; among those <35 years, numbers of weekly GBS hospitalizations were associated with weekly Campylobacter and Mycoplasma pneumoniae reports, whereas among those >35 years, positive associations were with influenza. Further studies should estimate the relative contribution of different pathogens to GBS incidence, overall and by age group, and determine whether influenza is a real trigger for GBS or a marker for influenza vaccination.
doi:10.3201/eid1212.051032
PMCID: PMC3291336  PMID: 17326939
Guillain-Barré syndrome; Campylobacter; influenza; Mycoplasma pneumoniae; Haemophilus influenzae; cytomegalovirus; Epstein-Barr virus; sequelae; polyradiculoneuropathy; time-series analysis; research

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