Meaningful and feasible composite clinical worsening definitions in paediatric pulmonary arterial hypertension: An analysis of the TOPP registry.

BACKGROUND: Composite clinical worsening (cCW) outcomes might allow measurement of disease progression in paediatric pulmonary arterial hypertension (PAH). This TOPP registry analysis investigated three cCW outcomes and their predictive strength for lung transplantation/death. METHODS: Patients ≤17 years with idiopathic/familial PAH or PAH-associated congenital heart disease diagnosed ≤3 months before enrolment were included. cCW outcomes included the following variables at enrolment and/or follow-up: all-cause death, PAH-related hospitalisation, lung transplantation, atrial septostomy (cCW1, 2 and 3), WHO FC deterioration, intravenous/subcutaneous prostanoids initiation, syncope (cCW2,3) and occurrence/worsening of ≥2 PAH symptoms (cCW3). The predictive value of CW (excluding transplantation and death) to transplantation or death was assessed. Predictive values of each cCW for lung transplantation/death were analysed by Cox proportional hazards models. RESULTS: From 255 patients, first-event rate/100 person-years (95% CI) were cCW1: 23.1(19.3,27.6), cCW2: 43.6(37.6,50.6), and cCW3: 46.3(40.0,53.7) with PAH-related hospitalisation as the most frequent first event in each. The cCW definitions comprised from endpoints (excluding transplantation and death), were associated with higher risk [hazard ratio (95% CI)] for lung transplantation/death [4.23(2.27,7.91), 3.25(1.65,6.39), 2.74(1.41,5.34), respectively]; individual parameters with higher risks were WHO FC deterioration [3.49(1.47,8.29)], PAH-related hospitalisation [2.62(1.32,5.20)] and occurrence/worsening of ≥2 PAH symptoms [2.13(1.02,4.45)]. CONCLUSIONS: These data support the use of cCW outcomes in paediatric PAH research. WHO FC deterioration, PAH-related hospitalisation, occurrence/worsening of ≥2 PAH symptoms may be important for risk assessment during clinical management.

Growth in children with pulmonary arterial hypertension: a longitudinal retrospective multiregistry study.

BACKGROUND: To enable adequate interpretation of growth measurements in the management of children with pulmonary arterial hypertension (PAH), we assessed growth and its associated determinants in children with PAH. METHODS: We did a retrospective longitudinal study of height and body-mass index in reference to WHO growth standards by pooling data from four contemporary prospective registries of paediatric PAH representing 53 centres in 19 countries. The main outcome measures were median height for age and body-mass index for age percentiles and longitudinal deviation of height for age and body-mass index for age Z scores from WHO standards. FINDINGS: 601 children were followed up for a median of 2·9 years (IQR 1·5-4·4). Baseline median height for age percentile was 26 (IQR 4-54) and baseline median body-mass index for age percentile was 41 (IQR 12-79). Mean height for age Z score was significantly lower than the reference (-0·81, 95% CI -0·93 to -0·69; p<0·0001), as was body-mass index for age Z score (-0·12, -0·25 to -0·01; p=0·047). Height for age Z score was particularly decreased in young patients (aged ≤5 years) with idiopathic or hereditary PAH and in all patients with PAH associated with congenital heart disease. Although Z scores increased in some patients and decreased in others, we detected no significant trend in height for age Z score (p=0·57) or body-mass index for age Z score (p=0·48) before taking account of covariates. Multivariable linear mixed effects modelling showed that age, cause of PAH, ex-prematurity, WHO functional class, trisomy 21, and time since diagnosis were associated with height for age Z score, whereas age, ethnicity, and trisomy 21 were associated with body-mass index for age Z score. A favourable WHO functional class course was independently associated with increases in height for age Z score. INTERPRETATION: PAH is associated with impaired growth, especially in younger children and those with pulmonary arterial hypertension associated with congenital heart disease. The degree of impairment is independently associated with cause of PAH and comorbidities, but also with disease severity and duration. Because a favourable clinical course was associated with catch-up growth, height for age could serve as an additional and globally available clinical parameter to monitor patients' clinical condition. FUNDING: Actelion Pharmaceuticals.

Risk factors for shigellosis in Thailand.

OBJECTIVES: To assess the potential risk factors for shigellosis including housefly density. METHODS: A matched case-control study to investigate potential risk factors for shigellosis was conducted in a semi-urban area, Kaengkhoi District, Saraburi Province, central Thailand. Shigella cases were ascertained from a two-year population-based surveillance study detecting diarrhea and shigellosis in the area. The study evaluated a wide range of exposures, which were assessed by odds ratios (OR) adjusted for proxy markers of socioeconomic status: family income, and type of residence, using conditional logistic regression analysis. RESULTS: Hygiene behaviors such as regular hand washing (p<0.05), a clean environment surrounding the household (p<0.001), and the availability of water to flush the toilet (p=0.08) were associated with a reduced risk for shigellosis in the multivariate model. In contrast factors indicating a lower than average socioeconomic status, such as having to rent instead of owning one's housing (p<0.001) and a low family income (p<0.01) were associated with an increased risk for shigellosis. For children, breastfeeding showed a strong protective effect in reducing the risk of shigellosis (p<0.01). Prior to adjustment for environmental factors, fly density in the kitchen area was associated with an increased risk of shigellosis (p<0.01). CONCLUSIONS: We found a correlation between socioeconomic status and the risk for shigellosis. To reduce shigellosis in this setting, we recommend interventions focused on three aspects: improved water supply and sanitation (especially latrines and garbage disposal) including fly control, health education on hand washing, and the promotion of breastfeeding.

Micronutrient intake and the risk of herpes zoster: a case-control study.

BACKGROUND: Herpes zoster can seriously impair quality of life and may also be a marker for age-related immune decline (immunosenescence). Diets low in micronutrients may increase the risk of zoster by temporarily compromising cell-mediated immune function or by hastening immunosenescence. METHODS: Primary objectives were to examine the association between risk of zoster and (i) dietary intake of vitamins A, B(6), C, E, folic acid, zinc, and iron, and (ii) fruit and vegetable consumption. We conducted a community-based case-control study. Cases were adults with incident zoster presenting to 22 general practices in London. Controls were individuals with no zoster history, matched to cases by age, sex, and general practice. Diet was ascertained for 243 cases and 483 controls using an interviewer-administered food-frequency questionnaire. We used conditional logistic regression to estimate odds ratios. RESULTS: There was a strong graded association between lower fruit intake and increasing zoster risk; in adjusted analysis, individuals who ate less than one piece of fruit per week had more than three times the risk of zoster compared with individuals who ate more than three portions per day. None of the dietary intakes of the seven micronutrients examined had a statistically significant association with zoster risk when considered singly. However, amongst individuals aged >60 years, a measure of combined micronutrient intake and vegetable intake showed similar dose-related associations with zoster risk. CONCLUSION: A cocktail of nutrients such as those found in fruit and vegetables may act together, particularly in older individuals, to maintain immune health and prevent zoster.

Estimating the burden of shigellosis in Thailand: 36-month population-based surveillance study.

OBJECTIVE: To estimate incidence of shigellosis in the Kaengkhoi district, Saraburi Province, Thailand. METHODS: Population-based surveillance of shigellosis based in treatment centres. The detected rates of treated shigellosis were corrected for the number of cases missed due to the low sensitivity of microbiological culture methods and participants' use of health-care providers not participating in the study. FINDINGS: The overall uncorrected incidence of shigellosis was 0.6/1000 population per year (95% confidence interval (CI) = 0.5-0.8). The unadjusted incidence of treated shigellosis was highest among children less than 5 years old (4/1000 children per year; 95% CI = 3-6) and significantly lower among people aged > 5 years (0.3/1000 population per year; 95% CI = 0.2-0.5; P < 0.001). Adjusting for cases likely to be missed as a result of culture and surveillance methods increased estimates approximately five times. The majority of Shigella isolates (122/146; 84%) were S. sonnei; the rest were S. flexneri. Of the 22 S. flexneri isolates, the three most frequently encountered serotypes were 2a (36%), 1b (23%) and 3b (28%). A total of 90-95% of S. sonnei and S. flexneri isolates were resistant to tetracycline and co-trimoxazole. In contrast to S. sonnei isolates, more than 90% of the S. flexneri isolates were also resistant to ampicillin and chloramphenicol (P < 0.0001). CONCLUSION: Estimates of incidence of Shigella infection in the community are 10-fold to 100-fold greater than those found from routine government surveillance. The high prevalence of Shigella strains resistant to multiple antibiotics adds urgency to the development of a vaccine to protect against shigellosis in this region of Thailand.

Vaccine coverage with hepatitis B and other vaccines in the Colombian Amazon: do health worker knowledge and perception influence coverage?

OBJECTIVES: We conducted a vaccination coverage survey in the Colombian Amazon, an area highly endemic for hepatitis B (HB), where HB vaccine was introduced in 1992. The aim was to measure vaccine coverage and factors influencing it, especially those related to health services. METHODS: A total of 3573 children younger than 11 years were randomly selected from four populations. Vaccination status was ascertained through the vaccination card and a questionnaire on socio-demographic factors was applied to children's caretakers. Health workers (HW) in charge of vaccination in rural and urban areas were interviewed regarding knowledge and practices in vaccination. Individual and HW characteristics were related to individual vaccination using logistic regression. RESULTS: Overall cumulated vaccination coverage was high for polio (96%, 95% CI: 94-98), measles (94%, 95% CI: 92.8-95.2), BCG (91%, 95% CI: 90-93), DPT (90%, 95% CI: 88-92) and HB (88%, 95% CI: 86-90). However, <50% of children completed the primary course of vaccination in the first year of life. Individual factors improving the likelihood of being either fully or HB vaccinated were: age>1 year, living in Leticia, being affiliated to the social security, and living in a house with a roof made of tiles rather than palm tree leaf. Among the variables related to HWs, poor knowledge of vaccine contraindications predicted a lower chance of being fully or HB vaccinated in the population served by them, even after controlling for individual variables. CONCLUSIONS: The HB control program in Colombia has achieved good coverage in one of the most endemic areas of the country. However, barriers to vaccination arise from inequities in the distribution of health insurance and inadequate HW knowledge.

Serum uric acid and coronary heart disease in 9,458 incident cases and 155,084 controls: prospective study and meta-analysis.

BACKGROUND: It has been suggested throughout the past fifty years that serum uric acid concentrations can help predict the future risk of coronary heart disease (CHD), but the epidemiological evidence is uncertain. METHODS AND FINDINGS: We report a "nested" case-control comparison within a prospective study in Reykjavik, Iceland, using baseline values of serum uric acid in 2,456 incident CHD cases and in 3,962 age- and sex-matched controls, plus paired serum uric acid measurements taken at baseline and, on average, 12 y later in 379 participants. In addition, we conducted a meta-analysis of 15 other prospective studies in eight countries conducted in essentially general populations. Compared with individuals in the bottom third of baseline measurements of serum uric acid in the Reykjavik study, those in the top third had an age- and sex-adjusted odds ratio for CHD of 1.39 (95% confidence interval [CI], 1.23-1.58) which fell to 1.12 (CI, 0.97-1.30) after adjustment for smoking and other established risk factors. Overall, in a combined analysis of 9,458 cases and 155,084 controls in all 16 relevant prospective studies, the odds ratio was 1.13 (CI, 1.07-1.20), but it was only 1.02 (CI, 0.91-1.14) in the eight studies with more complete adjustment for possible confounders. CONCLUSIONS: Measurement of serum uric acid levels is unlikely to enhance usefully the prediction of CHD, and this factor is unlikely to be a major determinant of the disease in general populations.

Associations between differential leucocyte count and incident coronary heart disease: 1764 incident cases from seven prospective studies of 30,374 individuals.

AIMS: We aimed to assess potential associations between different leucocyte components and coronary heart disease (CHD) in a prospective cohort study, and to put these findings in context of other relevant prospective studies in a meta-analysis. METHODS AND RESULTS: We report data on differential leucocyte count and CHD derived from the first National Health and Nutrition Examination Survey (NHANES I) and the NHANES 1 Epidemiologic Follow-up Study (NHEFS) involving 4625 individuals followed, on average, for 18 years. The NHEFS involved 914 incident CHD cases and yielded an adjusted risk ratio of 1.09 (0.93-1.29) comparing individuals with neutrophil counts in the top third versus those in the bottom third of the population. In a meta-analysis involving the NHEFS and four other studies comprising a total of 1764 incident CHD cases, the association of CHD with neutrophil counts was somewhat stronger than those with other specific leucocyte components (combined risk ratio=1.33 [1.17-1.50]) but there was substantial heterogeneity between the separate studies (Chi2(4), p <0.001). CONCLUSIONS: Although the present synthesis provides the most comprehensive assessment so far of specific leucocyte components in CHD, additional prospective data will be needed to resolve whether neutrophil counts are much stronger predictors of CHD risk than other components.

C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease.

BACKGROUND: C-reactive protein is an inflammatory marker believed to be of value in the prediction of coronary events. We report data from a large study of C-reactive protein and other circulating inflammatory markers, as well as updated meta-analyses, to evaluate their relevance to the prediction of coronary heart disease. METHODS: Measurements were made in samples obtained at base line from up to 2459 patients who had a nonfatal myocardial infarction or died of coronary heart disease during the study and from up to 3969 controls without a coronary heart disease event in the Reykjavik prospective study of 18,569 participants. Measurements were made in paired samples obtained an average of 12 years apart from 379 of these participants in order to quantify within-person fluctuations in inflammatory marker levels. RESULTS: The long-term stability of C-reactive protein values (within-person correlation coefficient, 0.59; 95 percent confidence interval, 0.52 to 0.66) was similar to that of both blood pressure and total serum cholesterol. After adjustment for base-line values for established risk factors, the odds ratio for coronary heart disease was 1.45 (95 percent confidence interval, 1.25 to 1.68) in a comparison of participants in the top third of the group with respect to base-line C-reactive protein values with those in the bottom third, and similar overall findings were observed in an updated meta-analysis involving a total of 7068 patients with coronary heart disease. By comparison, the odds ratios in the Reykjavik Study for coronary heart disease were somewhat weaker for the erythrocyte sedimentation rate (1.30; 95 percent confidence interval, 1.13 to 1.51) and the von Willebrand factor concentration (1.11; 95 percent confidence interval, 0.97 to 1.27) but generally stronger for established risk factors, such as an increased total cholesterol concentration (2.35; 95 percent confidence interval, 2.03 to 2.74) and cigarette smoking (1.87; 95 percent confidence interval, 1.62 to 2.16). CONCLUSIONS: C-reactive protein is a relatively moderate predictor of coronary heart disease. Recommendations regarding its use in predicting the likelihood of coronary heart disease may need to be reviewed.

Quantitation of group A rotavirus by real-time reverse-transcription-polymerase chain reaction: correlation with clinical severity in children in South India.

The epidemiology and pathogenesis of rotaviruses are not completely understood, although recent developments in polymerase chain reaction (PCR) techniques now make it possible to quantify the viral load during an infective episode and investigate its relevance to clinical features of the disease. We studied rotavirus-positive stool samples collected from 10 children without symptoms of gastroenteritis and from 81 children with acute gastroenteritis and in whom the clinical severity of disease was recorded. A semi-quantitative real-time reverse-transcription (RT)-PCR was used to estimate the rotavirus load and to assess its correlation with the Vesikari score for severity of diarrhoea. There was a significant negative correlation (r = -0.80, P < 0.001) between severity and the PCR cycle at which the PCR amplicons were detectable (crossing point) on the assay, indicating that children with more severe diarrhoea excrete more virus than children with less severe disease.

Four paraoxonase gene polymorphisms in 11212 cases of coronary heart disease and 12786 controls: meta-analysis of 43 studies.

BACKGROUND: Although there have been suggestions that serum paraoxonase is important in protecting against coronary heart disease (CHD), a large number of studies of genetic determinants of serum paraoxonase have reported apparently conflicting results about their association with CHD. METHODS: We conducted a meta-analysis of 43 studies of the Q192R, L55M, and T(-107)C polymorphisms in the paraoxonase PON1 gene and the S311C polymorphism in the PON2 gene (all of which are in moderately strong linkage disequilibrium with one another), involving a total of 11212 CHD cases and 12786 controls. We explored potential sources of heterogeneity. FINDINGS: In a combined analysis of all studies, the per-allele relative risk of R192 for CHD was 1.12 (95% CI 1.07-1.16), but in the five largest studies it was only 1.05 (0.98-1.13). Combined analyses of studies of the M55, (-107)T, and C311 variants showed no significant overall associations with CHD, yielding per-allele relative risks of 1.00 (0.95-1.06), 1.02 (0.92-1.14), and 1.04 (0.93-1.17), respectively. INTERPRETATION: In contrast to previous suggestions, this meta-analysis shows no significant association of CHD with the L55M or T(-107)C polymorphism in PON1 or with the S311C polymorphism in PON2. The weak overall association between the Q192R polymorphism and CHD is of uncertain relevance, particularly since there was no significant association among the larger studies which should be less prone to selective publication. These findings reinforce the need for much larger and more rigorous investigations of the genetic determinants of complex diseases than is now customary, as well as for regularly updated systematic appraisals of such studies to help improve interpretation and prioritise hypotheses.

Contacts with varicella or with children and protection against herpes zoster in adults: a case-control study.

BACKGROUND: Whether exogenous exposure to varicella-zoster-virus protects individuals with latent varicella-zoster virus infection against herpes zoster by boosting immunity is not known. To test the hypothesis that contacts with children increase exposure to varicella-zoster virus and protect latently infected adults against zoster, we did a case-control study in south London, UK. METHODS: From 22 general practices, we identified patients with recently diagnosed zoster, and control individuals with no history of zoster, matched to patients by age, sex, and practice. Participants were asked about contacts with people with varicella or zoster in the past 10 years, and social and occupational contacts with children as proxies for varicella contacts. Odds ratios were estimated with conditional logistic regression. FINDINGS: Data from 244 patients and 485 controls were analysed. On multivariable analysis, protection associated with contacts with a few children in the household or via childcare seemed to be largely mediated by increased access to children outside the household. Social contacts with many children outside the household and occupational contacts with ill children were associated with graded protection against zoster, with less than a fifth the risk in the most heavily exposed groups compared with the least exposed. The strength of protection diminished after controlling for known varicella contacts; the latter remained significantly protective (odds ratio 0.29 [95% CI 0.10-0.84] for those with five contacts or more). INTERPRETATION: Re-exposure to varicella-zoster virus via contact with children seems to protect latently infected individuals against zoster. Reduction of childhood varicella by vaccination might lead to increased incidence of adult zoster. Vaccination of the elderly (if effective) should be considered in countries with childhood varicella vaccination programmes.

An inexpensive intervention for the control of larval Aedes aegypti assessed by an improved method of surveillance and analysis.

A sampling method coupled with statistical calibration factors was developed to accurately assess the numbers of larvae and pupae of Aedes aegypti in large water-storage containers of variable capacities and water levels. Aedes aegypti productivity in different types of breeding sites found in an urban study area in central Colombia was assessed and compared. In this study, water-storage tanks and drums were found to comprise 79% of the containers positive for larval Ae. aegypti, which contributed to 93 and 92% of the total production of populations of 4th-stage larvae and pupae, respectively. These main breeding sites of Ae. aegypti were found at an indoor to outdoor ratio of 2.4:1 and no correlation was found between temporal fluctuation of populations of larval Ae. aegypti and monthly rainfall. Netted lids that used inexpensive local materials were designed to prevent oviposition by Ae. aegypti. During a 6-month trial period, 56% of inspected containers had netted lids correctly in place. Of these, 78% had no mosquito larvae. Because only 37% of uncovered containers were free of mosquito larvae, a significant difference was demonstrated when these inexpensive mechanical barriers were used (chi2 = 138.7; P < 0.001). These netted lids and the improved methods described to assess the productivity of larval and pupal Ae. aegypti in this study are now being used in combination with other strategies to assess and control these populations of dengue virus vectors in the main port city on the Atlantic Coast of Colombia.