Simon J. Forsyth

Efficacy of an 11-valent pneumococcal conjugate vaccine against radiologically confirmed pneumonia among children less than 2 years of age in the Philippines: a randomized, double-blind, placebo-controlled trial.

Background: Pneumococcus is a leading cause of childhood pneumonia worldwide. Pneumococcal conjugate vaccines (PCV) have demonstrated efficacy against childhood invasive pneumococcal disease (IPD) and pneumonia in the United States and Africa. No information is available from Asia on the impact of PCV on childhood pneumonia. Methods: We conducted a randomized, placebo-controlled, double-blind trial in Bohol, the Philippines (ISRCTN 62323832). Children 6 weeks to <6 months of age were randomly allocated to receive 3 doses of either an 11-valent PCV (11PCV, sanofi pasteur, Lyon, France) or a saline placebo, with a minimum interval of 4 weeks between doses to determine vaccine efficacy (VE) against the primary outcome of a child experiencing first episode of community-acquired radiologically defined pneumonia in the first 2 years of life. Secondary end points were clinical pneumonia, IPD, safety, and immunogenicity. Results: Twelve thousand one hundred ninety-one children were enrolled. By per protocol (PP) analysis, 93 of 6013 fully vaccinated 11PCV recipient children had a first episode of radiologic pneumonia compared with 120 of 6018 placebo recipients. VE against radiologically defined pneumonia for the PP cohort of children 3 to 23 months old was 22.9% (95% CI: −1.1, 41.2; P = 0.06), for the prespecified subgroups of children 3 to 11 months of age, 34.0% (95% CI: 4.8, 54.3; P = 0.02), and of those 12 to 23 months old, 2.7% (95% CI: −43.5, 34.0; P = 0.88). By intent-to-treat (ITT) analysis, 119 of 6097 11PCV recipient children had an episode of radiologic pneumonia compared with 141 of 6094 placebo recipients. VE against radiologic pneumonia for the ITT cohort of children <2 years old was 16.0% (95% CI −7.3, 34.2; P = 0.16), for a subgroup of children <12 months of age, 19.8% (95% CI: −8.8, 40.8; P = 0.15). VE against clinical pneumonia by PP was not significant (VE 0.1%; 95% CI −9.4, 8.7; P = 0.99). IPD was rare: only 3 cases of IPD due to vaccine serotypes were observed during the study. 11PCV was immunogenic and well tolerated. Among 11PCV recipients, a small excess of serious adverse respiratory events was observed in the first 28 days after the first and second dose of vaccine, and of nonrespiratory events after the first dose. An excess of pneumonia episodes in 11PCV recipients in the month following the second dose of vaccination was the principal reason for lower VE by ITT analysis than by PP analysis. Conclusions: In PP analysis, a 22.9% reduction of community-acquired radiologically confirmed pneumonia in children younger than 2 years of age in the 11-valent tetanus-diphtheria toxoid-conjugated PCV vaccinated group was observed; a reduction similar as observed in other PCV trials. We could not demonstrate any VE against clinical pneumonia. Our finding confirms for the first time that in a low-income, low-mortality developing country in Asia, at least one-fifth of radiologically confirmed pneumonia is caused by pneumococcus, and thus preventable by PCV. Whether PCV should be included in national program in such settings, however, depends on careful country specific disease burden measurement and cost-effectiveness calculation.

A cluster-randomised intervention trial against Schistosoma japonicum in the Peoples' Republic of China: bovine and human transmission.

Background Zoonotic schistosomiasis japonica is a major public health problem in China. Bovines, particularly water buffaloes, are thought to play a major role in the transmission of schistosomiasis to humans in China. Preliminary results (1998–2003) of a praziquantel (PZQ)-based pilot intervention study we undertook provided proof of principle that water buffaloes are major reservoir hosts for S. japonicum in the Poyang Lake region, Jiangxi Province. Methods and Findings Here we present the results of a cluster-randomised intervention trial (2004–2007) undertaken in Hunan and Jiangxi Provinces, with increased power and more general applicability to the lake and marshlands regions of southern China. The trial involved four matched pairs of villages with one village within each pair randomly selected as a control (human PZQ treatment only), leaving the other as the intervention (human and bovine PZQ treatment). A sentinel cohort of people to be monitored for new infections for the duration of the study was selected from each village. Results showed that combined human and bovine chemotherapy with PZQ had a greater effect on human incidence than human PZQ treatment alone. Conclusions The results from this study, supported by previous experimental evidence, confirms that bovines are the major reservoir host of human schistosomiasis in the lake and marshland regions of southern China, and reinforce the rationale for the development and deployment of a transmission blocking anti-S. japonicum vaccine targeting bovines. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12609000263291

Systematic review of record linkage studies of mortality in ex-prisoners: why (good) methods matter

AIMS World-wide, more than 30 million people move through prisons annually. Record linkage studies have identified an increased risk of death in ex-prisoners. In order to inform preventive interventions it is necessary to understand who is most at risk, when and why. Limitations of existing studies have rendered synthesis and interpretation of this literature difficult. The aim of this study was to describe methodological characteristics of existing studies and make recommendations for the design, analysis and reporting of future studies. METHODS Systematic review of studies using record linkage to explore mortality in ex-prisoners. Based on analysis of these studies we illustrate how methodological limitations and heterogeneity of design, analysis and reporting both hamper data synthesis and create potential for misinterpretation of findings. Using data from a recent Australian study involving 42,015 ex-prisoners and 2329 observed deaths, we quantify the variation in findings associated with various approaches. RESULTS We identified 29 publications based on 25 separate studies published 1998-2011, mainly from the United Kingdom, United States and Australia. Mortality estimates varied systematically according to features of study design and data analysis. A number of common, avoidable and significant methodological limitations were identified. Substantial heterogeneity in study design, methods of data analysis and reporting of findings was observed. CONCLUSIONS Record linkage studies examining mortality in ex-prisoners show widely varying estimates that are influenced substantially by avoidable methodological limitations and reducible heterogeneity. Future studies should adopt best practice methods and more consistent methods of analysis and reporting, to maximize policy relevance and impact.

Measuring exposure to S. japonicum in China. I. Activity diaries to assess water contact and comparison to other measures

We introduce a new method, activity diaries, in order to evaluate human water contact among fishing communities in an area moderately endemic for Schistosoma japonicum in the Dongting Lake region of Southern China. Two hundred and forty-nine subjects (76% male) were followed prospectively over a 9-month-period in order to verify exposure and reinfection. Exposure was determined crudely with questionnaires, direct 12-h water observations, and more precisely with activity diaries and an adjusted exposure model which took into account the time of day, the duration of contact and the percent body surface area in contact with water. Cohort subjects filled in activity diaries for an average of 85 days as compared with 2 days for the direct water observations. The typical unadjusted mean daily water contact (duration) based on the activity diaries was 53 min with 62% of this time spent in fishing. In contrast, the direct water observations revealed an average daily duration of 149 min with 53% of the time spent in fishing. Human water contact patterns (min/day) by site, activity and body part exposed were examined with the activity diaries. Individuals in the 36-49-year-old age range had the highest degree of water contact. Most of this daily contact occurred by males on the hands (mean+/-S.D.; 83.53+/-67.80 min/day) while fishing (mean+/-S.D.; 87.84+/-8.88 min/day) on the lake (mean+/-S.D.; 85.98+/-69.90 min/day). There was a strong positive log correlation (r=0.95) between the crude and adjusted (based on our derived exposure model) diary outcomes for the entire study sample, however, at higher exposure levels this relationship was differentially weaker (r=0.70). Results from this study suggest that current methods used in evaluating schistosomiasis exposure in China may overestimate and bias measures of the risk of infection. Activity diaries adjusted for the time of day, duration and the percent body surface area exposed are cost-effective and practical instruments to accurately quantify human exposure in the vast lake regions of Southern China where most of the endemic schistosomiasis japonica occurs.

Malaria on isolated Melanesian islands prior to the initiation of malaria elimination activities

The Australian Governments Pacific Malaria Initiative (PacMI) is supporting the National Malaria Program in both Solomon Islands and Vanuatu, complementing assistance from the Global Fund for AIDS, Tuberculosis and Malaria (GFATM). Two remote island groups - Tafea Province, Vanuatu and Temotu Province, Solomon Islands have been selected by the governments of both countries as possible malaria elimination areas. To provide information on the prevalence and distribution of the disease within these island groups, malariometric surveys were conducted during the wet seasons of 2008. In Tafea Province, a school-based survey was conducted which included the 2-12 y age group, while in Temotu a village based all-ages survey was conducted. An effort was made to sample villages or schools from a wide an area as possible on all islands. Diagnosis was initially based on Giemsa stained blood slides followed by molecular analysis using polymerase chain reaction (PCR). In Tafea Province, 73% (5238/7150) of children (2-12 y) were surveyed and in Temotu Province, in the all-ages survey, 50.2% (8742/17410) of the provincial population participated in the survey. In both Vanuatu and Solomon Islands malariometric surveys of their southern-most islands in 2008 showed relatively low over-all malaria parasite prevalence (2 to 3%). Other features of malaria in these island groups were low parasitaemia, low gametocyte carriage rates, low spleen rates, low malaria associated morbidity, a high incidence of asymptomatic infections, and a predominance of Plasmodium vivax over Plasmodium falciparum. For various reasons malaria rates are declining in these provinces providing a favourable situation for local malaria elimination. This will be advanced using mass distribution of bed nets and selective indoor residual spraying, the introduction of rapid diagnostic tests and artemisinin combination therapy, and intensive case detection and surveillance. It is as yet uncertain whether malaria parasites can themselves be sustainably eliminated from entire Melanesian islands, where they have previously been endemic. Key issues on the road to malaria elimination will be continued community involvement, improved field diagnostic methods and elimination of residual P. vivax parasites from the liver of asymptomatic persons.BackgroundThe Australian Governments Pacific Malaria Initiative (PacMI) is supporting the National Malaria Program in both Solomon Islands and Vanuatu, complementing assistance from the Global Fund for AIDS, Tuberculosis and Malaria (GFATM). Two remote island groups - Tafea Province, Vanuatu and Temotu Province, Solomon Islands have been selected by the governments of both countries as possible malaria elimination areas. To provide information on the prevalence and distribution of the disease within these island groups, malariometric surveys were conducted during the wet seasons of 2008.MethodsIn Tafea Province, a school-based survey was conducted which included the 2-12 y age group, while in Temotu a village based all-ages survey was conducted. An effort was made to sample villages or schools from a wide an area as possible on all islands. Diagnosis was initially based on Giemsa stained blood slides followed by molecular analysis using polymerase chain reaction (PCR).ResultsIn Tafea Province, 73% (5238/7150) of children (2-12 y) were surveyed and in Temotu Province, in the all-ages survey, 50.2% (8742/17410) of the provincial population participated in the survey. In both Vanuatu and Solomon Islands malariometric surveys of their southern-most islands in 2008 showed relatively low over-all malaria parasite prevalence (2 to 3%). Other features of malaria in these island groups were low parasitaemia, low gametocyte carriage rates, low spleen rates, low malaria associated morbidity, a high incidence of asymptomatic infections, and a predominance of Plasmodium vivax over Plasmodium falciparum.ConclusionFor various reasons malaria rates are declining in these provinces providing a favourable situation for local malaria elimination. This will be advanced using mass distribution of bed nets and selective indoor residual spraying, the introduction of rapid diagnostic tests and artemisinin combination therapy, and intensive case detection and surveillance. It is as yet uncertain whether malaria parasites can themselves be sustainably eliminated from entire Melanesian islands, where they have previously been endemic. Key issues on the road to malaria elimination will be continued community involvement, improved field diagnostic methods and elimination of residual P. vivax parasites from the liver of asymptomatic persons.

An innovative database for epidemiological field studies of neglected tropical diseases

miasis, rather than for the evaluation of a complex epidemiological study, requiring expertise in the principles and practice of data management. Language barriers provided additional challenges in implementing an efficient data management system. Accordingly, we present details of the innovative database we developed, which allowed us to produce data that were protected against data entry errors and therefore more likely to be of high quality and reliability. Furthermore, it also provided us with evidence of protection. This database can also serve as a template for other epidemiological studies of NTDs in the future.

Risk of death for young ex-prisoners in the year following release from adult prison

Background : In the community, all‐cause mortality rates among those younger than 25 years are considerably lower than those of older adults and are largely attributable to risk‐taking behaviours. However, given the unique health profiles of prisoners, this pattern may not be replicated among those leaving prison. We compared rates and patterns of mortality among young and older ex‐prisoners in Queensland, Australia.

Measuring exposure to Schistosoma japonicum in China. III. Activity diaries, snail and human infection, transmission ecology and options for control

We used activity diaries and snail detection to relate water contact and Schistosoma japonicum infection among a cohort of 178 residents on two islands in the Dongting Lake, China. Water exposure to each of 12 mapped water zones around the islands was calculated (m(2) min/day) for each subject. Infected Oncomelania hupensis hupensis snails in this area are focal and were found in only five of the 12 zones, with the highest rate being 5.7%. Thirty-one subjects (17%) were re-infected with a mean intensity of 63.2 epg. Mean water contact was 7.9 m(2) min/day; 98% of water exposure was due to economic activity and only 2% due to swimming or bathing, washing and other necessities of daily life. Males had more exposure and infection than females (P<0.05). Infected subjects had more exposure (10.2 m(2) min/day) than those not infected (7.44 m(2) min/day) (P<0.05). Compared with uninfected subjects, those infected had 2.9 times more exposure in infected-snail zones (P<0.01). Also, human infection intensity (epg) correlated well with exposure to infected snail zones (r=0.552, P<0.01). People <20 years old had the highest re-infection (21.4%) and intensity (3.77 epg). Median exposure for 20-49-year-olds (9.00 m(2) min/day) was nearly double that of those aged <20 or >50 years old (5.5 m(2) min/day). We conclude that map-referenced water contact and snail evaluation boosts accuracy of activity-diary measurements in large transmission foci for the Asian schistosome. Protecting against faecal contamination of snail inhabited sites, and against occupational exposure for island residents, should be a priority of future research. Potential strategies for migrating buffaloes and families living on visiting fishing boats are explored.

Why do psychiatric patients have higher cancer mortality rates when cancer incidence is the same or lower

Objective: Studies of overall cancer incidence and mortality in psychiatric patients have had mixed results. Some have reported lower than expected cancer incidence or mortality, while others have found no association or an increased risk depending on sample, psychiatric diagnosis, cancer site and methodology. Few studies have compared cancer incidence and mortality using the same population and methodology. Method: A population-based record-linkage analysis to compare cancer incidence and mortality in psychiatric patients with that for the general Queensland population, using an historical cohort to calculate age- and sex-standardised rate ratios and hazard ratios. Mental health records were linked with cancer registrations and death records from 2002 to 2007. Results: There were 89,992 new cancer cases, of which 3349 occurred in people with mental illness. Cancer incidence was the same as the general population for most psychiatric disorders. Rates were actually lower for dementia (hazard ratio = 0.77; 95% confidence interval = [0.67, 0.88]) and schizophrenia (hazard ratio = 0.84; 95% confidence interval = [0.72, 0.98]). By contrast, mortality was increased in psychiatric patients (hazard ratio = 2.27; 95% confidence interval = [2.15, 2.39]) with elevated hazard ratios for all the main psychiatric diagnoses. Conclusions: Lifestyle, such as alcohol or tobacco use, would not explain our findings that people with mental illness are no more likely than the general population to develop cancer but more likely to die of it. Other factors may be the difficulty in differentiating medically explained and unexplained symptoms, greater case fatality or inequity in access to specialist procedures. The study highlights the need for improved cancer screening, detection and intervention in this population.

Striking subgroup differences in substance‐related mortality after release from prison

AIMS To compare the incidence, timing and risk factors for substance-related death between Indigenous and non-Indigenous ex-prisoners in Queensland, Australia. DESIGN Retrospective cohort study. SETTING All adult prisons in the state of Queensland, Australia, linked to deaths registered in Australia. PARTICIPANTS/CASES We obtained records for all adults released from prison in Queensland, Australia from 1 January 1994 to 31 December 2007. Among this cohort of 42 015 individuals we observed 82 315 releases from prison and 2158 deaths in the community by the end of 2007, of which 661 were substance-related deaths. MEASUREMENTS Incarceration data were obtained from Queensland Corrective Services and linked probabilistically with deaths recorded in the Australian National Death Index. FINDINGS In the first year after release, Indigenous ex-prisoners were more likely to die from alcohol-related causes [hazard ratio (HR) = 1.9, 95% confidence interval (CI) = 1.1-3.1)] but less likely to die of drug-related causes (HR = 0.34, 95%CI = 0.21-0.53) than were non-Indigenous ex-prisoners. Among non-Indigenous prisoners only, the risk of substance-related death was significantly higher in the first 4 weeks [relative risk (RR) = 5.1, 95% CI = 3.7-6.9] when compared with the risk after 1 year post-release. Most evaluated risk factors for substance-related death were similar for Indigenous and non-Indigenous ex-prisoners; however, the hazard of death increased with age more for Indigenous ex-prisoners (HR = 1.7 per decade of age, 95% CI = 1.4-2.1) than for non-Indigenous ex-prisoners (HR = 1.3, 95% CI = 1.2-1.4). CONCLUSIONS In Australia, patterns of substance-related death in ex-prisoners differ markedly according to Indigenous status. Efforts to prevent substance-related deaths in ex-prisoners should consider heterogeneity in the target population and tailor responses accordingly.