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1.  Adapting to the health impacts of climate change in a sustainable manner 
Globalization and Health  2014;10(1):82.
The climate is changing and this poses significant threats to human health. Climate change is one of the greatest challenges facing Pacific Island countries and territories due to their unique geophysical features, and their social, economic and cultural characteristics. The Pacific region also faces challenges with widely dispersed populations, limited resources and fragmented health systems. Over the past few years, there has been a substantial increase in international aid for health activities aimed at adapting to the threats of climate change. This funding needs to be used strategically to ensure an effective approach to reducing the health risk from climate change. Respecting the principles of development effectiveness will result in more effective and sustainable adaptation, in particular, 1) processes should be owned and driven by local communities, 2) investments should be aligned with existing national priorities and policies, and 3) existing systems must not be ignored, but rather expanded upon and reinforced.
PMCID: PMC4271334  PMID: 25498769
Climate; Change; Adaptation; Health; Resilience; Development effectiveness; Harmonisation; Alignment
2.  Investigating an outbreak of acute fever in Chuuk, Federated States of Micronesia 
In September 2012, there was an unexpected increase of acute febrile illness (AFI) in Chuuk State of the Federated States of Micronesia. At the same time, dengue outbreaks were occurring in two of the Federated States of Micronesia’s other three states. The cause of AFI was suspected to be dengue; however, by the end of October, only one of 39 samples was positive for dengue. The objective of the investigation was to establish the cause of the outbreak.
A line list was created and data analysed by time, place, person and clinical features. Reported symptoms were compared with the published symptoms of several diagnoses and laboratory testing undertaken.
Of the 168 suspected cases, 62% were less than 20 years of age and 60% were male. The clinical features of the cases were not typical for dengue but suggestive of respiratory illness. Nasopharyngeal swabs were subsequently collected and found to be positive for influenza. Public health measures were undertaken and the AFI returned to expected levels.
Clinical diagnosis of acute febrile illness (AFI) can often be difficult and misleading. This can mean that opportunities for preventive measures early on in an outbreak are missed. In any outbreak, descriptive epidemiological analyses are valuable in helping to ascertain the cause of the outbreak.
PMCID: PMC4318975
3.  Widespread Genetic Switches and Toxicity Resistance Proteins for Fluoride 
Science (New York, N.Y.)  2011;335(6065):233-235.
Most riboswitches are metabolite-binding RNA structures located in bacterial messenger RNAs where they control gene expression. We have discovered a riboswitch class in many bacterial and archaeal species whose members are selectively triggered by fluoride but reject other small anions, including chloride. These fluoride riboswitches activate expression of genes that encode putative fluoride transporters, enzymes that are known to be inhibited by fluoride, and additional proteins of unknown function. Our findings indicate that most organisms are naturally exposed to toxic levels of fluoride and that many species use fluoride-sensing RNAs to control the expression of proteins that alleviate the deleterious effects of this anion.
PMCID: PMC4140402  PMID: 22194412
4.  Preparedness for Threat of Chikungunya in the Pacific 
Emerging Infectious Diseases  2014;20(8):e130696.
Chikungunya virus (CHIKV) caused significant outbreaks of illness during 2005–2007 in the Indian Ocean region. Chikungunya outbreaks have also occurred in the Pacific region, including in Papua New Guinea in 2012; New Caledonia in April 2013; and Yap State, Federated States of Micronesia, in August 2013. CHIKV is a threat in the Pacific, and the risk for further spread is high, given several similarities between the Pacific and Indian Ocean chikungunya outbreaks. Island health care systems have difficulties coping with high caseloads, which highlights the need for early multidisciplinary preparedness. The Pacific Public Health Surveillance Network has developed several strategies focusing on surveillance, case management, vector control, laboratory confirmation, and communication. The management of this CHIKV threat will likely have broad implications for global public health.
PMCID: PMC4111160  PMID: 25062306
chikungunya; CHIKV; Pacific; Pacific Public Health Surveillance Network; PPHSN; Aedes aegypti; Aedes albopictus; outbreak; preparedness; viruses; vector-borne infections; mosquitos; Indian Ocean; Papua New Guinea; Yap State; Federated States of Micronesia; New Caledonia
5.  A widespread self-cleaving ribozyme class is revealed by bioinformatics 
Nature chemical biology  2013;10(1):10.1038/nchembio.1386.
Ribozymes are noncoding RNAs that promote chemical transformations with rate enhancements approaching those of protein enzymes. Although ribozymes are likely to have been abundant during the RNA world era, only ten classes are known to exist among contemporary organisms. We report the discovery and analysis of an additional self-cleaving ribozyme class, called twister, which is present in many species of bacteria and eukarya. Nearly 2700 twister ribozymes were identified that conform to a secondary structure consensus that is small yet complex, with three stems conjoined by internal and terminal loops. Two pseudoknots provide tertiary structure contacts that are critical for catalytic activity. The twister ribozyme motif provides another example of a natural RNA catalyst and calls attention to the potentially varied biological roles of this and other classes of widely distributed self-cleaving RNAs.
PMCID: PMC3867598  PMID: 24240507
6.  Increased incidence of invasive bacterial disease in chronic obstructive pulmonary disease compared to the general population-a population based cohort study 
BMC Infectious Diseases  2014;14:163.
Innate defence mechanisms of the airways are impaired in chronic obstructive pulmonary disease (COPD), predisposing patients to lower respiratory tract infections, but less is known about the association with other infections. In this population-based cohort study, we investigated the associations between COPD and invasive bacterial disease by comparing incidence rates of bacteraemia in COPD patients and randomly selected reference individuals from the general population.
In this population based cohort study all patients with COPD, ≥40 years of age, who were discharged from hospitals in southern Sweden between 1990 and 2003 were identified in the Swedish Inpatient Register (n = 15,403). Age and gender matched reference individuals were randomly selected from the general population. Records were cross-referenced to the microbiological databases covering the region, 1990–2010. The hazard ratios (HR) of bloodstream infections and hospitalisations for infections were estimated by Cox proportional hazards regression.
We found that individuals with COPD had a 2.5-fold increased incidence of bacteraemia compared to the reference individuals from the general population adjusted for other co-morbidity and socio-economic status (hazard ratio: 2.5, 95% confidence interval: 2.2-2.7). The increased incidence of bacteraemia was paralleled by an increased incidence of hospitalisation for non-respiratory infections, i.e., skin infections, pyelonephritis, or septic arthritis. Despite higher absolute rates of bloodstream infections among COPD patients than among the general population, the distribution of different pathogens was similar.
In summary this population-based study shows COPD is associated with an increased incidence of invasive bacterial infections compared to the general population, indicating a general frailty of acquiring severe infections in addition to the specific susceptibility to infections of respiratory origin. The underlying contributory factors (e.g. smoking, corticosteroid use, co-morbid diseases or a frailty inherent to COPD itself) need to be disentangled in further studies.
PMCID: PMC3976148  PMID: 24661335
Bacteraemia; Epidemiology; Chronic obstructive pulmonary disease; Infection; Sepsis
7.  Findings and Implications of the Global Burden of Disease 2010 Study for the Pacific Islands 
The Global Burden of Disease 2010 Study is the largest study of its kind. It provides a large volume of information about the global burden of disease and associated risk factors. It estimates that lower respiratory infections, diabetes, diarrhea, and tuberculosis cause the greatest burden in the Pacific, and noncommunicable diseases caused a substantially greater burden in 2010 compared with 1990. Although the Pacific is considered to be a region rich in data, very little of these data has been analyzed, synthesized, and made publically available. Consequently, burden estimates for the Pacific are derived from models built with very limited data, and it is difficult to know how accurate they are. Health information in the Pacific needs strengthening, particularly in relation to data collection, analysis, use, and sharing. This will improve the reliability and comparability of burden of disease estimates.
PMCID: PMC4015300  PMID: 24809361
8.  Identification of Hammerhead Ribozymes in All Domains of Life Reveals Novel Structural Variations 
PLoS Computational Biology  2011;7(5):e1002031.
Hammerhead ribozymes are small self-cleaving RNAs that promote strand scission by internal phosphoester transfer. Comparative sequence analysis was used to identify numerous additional representatives of this ribozyme class than were previously known, including the first representatives in fungi and archaea. Moreover, we have uncovered the first natural examples of “type II” hammerheads, and our findings reveal that this permuted form occurs in bacteria as frequently as type I and III architectures. We also identified a commonly occurring pseudoknot that forms a tertiary interaction critical for high-speed ribozyme activity. Genomic contexts of many hammerhead ribozymes indicate that they perform biological functions different from their known role in generating unit-length RNA transcripts of multimeric viroid and satellite virus genomes. In rare instances, nucleotide variation occurs at positions within the catalytic core that are otherwise strictly conserved, suggesting that core mutations are occasionally tolerated or preferred.
Author Summary
The expanding diversity of noncoding RNA discoveries is revealing a broader spectrum of roles RNA plays in cellular signaling and in biochemical functions. These discoveries in part are being facilitated by the expanding collection of genomic sequence data and by computational methods used to search for novel RNAs. In addition to searching for new classes of structured RNAs, these methods can be used to reevaluate the distributions of long-known RNAs. We have used a bioinformatics search strategy to identify many novel variants of hammerhead self-cleaving ribozymes, including examples from species in all three domains of life. New architectural features and novel catalytic core variants were identified, and the genomic locations of some hammerhead ribozymes suggest important biological functions. This ribozyme class promotes RNA cleavage by an internal phosphoester transfer reaction by using a small catalytic core. The simple sequence and structural architecture coupled with the general utility of RNA strand scission may explain its great abundance in many organisms.
PMCID: PMC3088659  PMID: 21573207
9.  Challenges of ligand identification for riboswitch candidates 
RNA Biology  2011;8(1):5-10.
Expanding DNA sequence databases and improving methods for comparative analysis are being exploited to identify numerous noncoding RNA elements including riboswitches. Ligands for many riboswitch classes usually can be inferred based on the genomic contexts of representative RNAs, and complex formation or genetic regulation subsequently demonstrated experimentally. However, there are several candidate riboswitches for which ligands have not been identified. In this report, we discuss three of the most compelling riboswitch candidates: the ykkC/yzkD, yybP/ykoY and pfl RNAs. Each of these RNAs is numerous, phylogenetically widespread and carries features that are hallmarks of metabolite-binding riboswitches, such as a well-conserved aptamer-like structure and apparent interactions with gene regulation elements such as ribosome binding sites or intrinsic transcription termination stems. These RNAs likely represent only a small sampling of the challenging motifs that researchers will encounter as new noncoding RNAs are identified.
PMCID: PMC3142362  PMID: 21317561
riboswitch; purine biosynthesis; alkaline response; formyl-tetrahydrofolate biosynthesis
10.  Oral Polio Vaccine Influences the Immune Response to BCG Vaccination. A Natural Experiment 
PLoS ONE  2010;5(5):e10328.
Oral polio vaccine (OPV) is recommended to be given at birth together with BCG vaccine. While we were conducting two trials including low-birth-weight (LBW) and normal-birth-weight (NBW) infants in Guinea-Bissau, OPV was not available during some periods and therefore some infants did not receive OPV at birth, but only BCG. We investigated the effect of OPV given simultaneously with BCG at birth on the immune response to BCG vaccine.
Methods and Findings
We compared the in vitro and the in vivo response to PPD in the infants who received OPV and BCG with that of infants who received BCG only. At age 6 weeks, the in vitro cytokine response to purified protein derivate (PPD) of M. Tuberculosis was reduced in LBW and NBW infants who had received OPV with BCG. In a pooled analysis receiving OPV with BCG at birth was associated with significantly lower IL-13 (p = 0.041) and IFN-γ (p = 0.004) and a tendency for lower IL-10 (p = 0.054) in response to PPD. Furthermore, OPV was associated with reduced in vivo response to PPD at age 2 months, the prevalence ratio (PR) of having a PPD reaction being 0.75 (0.58–0.98), p = 0.033, and with a tendency for reduced likelihood of having a BCG scar (0.95 (0.91–1.00), p = 0.057)). Among children with a scar, OPV was associated with reduced scar size, the regression coefficient being −0.24 (−0.43—0.05), p = 0.012.
This study is the first to address the consequences for the immune response to BCG of simultaneous administration with OPV. Worryingly, the results indicate that the common practice in low-income countries of administering OPV together with BCG at birth may down-regulate the response to BCG vaccine.
PMCID: PMC2873948  PMID: 20502641
11.  Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau 
Objective To determine whether BCG revaccination at 19 months of age reduces overall child mortality.
Design Randomised trial, with follow-up to age 5.
Setting A health project in Bissau, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area with 90 000 inhabitants.
Participants 2871 children aged 19 months to 5 years with low or no reactivity to tuberculin and who were not severely sick on the day of enrolment.
Intervention BCG vaccination or no vaccination (control).
Main outcome measure Hazard ratios for mortality.
Results 77 children died during follow-up. Compared with controls, the BCG revaccinated children had a hazard ratio of 1.20 (95% confidence interval 0.77 to 1.89). Two hundred and fifty children were admitted to hospital for the first time between enrolment and the end of the study, with an incidence rate ratio for BCG revaccinated children versus controls of 1.04 (0.81 to 1.33). The trial was stopped prematurely because of a cluster of deaths in the BCG arm of the study. This increase in mortality occurred at a time when many children had received missing vaccinations or vitamin A or iron supplementation; the hazard ratio for BCG revaccinated children compared with controls was 2.69 (1.05 to 6.88) in the period after these campaigns. Throughout the trial, the effect of BCG revaccination on mortality was significantly different (P=0.006) in children who had received diphtheria-tetanus-pertussis (DTP) booster vaccination before enrolment (hazard ratio 0.36, 0.13 to 0.99) and children who had not received the booster before enrolment (1.78, 1.04 to 3.04).
Conclusions There was no overall beneficial effect of being revaccinated with BCG. The effect of BCG revaccination on mortality might depend on other health interventions.
Trial registration Clinical Trials ICA4-CT-2002-10053-REVAC.
PMCID: PMC2839082  PMID: 20231251
12.  Vitamin A supplementation and BCG vaccination at birth in low birthweight neonates: two by two factorial randomised controlled trial 
Objective To investigate the effect of vitamin A supplementation and BCG vaccination at birth in low birthweight neonates.
Design Randomised, placebo controlled, two by two factorial trial.
Setting Bissau, Guinea-Bissau.
Participants 1717 low birthweight neonates born at the national hospital.
Intervention Neonates who weighed less than 2.5 kg were randomly assigned to 25 000 IU vitamin A or placebo, as well as to early BCG vaccine or the usual late BCG vaccine, and were followed until age 12 months.
Main outcome measure Mortality, calculated as mortality rate ratios (MRRs), after follow-up to 12 months of age for infants who received vitamin A supplementation compared with those who received placebo.
Results No interaction was observed between vitamin A supplementation and BCG vaccine allocation (P=0.73). Vitamin A supplementation at birth was not significantly associated with mortality: the MRR of vitamin A supplementation compared with placebo, controlled for randomisation to “early BCG” versus “no early BCG” was 1.08 (95% CI 0.79 to 1.47). Stratification by sex revealed a significant interaction between vitamin A supplementation and sex (P=0.046), the MRR of vitamin A supplementation being 0.74 (95% CI 0.45 to 1.22) in boys and 1.42 (95% CI 0.94 to 2.15) in girls. When these data were combined with data from a complementary trial among normal birthweight neonates in Guinea-Bissau, the combined estimate of the effect of neonatal vitamin A supplementation on mortality was 1.08 (95% CI 0.87 to 1.33); 0.80 (95% CI 0.58 to 1.10) in boys and 1.41 (95% CI 1.04 to 1.90) in girls (P=0.01 for interaction between neonatal vitamin A and sex).
Conclusions The combined results of this trial and the complementary trial among normal birthweight neonates have now shown that, overall, it would not be beneficial to implement a neonatal vitamin A supplementation policy in Guinea-Bissau. Worryingly, the trials show that vitamin A supplementation at birth can be harmful in girls. Previous studies and future trials should investigate the possibility that vitamin A supplementation has sex differential effects.
Trial registration NCT00168610.
PMCID: PMC2835853  PMID: 20215360
13.  Effect of 50 000 IU vitamin A given with BCG vaccine on mortality in infants in Guinea-Bissau: randomised placebo controlled trial 
BMJ : British Medical Journal  2008;336(7658):1416-1420.
Objective To investigate the effect of high dose vitamin A supplementation given with BCG vaccine at birth in an African setting with high infant mortality.
Design Randomised placebo controlled trial.
Setting Bandim Health Project’s demographic surveillance system in Guinea-Bissau, covering approximately 90 000 inhabitants.
Participants 4345 infants due to receive BCG.
Intervention Infants were randomised to 50 000 IU vitamin A or placebo and followed until age 12 months.
Main outcome measure Mortality rate ratios.
Results 174 children died during follow-up (mortality=47/1000 person-years). Vitamin A supplementation was not significantly associated with mortality; the mortality rate ratio was 1.07 (95% confidence interval 0.79 to 1.44). The effect was 1.00 (0.65 to 1.56) during the first four months and 1.13 (0.75 to 1.68) from 4 to 12 months of age. The mortality rate ratio in boys was 0.84 (0.55 to 1.27) compared with 1.39 (0.90 to 2.14) in girls (P for interaction=0.10). An explorative analysis revealed a strong interaction between vitamin A and season of administration.
Conclusions Vitamin A supplementation given with BCG vaccine at birth had no significant benefit in this African setting. Although little doubt exists that vitamin A supplementation reduces mortality in older children, a global recommendation of supplementation for all newborn infants may not contribute to better survival.
Trial registration Clinical trials NCT00168597.
PMCID: PMC2432170  PMID: 18558641
14.  Identification of 22 candidate structured RNAs in bacteria using the CMfinder comparative genomics pipeline 
Nucleic Acids Research  2007;35(14):4809-4819.
We applied a computational pipeline based on comparative genomics to bacteria, and identified 22 novel candidate RNA motifs. We predicted six to be riboswitches, which are mRNA elements that regulate gene expression on binding a specific metabolite. In separate studies, we confirmed that two of these are novel riboswitches. Three other riboswitch candidates are upstream of either a putative transporter gene in the order Lactobacillales, citric acid cycle genes in Burkholderiales or molybdenum cofactor biosynthesis genes in several phyla. The remaining riboswitch candidate, the widespread Genes for the Environment, for Membranes and for Motility (GEMM) motif, is associated with genes important for natural competence in Vibrio cholerae and the use of metal ions as electron acceptors in Geobacter sulfurreducens. Among the other motifs, one has a genetic distribution similar to a previously published candidate riboswitch, ykkC/yxkD, but has a different structure. We identified possible non-coding RNAs in five phyla, and several additional cis-regulatory RNAs, including one in ε-proteobacteria (upstream of purD, involved in purine biosynthesis), and one in Cyanobacteria (within an ATP synthase operon). These candidate RNAs add to the growing list of RNA motifs involved in multiple cellular processes, and suggest that many additional RNAs remain to be discovered.
PMCID: PMC1950547  PMID: 17621584
15.  Vaccinia Scars Associated with Improved Survival among Adults in Rural Guinea-Bissau 
PLoS ONE  2006;1(1):e101.
In urban Guinea-Bissau, adults with a vaccinia scar had better survival but also a higher prevalence of HIV-2 infection. We therefore investigated the association between vaccinia scar and survival and HIV infection in a rural area of Guinea-Bissau.
Methodology/Principal Findings
In connection with a study of HIV in rural Guinea-Bissau, we assessed vaccinia and BCG scars in 193 HIV-1 or HIV-2 infected and 174 uninfected participants. Mortality was assessed after 2½–3 years of follow-up. The analyses were adjusted for age, sex, village, and HIV status. The prevalence of vaccinia scar was associated with age, village, and HIV-2 status but not with sex and schooling. Compared with individuals without any scar, individuals with a vaccinia scar had better survival (mortality rate ratio (MR) = 0.22 (95% CI 0.08–0.61)), the MR being 0.19 (95% CI 0.06–0.57) for women and 0.40 (95% CI 0.04–3.74) for men. Estimates were similar for HIV-2 infected and HIV-1 and HIV-2 uninfected individuals. The HIV-2 prevalence was higher among individuals with a vaccinia scar compared to individuals without a vaccinia scar (RR = 1.57 (95% CI 1.02–2.36)).
The present study supports the hypothesis that vaccinia vaccination may have a non-specific beneficial effect on adult survival.
PMCID: PMC1762358  PMID: 17183634
16.  Early diphtheria-tetanus-pertussis vaccination associated with higher female mortality and no difference in male mortality in a cohort of low birthweight children: an observational study within a randomised trial 
Archives of Disease in Childhood  2012;97(8):685-691.
Studies from low-income countries have suggested that diphtheria-tetanus-pertussis (DTP) vaccine provided after Bacille Calmette-Guerin (BCG) vaccination may have a negative effect on female survival. The authors examined the effect of DTP in a cohort of low birthweight (LBW) infants.
2320 LBW newborns were visited at 2, 6 and 12 months of age to assess nutritional and vaccination status. The authors examined survival until the 6-month visit for children who were DTP vaccinated and DTP unvaccinated at the 2-month visit.
Two-thirds of the children had received DTP at 2 months and 50 deaths occurred between the 2-month and 6-month visits. DTP vaccinated children had a better anthropometric status for all indices than DTP unvaccinated children. Small mid-upper arm circumference (MUAC) was the strongest predictor of mortality. The death rate ratio (DRR) for DTP vaccinated versus DTP unvaccinated children differed significantly for girls (DRR 2.45; 95% CI 0.93 to 6.45) and boys (DRR 0.53; 95% CI 0.23 to 1.20) (p=0.018, homogeneity test). Adjusting for MUAC, the overall effect for DTP vaccinated children was 2.62 (95% CI 1.34 to 5.09); DRR was 5.68 (95% CI 1.83 to 17.7) for girls and 1.29 (95% CI 0.56 to 2.97) for boys (p=0.023, homogeneity test). While anthropometric indices were a strong predictor of mortality among boys, there was little or no association for girls.
Surprisingly, even though the children with the best nutritional status were vaccinated early, early DTP vaccination was associated with increased mortality for girls.
PMCID: PMC3409557  PMID: 22331681

Results 1-16 (16)