Category Archives: Public Health

Scale up diarrhoea prevention to save lives

A widespread scale up of existing low-cost and effective tools to prevent and treat diarrhoea could substantially reduce diarrhoeal deaths and could be a major step towards achieving the Millenium Development Goal 4 of reducing child mortality by 2015, according to research published in PLoS Medicine.

Depressingly, in this modern era, diarrhoea—three or more loose bowel movements a day—is still a common cause of death in developing countries and is the 2nd biggest killer of young children (under 5 years) worldwide. Poor hygiene, inadequate sanitation and lack of clean, safe drinking water all contribute to the spread of the harmful viruses, bacteria and parasites that cause diarrhoea. Now, Fischer Walker and colleagues use their Lives Saved Tool (LiST) to estimate the potential lives saved after implementing two different scale-up scenarios for key diarrhoeal prevention (breastfeeding, vitamin A supplements, basic water, sanitation, hygiene, and rotavirus vaccination) and treatment (oral rehydration salts, zinc supplementation, and antibiotics for dysentery) intervention strategies in 68 countries with high childhood mortality.

The researchers put forward two scenarios for the priority countries, which included Bangladesh, China and Haiti, for a 5-year period (between 2010 and 2015)—the “ambitious” (which assumed feasible improvement in all interventions) and the “universal” (which assumed near 100% coverage for all interventions). By 2015, diarrhoeal deaths could be reduced by 78% and 92% in the ambitious and universal scenarios, respectively. With the universal scenario, nearly 5 million deaths could be averted at an additional costs of US$0.80 per capita using some of the key diarrhoea prevention and treatment interventions (such as rotavirus vaccination and oral rehydration salts) and $3.24 per capita when all sanitation and water interventions (such as handwashing, improved sanitation and access to safe, clean water) implemented.

Fischer Walker and co-workers argue that “real progress” could be made in the treatment and management of diarrhoeal diseases if intervention strategies are made an international priority and the global health community works together to eliminate this harmful disease. Furthermore, the research acts as a pertinent reminder that we already have the technologies and interventions needed to prevent and reduce the devastating effects of diarrhoea, we just need to use them in the right scenario.

ResearchBlogging.orgWalker, C., Friberg, I., Binkin, N., Young, M., Walker, N., Fontaine, O., Weissman, E., Gupta, A., & Black, R. (2011). Scaling Up Diarrhea Prevention and Treatment Interventions: A Lives Saved Tool Analysis PLoS Medicine, 8 (3) DOI: 10.1371/journal.pmed.1000428


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Monkeypox infections on the increase in Africa

The incidence of a smallpox-like disease—caused by the monkeypox virus—has increased 20-fold in the Demoncratic Republic of Congo (DRC) over the past 30 years, according to new research published online in the journal PNAS. The findings suggest that, as smallpox vaccination programmes ceased in the DRC in 1980, people are now immunologically ‘naïve’ to orthopoxviruses (including monkeypox and smallpox viruses) and could be at an increased risk of infection by this family of viruses.

The monkeypox virus can cause a serious zoonotic disease (potentially transmitted to humans from rodent species such as squirrels as well as primates such as monkeys) that is similar to smallpox. Smallpox vaccinations not only helped eradicate the smallpox virus, but also provided cross-protective immunity to monkeypox virus infection.

Anne Rimoin and colleagues assessed the burden of human monkeypox in the DRC by analyzing surveillance data for this disease from 2005–2007 in regions known to be endemic for the virus, a feat which had not been conducted since the early 1980s. In their up-to-date surveillance data across nine health zones in central DRC, 760 human monkeypox cases were confirmed by laboratory tests and the researchers found that the average annual cumulative incidence of monkeypox virus infection was 5.53 cases per 10,000 people across all zones. Men, children under the age of 15 years and people living in forested areas or who had not received a prior smallpox vaccination were at an increased risk of monkeypox infection whilst those who had been vaccinated against smallpox had a 5.2-fold lower risk of infection by the monkeypox virus than unvaccinated individuals. Rimoin et al. then compared the 1980s active surveillance data with their new 2000s findings from the same health zone and found that the incidence of human monkeypox in this zone increased substantially from 0.72 cases per 10,000 people in the 1980s to 14.42 cases per 10,000 people between 2005 and 2007.

The investigators add that “entire households are now mostly or completely [smallpox] vaccine naive”, which could result in increased human-human transmission between different generations within the same house. Furthermore, Rimoin and colleagues argue that because of several limitations (including poor access to remote areas) their study could have under-reported the true incidence of human monkeypox and the observed dramatic increase in disease incidence could in fact be a “conservative estimate”. Improved and continued disease surveillance will be needed to assess the true burden of monkeypox virus infection on public health in African populations, and could aid the development and implementation of strategies to reduce the risk of monkeypox virus infection.

ResearchBlogging.orgAnne W. Rimoin, Prime M. Mulembakani, Sara C. Johnston, James O. Lloyd Smith, Neville K. Kisalu, Timothee L. Kinkela, Seth Blumberg, Henri A. Thomassen, Brian L. Pike, Joseph N. Fair, Nathan D. Wolfe, Robert L. Shongo, Barney S. Graham, Pierre Formenty, E, & Major (2010). Major increase in human monkeypox incidence
30 years after smallpox vaccination campaigns
cease in the Democratic Republic of Congo Proceedings of the National Academy of Sciences USA (Published ahead of print 30th August 2010) DOI: 10.1073/pnas.1005769107

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Racial background affects risk of severe sepsis

High infection rates and increased risk of acute organ dysfunction in black individuals explains why people from this racial background are more likely to have (and die from) severe sepsis than white individuals, according to a new study published in JAMA.

Severe sepsis (when the body has a systemic inflammatory response to infection that can lead to multiple organ failure and death) is well-known to be more frequent in black individuals than white people. However, just why the incidence of severe sepsis is higher in this racial group is unknown and it is particularly important to investigate whether these racial disparities are because of different susceptibilities to infection or organ failure—a critical distinction that could influence treatment. High infection rates can be combated with vaccination programmes in at-risk individuals whilst high incidence rates of organ failure can be improved with better care in hospitals.

In what can only be described as a mammoth retrospective study (that included data from all hospitalisations across seven US states, that is, a potential total number of over 63 million people in the study), Florian B. Mayr and colleagues wanted to examine exactly why black people have a higher incidence of severe sepsis than white people.

The researchers found that of more than 8.6 million hospital admissions (not related to childbirth) in black and white individuals, over 2.2 million of the cases were because of infection and 381,787 of these cases (67,812 black patients; 313,975 white patients) had severe sepsis. They found that black patients had 67% higher hospitalization rates (after standardising for both age and sex) because of severe sepsis than did white patients. Furthermore, black patients also had both increased infection rates, risk of developing organ dysfunction and mortality compared with white patients. Differences in infection-related hospitalisations between the races were especially pronounced in younger adults (20–65 years old).

Findings from this large, retrospective cohort study clearly demonstrate that high severe sepsis rates in black people are because of a “higher likelihood of being hospitalised with infection and a higher risk of developing acute organ dysfunction”. These results have implications for public health; interventions to reduce infection (such as vaccinations) and better quality of care and management of hospitalised patients should be promoted, especially in healthcare providers that serve black communities. Furthermore, more research is needed to investigate risk of severe sepsis in people from other racial groups.

ResearchBlogging.orgMayr, F., Yende, S., Linde-Zwirble, W., Peck-Palmer, O., Barnato, A., Weissfeld, L., & Angus, D. (2010). Infection Rate and Acute Organ Dysfunction Risk as Explanations for Racial Differences in Severe Sepsis JAMA: The Journal of the American Medical Association, 303 (24), 2495-2503 DOI: 10.1001/jama.2010.851

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A little incentive goes a long way when it comes to vaccine uptake

Offering people free lentils and metal food dishes substantially improves the number of young children that receive a full course of childhood immunisations in resource poor areas, and is more cost effective than just improving the vaccine services available in the region, according to a new study published free in the British Medical Journal.

Abhijit Vinayak Banerjee and colleagues wanted to assess how effective non-financial incentives—1 kg raw lentils per vaccine and a set of metal thali plates once a child has received all their immunisations—and increased availability of vaccine services were at improving immunisation rates in young children in rural Rajasthan, India. Their study included 1,640 children (aged 1–3 years) from 134 villages who were randomly assigned to three groups:

–          the ‘immunisation camp’ who received reliable, monthly vaccinations from healthcare professionals

–          the ‘immunisation plus camp’ who in addition to reliable, monthly vaccines were also offered cheap little extras of free lentils (costing about $1) for every vaccine and a set of thalis (a snip at $1.50) for a complete set of vaccines (BCG, diphtheria-pertussis, tetanus, polio and measles) received by the children

–          a control group who did not receive any interventions

Taken from Banerjee, A. V. et al. BMJ 2010;340:c2220

The researchers showed that immunisation rates were higher in the children that were offered reliable immunisations plus a little extra (39%) compared with the rates in children who were just offered the reliable immunisations (16%). Interestingly, children in districts neighbouring the immunisation plus camp also had bigger improvements in immunisation rates than those living near the immunisation camp villages. Not only that, these small incentives were cost effective (costing an estimated $17.35 per fully immunised child in camps with incentives compared with $25.18 per fully immunised child in camps without these extras).

The findings from this study by Banerjee et al. could have important implications for vaccine policies. Moreover, the authors question whether offering lentils can even be considered a “cost” as they clearly will have immediate, nutritional benefits to both the vaccinated children and their families.

ResearchBlogging.orgBanerjee, A., Duflo, E., Glennerster, R., & Kothari, D. (2010). Improving immunisation coverage in rural India: clustered randomised controlled evaluation of immunisation campaigns with and without incentives BMJ, 340 (may17 1) DOI: 10.1136/bmj.c2220

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A gene polymorphism helps protect against malaria, but makes you vulnerable to lupus

A polymorphism in the human gene FCGR2B is associated with susceptibility to systemic lupus erythematosus (SLE), but it is also associated with protection against malaria, according to a new study published in PNAS. The polymorphism was most common in people of Southeast Asian and African origin (i.e. populations from areas endemic for malaria), implying that its protective effects against malaria could provide a survival advantage and explain its prevalence in these populations despite the increased risk of SLE.

Systemic lupus erythematosus is a chronic and systemic autoimmune disorder whilst malaria is an infectious disease caused by Plasmodium parasites. These two disparate diseases are in fact linked by their association with the gene FCGR2B, which is involved in immune regulation and encodes the Fc gamma receptor IIb. A single nucleotide change in FCGR2B, termed rs1050501, codes for a threonine instead of isoleucine in the FCGR2B protein, which in turn leads to a non-functional Fc gamma receptor IIb (FcγRIIbT232) that has been shown to be important for resistance against Plasmodium. Furthermore, rs1050501 had already been associated with SLE and the frequency of this allele was found to vary between people of different ethnicities—it is more common in Southeast Asians or East Africans than Caucasians.

Lisa. C. Willcocks and colleagues analysed the genotypes of 819 people with SLE from Hong Kong compared with 1,026 ethnically matched controls, and 326 Caucasian patients with SLE compared with 1,296 controls in the “largest study of this FCGR2B SNP in SLE performed so far.” They found that SLE was strongly associated with FcγRIIbT232 in both ethnic groups. Next, the investigators genotyped rs1050501 in children from an area in Kenya endemic for malaria—they analysed control children as well as children who had suffered from either repeated episodes of mild malaria or a severe form of malaria. They found children homozygous for FcγRIIbT232 (the rs1050501 allele was present on each chromosome pair) were protected against severe malaria. In contrast, the same allele did not protect against bacterial infection.

Willcocks et al. state that “the high mortality from malaria has resulted in the strongest known force for evolutionary selection in the recent history of the human genome.” They argue that the protective effects of FcγRIIbT232 against malaria could explain why the mutant receptor is most common in Africans and Southeast Asians; the frequency of the rs1050501 allele, like sickle-cell disease and thalassemia, being related to malarial endemicity. “Malaria seems to have driven retention of a polymorphism predisposing to a polygenic autoimmune disease, and this may begin to explain the ethnic differences seen in frequency of that disease,” write the authors.

ResearchBlogging.orgWillcocks, L., Carr, E., Niederer, H., Rayner, T., Williams, T., Yang, W., Scott, J., Urban, B., Peshu, N., Vyse, T., Lau, Y., Lyons, P., & Smith, K. (2010). A defunctioning polymorphism in FCGR2B is associated with protection against malaria but susceptibility to systemic lupus erythematosus Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0915133107

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Sleeping sickness—a new cure for a neglected disease?

Scientists have validated a new drug target, the Trypanosoma brucei enzyme N-myristoyltransferase, in the fight against sleeping sickness, and have already identified and tested an inhibitor against this enzyme that successfully cures T. brucei infection in mice.

The study, published in the journal Nature, provides a much-needed boost to research into neglected tropical diseases, which are often associated with poverty.

Image provided by Wikipedia

Sleeping sickness—also known as African trypanosomiasis—is a disease caused by by the parasite T. brucei, which itself is transmitted to humans via the tsetse fly. African trypanosomiasis is endemic in regions of Sub-Saharan Africa and WHO estimates suggest that 50,000-70,000 people are currently infected with the parasite and 30,000 people die from the infection every year. The disease can cause significant morbidity and mortality and consists of two stages; stage 1, where parasites are present in the blood, lymph and interstitial fluid, and the more serious stage 2, with parasites present in the central nervous system (CNS). Without treatment, the severe neurological symptoms of the disease—confusion, extreme fatigue and sleep cycle disturbances—can ultimately lead to an irreversible and progressive mental decline ending in coma and death.

The few treatments available in our arsenal against African trypanosomiasis are out-dated and can have poor efficacy and serious side effects. Previous work has already proposed that N-myristoyltransferase is a potential target for the treatment of parasitics diseases, including African trypanosomiasis. This enzyme adds myristate (a common saturated fatty acid) to many eukaryotic and microbial proteins, a process which is required for their biological activity. Julie Frearson and colleagues, have now made a breakthrough in the discovery and development of effective, low toxicity drugs to treat sleeping sickness by investigating compounds that affect T. brucei N-myristoyltransferase.

The researchers first screened a library of 62,000 lead-based compounds to test their effectiveness at inhibiting N-myristoyltrasnferease and in preventing proliferation of the blood stage form of T. brucei. They found one compound—DDD85646—was very potent at inhibiting myristoylation and trypanosome growth during in vitro tests. The scientists then tested the efficacy of this compound in animal models of trypanosomiasis. They found that DDD85646 was well-tolerated and effectively cured acute trypanosomiasis in mice. Furthermore, DDD85646 is trypanocidal—it rapidly killed trypanosomes in both in vitro and in vivo assays. Finally, the investigators confirmed that DDD85646 truly acts “on target” against the T. brucei N-myristoyltransferase, and they also characterised the peptide pocket in which the inhibitor binds the target enzyme.

A possible drawback in using an inhibitor against N-myristoyltransferase as a trypanocidal drug is that humans also produce this enzyme. More research is needed into the inhibitor DDD85646 to improve its selectivity (ensuring that it is specific only for ­N-myristoyltransferase produced by trypanosomes) and to determine whether it can also penetrate the CNS and effectively kill parasites during the late-stage of trypanosomiasis. Crucially, clinical trials will be needed to ensure the compound is safe to use in humans. Only then will any future drugs for sleeping sickness, based on this research by Frearson et al., be seriously considered for production by big pharmaceutical companies.

ResearchBlogging.orgFrearson, J., Brand, S., McElroy, S., Cleghorn, L., Smid, O., Stojanovski, L., Price, H., Guther, M., Torrie, L., Robinson, D., Hallyburton, I., Mpamhanga, C., Brannigan, J., Wilkinson, A., Hodgkinson, M., Hui, R., Qiu, W., Raimi, O., van Aalten, D., Brenk, R., Gilbert, I., Read, K., Fairlamb, A., Ferguson, M., Smith, D., & Wyatt, P. (2010). N-myristoyltransferase inhibitors as new leads to treat sleeping sickness Nature, 464 (7289), 728-732 DOI: 10.1038/nature08893

*see also African trypanosomes just love social networking

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Weak link in TB bacteria cell wall

The Mycobacterium tuberculosis protein LdtM2, involved in making “nonclassical” crosslinks in the bacterial cell wall, is required for virulence and antibiotic resistance. The study results, published online in Nature Medicine, could help identify new treatment combinations to tackle chronic tuberculosis infections.

Tuberculosis is a major global health threat. Drug resistance in TB is becoming a monumental problem and the very nature of the treatment schedule—usually a combination of four anti-TB drugs taken daily for six months—directly contributes to this problem. The majority of the TB bacteria are killed within the first two weeks of treatment but the remaining “persisters” need six months or more of treatment to effectively kill them. If this drug regime is misused or mismanaged then multidrug resistant and extensively drug resistant (XDR) strains of M. tuberculosis can develop …you only have to watch this slideshow of James Nachtwey’s photographs for to see for yourself the devastating effects of XDR-TB.

Gupta and colleagues investigated the role of the M. tuberculosis cell wall in chronic TB infection—the physiology of which is poorly understood in the persistent stationary phase of bacterial growth. They examined the M. tuberculosis gene MT2594 (renamed in this paper ldtM2), which is a L,D-transpeptidase that helps create the “nonclassical” 3→3 crosslinks in the bacterial cell wall—a process which helps give the cell wall strength.

The researchers found that mutants lacking ldtM2 had an altered colony morphology compared with the wild-type strain—small, smooth, tower block-like colonies growing up from the agar surface into the air compared with the larger, rougher and flatter colonies of the wild-type. By making the mutants express ldtM2 again, they successfully restored the wild-type growth phenotype. They then infected mice with these mutant TB bacteria to see whether LdtM2 was important for bacterial virulence. After four weeks, mice were heavily infected with the wild-type and complemented bacterial strains and subsequently died, however, mice infected with ldtM2 mutant did not die nor were they significantly ill despite having bacteria present in their lungs. Moreover, during chronic TB infection in mice, ldtM2 mutants were more susceptible than wild-type bacteria to the antibiotic amoxicillin, in combination with clavulanate—added to inhibit the natural β-lactamases produced by TB bacteria, which normally allow the bacteria to resist the effects of β-lactam antibiotics like amoxicillin.

The authors suggest that the unusual 3→3 crosslinks made by the LdtM2 L,D-transpeptidase are “vital to the physiology of the peptidoglycan layer” and that these linkages, along with the classical 4→3 crosslinks, are involved in “maintaining and remodelling” the cell wall of the TB bacteria. Interestingly, this new data indicates that a combination of drugs to inhibit the L,D-transpeptidases and β-lactamases produced by TB bacteria could effectively kill the persistent bacteria that contribute  to chronic TB infection—something that would be most welcome on World TB day today.

ResearchBlogging.orgGupta, R., Lavollay, M., Mainardi, J., Arthur, M., Bishai, W., & Lamichhane, G. (2010). The Mycobacterium tuberculosis protein LdtMt2 is a nonclassical transpeptidase required for virulence and resistance to amoxicillin Nature Medicine DOI: 10.1038/nm.2120

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