Analysis of the Health Product Profile Directory - a new tool to inform priority-setting in global public health

Background: The Health Product Profile Directory (HPPD) is an online database describing 8–10 key characteristics (such as target population, measures of efficacy and dosage) of product profiles for medicines, vaccines, diagnostics and other products that are intended to be accessed by populations in low- and middle-income countries. The HPPD was developed by TDR on behalf of WHO and launched on 15 May 2019. Methods: The contents of the HPPD were downloaded into an Excel™ spreadsheet via the open access interface and analysed to identify the number of health product profiles by type, disease, year of publication, status, author organization and safety information. Results: The HPPD contains summaries of 215 health product profiles published between 2008 and May 2019, 117 (54%) of which provide a hyperlink to the detailed publication from which the summary was extracted, and the remaining 98 provide an email contact for further information. A total of 55 target disease or health conditions are covered, with 210 profiles describing a product with an infectious disease as the target. Only 5 product profiles in the HPPD describe a product for a non-communicable disease. Four diseases account for 40% of product profiles in the HPPD; these are tuberculosis (33 profiles, 15%), malaria (31 profiles, 14%), HIV (13 profiles, 6%) and Chagas (10 profiles, 5%). Conclusion: The HPPD provides a new tool to inform priority-setting in global health — it includes all product profiles authored by WHO (n = 51). There is a need to standardise nomenclature to more clearly distinguish between strategic publications (describing research and development (R&D) priorities or preferred characteristics) compared to target product profiles to guide a specific candidate product undergoing R&D. It is recommended that all profiles published in the HPPD define more clearly what affordability means in the context where the product is intended to be used and all profiles should include a statement of safety. Combining the analysis from HPPD to a mapping of funds available for R&D and those products in the R&D pipeline would create a better overview of global health priorities and how they are supported. Such analysis and increased transparency should take us a step closer to measuring and improving coordination of efforts in global health R&D

Flight Measurements of Flying Qualities of a P-47D-30 Airplane (AAF No. 43-3441) to Determine Longitudinal Stability and Control and Stalling Characteristics

Flight tests have been made to determine the longitudinal stability and control and stalling characteristics of the P-47.E-30 airplane. The teat results show the airplane to be unstable stick free in any power-on condition even at the most forward center-of-gravity position tested. At the rearward center-of-gravity position tested the airplane also had neutral to negative stick-fixed stability with power on. The characteristics in accelerated flight were acceptable at the forward center-of-gravity position at low and high altitudes except at high speed where the control-force variations with acceleration were high. At the rearward center-of-gravity position, elevator-force reversals were experienced in turns at low speeds, and the force per g was low at all the other speeds. Ample stall warning was afforded in all the conditions tested and the stalling characteristics were very satisfactory except in the approach and wave-off conditions

Population genetic analysis of the Plasmodium falciparum 6-cys protein Pf38 in Papua New Guinea reveals domain-specific balancing selection

<p>Abstract</p> <p>Background</p> <p>The <it>Plasmodium falciparum </it>merozoite surface protein Pf38 is targeted by antibodies of malaria immune adults and has been shown to be under balancing (immune) selection in a Gambian parasite population, indicating potential as a malaria vaccine candidate. This study explores the population genetics of <it>Pf</it>38 in Papua New Guinea, to determine the extent and geographic distribution of diversity and to measure selective pressure along the length of the gene.</p> <p>Methods</p> <p>Using samples collected during community-based cross-sectional surveys in the Mugil and Wosera regions, the <it>Pf38 </it>genes of 59 <it>P. falciparum </it>isolates were amplified and sequenced. These sequences, along with previously sequenced Gambian and laboratory isolates, were then subjected to an array of population genetic analyses, examining polymorphisms, haplotype diversity and balancing selection. In addition to whole-gene analysis, the two 6-cys domains were considered separately, to investigate domain specific polymorphism and selection.</p> <p>Results</p> <p>Nineteen polymorphic sites were identified in the <it>Pf </it>38 gene. Of these, 13 were found in the Gambia, 10 in Mugil and 8 in Wosera. Notably, the majority of common polymorphisms were confined to domain I. Although only moderate levels of nucleotide diversity were observed, the haplotype diversity was high in all populations, suggesting extensive recombination. Analyses of the full-length sequence provided only modest evidence for balancing selection. However, there was a strong contrast between domain I, which showed strong evidence for positive balancing selection, and domain II which was neutral. Analyses of the geographic distribution of Pf38 haplotypes showed that four haplotypes accounted for the majority of sequences found world-wide, but there were many more haplotypes unique to the African than the PNG populations.</p> <p>Conclusion</p> <p>This study confirmed previous findings that <it>Pf38 </it>is a polymorphic gene under balancing selection. However, analysing polymorphism and selection across the length of the gene painted a considerably different picture. Domain I is highly polymorphic and the target of significant balancing selection. In contrast, domain II is relatively conserved and does not show evidence of immune selective pressure. The findings have implications for future population genetic studies on vaccine candidates, showing that the biological context must also be considered as a framework for analysis.</p

Population Hemoglobin Mean and Anemia Prevalence in Papua New Guinea: New Metrics for Defining Malaria Endemicity?

The hypothesis is that hemoglobin-based metrics are useful tools for estimating malaria endemicity and for monitoring malaria control strategies. The aim of this study is to compare population hemoglobin mean and anemia prevalence to established indicators of malaria endemicity, including parasite rates, rates of enlarged spleens in children, and records of (presumptive) malaria diagnosis among populations living with different levels of malaria transmission. Convenience sample, multisite cross-sectional household surveys conducted in Papua New Guinea. Correlations (r(2)) between population Hb mean and anemia prevalence and altitude, parasite rate, and spleen rate were investigated in children ages 2 to 10 years, and in the general population; 21,664 individuals from 156 different communities were surveyed. Altitude ranged from 5 to 2120 meters. In young children, correlations between altitude and parasite rate, population Hb mean, anemia prevalence, and spleen rate were high (r(2): -0.77, 0.73, -0.81, and -0.68; p&lt;0.001). In the general population, correlations between altitude and population Hb mean and anemia prevalence were 0.83 and 0.85, respectively. Among young children, parasite rate correlated highly with anemia prevalence, population Hb mean, and spleen rate (r(2): 0.81, -0.81, and 0.86; p&lt;0.001). Population Hb mean (corrected for direct altitude effects) increased with altitude, from 10.5 g/dl at &lt;500 m to 12.8 g/dl at &gt;1500 m (p&lt;0.001). In PNG, where Plasmodium vivax accounts for an important part of all malaria infections, population hemoglobin mean and anemia prevalence correlate well with altitude, parasite, and spleen rates. Hb measurement is simple and affordable, and may be a useful new tool, alone or in association with other metrics, for estimating malaria endemicity and monitoring effectiveness of malaria control programs. Further prospective studies in areas with different malaria epidemiology and different factors contributing to the burden of anemia are warranted to investigate the usefulness of Hb metrics in monitoring malaria transmission intensity

What if communities held the solutions for universal health coverage?

Abstract This commentary highlights the value of community-engaged social innovations to advance health care delivery in low- and middle-income countries and to accelerate universal health coverage. It emphasizes the importance of research to guide the innovators on what works, what does not work to make their innovations sustainable and to replicate and scale them up as relevant. It also helps to demonstrate impact and to enhance uptake within the health systems

Effectiveness of Artemether/Lumefantrine for the Treatment of Uncomplicated Plasmodium vivax and P. falciparum Malaria in Young Children in Papua New Guinea

This study shows that artemether/lumefantrine provides a rapid clinical response against both Plasmodium falciparum and Plasmodium vivax clinical malaria, but is associated with a high rate of P. vivax recurrent clinical episodes due to relapsing infections from long-lasting hypnozoite

The usefulness of twenty-four molecular markers in predicting treatment outcome with combination therapy of amodiaquine plus sulphadoxine-pyrimethamine against falciparum malaria in Papua New Guinea

<p>Abstract</p> <p>Background</p> <p>In Papua New Guinea (PNG), combination therapy with amodiaquine (AQ) or chloroquine (CQ) plus sulphadoxine-pyrimethamine (SP) was introduced as first-line treatment against uncomplicated malaria in 2000.</p> <p>Methods</p> <p>We assessed <it>in vivo </it>treatment failure rates with AQ+SP in two different areas in PNG and twenty-four molecular drug resistance markers of <it>Plasmodium falciparum </it>were characterized in pre-treatment samples. The aim of the study was to investigate the association between infecting genotype and treatment response in order to identify useful predictors of treatment failure with AQ+SP.</p> <p>Results</p> <p>In 2004, Day-28 treatment failure rates for AQ+SP were 29% in the Karimui and 19% in the South Wosera area, respectively. The strongest independent predictors for treatment failure with AQ+SP were <it>pfmdr1 </it>N86Y (OR = 7.87, <it>p </it>< 0.01) and <it>pfdhps </it>A437G (OR = 3.44, <it>p </it>< 0.01). Mutations found in CQ/AQ related markers <it>pfcrt </it>K76T, A220S, N326D, and I356L did not help to increase the predictive value, the most likely reason being that these mutations reached almost fixed levels. Though mutations in SP related markers <it>pfdhfr </it>S108N and C59R were not associated with treatment failure, they increased the predictive value of <it>pfdhps </it>A437G. The difference in treatment failure rate in the two sites was reflected in the corresponding genetic profile of the parasite populations, with significant differences seen in the allele frequencies of mutant <it>pfmdr1 </it>N86Y, <it>pfmdr1 </it>Y184F, <it>pfcrt </it>A220S, and <it>pfdhps </it>A437G.</p> <p>Conclusion</p> <p>The study provides evidence for high levels of resistance to the combination regimen of AQ+SP in PNG and indicates which of the many molecular markers analysed are useful for the monitoring of parasite resistance to combinations with AQ+SP.</p

Significant geographical differences in prevalence of mutations associated with Plasmodium falciparum and Plasmodium vivax drug resistance in two regions from Papua New Guinea

Drug resistance remains a major obstacle to malaria treatment and control. It can arise and spread rapidly, and vary substantially even at sub-national level. National malaria programmes require cost-effective and timely ways of characterizing drug-resistance at multiple sites within their countries.; An improved multiplexed post-PCR ligase detection reaction-fluorescent microsphere assay (LDR-FMA) was used to simultaneously determine the presence of mutations in chloroquine resistance transporter (crt), multidrug resistance 1 (mdr1), dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes in Plasmodium falciparum (n = 727) and Plasmodium vivax (n = 574) isolates collected in 2006 from cross-sectional community population surveys in two geographically distinct regions (Madang and East Sepik) of Papua New Guinea (PNG) where strong regional differences in in vivo aminoquinoline and antifolate therapeutic efficacy had previously been observed. Data were compared to those of a follow-up survey conducted in 2010.; Despite some very low parasite densities, the assay successfully amplified all P. falciparum and P. vivax loci in 77 and 69 % of samples, respectively. In 2006, prevalences of pfdhfr (59R-108 N) double mutation/wild type pfdhps haplotype, pfcrt SVMNT haplotype (72S-76T double mutation), and 86Y pfmdr1 mutation all exceeded 90 %. For P. vivax, 65 % carried at least two pvdhfr mutations, 97 % the 647P pvdhps mutation and 54 % the 976F pvmdr1 mutation. Prevalence of mutant haplotypes was higher in Madang than East Sepik for pfcrt SVMNT (97.4 vs 83.3 %, p = 0.001), pfdhfr (59R-108 N) (100 vs 90.6 %, p = 0.001), pvdhfr haplotypes (75.8 vs 47.6 %, p = 0.001) and pvmdr1 976F (71.2 vs 26.2 %, p &lt; 0.001). Data from a subsequent Madang survey in 2010 showed that the prevalence of pfdhps mutations increased significantly from &lt;5 % to &gt;30 % (p &lt; 0.001) as did the prevalence of pvdhfr mutant haplotypes (from 75.8 to 97.4 %, p = 0.012).; This LDR-FMA multiplex platform shows feasibility for low-cost, high-throughput, rapid characterization of a broad range of drug-resistance markers in low parasitaemia infections. Significant geographical differences in mutation prevalence correlate with previous genotyping surveys and in vivo trials and may reflect variable drug pressure and differences in health-care access in these two PNG populations