Does test-based prescription of evidence-based treatment for malaria improve treatment seeking and satisfaction? Findings of repeated cross-sectional surveys in Papua New Guinea

IntroductionThe presumptive treatment of febrile illness with antimalarial medication is becoming less common in low-income and middle-income countries as access to reliable diagnostic tests improves. We explore whether the shift towards test-based antimalarial prescription, and the introduction of highly efficacious artemisinin combination therapies (ACTs), reduces critical delays in seeking treatment for febrile illness or increases patient satisfaction.MethodsWe conducted countrywide repeat, cross-sectional surveys in 118 randomly selected primary healthcare services in Papua New Guinea. The clinical case management of 1765 consecutively presenting febrile patients was observed and exit interviews were completed at discharge. This was done prior to implementation of test-based ACT prescription (2011) and at 12 (2012) and 60  months (2016) postimplementation. We conducted multiple logistic regressions. Treatment response time was dichotomised as Results62% (322/517) of febrile patients reported seeking treatment within 24  hours of symptom onset in 2011 compared with 53% (230/434) in 2012 and 42% (339/814) in 2016. Adjusted ORs for reporting a treatment response time ConclusionNationwide implementation of test-based ACT prescription in Papua New Guinea has increased the likelihood of critical treatment seeking delays and decreased patient satisfaction with the service received

Il buio oltre i partiti? Partecipazione dal basso e partecipazione istituzionale ai tempi della politica reticolare

Political participation is living a deep process of transformation. Practices, subjects, meanings and goals of participation are changing. In this article, on the basis of a critical assessment of the patterns of change affecting institutional political actors (mainly political parties) and bottom-up forms of participation in the Italian context, we analyze two major instruments implemented to fill the gap between institutional domain and bottom-up participation: primary elections and participative-deliberative processes. Both instruments produce ambiguous and ambivalent effects in terms of empowerment of citizens: they often appear to be more instruments of manipulation and symbolic legitimization than instrument of participation

Point-of-care testing and treatment of sexually transmitted and genital infections during pregnancy in Papua New Guinea (WANTAIM trial): protocol for an economic evaluation alongside a cluster-randomised trial

INTRODUCTION: Left untreated, sexually transmitted and genital infections (henceforth STIs) in pregnancy can lead to serious adverse outcomes for mother and child. Papua New Guinea (PNG) has among the highest prevalence of curable STIs including syphilis, chlamydia, gonorrhoea, trichomoniasis and bacterial vaginosis, and high neonatal mortality rates. Diagnosis and treatment of these STIs in PNG rely on syndromic management. Advances in STI diagnostics through point-of-care (PoC) testing using GeneXpert technology hold promise for resource-constrained countries such as PNG. This paper describes the planned economic evaluation of a cluster-randomised cross-over trial comparing antenatal PoC testing and immediate treatment of curable STIs with standard antenatal care in two provinces in PNG. METHODS AND ANALYSIS: Cost-effectiveness of the PoC intervention compared with standard antenatal care will be assessed prospectively over the trial period (2017-2021) from societal and provider perspectives. Incremental cost-effectiveness ratios will be calculated for the primary health outcome, a composite measure of the proportion of either preterm birth and/or low birth weight; for life years saved; for disability-adjusted life years averted; and for non-health benefits (financial risk protection and improved health equity). Scenario analyses will be conducted to identify scale-up options, and budget impact analysis will be undertaken to understand short-term financial impacts of intervention adoption on the national budget. Deterministic and probabilistic sensitivity analysis will be conducted to account for uncertainty in key model inputs. ETHICS AND DISSEMINATION: This study has ethical approval from the Institutional Review Board of the PNG Institute of Medical Research; the Medical Research Advisory Committee of the PNG National Department of Health; the Human Research Ethics Committee of the University of New South Wales; and the Research Ethics Committee of the London School of Hygiene and Tropical Medicine. Findings will be disseminated through national stakeholder meetings, conferences, peer-reviewed publications and policy briefs. TRIAL REGISTRATION NUMBER: ISRCTN37134032

Genetic determinants of co-accessible chromatin regions in activated T cells across humans.

Over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4+ T cells in up to 105 healthy donors. We found that regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution, consistent with the three-dimensional chromatin organization measured by in situ Hi-C in T cells. Fifteen percent of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak (local-ATAC-QTLs). Local-ATAC-QTLs have the largest effects on co-accessible peaks, are associated with gene expression and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression

Does test-based prescription of evidence-based treatment for malaria improve treatment seeking and satisfaction? Findings of repeated cross-sectional surveys in Papua New Guinea.

Introduction: The presumptive treatment of febrile illness with antimalarial medication is becoming less common in low-income and middle-income countries as access to reliable diagnostic tests improves. We explore whether the shift towards test-based antimalarial prescription, and the introduction of highly efficacious artemisinin combination therapies (ACTs), reduces critical delays in seeking treatment for febrile illness or increases patient satisfaction. Methods: We conducted countrywide repeat, cross-sectional surveys in 118 randomly selected primary healthcare services in Papua New Guinea. The clinical case management of 1765 consecutively presenting febrile patients was observed and exit interviews were completed at discharge. This was done prior to implementation of test-based ACT prescription (2011) and at 12 (2012) and 60  months (2016) postimplementation. We conducted multiple logistic regressions. Treatment response time was dichotomised as <24  hours from symptom onset vs 24+ hours. Satisfaction was dichotomised as a 'high' vs 'low' rating based on participant response to a visual, 7-point Likert-type scale. Results: 62% (322/517) of febrile patients reported seeking treatment within 24  hours of symptom onset in 2011 compared with 53% (230/434) in 2012 and 42% (339/814) in 2016. Adjusted ORs for reporting a treatment response time <24  hours in the postimplementation surveys were 0.77 (95% CI 0.48 to 1.26) and 0.45 (95% CI 0.31 to 0.65), respectively when compared with the preimplementation period. 53% (230/533) of febrile patients reported 'high' satisfaction with the service received in 2011 compared with 32% (143/449) in 2012 and 35% (278/803) in 2016. Adjusted ORs for reporting high satisfaction in the postimplementation surveys were 0.52 (95% CI 0.32 to 0.85) and 0.65 (95% CI 0.39 to 1.10), respectively when compared with the preimplementation period. Conclusion: Nationwide implementation of test-based ACT prescription in Papua New Guinea has increased the likelihood of critical treatment seeking delays and decreased patient satisfaction with the service received

Investigating the spatial variations of high prevalences of severe malnutrition among children in Papua New Guinea: results from geoadditive models

BACKGROUND: Papua New Guinea (PNG) is one of the nutritionally vulnerable countries with a high rate of children death without showing a sign of improvement in last two decades. Current study investigated the prevalences of stunting and wasting among a cohort of children in PNG and described the spatial features of these outcomes at the province and district-levels.OBJECTIVE: To determine the prevalences of stunting and wasting among a cohort of children in PNG and to describe the spatial features of these outcomes at the province and district-levels. We also described the spatial features of these outcomes at province and district-levels.METHODS: The health and nutritional status of 683 children aged less than five years was assessed using a cross-sectional multi-stage household survey conducted in the Eastern Highlands and Madang Provinces of PNG during the period of 2003-2004. Growth z-scores such as height-for-age and weight-for-age were generated using World Health Organization classifications.RESULTS: The prevalences of stunting (height-for-age z-score less than -2.0) were 59% and 49% in the Eastern Highlands and Madang respectively (P = 0.019). The prevalences of wasting (weight-for-height z-score less than -2.0) were 14% and 22% in Eastern Highlands and Madang respectively, (P = 0.039); overall, only 21% of the children had completed all their scheduled vaccines and 95% of the caregivers had less than primary school education. Our statistical maps showed considerable spatial variations (province- and district-levels) with regard to the stunting, wasting and other key factors within a relatively small geographical region.CONCLUSIONS: Current study determined one of the highest prevalence of stunting among children in PNG. The impact of geographical locations on the risk factors must be recognized as it affects epidemiology and intervention coverage

Peripheral Blood Mononuclear Cells Derived from Grand Multigravidae Display a Distinct Cytokine Profile in Response to P. falciparum Infected Erythrocytes

Immunopathology of placental malaria is most significant in women in their first pregnancy especially in endemic areas, due to a lack of protective immunity to Plasmodium falciparum, which is acquired in successive pregnancies. In some studies (but not all), grand multigravidae (defined as 5 or more pregnancies, G5-7) are more susceptible to poor birth outcomes associated with malaria compared to earlier gravidities. By comparing peripheral cellular responses in primigravidae (G1), women in their second to fourth pregnancy (G2-4) and grand multigravidae we sought to identify key components of the dysregulated immune response. PBMC were exposed to CS2-infected erythrocytes (IE) opsonised with autologous plasma or unopsonised IE, and cytokine and chemokine secretion was measured. Higher levels of opsonising antibody were present in plasma derived from multigravid compared to primigravid women. Significant differences in the levels of cytokines and chemokines secreted in response to IE were observed. Less IL-10, IL-1β, IL-6 and TNF but more CXCL8, CCL8, IFNγ and CXCL10 were detected in G5-7 compared to G2-4 women. Our study provides fresh insight into the modulation of peripheral blood cell function and effects on the balance between host protection and immunopathology during placental malaria infection

Iron deficiency during pregnancy is associated with a reduced risk of adverse birth outcomes in a malaria-endemic area in a longitudinal cohort study

BACKGROUND: Low birth weight (LBW) and preterm birth (PTB) are major contributors to infant mortality and chronic childhood morbidity. Understanding factors that contribute to or protect against these adverse birth outcomes is an important global health priority. Anaemia and iron deficiency are common in malaria-endemic regions, but there are concerns regarding the value of iron supplementation among pregnant women in malaria-endemic areas due to reports that iron supplementation may increase the risk of malaria. There is a lack of evidence on the impact of iron deficiency on pregnancy outcomes in malaria-endemic regions. METHODS: We determined iron deficiency in a cohort of 279 pregnant women in a malaria-endemic area of Papua New Guinea. Associations with birth weight, LBW and PTB were estimated using linear and logistic regression. A causal model using sequential mediation analyses was constructed to assess the association between iron deficiency and LBW, either independently or mediated through malaria and/or anaemia. RESULTS: Iron deficiency in pregnant women was common (71% at enrolment) and associated with higher mean birth weights (230 g; 95% confidence interval, CI 118, 514; p < 0.001), and reduced odds of LBW (adjusted odds ratio, aOR = 0.32; 95% CI 0.16, 0.64; p = 0.001) and PTB (aOR = 0.57; 95% CI 0.30, 1.09; p = 0.089). Magnitudes of effect were greatest in primigravidae (birth weight 351 g; 95% CI 188, 514; p < 0.001; LBW aOR 0.26; 95% CI 0.10, 0.66; p = 0.005; PTB aOR = 0.39, 95% CI 0.16, 0.97; p = 0.042). Sequential mediation analyses indicated that the protective association of iron deficiency on LBW was mainly mediated through mechanisms independent of malaria or anaemia. CONCLUSIONS: Iron deficiency was associated with substantially reduced odds of LBW predominantly through malaria-independent protective mechanisms, which has substantial implications for understanding risks for poor pregnancy outcomes and evaluating the benefit of iron supplementation in pregnancy. This study is the first longitudinal study to demonstrate a temporal relationship between antenatal iron deficiency and improved birth outcomes. These findings suggest that iron supplementation needs to be integrated with other strategies to prevent or treat infections and undernutrition in pregnancy to achieve substantial improvements in birth outcomes

Association of antibodies to Plasmodium falciparum reticulocyte binding protein homolog 5 with protection from clinical malaria

Emerging evidence suggests that antibodies against merozoite proteins involved in Plasmodium falciparum invasion into the red blood cell (RBC) play an important role in clinical immunity to malaria. The protein family of parasite antigens known as P. falciparum reticulocyte binding protein-like homolog (PfRh) is required for RBC invasion. PfRh5 is the only member within the PfRh family that cannot be genetically deleted, suggesting it plays an essential role in parasite survival. This antigen forms a complex with the cysteine-rich P. falciparum Rh5 interacting protein (PfRipr), on the merozoite surface during RBC invasion. The PfRh5 ectodomain sequence and a C-terminal fragment of PfRipr were cloned and expressed in Escherichia coli and baculovirus-infected cells, respectively. Immunization of rabbits with these recombinant proteins induced antibodies able to inhibit growth of various P. falciparum strains. Antibody responses to these proteins were investigated in a treatment-re-infection study conducted in an endemic area of Papua New Guinea (PNG) to determine their contribution to naturally acquired immunity. Antibody titers to PfRh5 but not PfRipr showed strong association with protection against P. falciparum clinical episodes. When associations with time-to-first infection were analyzed, high antibody levels against PfRh5 were also found to be associated with protection from high-density infections but not from re-infection. Together these results indicate that PfRh5 is an important target of protective immunity and constitutes a promising vaccine candidate