Improving the quality of maternal and newborn care in the Pacific region: A scoping review.

BACKGROUND: Quality care is essential for improving maternal and newborn health. Low- and middle-income Pacific Island nations face challenges in delivering quality maternal and newborn care. The aim of this review was to identify all published studies of interventions which sought to improve the quality of maternal and newborn care in Pacific low-and middle-income countries. METHODS: A scoping review framework was used. Databases and grey literature were searched for studies published between January 2000 and July 2019 which described actions to improve the quality of maternal and newborn care in Pacific low- and middle-income countries. Interventions were categorised using a four-level health system framework and the WHO quality of maternal and newborn care standards. An expert advisory group of Pacific Islander clinicians and researchers provided guidance throughout the review process. RESULTS: 2010 citations were identified and 32 studies included. Most interventions focused on the clinical service or organisational level, such as healthcare worker training, audit processes and improvements to infrastructure. Few addressed patient experiences or system-wide improvements. Enablers to improving quality care included community engagement, collaborative partnerships, adequate staff education and training and alignment with local priorities. CONCLUSIONS: There are several quality improvement initiatives in low- and middle-income Pacific Island nations, most at the point of health service delivery. To effectively strengthen quality maternal and newborn care in this region, efforts must broaden to improve health system leadership, deliver sustaining education programs and encompass learnings from women and their communities.

IgM in human immunity to Plasmodium falciparum malaria.

Most studies on human immunity to malaria have focused on the roles of immunoglobulin G (IgG), whereas the roles of IgM remain undefined. Analyzing multiple human cohorts to assess the dynamics of malaria-specific IgM during experimentally induced and naturally acquired malaria, we identified IgM activity against blood-stage parasites. We found that merozoite-specific IgM appears rapidly in Plasmodium falciparum infection and is prominent during malaria in children and adults with lifetime exposure, together with IgG. Unexpectedly, IgM persisted for extended periods of time; we found no difference in decay of merozoite-specific IgM over time compared to that of IgG. IgM blocked merozoite invasion of red blood cells in a complement-dependent manner. IgM was also associated with significantly reduced risk of clinical malaria in a longitudinal cohort of children. These findings suggest that merozoite-specific IgM is an important functional and long-lived antibody response targeting blood-stage malaria parasites that contributes to malaria immunity.

Malaria and immunity during pregnancy and postpartum: a tale of two species.

It is well established that pregnant women are at an increased risk of Plasmodium falciparum infection when compared to non-pregnant individuals and limited epidemiological data suggest Plasmodium vivax risk also increases with pregnancy. The risk of P. falciparum declines with successive pregnancies due to the acquisition of immunity to pregnancy-specific P. falciparum variants. However, despite similar declines in P. vivax risk with successive pregnancies, there is a paucity of evidence P. vivax-specific immunity. Cross-species immunity, as well as immunological and physiological changes that occur during pregnancy may influence the susceptibility to both P. vivax and P. falciparum. The period following delivery, the postpartum period, is relatively understudied and available epidemiological data suggests that it may also be a period of increased risk of infection to Plasmodium spp. Here we review the literature and directly compare and contrast the epidemiology, clinical pathogenesis and immunological features of P. vivax and P. falciparum in pregnancy, with a particular focus on studies performed in areas co-endemic for both species. Furthermore, we review the intriguing epidemiology literature of both P. falciparum and P. vivax postpartum and relate observations to the growing literature pertaining to malaria immunology in the postpartum period.

The immunology and pathogenesis of malaria during pregnancy.

Women in endemic areas become highly susceptible to malaria during first and second pregnancies, despite immunity acquired after years of exposure. Recent insights have advanced our understanding of pregnancy malaria caused by Plasmodium falciparum, which is responsible for the bulk of severe disease and death. Accumulation of parasitized erythrocytes in the blood spaces of the placenta is a key feature of maternal infection with P. falciparum. Placental parasites express surface ligands and antigens that differ from those of other P. falciparum variants, facilitating evasion of existing immunity, and mediate adhesion to specific molecules, such as chondroitin sulfate A, in the placenta. The polymorphic and clonally variant P. falciparum erythrocyte membrane protein 1, encoded by var genes, binds to placental receptors in vitro and may be the target of protective antibodies. An intense infiltration of immune cells, including macrophages, into the placental intervillous spaces, and the production of pro-inflammatory cytokines often occur in response to infection, and are associated with low birth weight and maternal anemia. Expression of alpha and beta chemokines may initiate or facilitate this cellular infiltration during placental malaria. Specific immunity against placental-binding parasites may prevent infection or facilitate clearance of parasites prior to the influx of inflammatory cells, thereby avoiding a cascade of events leading to disease and death. Much less is known about pathogenic processes in P. vivax infections, and corresponding immune responses. Emerging knowledge of the pathogenesis and immunology of malaria in pregnancy will increasingly lead to new opportunities for the development of therapeutic and preventive interventions and new tools for diagnosis and monitoring.

The application of cryosurgery in the treatment of lung cancer.

Lung cancer is the commonest cause of cancer death, with a very poor survival rate. By the time of diagnosis, most cases are at an advanced stage and about 30% present with symptoms caused by central endobronchial obstruction. Endobronchial cryosurgery is an effective technique, which can be used to relieve tracheobronchial obstruction caused by lung cancer. This report describes the technique, using a nitrous oxide cooled cryoprobe, inserted through a bronchoscope, to remove the obstruction and reopen the airway. In this study, 476 consecutive patients (mean age 68.3 years, M:F ratio 1.9:1) with obstructive tracheobronchial tumours underwent a mean of 2.4 cryosurgical treatments. Their TNM staging was, stage II 6.7%, IIIa 21.0%, IIIb 23.9%, IV 48.4%. Improvement in symptom quantification was found with 76.4, 69.0, 59.2, and 42.6% of symptomatic patients for haemoptysis, cough, dyspnoea, and chest pain, respectively. Mean values for respiratory function improved from 1.38 to 1.41 litres for FEV1 and 1.91 to 2.04 litres for FVC (p

An alternative agglutination assay to measure antibodies to variant surface antigens of Plasmodium falciparum-infected erythrocytes.

Agglutination assays detect antibodies to variant parasite antigens expressed on the surface of Plasmodium falciparum-infected erythrocytes. Standard techniques require immediate analysis limiting the number of samples that can be processed simultaneously and preclude re-examination of slides. Fixed Giemsa-stained smears allow long-term storage and re-examination, without fluorescence microscopy.

Pathogenesis of Plasmodium falciparum malaria: the roles of parasite adhesion and antigenic variation.

Malaria results in up to 2.5 million deaths annually, with young children and pregnant women at greatest risk. The great majority of severe disease is caused by Plasmodium falciparum. A characteristic feature of infection with Pfalciparum is the accumulation or sequestration of parasite-infected red blood cells (RBCs) in various organs, such as the brain, lung and placenta, and together with other factors is important in the pathogenesis of severe forms of malaria. Sequestration results from adhesive interactions between parasite-derived proteins expressed on the surface of infected RBCs and a number of host molecules on the surface of endothelial cells, placental cells and uninfected RBCs. Some receptors for parasite adhesion have been implicated in particular malaria syndromes, such as intercellular adhesion molecule 1 in cerebral malaria and chondroitin sulfate A and hyaluronic acid in placental infection. The principal parasite ligand and antigen on the RBC surface, P falciparum erythrocyte membrane protein 1 encoded by a multigene family termed var, is clonally variant, enabling evasion of specific immune responses. An understanding of these host-parasite interactions in the context of clinical disease and immunity may reveal potential targets to prevent or treat severe forms of malaria.

Parasite adhesion and immune evasion in placental malaria.

Parasite sequestration in the placenta is a key feature of infection by Plasmodium falciparum during pregnancy and is associated with severe adverse outcomes for both mother and baby. Here, James Beeson and colleagues draw together the findings of recent studies on parasite mechanisms that mediate this process. They review evidence for novel parasite variants that appear able to evade pre-existing immunity, for the adhesion of P. falciparum-infected erythrocytes to placental glycosaminoglycans (and the molecular basis of these parasite properties) and for the expression of var genes encoding the variant antigen and adhesive ligand P. falciparum-erythrocyte membrane protein 1 (PfEMP1).

Inhibition of adhesion of Plasmodium falciparum-infected erythrocytes by structurally defined hyaluronic acid dodecasaccharides.

We recently reported that Plasmodium falciparum-infected erythrocytes (IRBCs) can adhere to hyaluronic acid (HA), which appears to be a receptor, in addition to chondroitin sulfate A (CSA), for parasite sequestration in the placenta. Further investigations of the nature and specificity of this interaction indicate that HA oligosaccharide fragments competitively inhibit parasite adhesion to immobilized purified HA in a size-dependent manner, with dodecasaccharides being the minimum size for maximum inhibition. Rigorously purified and structurally defined HA dodecasaccharides, free of contamination by CSA or other glycosaminoglycans, effectively inhibited IRBC adhesion to HA but not CSA, providing compelling evidence of a specific interaction between IRBCs and HA.

Identification of glycosaminoglycan binding domains in Plasmodium falciparum erythrocyte membrane protein 1 of a chondroitin sulfate A-adherent parasite.

Accumulation of Plasmodium falciparum-infected erythrocytes in the placenta is a key feature of maternal malaria. This process is mediated in part by the parasite ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1) at the surface of the infected erythrocyte interacting with the host receptor chondroitin sulfate A (CSA) on the placental lining. We have localized CSA binding activity to two adjacent domains in PfEMP1 of an adherent parasite line and shown the presence of at least three active glycosaminoglycan binding sites. A putative CSA binding sequence was identified in one domain, but nonlinear binding motifs are also likely to be present, since binding activity in the region was shown to be dependent on conformation. Characterization of this binding region provides an opportunity to investigate further its potential as a target for antiadhesion therapy.

Plasmodium falciparum rosette formation is uncommon in isolates from pregnant women.

We examined the formation of Plasmodium falciparum erythrocyte rosettes using parasite isolates from placental or peripheral blood of pregnant Malawian women and from peripheral blood of children. Five of 23 placental isolates, 23 of 38 maternal peripheral isolates, and 136 of 139 child peripheral isolates formed rosettes. Placental isolates formed fewer rosettes than maternal isolates (range, 0 to 7. 5% versus 0 to 33.5%; P = 0.002), and both formed fewer rosettes than isolates cultured from children (range, 0 to 56%; P < 0.0001). Rosette formation is common in infections of children but uncommon in pregnancy and rarely detected in placental isolates.

Adhesion of Plasmodium falciparum-infected erythrocytes to hyaluronic acid in placental malaria.

Infection with Plasmodium falciparum during pregnancy leads to the accumulation of parasite-infected erythrocytes in the placenta, and is associated with excess perinatal mortality, premature delivery and intrauterine growth retardation in the infant, as well as increased maternal mortality and morbidity. P. falciparum can adhere to specific receptors on host cells, an important virulence factor enabling parasites to accumulate in various organs. We report here that most P. falciparum isolates from infected placentae can bind to hyaluronic acid, a newly discovered receptor for parasite adhesion that is present on the placental lining. In laboratory isolates selected for specific high-level adhesion, binding to hyaluronic acid could be inhibited by dodecamer or larger oligosaccharide fragments or polysaccharides, treatment of immobilized receptor with hyaluronidase, or treatment of infected erythrocytes with trypsin. In vitro flow-based assays demonstrated that high levels of adhesion occurred at low wall shear stress, conditions thought to prevail in the placenta. Our findings indicate that adhesion to hyaluronic acid is involved in mediating placental parasite accumulation, thus changing the present understanding of the mechanisms of placental infection, with implications for the development of therapeutic and preventative interventions.

Plasmodium falciparum isolates from infected pregnant women and children are associated with distinct adhesive and antigenic properties.

Plasmodium falciparum malaria during pregnancy is an important cause of maternal and infant morbidity and mortality. Accumulation of large numbers of P. falciparum-infected erythrocytes in the maternal blood spaces of the placenta may be mediated by adhesion of infected erythrocytes to molecules presented on the syncytiotrophoblast surface. In this study, isolates from placentas and peripheral blood of infected pregnant women and from children were tested for binding to purified receptors and for agglutination with adult sera. Results suggest that adhesion to chondroitin sulfate A may be involved in placental parasite sequestration in most cases, but other factors are also likely to be important. Agglutination assay results suggest that parasites infecting pregnant women are antigenically distinct from those common in childhood disease. The prevalence of agglutinating antibodies to pregnancy isolates was generally low, but it was highest in multigravidae who are likely to have had the greatest exposure.

The adhesion of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate A is mediated by P. falciparum erythrocyte membrane protein 1.

Chondroitin sulfate A (CSA) is an important receptor for the sequestration of Plasmodium falciparum in the placenta, but the parasite ligand involved in adhesion has not previously been identified. Here we report the identification of a var gene transcribed in association with binding to CSA and present evidence that the P. falciparum erythrocyte membrane protein 1 product of the gene is the parasite ligand mediating CSA binding. Description of this gene and the implication of P. falciparum erythrocyte membrane protein 1 as the parasite ligand paves the way to a more detailed understanding of the pathogenesis of placental infection and potential therapeutic strategies targeting the interaction.

The placenta in malaria: mechanisms of infection, disease and foetal morbidity.

There is still much to discover about the reasons for the increased susceptibility of pregnant women to malaria or the pathogenesis of placental malaria. More systematic and detailed examination of the placenta may help. In many ways, the placenta can be seen as the flight recorder of the pregnancy; by examining it carefully it should be possible to tell much about how smooth a 'flight' the mother and baby experienced. It is hoped that, by probing the secrets of this 'squishy black box', the causes of adverse effects in pregnancy are elucidated, and the safe 'travel' of babies and their mothers in the future is ensured. In this review, the features of parasite accumulation in the placenta, parasite adherence, and hormonal and inflammatory responses to placental malaria are discussed, focussing on infection with Plasmodium falciparum. The results of recent research indicating an interaction between HIV and malaria in pregnancy are summarized. Ten questions for basic researchers are posed. The answers may help direct future efforts to control malaria in pregnancy.

2'-Fluoropyrimidine RNA-based aptamers to the 165-amino acid form of vascular endothelial growth factor (VEGF165). Inhibition of receptor binding and VEGF-induced vascular permeability through interactions requiring the exon 7-encoded domain.

Vascular endothelial growth factor (VEGF) has been implicated in the pathological induction of new blood vessel growth in a variety of proliferative disorders. Using the SELEX process (systematic evolution of ligands by exponential enrichment), we have isolated 2'-F-pyrimidine RNA oligonucleotide ligands (aptamers) to human VEGF165. Representative aptamers from three distinct sequence families were truncated to the minimal sequence capable of high affinity binding to VEGF (23-29 nucleotides) and were further modified by replacement of 2'-O-methyl for 2'-OH at all ribopurine positions where the substitution was tolerated. Equilibrium dissociation constants for the interaction of VEGF with the truncated, 2'-O-methyl-modified aptamers range between 49 and 130 pM. These aptamers bind equally well to murine VEGF164, do not bind to VEGF121 or the smaller isoform of placenta growth factor (PlGF129), and show reduced, but significant affinity for the VEGF165/PlGF129 heterodimer. Cysteine 137 in the exon 7-encoded domain of VEGF165 forms a photo-inducible cross-link to a single uridine residue in each of the three aptamers. The aptamers potently inhibit the binding of VEGF to the human VEGF receptors, KDR and Flt-1, expressed by transfected porcine aortic endothelial cells. Furthermore, one of the aptamers is able to significantly reduce intradermal VEGF-induced vascular permeability in vivo.

Inhibition of binding of malaria-infected erythrocytes by a tetradecasaccharide fraction from chondroitin sulfate A.

Adherence of parasite-infected erythrocytes (IEs) to the microvascular endothelium of various organs, a process known as sequestration, is a feature of Plasmodium falciparum malaria. This event is mediated by specific adhesive interactions between parasite proteins, expressed on the surface of IEs, and host molecules. P. falciparum IEs can bind to purified chondroitin sulfate A (CS-A), to the proteoglycan thrombomodulin through CS-A side chains, and to CS-A present on the surface of brain and lung endothelial cells and placental syncytiotrophoblasts. In order to identify structural characteristics of CS-A important for binding, oligosaccharide fragments ranging in size from 2 to 20 monosaccharide units were isolated from CS-A and CS-C, following controlled chondroitin lyase digestion, and used as competitive inhibitors of IE binding to immobilized ligands. Inhibition of binding to CS-A was highly dependent on molecular size: a CS-A tetradecasaccharide fraction was the minimum length able to almost completely inhibit binding. The effect was dose dependent and similar to that of the parent polysaccharide, and the same degree of inhibition was not found with the CS-C oligosaccharides. There was no effect on binding of IEs to other ligands, e.g., CD36 and intercellular adhesion molecule 1. Hexadeca- and octadecasaccharide fractions of CS-A were required for maximum inhibition of binding to thrombomodulin. Analyses of oligosaccharide fractions and polysaccharides by electrospray mass spectrometry and high-performance liquid chromatography suggest that the differences between the activities of CS-A and CS-C oligosaccharides can be attributed to differences in sulfate content and sulfation pattern and that iduronic acid is not involved in IE binding.