Urban living in healthy Tanzanians is associated with an inflammatory status driven by dietary and metabolic changes.

Sub-Saharan Africa currently experiences an unprecedented wave of urbanization, which has important consequences for health and disease patterns. This study aimed to investigate and integrate the immune and metabolic consequences of rural or urban lifestyles and the role of nutritional changes associated with urban living. In a cohort of 323 healthy Tanzanians, urban as compared to rural living was associated with a pro-inflammatory immune phenotype, both at the transcript and protein levels. We identified different food-derived and endogenous circulating metabolites accounting for these differences. Serum from urban dwellers induced reprogramming of innate immune cells with higher tumor necrosis factor production upon microbial re-stimulation in an in vitro model of trained immunity. These data demonstrate important shifts toward an inflammatory phenotype associated with an urban lifestyle and provide new insights into the underlying dietary and metabolic factors, which may affect disease epidemiology in sub-Sahara African countries.

Increased erythroferrone levels in malarial anaemia.

We assessed the diagnostic potential of erythroferrone as a biomarker for iron homeostasis comparing iron deficiency cases with anaemia of inflammation and controls. The dysregulation of the hepcidin axis was observed by Latour et al. in a mouse model of malarial anaemia induced by prolonged Plasmodium infection leading to increased erythroferrone concentrations. In line with that, we found significantly higher erythroferrone levels in cases with malaria and anaemia in an African population, compared to asymptomatic controls. Therefore, our findings extend the previous ones of the mouse model, suggesting also a dysregulation of the hepcidin axis in humans, which should be further corroborated in prospective studies and may lay the basis for the development of improved treatment strategies according to ERFE concentrations in such patients.

Exploring the host factors affecting asymptomatic Plasmodium falciparum infection: insights from a rural Burkina Faso study.

BACKGROUND: Asymptomatic Plasmodium falciparum parasitaemia forms a reservoir for the transmission of malaria disease in West Africa. Certain haemoglobin variants are known to protect against severe malaria infection. However, data on the potential roles of haemoglobin variants and nongenetic factors in asymptomatic malaria infection is scarce and controversial. Therefore, this study investigated the associations of iron homeostasis, inflammation, nutrition, and haemoglobin mutations with parasitaemia in an asymptomatic cohort from a P. falciparum-endemic region during the high transmission season. METHODS: A sub-study population of 688 asymptomatic individuals (predominantly children and adolescents under 15 years, n = 516) from rural Burkina Faso previously recruited by the NOVAC trial (NCT03176719) between June and October 2017 was analysed. Parasitaemia was quantified with conventional haemocytometry. The haemoglobin genotype was determined by reverse hybridization assays targeting a selection of 21 HBA and 22 HBB mutations. Demographics, inflammatory markers (interleukins 6 and 10, hepcidin), nutritional status (mid upper-arm circumference and body mass index), and anaemia (total haemoglobin, ferritin, soluble transferrin receptor) were assessed as potential predictors through logistic regression. RESULTS: Malaria parasites were detected in 56% of subjects. Parasitaemia was associated most strongly with malnutrition. The effect size increased with malnutrition severity (OR = 6.26, CI95: 2.45-19.4, p < 0.001). Furthermore, statistically significant associations (p < 0.05) with age, cytokines, hepcidin and heterozygous haemoglobin S were observed. CONCLUSIONS: According to these findings, asymptomatic parasitaemia is attenuated by haemoglobin S, but not by any of the other detected genotypes. Aside from evidence for slight iron imbalance, overall undernutrition was found to predict parasitaemia; thus, further investigations are required to elucidate causality and inform strategies for interventions.

Evaluation and optimization of the syndromic management of female genital tract infections in Nairobi, Kenya.

BACKGROUND: Genital tract infections pose a public health concern. In many low-middle-income countries, symptom-based algorithms guide treatment decisions. Advantages notwithstanding, this strategy has important limitations. We aimed to determine the infections causing lower genital tract symptoms in women, evaluated the Kenyan syndromic treatment algorithm for vaginal discharge, and proposed an improved algorithm. METHODS: This cross-sectional study included symptomatic non-pregnant adult women presenting with lower genital tract symptoms at seven outpatient health facilities in Nairobi. Clinical, socio-demographic information and vaginal swabs microbiological tests were obtained. Multivariate logistic regression analyses were performed to find predictive factors for the genital infections and used to develop an alternative vaginal discharge treatment algorithm (using 60% of the dataset). The other 40% of data was used to assess the performance of each algorithm compared to laboratory diagnosis. RESULTS: Of 813 women, 66% had an infection (vulvovaginal candidiasis 40%, bacterial vaginosis 17%, Neisseria gonorrhoea 14%, multiple infections 23%); 56% of women reported ≥ 3 lower genital tract symptoms episodes in the preceding 12 months. Vulvovaginal itch predicted vulvovaginal candidiasis (odds ratio (OR) 2.20, 95% CI 1.40-3.46); foul-smelling vaginal discharge predicted bacterial vaginosis (OR 3.63, 95% CI 2.17-6.07), and sexually transmitted infection (Neisseria gonorrhoea, Trichomonas vaginalis, Chlamydia trachomatis, Mycoplasma genitalium) (OR 1.64, 95% CI 1.06-2.55). Additionally, lower abdominal pain (OR 1.73, 95% CI 1.07-2.79) predicted sexually transmitted infection. Inappropriate treatment was 117% and 75% by the current and alternative algorithms respectively. Treatment specificity for bacterial vaginosis/Trichomonas vaginalis was 27% and 82% by the current and alternative algorithms, respectively. Performance by other parameters was poor to moderate and comparable between the two algorithms. CONCLUSION: Single and multiple genital infections are common among women presenting with lower genital tract symptoms at outpatient clinics in Nairobi. The conventional vaginal discharge treatment algorithm performed poorly, while the alternative algorithm achieved only modest improvement. For optimal care of vaginal discharge syndrome, we recommend the inclusion of point-of-care diagnostics in the flowcharts.

Clonal Hematopoiesis Is Associated With Low CD4 Nadir and Increased Residual HIV Transcriptional Activity in Virally Suppressed Individuals With HIV.

Clonal hematopoiesis, a common age-related phenomenon marked by expansion of cells with clonal hematopoiesis driver mutations, has been associated with all-cause mortality, cancer, and cardiovascular disease. People with HIV (PWH) are at risk for non-AIDS-related comorbidities such as atherosclerotic cardiovascular disease and cancer. In a cross-sectional cohort study, we compared clonal hematopoiesis prevalence in PWH on stable antiretroviral therapy with prevalence in a cohort of overweight individuals and a cohort of age- and sex-matched population controls. The prevalence of clonal hematopoiesis adjusted for age was increased and clone size was larger in PWH compared to population controls. Clonal hematopoiesis is associated with low CD4 nadir, increased residual HIV-1 transcriptional activity, and coagulation factors in PWH. Future studies on the effect of clonal hematopoiesis on the HIV reservoir and non-AIDS-related comorbidities are warranted.

Effectiveness of a group intervention to reduce sexual transmission risk behavior among MSM living with HIV: a non-randomized controlled pilot study.

ABSTRACTWith an annual incidence of about 1.5 million new infections, HIV is an ongoing public health concern. Sexual transmission risk behavior (STRB) is a main driver of the HIV epidemic in most Western countries, particularly among specific populations such as men who have sex with men (MSM). This quasi-experimental pilot study examined the effectiveness of a ten-session group intervention, aiming to reduce STRB among a high-risk subpopulation of MSM living with HIV. Self-reported STRB, impulsivity, mental health symptoms, and functional impairment were compared between the intervention group (n = 12) and a control group (n = 16). At baseline, participants in the intervention group had higher levels of STRB, impulsivity, mental health problems, and functional impairment, compared to the control group. A significant time-by-group interaction effect revealed that after the intervention, STRB, impulsivity, and functional impairment reduced in the intervention group to levels comparable to the control group. These findings suggest that a targeted behavioral intervention might be an effective strategy to reduce persistent STRB and related factors in MSM living with HIV. Future studies should confirm these findings in larger samples, using randomized designs.

Nasopharyngeal colonisation dynamics of bacterial pathogens in patients with fever in rural Burkina Faso: an observational study.

BACKGROUND: Nasopharyngeal colonisation with clinically relevant bacterial pathogens is a risk factor for severe infections, such as pneumonia and bacteraemia. In this study, we investigated the determinants of nasopharyngeal carriage in febrile patients in rural Burkina Faso. METHODS: From March 2016 to June 2017, we recruited 924 paediatric and adult patients presenting with fever, hypothermia or suspicion of severe infection to the Centre Medical avec Antenne Chirurgicale Saint Camille de Nanoro, Burkina Faso. We recorded a broad range of clinical data, collected nasopharyngeal swabs and tested them for the presence of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus and Klebsiella pneumoniae by quantitative polymerase chain reaction. Using logistic regression, we investigated the determinants of carriage and aimed to find correlations with clinical outcome. RESULTS: Nasopharyngeal colonisation with S. pneumoniae, H. influenzae and M. catarrhalis was highly prevalent and strongly dependent on age and season. Females were less likely to be colonised with S. pneumoniae (OR 0.71, p = 0.022, 95% CI 0.53-0.95) and M. catarrhalis (OR 0.73, p = 0.044, 95% CI 0.54-0.99) than males. Colonisation rates were highest in the age groups < 1 year and 1-2 years of age and declined with increasing age. Colonisation also declined towards the end of the rainy season and rose again during the beginning of the dry season. K. pneumoniae prevalence was low and not significantly correlated with age or season. For S. pneumoniae and H. influenzae, we found a positive association between nasopharyngeal carriage and clinical pneumonia [OR 1.75, p = 0.008, 95% CI 1.16-2.63 (S. pneumoniae) and OR 1.90, p = 0.004, 95% CI 1.23-2.92 (H. influenzae)]. S. aureus carriage was correlated with mortality (OR 4.01, p < 0.001, 95% CI 2.06-7.83), independent of bacteraemia caused by this bacterium. CONCLUSIONS: Age, sex and season are important determinants of nasopharyngeal colonisation with S. pneumoniae, H. influenzae and M. catarrhalis in patients with fever in Burkina Faso. S. pneumoniae and H. influenzae carriage is associated with clinical pneumonia and S. aureus carriage is associated with mortality in patients with fever. These findings may help to understand the dynamics of colonisation and the associated transmission of these pathogens. Furthermore, understanding the determinants of nasopharyngeal colonisation and the association with disease could potentially improve the diagnosis of febrile patients.

Platelets Modulate IFN-γ Production against Candida albicans in Peripheral Blood Mononuclear Cells via Prostaglandins.

Platelets are known to have immunomodulatory properties. They modulate immune responses of leukocytes against various pathogens, including fungi. Candida albicans can cause systemic infection in immunocompromised individuals that is associated with a high mortality and morbidity. In the current study, we explored the role of platelets in antifungal host defense against C. albicans PBMCs were stimulated with heat-killed (HK) C. albicans in the presence or absence of isolated washed platelets. Cytokines were quantified from culture supernatants by ELISA. Inhibition of platelet receptors and cytokine pathways were used to elucidate the mechanisms involved in platelet-leukocyte interaction. In the presence of platelets, PBMCs produced less IFN-γ upon stimulation with HK C. albicans This effect was dependent on the direct contact between platelets and leukocytes but was independent of the platelet GPIb and P-selectin receptors. The attenuation of IFN-γ was not a direct effect on T cells but was dependent on the presence of APC and T cells. Platelets did not modulate the Th-1-polarizing cytokines IL-12 and IL-18. The addition of PG (PGE2) further diminished IFN-γ levels in PBMCs, and supplementation of cells with nonsteroidal anti-inflammatory drugs was able to restore the level of IFN-γ. Overall, we show that modulation of the Th1 response against C. albicans by platelets is dependent on PGs.

The XN-30 hematology analyzer for rapid sensitive detection of malaria: a diagnostic accuracy study.

BACKGROUND: Accurate and timely diagnosis of malaria is essential for disease management and surveillance. Thin and thick blood smear microscopy and malaria rapid diagnostic tests (RDTs) are standard malaria diagnostics, but both methods have limitations. The novel automated hematology analyzer XN-30 provides standard complete blood counts (CBC) as well as quantification of malaria parasitemia at the price of a CBC. This study assessed the accuracy of XN-30 for malaria detection in a controlled human malaria infection (CHMI) study and a phase 3 diagnostic accuracy study in Burkina Faso. METHODS: Sixteen healthy, malaria-naive CHMI participants were challenged with five Plasmodium falciparum-infected mosquitoes. Blood was sampled daily for XN-30, blood smear microscopy, and malaria qPCR. The accuracy study included patients aged > 3 months presenting with acute febrile illness. XN-30, microscopy, and rapid diagnostic tests (HRP-2/pLDH) were performed on site; qPCR was done in retrospect. The malaria reference standard was microscopy, and results were corrected for sub-microscopic cases. RESULTS: All CHMI participants became parasitemic by qPCR and XN-30 with a strong correlation for parasite density (R2 = 0.91; p < .0001). The XN-30 accurately monitored treatment and allowed detection of recrudescence. Out of 908 patients in the accuracy study, 241 had microscopic malaria (density 24-491,802 parasites/µL). The sensitivity and specificity of XN-30 compared to microscopy were 98.7% and 99.4% (PPV = 98.7%, NPV = 99.4%). Results were corrected for qPCR-confirmed sub-microscopic cases. Three microscopy-confirmed cases were not detected by XN-30. However, XN-30 detected 19/134 (14.2%) qPCR-confirmed cases missed by microscopy. Among qPCR-confirmed cases, XN-30 had a higher sensitivity (70.9% versus 66.4%; p = .0009) and similar specificity (99.6% versus 100%; p = .5) as microscopy. The accuracy of XN-30 for microscopic malaria was equal to or higher than HRP-2 and pLDH RDTs, respectively. CONCLUSIONS: The XN-30 is a novel, automated hematology analyzer that combines standard hemocytometry with rapid, objective, and robust malaria detection and quantification, ensuring prompt treatment of malaria and malaria anemia and follow-up of treatment response. TRIAL REGISTRATION: Both trials were registered on clinicaltrials.gov with respective identifiers NCT02836002 (CHMI trial) and NCT02669823 (diagnostic accuracy study).

Effect of diabetes mellitus on TB drug concentrations in Tanzanian patients.

BACKGROUND: Diabetes mellitus (DM) is associated with poor TB treatment outcome. Previous studies examining the effect of DM on TB drug concentrations yielded conflicting results. No studies have been conducted to date in an African population. OBJECTIVES: To compare exposure to TB drugs in Tanzanian TB patients with and without DM. PATIENTS AND METHODS: A prospective pharmacokinetic study was performed among 20 diabetic and 20 non-diabetic Tanzanian TB patients during the intensive phase of TB treatment. Plasma pharmacokinetic parameters of isoniazid, rifampicin, pyrazinamide and ethambutol were compared using an independent-sample t-test on log-transformed data. Multiple linear regression analysis was performed to assess the effects of DM, gender, age, weight, HIV status and acetylator status on exposure to TB drugs. RESULTS: A trend was shown for 25% lower total exposure (AUC0-24) to rifampicin among diabetics versus non-diabetics (29.9 versus 39.9 mg·h/L, P=0.052). The AUC0-24 and peak concentration (Cmax) of isoniazid were also lower in diabetic TB patients (5.4 versus 10.6 mg·h/L, P=0.015 and 1.6 versus 2.8 mg/L, P=0.013). Pyrazinamide AUC0-24 and Cmax values were non-significantly lower among diabetics (P=0.08 and 0.09). In multivariate analyses, DM remained an independent predictor of exposure to isoniazid and rifampicin, next to acetylator status for isoniazid. CONCLUSIONS: There is a need for individualized dosing of isoniazid and rifampicin based on plasma concentration measurements (therapeutic drug monitoring) and for clinical trials on higher doses of these TB drugs in patients with TB and DM.

Exploring the Role of IL-32 in HIV-Related Kaposi Sarcoma.

The intracellular proinflammatory mediator IL-32 is associated with tumor progression; however, the mechanisms remain unknown. We studied IL-32 mRNA expression as well as expression of other proinflammatory cytokines and mediators, including IL-1α, IL-1ß, IL-6, IL-8, tumor necrosis factor (TNF)-α, the proangiogenic and antiapoptotic enzyme cyclooxygenase-2, the IL-8 receptor C-X-C chemokine receptor (CXCR) 1, and the intracellular kinase focal adhesion kinase-1. The interaction of IL-32 expression with expression of IL-6, TNF-α, IL-8, and cyclooxygenase-2 was also investigated. Biopsy specimens of 11 HIV-related, 7 non-HIV-related Kaposi sarcoma (KS), and 7 normal skin tissues (NSTs) of Dutch origin were analyzed. RNA was isolated from the paraffin material, and gene expression levels of IL-32 α, ß, and γ isoforms, IL1a, IL1b, IL6, IL8, TNFA, PTGS2, CXCR1, and PTK2 were determined using real-time quantitative PCR. Significantly higher expression of IL-32ß and IL-32γ isoforms was observed in HIV-related KS biopsy specimens compared with non-HIV-related KS and NST. The splicing ratio of the IL-32 isoforms showed IL-32γ as the highest expressed isoform, followed by IL-32ß, in HIV-related KS cases compared with non-HIV-related KS and NST. Our data suggest a possible survival mechanism by the splicing of IL-32γ to IL-32ß and also IL-6, IL-8, and CXCR1 signaling pathways to reverse the proapoptotic effect of the IL-32γ isoform, leading to tumor cell survival and thus favoring tumor progression.

The influence of hypoxia on platelet function and plasmatic coagulation during systemic inflammation in humans in vivo.

Systemic inflammation and hypoxia frequently occur simultaneously in critically ill patients, and are both associated with platelet activation and coagulopathy. However, human in vivo data on the effects of hypoxia on platelet function and plasmatic coagulation under systemic inflammatory conditions are lacking. In the present study, 20 healthy male volunteers were randomized to either 3.5 h of hypoxia (peripheral saturation 80-85%) or normoxia (room air), and systemic inflammation was elicited by intravenous administration of 2 ng/kg endotoxin. Various parameters of platelet function and plasmatic coagulation were determined serially. Endotoxemia resulted in increased circulating platelet-monocyte complexes and enhanced platelet reactivity, effects which were attenuated by hypoxia. Furthermore, endotoxin administration resulted in decreased plasma levels of platelet factor-4 levels and increased concentrations of von Willebrand factor. These endotoxemia-induced effects were not influenced by hypoxia. Neither endotoxemia nor hypoxia affected thrombin generation. In conclusion, our data reveal that hypoxia attenuates the endotoxemia-induced increases in platelet-monocyte formation and platelet reactivity, while leaving parameters of plasmatic coagulation unaffected.

Desialylation of Platelets by Pneumococcal Neuraminidase A Induces ADP-Dependent Platelet Hyperreactivity.

Platelets are increasingly recognized to play a role in the complications of Streptococcus pneumoniae infections. S. pneumoniae expresses neuraminidases, which may alter glycans on the platelet surface. In the present study, we investigated the capability of pneumococcal neuraminidase A (NanA) to remove sialic acid (desialylation) from the platelet surface, the consequences for the platelet activation status and reactivity, and the ability of neuraminidase inhibitors to prevent these effects. Our results show that soluble NanA induces platelet desialylation. Whereas desialylation itself did not induce platelet activation (P-selectin expression and platelet fibrinogen binding), platelets became hyperreactive to ex vivo stimulation by ADP and cross-linked collagen-related peptide (CRP-XL). Platelet aggregation with leukocytes also increased. These processes were dependent on the ADP pathway, as inhibitors of the pathway (apyrase and ticagrelor) abrogated platelet hyperreactivity. Inhibition of NanA-induced platelet desialylation by neuraminidase inhibitors (e.g., oseltamivir acid) also prevented the platelet effects of NanA. Collectively, our findings show that soluble NanA can desialylate platelets, leading to platelet hyperreactivity, which can be prevented by neuraminidase inhibitors.

Thrombocytopenia and Platelet Dysfunction in Acute Tropical Infectious Diseases.

Thrombocytopenia is a well-known manifestation of acute tropical infectious diseases. The role of platelets in infections has received much attention recently because of their emerging activities in modulation of inflammatory responses, host defense, and vascular integrity. However, while many studies have addressed thrombocytopenia in tropical infections, abnormalities in platelet function have been largely overlooked. This is an important research gap, as platelet dysfunction may contribute to the bleeding tendency that characterizes some tropical infections. The development of novel platelet function assays that can be used in thrombocytopenic conditions (e.g., flow cytometry assays) has contributed to important new insights in recent years. In this review, the importance of platelets in tropical infections is discussed with special emphasis on the underlying mechanisms and consequences of thrombocytopenia and platelet dysfunction in these infections. Special attention is paid to malaria, a disease characterized by microvascular obstruction in which bleeding is rare, and to infections in which bleeding is common, such as dengue, other viral hemorrhagic fevers, and the bacterial infection leptospirosis. Given the importance of platelet function abnormalities in these infections, the development of affordable assays for monitoring of platelet function in low-resource countries, as well as pharmacologic interventions to prevent or reverse platelet function abnormalities, might improve clinical care and the prognosis of these infections.

Platelet microparticles inhibit IL-17 production by regulatory T cells through P-selectin.

Self-tolerance and immune homeostasis are orchestrated by FOXP3(+)regulatory T cells (Tregs). Recent data have revealed that upon stimulation, Tregs may exhibit plasticity toward a proinflammatory phenotype, producing interleukin 17 (IL-17) and/or interferon γ (IFN-γ). Such deregulation of Tregs may contribute to the perpetuation of inflammatory processes, including graft-versus-host disease. Thus, it is important to identify immunomodulatory factors influencing Treg stability. Platelet-derived microparticles (PMPs) are involved in hemostasis and vascular health and have recently been shown to be intimately involved in (pathogenic) immune responses. Therefore, we investigated whether PMPs have the ability to affect Treg plasticity. PMPs were cocultured with healthy donor peripheral blood-derived Tregs that were stimulated with anti-CD3/CD28 monoclonal antibodies in the presence of IL-2, IL-15, and IL-1ß. PMPs prevented the differentiation of peripheral blood-derived Tregs into IL-17- and IFN-γ-producing cells, even in the presence of the IL-17-driving proinflammatory cytokine IL-1ß. The mechanism of action by which PMPs prevent Treg plasticity consisted of rapid and selective P-selectin-dependent binding of PMPs to a CCR6(+)HLA-DR(+)memory-like Treg subset and their ability to inhibit Treg proliferation, in part through CXCR3 engagement. The findings that ~8% of Tregs in the circulation of healthy individuals are CD41(+)P-selectin(+)and that distinct binding of patient plasma PMPs to Tregs was observed support in vivo relevance. These findings open the exciting possibility that PMPs actively regulate the immune response at sites of (vascular) inflammation, where they are known to accumulate and interact with leukocytes, consolidating the (vascular) healing process.

The effects of signal transducer and activator of transcription three mutations on human platelets.

Involvement of signal transducer and activator of transcription 3 (STAT3) in inflammation is well known. Recently, a role for STAT3 in platelet activation and platelet production has been suggested. Platelets exhibit important immune functions and engagement of STAT3 in platelet physiology may link inflammation and hemostasis. This study investigated the effects of STAT3 loss-of-function mutations and single nucleotide polymorphisms (SNPs) in STAT3 on glycoprotein VI (GPVI)-mediated platelet activation and platelet numbers in humans. Two cohorts were studied. The first cohort concerned patients with STAT3 loss-of-function mutations. Platelet numbers were investigated in eight patients and GPVI-mediated platelet activation was functionally tested in four patients. Additional experiments were performed to investigate underlying mechanisms. The second cohort concerned 334 healthy volunteers and investigated the consequences of SNPs in STAT3 on GPVI-mediated platelet activation and platelet numbers. Platelet activation was lower in STAT3 loss-of-function patients at baseline and after stimulation of the GPVI receptor, reflected by decreased P-selectin expression. This was independent of gene transcription. Blockade of the adenosine di-phosphate (ADP) pathway resulted in a further decrease of P-selectin expression, particularly in STAT3 loss-of-function patients. In contrast, the SNPs in STAT3 did not influence GPVI-mediated platelet activation. Also, platelet numbers were not affected by STAT3 loss-of-function mutations, nor was there an association with the SNPs. In conclusion, STAT3 signaling does not seem to play a major role in thrombopoiesis. We confirm that STAT3 is involved in GPVI-mediated platelet activation in humans, independent of gene transcription. GPVI-mediated platelet activation is highly dependent on secondary ADP release. Our findings suggest that STAT3 modulation may affect inflammation, hemostasis, and their interaction.

Increased Platelet-Monocyte Interaction in Stable COPD in the Absence of Platelet Hyper-Reactivity.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is well known for its cardiovascular co-morbidities. Increased platelet-monocyte interaction is found in COPD and may reflect altered platelet function and a potential role for anti-platelet therapy. OBJECTIVES: The objectives were to investigate platelet-monocyte interaction, platelet activation and reactivity and plasmatic coagulation in stable COPD. METHODS: Platelet-monocyte interaction and platelet activation were determined by flow cytometry in 30 stable COPD patients and 25 controls. Platelet activation was measured by binding of fibrinogen to the activated fibrinogen receptor and platelet P-selectin expression at baseline and after platelet stimulation with platelet agonists. Plasmatic coagulation was measured by D-dimer and thrombin generation. RESULTS: Platelet-monocyte interaction was increased in stable COPD (median fluorescence intensity of platelet CD61 was 19.8 [IQR 14.0-33.2] vs. 10.0 [IQR 8.7-16.7], p = 0.002). In contrast, platelet activation and reactivity, reflected by fibrinogen binding and P-selectin expression, were the same in both groups. Plasma P-selectin and interleukin-6 were increased in COPD (p = 0.01 and p = 0.02, respectively), whereas soluble fibrinogen, D-dimer and thrombin generation were similar. CONCLUSIONS: Increased platelet-monocyte interaction was found in the absence of platelet hyper-reactivity and activation of plasmatic coagulation in stable COPD. Future clinical evaluation of the effects of different anti-platelet drugs in COPD is warranted, as anti-platelet therapy may interfere with platelet-monocyte interaction.

Modest heterologous protection after Plasmodium falciparum sporozoite immunization: a double-blind randomized controlled clinical trial.

BACKGROUND: A highly efficacious vaccine is needed for malaria control and eradication. Immunization with Plasmodium falciparum NF54 parasites under chemoprophylaxis (chemoprophylaxis and sporozoite (CPS)-immunization) induces the most efficient long-lasting protection against a homologous parasite. However, parasite genetic diversity is a major hurdle for protection against heterologous strains. METHODS: We conducted a double-blind, randomized controlled trial in 39 healthy participants of NF54-CPS immunization by bites of 45 NF54-infected (n = 24 volunteers) or uninfected mosquitoes (placebo; n = 15 volunteers) against a controlled human malaria infection with the homologous NF54 or the genetically distinct NF135.C10 and NF166.C8 clones. Cellular and humoral immune assays were performed as well as genetic characterization of the parasite clones. RESULTS: NF54-CPS immunization induced complete protection in 5/5 volunteers against NF54 challenge infection at 14 weeks post-immunization, but sterilely protected only 2/10 and 1/9 volunteers against NF135.C10 and NF166.C8 challenge infection, respectively. Post-immunization plasma showed a significantly lower capacity to block heterologous parasite development in primary human hepatocytes compared to NF54. Whole genome sequencing showed that NF135.C10 and NF166.C8 have amino acid changes in multiple antigens targeted by CPS-induced antibodies. Volunteers protected against heterologous challenge were among the stronger immune responders to in vitro parasite stimulation. CONCLUSIONS: Although highly protective against homologous parasites, NF54-CPS-induced immunity is less effective against heterologous parasite clones both in vivo and in vitro. Our data indicate that whole sporozoite-based vaccine approaches require more potent immune responses for heterologous protection. TRIAL REGISTRATION: This trial is registered in clinicaltrials.gov, under identifier NCT02098590 .

Effect of a short course of iron polymaltose on acquisition of malarial parasitaemia in anaemic Indonesian schoolchildren: a randomized trial.

BACKGROUND: Concern exists about the safety of iron supplementation given to individuals in malarious areas. The possible unfavourable impact of iron supplementation on malaria might be less when slow-release iron compounds are used instead of ferrous salts, because no toxic non-transferrin bound iron is formed. The aim of this study was to determine the effect of iron supplementation using the slow-release iron compound iron polymaltose (IPM) on the acquisition of malarial parasitaemia. METHODS: A randomized, placebo-controlled trial was performed in schoolchildren aged 5-18 years with mild or moderate anaemia on the Indonesian island Flores. Microscopic malaria-negative children were randomized to receive 8 weeks of IPM (6 mg elemental iron/kg/day) or placebo . The primary outcomes were the occurrence of microscopically detectable malarial parasitaemia at week 4, 8, 12 and 16 after start of treatment and the proportion of participants with real-time (RT) PCR positive malarial parasitaemia at week 16. RESULTS: 294 Children were assigned to the IPM group and 297 to the placebo group. Whereas IPM supplementation failed to increased haemoglobin or ferritin concentrations, the IPM group had a significantly higher rate of occurrence of microscopically detectable parasitaemia [hazard ratio 2.2, 95% C.I. 1.2-4.0; P = 0.01]. This higher rate was confined to iron-replete children. At the end of the study, 89% of the children in the IPM group had remained free from microscopically detectable parasitaemia vs 95% of children in the placebo group. The proportion of plasmodial RT-PCR positive children was similar in both groups at week 16 (IPM group 16.6% vs placebo group 14.3%; P = 0.47). When analysis was restricted to iron-replete children (serum ferritin ≥30 µg/l), there was a trend for a higher proportion being RT-PCR positive at week 16 in the IPM group compared with the placebo group (20 vs 13.3%; P = 0.07). Erythrocyte microcytosis was an independent risk factor for microscopically detectable malarial parasitaemia. CONCLUSIONS: A short course of IPM should be used cautiously in anaemic children in malaria endemic areas, as it has limited efficacy in treating iron deficiency, while it increases the rate of microscopic malarial parasitaemia in those with replete iron stores. Trial registration ISRCTN 83091970. Registered 16 May 2012 (retrospectively registered).

Antiphospholipid Antibodies and the Risk of Stroke in Urban and Rural Tanzania: A Community-Based Case-Control Study.

BACKGROUND AND PURPOSE: The burden of stroke is high in sub-Saharan Africa, and improved knowledge of risk factors is needed. Antiphospholipid antibodies are a common acquired stroke risk factor in young individuals. Antiphospholipid antibodies may be induced by infectious diseases. Sub-Saharan Africa has a high infectious burden, and we analyzed the contribution of antiphospholipid antibodies to the risk of stroke in an incident population from rural and urban Tanzania. METHODS: Stroke cases and age- and sex-matched community-acquired controls from the rural Hai district and urban Dar-es-Salaam areas of Tanzania were recruited in a wider study of stroke incidence between June 2003 and June 2006. Lupus anticoagulant, anticardiolipin, anti-ß2-glycoprotein I, and antiphosphatidylserine/prothrombin antibodies were determined in stored plasma, as well as IgG antibodies against Treponema pallidum. RESULTS: Data from 158 stroke cases and 369 controls were analyzed. Thirty cases (19%) and 4 controls (1%) had a lupus anticoagulant (odds ratio, 20.8; 95% confidence interval, 7.2-60.5). Anticardiolipin IgG was the only other antiphospholipid antibody subtype associated with increased stroke risk (odds ratio, 2.1; 95% confidence interval, 1.0-4.3), but this association disappeared when corrected for IgG antibodies against Treponema pallidum results. The prevalence of anti-ß2-glycoprotein I IgG antibodies in the Tanzanian healthy population was high when Dutch cutoff values were applied (67%), whereas presence of anti-ß2-glycoprotein I IgM was associated with a reduced stroke risk (odds ratio 0.3; 95% confidence interval, 0.1-1.1). CONCLUSIONS: The presence of lupus anticoagulant is a strong, and to date unrecognized, risk factor for stroke in Tanzania, especially in young and middle-aged individuals.