The kidney-brain pathogenic axis in severe falciparum malaria.

Severe falciparum malaria is a medical emergency and a leading cause of death and neurodisability in endemic areas. Common complications include acute kidney injury (AKI) and cerebral malaria, and recent studies have suggested links between kidney and brain dysfunction in Plasmodium falciparum infection. Here, we review these new findings and present the hypothesis of a pivotal pathogenic crosstalk between the kidneys and the brain in severe falciparum malaria. We highlight the evidence of a role for distant organ involvement in the development of cerebral malaria and subsequent neurocognitive impairment post-recovery, describe the challenges associated with current diagnostic shortcomings for both AKI and brain involvement in severe falciparum malaria, and explore novel potential therapeutic strategies

Pediatric Malaria with Respiratory Distress: Prognostic Significance of Point-of-Care Lactate

Respiratory distress (RD) in pediatric malaria portends a grave prognosis. Lactic acidosis is a biomarker of severe disease. We investigated whether lactate, measured at admission using a handheld device among children hospitalized with malaria and RD, was predictive of subsequent mortality. We performed a pooled analysis of Ugandan children under five years of age hospitalized with malaria and RD from three past studies. In total, 1324 children with malaria and RD (median age 1.4 years, 46% female) from 21 health facilities were included. Median lactate level at admission was 4.6 mmol/L (IQR 2.6–8.5) and 586 patients (44%) had hyperlactatemia (lactate \u3e 5 mmol/L). The mortality was 84/1324 (6.3%). In a mixed-effects Cox proportional hazard model adjusting for age, sex, clinical severity score (fixed effects), study, and site (random effects), hyperlactatemia was associated with a 3-fold increased hazard of death (aHR 3.0, 95%CI 1.8–5.3, p \u3c 0.0001). Delayed capillary refill time (τ = 0.14, p \u3c 0.0001), hypotension (τ = −0.10, p = 0.00049), anemia (τ = −0.25, p \u3c 0.0001), low tissue oxygen delivery (τ = −0.19, p \u3c 0.0001), high parasite density (τ = 0.10, p \u3c 0.0001), and acute kidney injury (p = 0.00047) were associated with higher lactate levels. In children with malaria and RD, bedside lactate may be a useful triage tool, predictive of mortality

WCN24-2067 Regional differences in acute kidney injury in Ugandan children hospitalized for Hypoxemia

Introduction: Acute kidney injury (AKI) is associated with increased mortality in hospitalized patients and incidence is highest in resource limited settings. The objective of this study was to assess sub-National regional differences in the incidence of AKI in children \u3c5 years of age hospitalized with an acute febrile illness and hypoxemia. Methods: This was a secondary analysis of a stepped wedge cluster randomized controlled trial, which enrolled children \u3c5 years of age hospitalized with hypoxemia between 2019 and 2021. At least one measure of kidney function was available in 1452 children. A single creatinine was measured at enrolment in a sub-set of 495 children with serum stored and AKI defined using KDIGO criteria where baseline creatinine was estimated using the age-based Pottel equation assuming a normal glomerular filtration rate of 120mL/min per 1.73m2. Markers were divided into structural (uNGAL positive, proteinuria, hematuria) or functional (AKI, saliva urea nitrogen (SUN)) measures of kidney injury. Results: 1452 children were included in this AKI sub-study (Figure 1). The mean age of participants was 1.49 years (standard deviation (SD), 1.21) and 55.7% were male (809/1452). Overall 2.6% of children died (38/1452). The majority of participants enrolled were from the West (31.3%) followed by the East (25.3%), North (24.1%), and Central (19.4%) regions. In general, 48.5% of children had AKI (240/495), the prevalence was highest in Eastern Uganda with 62.4% of children having AKI compared to 25.0% of children in Western Uganda, 44% in Central region and 53% in Northern region (p\u3c0.001). Over a third of children had urine NGAL levels ≥150ng/mL, a marker of structural damage, irrespective of site and rates comparable across sites (p=0.095). Other measures of functional and structural kidney injury varied across sites, proteinuria ranged from 6.3% to 14.0% with rates lower in Central and Eastern Uganda compared to Northern and Western Uganda. Hematuria was over two times more common in Eastern and Northern Uganda compared to Central and Western Uganda. Of all the children 49.0 % were positive for malaria based on rapid diagnostic test (RDT) either as positive pLDH or both pLDH and HRP-2. The presence of a single band positive RDT for HRP-2 alone was associated with increased risk of AKI, severe AKI, elevated BUN, a positive SUN test and urinalysis positive for hematuria or urobilinogen (unadjusted p\u3c0.05). Children with a 3-band positive RDT were more likely to have proteinuria, hematuria, bilirubinuria and urobilinogen by dipstick (unadjusted p\u3c0.05). Regional differences in AKI persisted after adjusting for malaria, age, and sex. Conclusions: As we move towards the ISN 0by25 initiative which aims to eliminate preventable deaths from AKI worldwide by 2025. This study provides key in-country data from a resource limited setting, demonstrating marked regional differences in the incidence of AKI in children hospitalized with hypoxaemia and malaria remains an important predictor of AKI. The substantial within-country heterogeneity of AKI highlights the need for further studies to evaluate regional contributors to local patterns of AKI

WCN24-931 AKI Phenotypes in Ugandan children hospitalized with Hypoxemia and Malaria

Introduction: Acute kidney injury (AKI) is a frequent life-threatening complication in hospitalized children. Emerging data suggest AKI is a heterogeneous condition that varies based on the underlying cause and is composed of distinct phenotypes. The objective of this study was to define AKI phenotypes using proposed classification systems in Ugandan children hospitalized with hypoxemia and to evaluate differences in phenotypes by malaria infection. Methods: Between 2019 and 2021, 2402 Ugandan children \u3c5 years of age hospitalized with hypoxemia were enrolled in a cluster randomized trial of solar powered oxygen delivery across 20 districts in Uganda. At enrollment, urine NGAL was measured using a point-of-care lateral flow test with a positive test defined as a level ≥150ng/mL. Malaria was assessed using a threeband rapid diagnostic test. In an extended sub-study, 491 children had creatinine measured to define AKI. AKI was defined using a single creatinine measure at enrolment and phenotypically characterized using two acute dialysis quality initiative (ADQI) proposed AKI phenotypes. The AKI biomarker definition incorporated urine NGAL into the KDIGO definition[group 1, no AKI; group 2, subclinical AKI (biomarker positive); group 3, AKI; group 4, biomarker positive AKI]. The ADQI sepsis AKI phenotype groups stage 1 AKI as sepsis phenotype (SP)-1 irrespective of biomarker status and differentiates severe AKI (stage 2/3) based on biomarker positivity where severe AKI that is biomarker negative is (SP2) and severe biomarker positive AKI is SP3. Results: Overall, 491 children were included in the extended study with AKI defined and uNGAL measured. The median age was 1.3 years (interquartile range, 0.7 to 2.3) and 53.8% of children were male. There were 4 deaths (0.8%) and 24 children required transfer to a higher-level health facility (4.9%). Among children included, 91.2% met a clinical definition of pneumonia and 49.5% were positive for malaria. The frequency of creatinine defined AKI was 32.0% (157/491) and 36.5% (179/491) were biomarker positive. AKI was associated with a 3.24-fold increase in mortality (95% CI 0.34 to 31.4) but underpowered to show a difference. In children without malaria, 17.7% were biomarker positive and AKI negative (subclinical AKI, 44/248) while 37.5% of children had AKI (93/284) of whom 39.8% (37/93) were biomarker positive. In children with malaria, 14.0% had subclinical AKI, 34/243), 59.3% had AKI (144/243) with 44.4% of AKI cases biomarker positive (64/144). Children with malaria had a higher frequency of AKI compared to children without malaria (59.6% vs. 37.6%, p\u3c0.001) but comparable frequency of a positive biomarker test (41.3% vs. 36.2%, p=0.10). Using the sepsis phenotype criteria, 16.3% of children had SP1, 17.9% were SP2 and 14.1% were SP3. When evaluating the sepsis phenotype by malaria status, children with malaria were more likely to have SP2 (23.1% vs. 12.9%) and SP3 (18.1% vs.10.1%) compared to children without malaria (p\u3c0.001). Conclusions: In this population of children hospitalized with hypoxemia across 20 health centers in Uganda, KDIGO-defined AKI was more common in children with malaria. While there was no difference in the AKI-biomarker classification based on malaria status, children with malaria were more likely to have severe phenotypes of AKI

Central mass and luminosity of Milky Way satellites in the LCDM model

It has been pointed out that the Galactic satellites all have a common mass around 1e7 Msun within 300 pc (M03), while they span almost four order of magnitudes in luminosity (Mateo et al. 1993, Strigari et al. 2008). It is argued that this may reflect a specific scale for galaxy formation or a scale for dark matter clustering. Here we use numerical simulations coupled with a semi-analytic model for galaxy formation, to predict the central mass and luminosity of galactic satellites in the LCDM model. We show that this common mass scale can be explained within the Cold Dark Matter scenario when the physics of galaxy formation is taken into account. The narrow range of M03 comes from the narrow distribution of circular velocities at time of accretion (peaking around 20 km/s) for satellites able to form stars and the not tight correlation between halo concentration and circular velocity. The wide range of satellite luminosities is due to a combination of the mass at time of accretion and the broad distribution of accretion redshifts for a given mass. This causes the satellites baryonic content to be suppressed by photo-ionization to very different extents. Our results favor the argument that the common mass M03 reflects a specific scale (circular velocity ~ 20 km/s) for star formation.Comment: 5 pages, 3 figures. References added, discussion enlarged, new version of Figure 3. Minor changes to match the version accepted for publication on ApJ Letter

An overview of malaria in pregnancy

One hundred twenty-five million pregnant women are at risk for contracting malaria, a preventable cause of maternal and infant morbidity and death. Malaria parasites contribute to adverse pregnancy and birth outcomes due to their preferential accumulation in placental intervillous spaces. Pregnant women are particularly vulnerable to malaria infections, and malaria infections during pregnancy put their fetuses at risk. Malaria in pregnancy is associated with anemia, stillbirth, low birth weight and maternal and fetal death. We review the challenges to diagnosing malaria in pregnancy, as well as strategies to prevent and treat malaria in pregnancy. Finally, we discuss the current gaps in knowledge and potential areas for continued research

Occupancy of avian foraging guilds in soybean fields and borders in Entre Ríos, Argentina: responses to vegetation structure and prey resources

Reconciling agriculture and biodiversity conservation is a challenge given the growing demand for agricultural products. In recent decades, Argentina has witnessed agricultural expansion and intensification affecting biodiversity and associated ecosystem services. Within agroecosystems, the level of habitat quality is critical for birds, and may depend on vegetation structure, availability of invertebrate prey, and the use of pesticides. Although the relationship between vegetation structure and avian occurrence has been widely studied, to our knowledge, there are no studies that also incorporate prey availability throughout the cycle of soybean crops in Argentina. We estimated and predicted the effects of land cover and temporal variation on the occurrence of avian foraging guilds in Entre Ríos, Argentina, in order to guide management related to potential ecosystem services provided by birds. We also estimated temporal effects of vegetation structure and insecticides on the main arthropod orders consumed by birds to evaluate prey availability. Methods: We conducted bird and arthropod surveys for 2 years along transects located in 20 randomly selected soybean fields (N = 60) and their adjacent borders (N = 78) throughout the crop growing season, in four seasons. We estimated avian occupancy, accounting for imperfect detection, and arthropod counts fitting generalized linear mixed models. Results: The number of native trees in field borders positively influenced the occurrence of most bird species, mainly insectivores. Granivore foliage gleaners, also were positively affected by grass height. Salliers and aerial foragers were weakly affected by distance to forest and native trees. In general, the availability of invertebrates to birds was highest during the third season. Arthropod counts in borders were greater during the last three crop stages than during the pre-sowing period. Conclusions: We found that with 10 to 15 native tree species in borders, coupled with a complex vegetation structure with shrubs and grasses, we could conserve a wide spectrum of insectivorous birds, and may contribute to the invertebrate pest control service. Vegetated field borders function as a refuge for arthropods, especially agriculturally beneficial taxa such as Hymenopterans. Finally, several groups of birds use the interior of the fields and could help control pests.Instituto de Recursos BiológicosFil: Goijman, Andrea Paula. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Recursos Biológicos; Argentina. University of Georgia. D.B. Warnell School of Forestry and Natural Resources; Estados UnidosFil: Conroy, Michael J. University of Georgia. D.B. Warnell School of Forestry and Natural Resources; Estados UnidosFil: Varni, Vanina Delia. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Recursos Biológicos; ArgentinaFil: Thompson, Jeffrey. Guyra Paraguay – CONACYT; Paraguay. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Recursos Biológicos; Argentina.Fil: Zaccagnini, Maria Elena. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Recursos Biológicos; Argentin

Constraints on the relationship between stellar mass and halo mass at low and high redshift

We use a statistical approach to determine the relationship between the stellar masses of galaxies and the masses of the dark matter halos in which they reside. We obtain a parameterized stellar-to-halo mass (SHM) relation by populating halos and subhalos in an N-body simulation with galaxies and requiring that the observed stellar mass function be reproduced. We find good agreement with constraints from galaxy-galaxy lensing and predictions of semi-analytic models. Using this mapping, and the positions of the halos and subhalos obtained from the simulation, we find that our model predictions for the galaxy two-point correlation function (CF) as a function of stellar mass are in excellent agreement with the observed clustering properties in the SDSS at z=0. We show that the clustering data do not provide additional strong constraints on the SHM function and conclude that our model can therefore predict clustering as a function of stellar mass. We compute the conditional mass function, which yields the average number of galaxies with stellar masses in the range [m, m+dm] that reside in a halo of mass M. We study the redshift dependence of the SHM relation and show that, for low mass halos, the SHM ratio is lower at higher redshift. The derived SHM relation is used to predict the stellar mass dependent galaxy CF and bias at high redshift. Our model predicts that not only are massive galaxies more biased than low mass ones at all redshifts, but the bias increases more rapidly with increasing redshift for massive galaxies than for low mass ones. We present convenient fitting functions for the SHM relation as a function of redshift, the conditional mass function, and the bias as a function of stellar mass and redshift.Comment: 21 pages, 17 figures, discussion enlarged, one more figure, updated references, accepted for publication in Ap

Performance Characteristics of Combinations of Host Biomarkers to Identify Women with Occult Placental Malaria: A Case-Control Study from Malawi

Because of its propensity to sequester in the placental intervillous space, Plasmodium falciparum can evade detection by peripheral smear in women with placental malaria (PM). We evaluated host biomarkers as potential indicators of occult PM infections.Using a case-control design, we evaluated the ability of biomarkers to identify PM in the absence of circulating peripheral parasites (n = 24) compared to placental smear-negative controls (n = 326). We measured levels of biomarkers (C3a, C5a, CRP, angiopoietin-1, angiopoietin-2, sTie-2, sEndoglin, VEGF, sFlt-1, tissue factor, and leptin) in maternal peripheral plasma at delivery. Using ROC curve analysis, we assessed the ability of clinical parameters and biomarkers to accurately detect PM infections identified by placental smear. We show that decreases in sFlt-1 and leptin and increases in CRP were associated with occult PM infections (p<0.01) and correlated with placental parasitaemia (p<0.01). Individually, all markers had moderate ability to diagnose occult PM infections with areas under the ROC between 0.62 and 0.72. In order to improve diagnostic performance, we generated simple scoring systems to identify PM infections using either a clinical score (0-2), a biomarker score (0-3) or a clinical plus biomarker score (0-5). The combinatorial model that incorporated both clinical parameters and biomarkers had an area under curve (AUC) of 0.85 (95% CI, 0.81-0.89), which was significantly better at identifying occult PM infections than the clinical score alone (p = 0.001).These data suggest that host biomarkers in the maternal peripheral blood may improve the detection of PM in the absence of peripheral parasitaemia

Validation of two multiplex platforms to quantify circulating markers of inflammation and endothelial injury in severe infection

Biomarkers can prognosticate outcome and enable risk-stratification. In severe infection, focusing on multiple markers reflecting pathophysiological mechanisms of organ injury could enhance management and pathway-directed therapeutics. Limited data exist on the performance of multiplex biomarker platforms. Our goal was to compare endothelial and immune activation biomarkers in severe pediatric infections using two multiplex platforms. Frozen plasma from 410 children presenting to the Jinja Regional Hospital in Uganda with suspected infection was used to measure biomarkers of endothelial (Angiopoietin-2, sFlt-1, sVCAM-1, sICAM-1) and immune (IL-6, IP-10, sTNFR-1, CHI3L1) activation. Two multiplex platforms (Luminex®, EllaTM) based on monoclonal antibody sandwich immunoassays using biotin-streptavidin conjugate chemistry were selected with reagents from R&D Systems. The two platforms differed in ease and time of completion, number of samples per assay, and dynamic concentration range. Intra-assay variability assessed using a coefficient of variation (CV%) was 2.2-3.4 for Luminex® and 1.2-2.9 for EllaTM. Correlations for biomarker concentrations within dynamic range of both platforms were best for IL-6 (ρ = 0.96, p<0.0001), IP-10 (ρ = 0.94, p<0.0001) and sFlt-1 (ρ = 0.94, p<0.0001). Agreement between concentrations obtained by both methods assessed by the Bland-Altman test varied, with best agreement for CHI3L1. Our data suggest that biomarkers of endothelial and immune activation can be readily measured with multiplex platforms. Luminex® and EllaTM produced reliable results with excellent CV% values. The EllaTM platform was more automated and completed in 75 minutes, potentially compatible with near-patient use. Trends in concentrations obtained by these methods were highly correlated, although absolute values varied, suggesting caution is required when comparing data from different multiplex platforms