Genetic Evidence for Erythrocyte Receptor Glycophorin B Expression Levels Defining a Dominant Plasmodium falciparum Invasion Pathway into Human Erythrocytes.

Plasmodium falciparum, the parasite that causes the deadliest form of malaria, has evolved multiple proteins known as invasion ligands that bind to specific erythrocyte receptors to facilitate invasion of human erythrocytes. The EBA-175/glycophorin A (GPA) and Rh5/basigin ligand-receptor interactions, referred to as invasion pathways, have been the subject of intense study. In this study, we focused on the less-characterized sialic acid-containing receptors glycophorin B (GPB) and glycophorin C (GPC). Through bioinformatic analysis, we identified extensive variation in glycophorin B (GYPB) transcript levels in individuals from Benin, suggesting selection from malaria pressure. To elucidate the importance of the GPB and GPC receptors relative to the well-described EBA-175/GPA invasion pathway, we used an ex vivo erythrocyte culture system to decrease expression of GPA, GPB, or GPC via lentiviral short hairpin RNA transduction of erythroid progenitor cells, with global surface proteomic profiling. We assessed the efficiency of parasite invasion into knockdown cells using a panel of wild-type P. falciparum laboratory strains and invasion ligand knockout lines, as well as P. falciparum Senegalese clinical isolates and a short-term-culture-adapted strain. For this, we optimized an invasion assay suitable for use with small numbers of erythrocytes. We found that all laboratory strains and the majority of field strains tested were dependent on GPB expression level for invasion. The collective data suggest that the GPA and GPB receptors are of greater importance than the GPC receptor, supporting a hierarchy of erythrocyte receptor usage in P. falciparum

Mortality Surveillance Methods to Identify and Characterize Deaths in Child Health and Mortality Prevention Surveillance Network Sites

Despite reductions over the past 2 decades, childhood mortality remains high in low- and middle-income countries in sub-Saharan Africa and South Asia. In these settings, children often die at home, without contact with the health system, and are neither accounted for, nor attributed with a cause of death. In addition, when cause of death determinations occur, they often use nonspecific methods. Consequently, findings from models currently utilized to build national and global estimates of causes of death are associated with substantial uncertainty. Higher-quality data would enable stakeholders to effectively target interventions for the leading causes of childhood mortality, a critical component to achieving the Sustainable Development Goals by eliminating preventable perinatal and childhood deaths. The Child Health and Mortality Prevention Surveillance (CHAMPS) Network tracks the causes of under-5 mortality and stillbirths at sites in sub-Saharan Africa and South Asia through comprehensive mortality surveillance, utilizing minimally invasive tissue sampling (MITS), postmortem laboratory and pathology testing, verbal autopsy, and clinical and demographic data. CHAMPS sites have established facility- and community-based mortality notification systems, which aim to report potentially eligible deaths, defined as under-5 deaths and stillbirths within a defined catchment area, within 24-36 hours so that MITS can be conducted quickly after death. Where MITS has been conducted, a final cause of death is determined by an expert review panel. Data on cause of death will be provided to local, national, and global stakeholders to inform strategies to reduce perinatal and childhood mortality in sub-Saharan Africa and South Asia

Postmortem investigations and identification of multiple causes of child deaths: An analysis of findings from the Child Health and Mortality Prevention Surveillance (CHAMPS) network

BACKGROUND: The current burden of >5 million deaths yearly is the focus of the Sustainable Development Goal (SDG) to end preventable deaths of newborns and children under 5 years old by 2030. To accelerate progression toward this goal, data are needed that accurately quantify the leading causes of death, so that interventions can target the common causes. By adding postmortem pathology and microbiology studies to other available data, the Child Health and Mortality Prevention Surveillance (CHAMPS) network provides comprehensive evaluations of conditions leading to death, in contrast to standard methods that rely on data from medical records and verbal autopsy and report only a single underlying condition. We analyzed CHAMPS data to characterize the value of considering multiple causes of death. METHODS AND FINDINGS: We examined deaths identified from December 2016 through November 2020 from 7 CHAMPS sites (in Bangladesh, Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, and South Africa), including 741 neonatal, 278 infant, and 241 child <5 years deaths for which results from Determination of Cause of Death (DeCoDe) panels were complete. DeCoDe panelists included all conditions in the causal chain according to the ICD-10 guidelines and assessed if prevention or effective management of the condition would have prevented the death. We analyzed the distribution of all conditions listed as causal, including underlying, antecedent, and immediate causes of death. Among 1,232 deaths with an underlying condition determined, we found a range of 0 to 6 (mean 1.5, IQR 0 to 2) additional conditions in the causal chain leading to death. While pathology provides very helpful clues, we cannot always be certain that conditions identified led to death or occurred in an agonal stage of death. For neonates, preterm birth complications (most commonly respiratory distress syndrome) were the most common underlying condition (n = 282, 38%); among those with preterm birth complications, 256 (91%) had additional conditions in causal chains, including 184 (65%) with a different preterm birth complication, 128 (45%) with neonatal sepsis, 69 (24%) with lower respiratory infection (LRI), 60 (21%) with meningitis, and 25 (9%) with perinatal asphyxia/hypoxia. Of the 278 infant deaths, 212 (79%) had ≥1 additional cause of death (CoD) beyond the underlying cause. The 2 most common underlying conditions in infants were malnutrition and congenital birth defects; LRI and sepsis were the most common additional conditions in causal chains, each accounting for approximately half of deaths with either underlying condition. Of the 241 child deaths, 178 (75%) had ≥1 additional condition. Among 46 child deaths with malnutrition as the underlying condition, all had ≥1 other condition in the causal chain, most commonly sepsis, followed by LRI, malaria, and diarrheal disease. Including all positions in the causal chain for neonatal deaths resulted in 19-fold and 11-fold increases in attributable roles for meningitis and LRI, respectively. For infant deaths, the proportion caused by meningitis and sepsis increased by 16-fold and 11-fold, respectively; for child deaths, sepsis and LRI are increased 12-fold and 10-fold, respectively. While comprehensive CoD determinations were done for a substantial number of deaths, there is potential for bias regarding which deaths in surveillance areas underwent minimally invasive tissue sampling (MITS), potentially reducing representativeness of findings. CONCLUSIONS: Including conditions that appear anywhere in the causal chain, rather than considering underlying condition alone, markedly changed the proportion of deaths attributed to various diagnoses, especially LRI, sepsis, and meningitis. While CHAMPS methods cannot determine when 2 conditions cause death independently or may be synergistic, our findings suggest that considering the chain of events leading to death can better guide research and prevention priorities aimed at reducing child deaths

Adherence to Perinatal Asphyxia or Sepsis Management Guidelines in Low- and Middle-Income Countries

Importance :Most of the 2.3 million annual neonatal deaths occur in sub-Saharan Africa and South Asia, with perinatal asphyxia and neonatal sepsis being the leading causes of neonatal mortality. Most neonatal deaths are considered preventable through high-quality clinical care, which includes adherence to clinical care guidelines. Objective: To assess adherence to World Health Organization clinical care guidelines for management of perinatal asphyxia and neonatal sepsis and to identify patient-level factors in adherence among neonates who died from these conditions. Design, Setting, and Participants: This cross-sectional study obtained data from December 2015 through October 2023 from the Child Health and Mortality Prevention Surveillance (CHAMPS) catchment areas in 7 low- and middle-income countries in sub-Saharan Africa (Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, and South Africa) and South Asia (Bangladesh). Participants were neonates who were born alive and were aged 0 to 28 days at the time of death and had either perinatal asphyxia or neonatal sepsis. Exposure: Medical records of neonates who died from perinatal asphyxia or neonatal sepsis determined by postmortem diagnostics. Main Outcomes and Measures: The main outcome was the proportion of deceased neonates who received guideline-adherent treatments before they died. Mixed-effect multivariable logistic regression analyses were performed to identify factors associated with administration of at least bag-valve-mask (BVM) ventilation for perinatal asphyxia. Results: Of the 1194 neonates (median [IQR] age at the time of death, 2 [1-6] days; 692 males [58.0%]) who died and were enrolled in CHAMPS with available clinical data, 476 (39.9%) died from perinatal asphyxia, 562 (47.0%) died from neonatal sepsis, and 156 (13.1%) from both conditions. These neonates had a median (IQR) birth weight of 2130 (1266-2988) g. For cases with perinatal asphyxia, guideline adherence ranged from 12.2% (n = 77) for adrenaline administration to 85.4% (540) for supplemental oxygen administration. Only 4.4% of neonates (28) with perinatal asphyxia received all recommended treatments. Among cases with neonatal sepsis, antibiotics were administered to 86.8% (623), although the recommended treatment was administered to only 61.0% (438). In multivariable analyses, neonates in whom clinicians accurately identified perinatal asphyxia were more likely to receive BVM ventilation than those who had received discordant antemortem and postmortem diagnoses (adjusted odds ratio, 2.00; 95% CI, 1.29-3.12). Conclusions and Relevance: In this cross-sectional study, clinical care guideline adherence was suboptimal among neonates who died from perinatal asphyxia or neonatal sepsis. This finding underscores the critical need to increase adherence in regions with high rates of neonatal mortality and may inform strategies for strengthening health systems to support compliance with clinical care guidelines

Wood usage and its influence on the environment from the Neolithic until the Iron Age: a case study of the graves at Flintbek (Schleswig–Holstein, Northern Germany)

The investigated area near Flintbek (Schleswig-Holstein, Northern Germany) was used as a burial ground from the Neolithic until the Iron Age. Due to modern agriculture, the above-ground funerary monuments have been destroyed. Rescue excavations from 1976 to 1996 recovered the archaeological remains. In addition to the archaeological reassessment of the findings, further scientific analyses were carried out. The results of the charcoal analyses are presented in this paper. The overall spectrum of wood species represents the typical species composition of mixed oak forests. Over the whole investigated time span (Neolithic-Iron Age) these species alternate with a second group of taxa: species benefiting from better light conditions. In times of intensive human impact, these light-demanding taxa gained considerable importance, showing the opening of the wooded landscape. In phases with less human impact, a regeneration of mixed oak forest is detectable. For the Neolithic it was possible to develop a more detailed picture of wood usage based on 162 radiocarbon dates of 106 samples. These illustrate considerable changes during the Neolithic, which resulted in a varied pattern of open land and closed forest influenced by human presence and land use. Another important aspect of the Flintbek area is the handling of samples deriving from different contexts. While charcoal samples related to fire usage or grave constructions contain only slight contamination, samples from fillings (pits, burial layers) are characterized by charcoal dating being either too old or even too young for the archaeological context