Evolution of the capacity to form secondary outgrowths from the principal embryonic axes was a crucial innovation that potentiated the diversification of animal body plans. Precisely how such ...outgrowths develop in early-branching metazoan species remains poorly understood. Here we demonstrate that three fundamental processes contribute to embryonic tentacle development in the cnidarian Nematostella vectensis. First, a pseudostratified ectodermal placode forms at the oral pole of developing larvae and is transcriptionally patterned into four tentacle buds. Subsequently, Notch signaling-dependent changes in apicobasal epithelial thickness drive elongation of these primordia. In parallel, oriented cell rearrangements revealed by clonal analysis correlate with shaping of the elongating tentacles. Taken together, our results define the mechanism of embryonic appendage development in an early-branching metazoan, and thereby provide a novel foundation for understanding the diversification of body plans during animal evolution.
Neural tube defects are common birth defects resulting in severe morbidity and mortality; they can largely be prevented with periconceptional maternal intake of folic acid. Understanding the ...occurrence of neural tube defects and their contribution to mortality in settings where their burden is highest could inform prevention and health-care policy. We aimed to estimate the mortality attributed to neural tube defects in seven countries in sub-Saharan Africa and southeast Asia.
This analysis used data from the Child Health and Mortality Prevention Surveillance (CHAMPS) network and health and demographic surveillance systems from South Africa, Mozambique, Bangladesh, Kenya, Mali, Ethiopia, and Sierra Leone. All stillbirths and infants and children younger than 5 years who died, who were enrolled in CHAMPS, whose families consented to post-mortem minimally invasive tissue sampling (MITS) between Jan 1, 2017, and Dec 31, 2021, and who were assigned a cause of death by a determination of cause of death panel as of May 24, 2022, were included in this analysis, regardless the cause of death. MITS and advanced diagnostic methods were used to describe the frequency and characteristics of neural tube defects among eligible deaths, identify risk factors, and estimate the mortality fraction and mortality rate (per 10 000 births) by CHAMPS site.
Causes of death were determined for 3232 stillbirths, infants, and children younger than 5 years, of whom 69 (2%) died with a neural tube defect. Most deaths with a neural tube defect were stillbirths (51 74%); 46 (67%) were neural tube defects incompatible with life (ie, anencephaly, craniorachischisis, or iniencephaly) and 22 (32%) were spina bifida. Deaths with a neural tube defect were more common in Ethiopia (adjusted odds ratio 8·09 95% CI 2·84–23·02), among female individuals (4·40 2·44–7·93), and among those whose mothers had no antenatal care (2·48 1·12–5·51). Ethiopia had the highest adjusted mortality fraction of deaths with neural tube defects (7·5% 6·7–8·4) and the highest adjusted mortality rate attributed to neural tube defects (104·0 per 10 000 births 92·9–116·4), 4–23 times greater than in any other site.
CHAMPS identified neural tube defects, a largely preventable condition, as a common cause of death among stillbirths and neonatal deaths, especially in Ethiopia. Implementing interventions such as mandatory folic acid fortification could reduce mortality due to neural tube defects.
Bill & Melinda Gates Foundation.
IMPORTANCE: Although child mortality trends have decreased worldwide, deaths among children younger than 5 years of age remain high and disproportionately circumscribed to sub-Saharan Africa and ...Southern Asia. Tailored and innovative approaches are needed to increase access, coverage, and quality of child health care services to reduce mortality, but an understanding of health system deficiencies that may have the greatest impact on mortality among children younger than 5 years is lacking. OBJECTIVE: To investigate which health care and public health improvements could have prevented the most stillbirths and deaths in children younger than 5 years using data from the Child Health and Mortality Prevention Surveillance (CHAMPS) network. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used longitudinal, population-based, and mortality surveillance data collected by CHAMPS to understand preventable causes of death. Overall, 3390 eligible deaths across all 7 CHAMPS sites (Bangladesh, Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, and South Africa) between December 9, 2016, and December 31, 2021 (1190 stillbirths, 1340 neonatal deaths, 860 infant and child deaths), were included. Deaths were investigated using minimally invasive tissue sampling (MITS), a postmortem approach using biopsy needles for sampling key organs and fluids. MAIN OUTCOMES AND MEASURES: For each death, an expert multidisciplinary panel reviewed case data to determine the plausible pathway and causes of death. If the death was deemed preventable, the panel identified which of 10 predetermined health system gaps could have prevented the death. The health system improvements that could have prevented the most deaths were evaluated for each age group: stillbirths, neonatal deaths (aged <28 days), and infant and child deaths (aged 1 month to <5 years). RESULTS: Of 3390 deaths, 1505 (44.4%) were female and 1880 (55.5%) were male; sex was not recorded for 5 deaths. Of all deaths, 3045 (89.8%) occurred in a healthcare facility and 344 (11.9%) in the community. Overall, 2607 (76.9%) were deemed potentially preventable: 883 of 1190 stillbirths (74.2%), 1010 of 1340 neonatal deaths (75.4%), and 714 of 860 infant and child deaths (83.0%). Recommended measures to prevent deaths were improvements in antenatal and obstetric care (recommended for 588 of 1190 stillbirths 49.4%, 496 of 1340 neonatal deaths 37.0%), clinical management and quality of care (stillbirths, 280 23.5%; neonates, 498 37.2%; infants and children, 393 of 860 45.7%), health-seeking behavior (infants and children, 237 27.6%), and health education (infants and children, 262 30.5%). CONCLUSIONS AND RELEVANCE: In this cross-sectional study, interventions prioritizing antenatal, intrapartum, and postnatal care could have prevented the most deaths among children younger than 5 years because 75% of deaths among children younger than 5 were stillbirths and neonatal deaths. Measures to reduce mortality in this population should prioritize improving existing systems, such as better access to antenatal care, implementation of standardized clinical protocols, and public education campaigns.
The Child Health and Mortality Prevention Surveillance (CHAMPS) Network programme undertakes post-mortem minimally invasive tissue sampling (MITS), together with collection of ante-mortem clinical ...information, to investigate causes of childhood deaths across multiple countries. We aimed to evaluate the overall contribution of pneumonia in the causal pathway to death and the causative pathogens of fatal pneumonia in children aged 1–59 months enrolled in the CHAMPS Network.
In this observational study we analysed deaths occurring between Dec 16, 2016, and Dec 31, 2022, in the CHAMPS Network across six countries in sub-Saharan Africa (Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, and South Africa) and one in South Asia (Bangladesh). A standardised approach of MITS was undertaken on decedents within 24–72 h of death. Diagnostic tests included blood culture, multi-organism targeted nucleic acid amplifications tests (NAATs) of blood and lung tissue, and histopathology examination of various organ tissue samples. An interdisciplinary expert panel at each site reviewed case data to attribute the cause of death and pathogenesis thereof on the basis of WHO-recommended reporting standards.
Pneumonia was attributed in the causal pathway of death in 455 (40·6%) of 1120 decedents, with a median age at death of 9 (IQR 4–19) months. Causative pathogens were identified in 377 (82·9%) of 455 pneumonia deaths, and multiple pathogens were implicated in 218 (57·8%) of 377 deaths. 306 (67·3%) of 455 deaths occurred in the community or within 72 h of hospital admission (presumed to be community-acquired pneumonia), with the leading bacterial pathogens being Streptococcus pneumoniae (108 35·3%), Klebsiella pneumoniae (78 25·5%), and non-typeable Haemophilus influenzae (37 12·1%). 149 (32·7%) deaths occurred 72 h or more after hospital admission (presumed to be hospital-acquired pneumonia), with the most common pathogens being K pneumoniae (64 43·0%), Acinetobacter baumannii (19 12·8%), S pneumoniae (15 10·1%), and Pseudomonas aeruginosa (15 10·1%). Overall, viruses were implicated in 145 (31·9%) of 455 pneumonia-related deaths, including 54 (11·9%) of 455 attributed to cytomegalovirus and 29 (6·4%) of 455 attributed to respiratory syncytial virus.
Pneumonia contributed to 40·6% of all childhood deaths in this analysis. The use of post-mortem MITS enabled biological ascertainment of the cause of death in the majority (82·9%) of childhood deaths attributed to pneumonia, with more than one pathogen being commonly implicated in the same case. The prominent role of K pneumoniae, non-typable H influenzae, and S pneumoniae highlight the need to review empirical management guidelines for management of very severe pneumonia in low-income and middle-income settings, and the need for research into new or improved vaccines against these pathogens.
Bill & Melinda Gates Foundation.
BackgroundMost childhood deaths globally are considered preventable through high-quality clinical care, which includes adherence to clinical care recommendations. Our objective was to describe ...adherence to World Health Organization recommendations for the management of leading causes of death among children. MethodsWe conducted a retrospective, descriptive study examining clinical data for children aged 1-59 months who were hospitalized and died in a Child Health and Mortality Prevention Surveillance (CHAMPS) catchment, December 2016-June 2021. Catchment areas included: Baliakandi and Faridpur, Bangladesh; Kersa, Haramaya, and Harar, Ethiopia; Kisumu and Siaya, Kenya; Bamako, Mali; Manhiça and Quelimane, Mozambique; Makeni, Sierra Leone; Soweto, South Africa. We reviewed medical records of those who died from lower respiratory tract infections, sepsis, malnutrition, malaria, and diarrheal diseases to determine the proportion who received recommended treatments and compared adherence by hospitalization duration. FindingsCHAMPS enrolled 460 hospitalized children who died from the leading causes (median age 12 months, 53.0% male). Median hospital admission was 31 h. There were 51.0% (n = 127/249) of children who died from lower respiratory tract infections received supplemental oxygen. Administration of intravenous fluids for sepsis (15.9%, n = 36/226) and supplemental feeds for malnutrition (14.0%, n = 18/129) were uncommon. There were 51.4% (n = 55/107) of those who died from malaria received antimalarials. Of the 80 children who died from diarrheal diseases, 76.2% received intravenous fluids. Those admitted for ≥24 h more commonly received antibiotics for lower respiratory tract infections and sepsis, supplemental feeds for malnutrition, and intravenous fluids for sepsis than those admitted <24 h. InterpretationProvision of recommended clinical care for leading causes of death among young children was suboptimal. Further studies are needed to understand the reasons for deficits in clinical care recommendation adherence. FundingBill & Melinda Gates Foundation.
The transition to animal multicellularity involved the evolution of single cells organizing into sheets of tissue. The advent of tissues allowed for specialization and diversification, which led to ...the formation of complex structures and a variety of body plans. These epithelial tissues undergo morphogenesis during animal development, and the establishment and maintenance of their polarity and integrity is crucial for homeostasis and prevention of pathogenesis. This architecture is dynamically maintained through a variety of cellular processes including the regulation of intracellular transport, cytoskeletal modulation, and cell adhesion. While studies in established model organisms and cell culture have contributed to our current knowledge of these processes, evolutionary and in vivo perspectives are largely lacking. Our efforts to gain a better understanding of epithelial biology have centered around two main themes: 1) Ancient mechanisms of morphogenesis during animal development and 2) Modulation of epithelial architecture during pathogenesis. First, to address the ancient mechanisms of epithelial morphogenesis, we examine tentacle development in the cnidarian Nematostella vectensis as a model of outgrowth formation. Through drug treatments, transcriptional analysis and imaging experiments, our study identifies molecular and cellular mechanisms that act during elongation of the tentacles and body column. At the onset of tentacle development, we observe an ectodermal placode that forms at the oral end of the animal, which is transcriptionally patterned into four tentacle buds. Subsequently during morphogenesis, our results show that cell shape changes and cell rearrangements act during elongation of the bud into a mature tentacle. In the body column during elongation, we also observe a period of oriented cell divisions along the oral-aboral axis. Together, our results reveal ancient cellular and molecular mechanisms of epithelial morphogenesis during development in an early-branching metazoan. Second, to explore alterations in epithelial architecture and integrity during bacterial pathogenesis, we express a Shigella bacterial virulence protein, VirA, in Drosophila and vertebrate tissue. Previous reports on the function of VirA have only employed in vitro and cell culture assays, so the function of VirA in an epithelial context remains largely unknown. Through in vivo expression and imaging experiments, we show that VirA expression in Drosophila disrupts epithelial architecture and cell polarity, with no discernible effects on microtubule stability. In the Drosophila salivary gland and eye imaginal disc, cells expressing VirA round and lose polarity markers. We observe a similar apical cell rounding phenotype when VirA is expressed in chick neural tube, implying a conserved mechanism of VirA function in vertebrates. Finally, we demonstrate a mislocalization of Rab11 in VirA expressing epithelia, suggesting a potential defect in vesicle trafficking. Taken together, our results reveal a novel function for VirA in disruption of cell polarity or adhesion, possibly through vesicle trafficking, leading to a breakdown of epithelial integrity facilitating the pathogenesis of Shigella in the human intestinal epithelium.
Through a multi-university and interdisciplinary project we have involved undergraduate biology and computer science research students in the functional annotation of maize genes and the analysis of ...their microarray expression patterns. We have created a database to house the results of our functional annotation of >4400 genes identified as being differentially regulated in the maize shoot apical meristem (SAM). This database is located at http://sam.truman.edu and is now available for public use. The undergraduate students involved in constructing this unique SAM database received hands-on training in an intellectually challenging environment, which has prepared them for graduate and professional careers in biological sciences. We describe our experiences with this project as a model for effective research-based teaching of undergraduate biology and computer science students, as well as for a rich professional development experience for faculty at predominantly undergraduate institutions.
Understanding the control of Ag restimulation-induced T cell death (RICD), especially in cancer immunotherapy, where highly proliferating T cells will encounter potentially large amounts of tumor ...Ags, is important now more than ever. It has been known that growth cytokines make T cells susceptible to RICD, but the precise molecular mediators that govern this in T cell subsets is unknown until now. STAT proteins are a family of transcription factors that regulate gene expression programs underlying key immunological processes. In particular, STAT5 is known to favor the generation and survival of memory T cells. In this study, we report an unexpected role for STAT5 signaling in the death of effector memory T (TEM) cells in mice and humans. TEM cell death was prevented with neutralizing anti-IL-2 Ab or STAT5/JAK3 inhibitors, indicating that STAT5 signaling drives RICD in TEM cells. Moreover, we identified a unique patient with a heterozygous missense mutation in the coiled-coil domain of STAT5B that presented with autoimmune lymphoproliferative syndrome-like features. Similar to
mice, this patient exhibited increased CD4
TEM cells in the peripheral blood. The mutant STAT5B protein dominantly interfered with STAT5-driven transcriptional activity, leading to global downregulation of STAT5-regulated genes in patient T cells upon IL-2 stimulation. Notably, CD4
TEM cells from the patient were strikingly resistant to cell death by in vitro TCR restimulation, a finding that was recapitulated in
mice. Hence, STAT5B is a crucial regulator of RICD in memory T cells in mice and humans.
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