School feeding in Ethiopia: a scoping review.

INTRODUCTION: Undernutrition is a major public health problem in developing countries, especially in Sub-Saharan Africa. Undernourished children are smaller and have low weight. To solve this issue, school feeding (corn-soya blend, vegetable oil) started in 1994 in Ethiopia. Thus, this scoping review aims to map the evidence relating to school feeding programs and their potential role in managing children`s nutrition in Ethiopia. METHODS: This scoping review is informed by the methodological framework of Arksey & O'Malley for scoping reviews and recommendations on the framework by Levac and colleagues. The databases searched included the Education Resources Information Centre, International Initiative for Impact Evaluation, Cochrane Library, MEDLINE, and Google Scholar. To ensure its comprehensive search, grey literature sources were searched. The search was undertaken on 26 April 2023. Studies on school feeding, such as coverage, and studies that evaluate the educational and nutritional impacts of school feeding in Ethiopia, regardless of study designs, were included. Reports (publications) about school feeding without scientific methodology were excluded. RESULT: Twenty-seven studies were included in this review. It includes cross-sectional, prospective cohort, laboratory-based analysis, experimental, case study, and qualitative study designs. The school feeding program results were inconclusive, while some indicate a positive effect on body mass index, height, thinness, anemia, weight, dropout rate, class attendance, and enrollment. The others showed that the school feeding program did not affect stunting, thinness, weight, hemoglobin level, enrollment, attendance, dropout rate, and academic achievement. Factors affecting school feeding programs negatively include poor quality food and financial constraints. However, no literature on school feeding program coverage was found. CONCLUSION: School feeding programs improved nutritional status, and academic performance, although some studies show any effect. Poor-quality food provisions and financial constraints affect school feeding programs. There are mixed findings, and further research is required to determine the effect of school feeding programs conclusively. To ensure the program's sustainability, it should be supported by a national policy, and budget allocation is needed. In addition, more evidence should be generated to show the coverage of school feeding programs in Ethiopia.

Predictors of prediabetes/diabetes and hypertension in Ethiopia: Reanalysis of the 2015 NCD STEPS survey using causal path diagrams.

The objective of our study was to reanalyse the Ethiopia STEPwise approach to Surveillance Noncommunicable Disease Risk Factors survey (NCD STEPS), using causal path diagrams constructed using expert subject matter knowledge in conjunction with graphical model theory to map the underlying causal network of modifiable factors associated with prediabetes/diabetes and hypertension. We used data from the 2015 Ethiopia NCD STEPS representative cross-sectional survey (males; n = 3977 and females; n = 5823 aged 15-69 years) and performed directed acyclic graph-informed logistic regression analyses. In both sexes, a 1-unit higher in body mass index (BMI) and waist circumference (WC) were positively associated with prediabetes/diabetes (BMI: males: adjusted odds ratio [aOR]: 1.07 [95% confidence interval: 1.0, 1.1], females aOR: 1.03 [1.0, 1.1]; WC: males: aOR: 1.1 [0.9, 1.2], females: aOR: 1.2 [1.1, 1.3]) and hypertension (BMI: males: aOR: 1.2 [1.1, 1.2], females aOR: 1.1 [1.0, 1.1]; WC: males: aOR: 1.6 [1.4, 1.8], females: aOR: 1.3 [1.2, 1.5]). Although residing in urban settings was associated with higher odds of hypertension in both males (aOR: 1.79 [1.49, 2.16]) and females (aOR: 1.70 [1.49, 1.95]), it was only associated with prediabetes/diabetes in males (aOR: 1.56 [1.25, 1.96]). Males and females in pastoralist areas had lower odds of prediabetes/diabetes compared with their agrarian counterparts (males: aOR: 0.27 [0.14, 0.52], females: aOR: 0.31 [0.16, 0.58]). Physical activity was associated with lower odds of prediabetes/diabetes among females (aOR: 0.75 [0.58, 0.97]). Other diet-related modifiable factors such as consumption of fruit and vegetable, alcohol or salt were not associated with either prediabetes/diabetes or hypertension. Our findings highlight the need to implement interventions that prevent overweight/obesity and nutrition-related NCDs, particularly in urban areas.

Drivers of change in weight-for-height among children under 5 years of age in Ethiopia: Risk factors and data gaps to identify risk factors.

The prevention of wasting should be a public health priority as the global burden of acute malnutrition is still high. Gaps still exist in our understanding of context-specific risk factors and interventions that can be implemented to prevent acute malnutrition. We used data from the four rounds of the Ethiopia Demographic and Health Survey (2000-2016) to identify risk factors that have contributed to the change in weight-for-height z-score (WHZ) among children under 5 years of age. We performed a pooled linear regression analysis followed by a decomposition analysis to identify relevant risk factors and their relative contribution to the change in WHZ. Modest improvements in WHZ were seen between 2000 and 2016. The sharpest decrease in mean WHZ occurred from birth to 6 months of age. Perceived low weight at birth and recent diarrhoea predicted a decline in WHZ among children aged 0-5, 6-23 and 23-59 months. Less than 50% of the change in WHZ was accounted for by the change in risk factors included in our regression decomposition analysis. This finding highlights data gaps to identify context-specific wasting risk factors. The decline in the prevalence of recent diarrhoea (15% of the improvement), decline in low birth size (7%-9%), and an increase in wealth (15%-30%) were the main risk factors that accounted for the explained change in WHZ. Our findings emphasize the importance of interventions to reduce low birthweight, diarrhoea and interventions that address income inequities to prevent acute malnutrition.

Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung.

Prevailing dogma holds that cell-cell communication through Notch ligands and receptors determines binary cell fate decisions during progenitor cell divisions, with differentiated lineages remaining fixed. Mucociliary clearance in mammalian respiratory airways depends on secretory cells (club and goblet) and ciliated cells to produce and transport mucus. During development or repair, the closely related Jagged ligands (JAG1 and JAG2) induce Notch signalling to determine the fate of these lineages as they descend from a common proliferating progenitor. In contrast to such situations in which cell fate decisions are made in rapidly dividing populations, cells of the homeostatic adult airway epithelium are long-lived, and little is known about the role of active Notch signalling under such conditions. To disrupt Jagged signalling acutely in adult mammals, here we generate antibody antagonists that selectively target each Jagged paralogue, and determine a crystal structure that explains selectivity. We show that acute Jagged blockade induces a rapid and near-complete loss of club cells, with a concomitant gain in ciliated cells, under homeostatic conditions without increased cell death or division. Fate analyses demonstrate a direct conversion of club cells to ciliated cells without proliferation, meeting a conservative definition of direct transdifferentiation. Jagged inhibition also reversed goblet cell metaplasia in a preclinical asthma model, providing a therapeutic foundation. Our discovery that Jagged antagonism relieves a blockade of cell-to-cell conversion unveils unexpected plasticity, and establishes a model for Notch regulation of transdifferentiation.

Progress in Water, Sanitation and Hygiene (WASH) coverage and potential contribution to the decline in diarrhea and stunting in Ethiopia.

Inadequate safe water supply and poor sanitation and hygiene continue to be important risk factors for diarrhoea and stunting globally. We used data from the four rounds of the Ethiopian Demographic and Health Survey and applied the new World Health Organization (WHO)/UNICEF Joint Monitoring Program (JMP) service standards to assess progress in water, sanitation and hygiene (WASH) coverage between 2000 and 2016. We also performed an age-disaggregated pooled linear probability regression analysis followed by a decomposition analysis to determine whether changes in WASH practices have contributed to the changing prevalence of diarrhoea and stunting in children under 5 years of age. We observed a significant increase in the coverage of safe drinking water and adequate sanitation facilities over the period. At the national level, the use of a basic water source increased from 18% in 2000 to 50% in 2016. Open defecation declined from 82% to 32% over the same period. However, in 2016, only 6% of households had access to a basic sanitation facility, and 40% of households had no handwashing facilities. The reduction in surface water use between 2000 and 2016 explained 6% of the decline in diarrhoea observed among children aged 0-5 months. In children aged 6-59 months, between 7% and 9% of the reduction in stunting were attributable to the reduction in open defecation over this period. Despite progress, improvements are still needed to increase basic WASH coverage in Ethiopia. Our findings showed that improvements in water and sanitation only modestly explained reductions in diarrhoea and stunting.

Prevalence of iodine deficiency and associated factors among pregnant women in Ada district, Oromia region, Ethiopia: a cross- sectional study.

BACKGROUND: Maternal iodine deficiency (ID) during pregnancy has been recognized as a major cause of abortion, stillbirth, congenital abnormalities, perinatal mortality and irreversible mental retardation. In Ethiopia limited information is available regarding the epidemiology of maternal ID. The purpose of the present study was to assess the prevalence of iodine deficiency and associated factors among pregnant women in Ada district, Oromia region, Ethiopia. METHOD: A community based, cross-sectional study was conducted in rural areas of Ada district, October to November, 2014. Data were collected from 356 pregnant women selected by multistage cluster sampling technique. Presence of goiter was examined by palpation and urinary iodine concentration was measured using inductively-coupled-plasma mass spectrometry. Salt iodine concentration was determined using a digital electronic iodine checker. Statistical analysis was done primarily using binary logistic regression. The outputs of the analysis are presented using adjusted odds ratio (AOR) with the respective 95% confidence intervals (CI). RESULTS: The median urinary iodine concentration (UIC) was 85.7 (interquartile range (IQR): 45.7-136) µg/L. Based on UIC, 77.6% (95% CI: 73.0-82.0%) of the study subjects had insufficient iodine intake (UIC < 150 µg/L). The goiter rate was 20.2% (95% CI: 16.0-24.0%). The median iodine concentration of the household salt samples was 12.2 (IQR: 6.9-23.8) ppm. Of the households, only 39.3% (95% CI: 34.0-44.0%) consumed adequately iodized salt (≥15 ppm). Prevalence of goiter was significantly higher among pregnant women aged 30-44 years (AOR = 2.32 (95% CI: 1.05-5.14)) than among younger women and among illiterate women (AOR = 2.71 (95% CI: 1.54-4.79)). Compared to nulliparous, women with parity of 1, 2 and 3 or more had 2.28 (95% CI: 1.01-5.16), 2.81 (95% CI: 1.17-6.74) and 4.41 (95% CI: 1.58-12.26) times higher risk of goiter. CONCLUSION: Iodine deficiency was a public health problem in the study area. This indicates the need for further strengthening of the existing salt iodization program in order to avail homogenously and adequately iodized salt. Also it is necessary to find ways to provide iodine supplements as needed until universal salt iodization (USI) is fully established.

Conditional Deletion of NF-κB-Inducing Kinase (NIK) in Adult Mice Disrupts Mature B Cell Survival and Activation.

NF-κB-inducing kinase (NIK) is a primary regulator of the noncanonical NF-κB signaling pathway, which plays a vital role downstream of BAFF, CD40L, lymphotoxin, and other inflammatory mediators. Germline deletion or inactivation of NIK in mice results in the defective development of B cells and secondary lymphoid organs, but the role of NIK in adult animals has not been studied. To address this, we generated mice containing a conditional allele of NIK. Deletion of NIK in adult mice results in decreases in B cell populations in lymph nodes and spleen, similar to what is observed upon blockade of BAFF. Consistent with this, B cells from mice in which NIK is acutely deleted fail to respond to BAFF stimulation in vitro and in vivo. In addition, mice with induced NIK deletion exhibit a significant decrease in germinal center B cells and serum IgA, which is indicative of roles for NIK in additional pathways beyond BAFF signaling. Our conditional NIK-knockout mice may be broadly useful for assessing the postdevelopmental and cell-specific roles of NIK and the noncanonical NF-κB pathway in mice.

The effect of UNIMMAP multiple micronutrient supplements versus iron-folic acid and placebo in anemia reduction among women of reproductive age in Kebribeyah Woreda, Somali Regional State, Ethiopia: a study protocol for a community-based individual RCT.

BACKGROUND: Women of reproductive age (WRA) in developing countries are often at risk of micronutrient deficiencies due to inadequate intakes and excessive losses. OBJECTIVE: The purpose of this trial is to assess the effectiveness of United Nations International Multiple Micronutrient Antenatal Preparation-Multiple Micronutrient Supplements (UNIMMAP-MMS) versus iron-folic acid (IFA) among WRA in reducing anemia. METHODS: Three parallel groups of WRA will participate in a community-based, individually randomized, double-blinded, placebo-controlled superiority trial. After consent, the sample of 375 mildly or moderately anemic women based on hemoglobin by Hemocue will be randomly assigned across two interventions and one control arm. Trial participants in intervention arms will receive UNIMMAP-MMS or IFA while those in the control arm will receive placebos twice a week for 17 weeks. The primary outcome will be a change in mean hemoglobin (Hb) concentrations. Outcome assessors and study participants will be blinded to the type of supplements and study arm. DISCUSSION: The World Health Organization (WHO) added UNIMMAP-MMS to its essential medicine lists in 2021 but recommended rigorous study. Several factors in addition to inadequate intakes of iron and folic acid contribute to the high prevalence of anemia among WRA in the Somali region. The findings of this study will provide evidence on the effect of UNIMMAP-MMS and IFA on Hb concentrations and anemia prevalence among anemic WRA. TRIAL REGISTRATION: ClinicalTrials.gov NCT05682261. Registered on January 12, 2023.

Feeding practices, nutritional status and associated factors of lactating women in Samre Woreda, South Eastern Zone of Tigray, Ethiopia.

BACKGROUND: Lactating mothers from low-income settings are considered as a nutritionally vulnerable group. Due to the nursing process, mothers are subjected to nutritional stresses. Frequent pregnancies followed by lactation increase the health risk of mothers resulting in a high maternal mortality. OBJECTIVE: To assess the feeding practices, nutritional status and associated factors of lactating women from Samre Woreda, South Eastern Tigray, Ethiopia. DESIGN: Community based cross-sectional survey SETTING: Four kebeles of Samre Woreda (2 urban & 2 rural kebeles) METHODS: Four hundred lactating mothers were recruited from 400 randomly selected households. Data on socio-demographic characteristics, maternal characteristics, feeding practices, frequency of foods eaten and dietary diversity was collected using a pre-tested and structured questionnaire. Anthropometric measurements were taken from each mother using calibrated equipments and standardized techniques. A one-day weighed food record was also collected from randomly selected sub sample (n=60) of mothers. The nutrient and energy content of foods consumed by the mothers was calculated by using ESHA Food Processor and the Ethiopian Food Composition Tables. To investigate the socio-economic and demographic factors affecting the nutritional status of the women, logistic regression was used. ANOVA and t-test were also used to see if there was a mean difference in nutritional status among the lactating mothers. RESULTS: Majority (71.2%) of the participants did not take additional meals during lactation. The median dietary diversity score of the study participants was 5 out of 14 food groups. The prevalence of underweight, chronic energy deficiency and stunting were 31%, 25% and 2.2% respectively. Using logistic regression model, factors significantly associated with the nutritional status of the study participants (as determined by BMI and MUAC) were size of farm land, length of years of marriage, maize cultivation, frequency of antenatal care visit and age of breastfeeding child. CONCLUSIONS: The feeding practices, dietary intakes and nutritional status of the lactating women were short of the national and international recommendations. Therefore, sustained health and nutrition education is recommended to the women and their families and communities on increased food intake, proper dietary practices and dietary diversification during lactation in order to improve health and nutrition outcomes of lactating women.

Absent in melanoma 2 is required for innate immune recognition of Francisella tularensis.

Macrophages respond to cytosolic nucleic acids by activating cysteine protease caspase-1 within a complex called the inflammasome. Subsequent cleavage and secretion of proinflammatory cytokines IL-1beta and IL-18 are critical for innate immunity. Here, we show that macrophages from mice lacking absent in melanoma 2 (AIM2) cannot sense cytosolic double-stranded DNA and fail to trigger inflammasome assembly. Caspase-1 activation in response to intracellular pathogen Francisella tularensis also required AIM2. Immunofluorescence microscopy of macrophages infected with F. tularensis revealed striking colocalization of bacterial DNA with endogenous AIM2 and inflammasome adaptor ASC. By contrast, type I IFN (IFN-alpha and -beta) secretion in response to F. tularensis did not require AIM2. IFN-I did, however, boost AIM2-dependent caspase-1 activation by increasing AIM2 protein levels. Thus, inflammasome activation was reduced in infected macrophages lacking either the IFN-I receptor or stimulator of interferon genes (STING). Finally, AIM2-deficient mice displayed increased susceptibility to F. tularensis infection compared with wild-type mice. Their increased bacterial burden in vivo confirmed that AIM2 is essential for an effective innate immune response.

Biofortification in Ethiopia: Opportunities and Challenges.

BACKGROUND: Children younger than 5 years and women of reproductive age often suffer from micronutrient deficiencies. Biofortification, which involves enriching staple crops with micronutrients, is a nutritional intervention focused on addressing micronutrient deficiencies. It is equitable, sustainable, and costs less than other nutritional interventions. OBJECTIVE: This study investigates biofortification in Ethiopia, considering 6 globally biofortified crops, 5 of which are currently being biofortified in Ethiopia. However, only 2 of these crops are important in the consumption baskets of most Ethiopians. Therefore, efforts to mainstream biofortification should begin with studies to identify crops that have larger impacts in reducing local micronutrient deficiencies and their cost-effectiveness. METHODS: Literature was searched between July and December 2021 using Google Scholar to provide insights into the state of biofortification in Ethiopia. Key-informant interviews were conducted to gain insights into the state of biofortification in Ethiopia and to identify bottlenecks for scaling up the production and consumption of biofortified foods. Furthermore, Annual Agriculture Sample Survey and 2015/16 Ethiopian Household Consumption and Expenditure Survey data were used to describe the area under production of biofortifiable crops and their importance in total consumption, respectively. RESULTS: Mainstreaming biofortification in Ethiopia faces several challenges. Policy documents appear to be inconsistent, regressive, and vague regarding biofortification. Critically, there is no specific institution to oversee and/or coordinate biofortification-related activities. CONCLUSION: Overall, the success of biofortification depends upon a strong coordination body with clear mandates from detailed policies; adequate funding for research and development; and robust monitoring and evaluation of the identified production, adoption, and consumption issues.

Perspectives on National Institutes of Health Funding Requirements for Racial and Ethnic Diversity Among Medical Scientist Training Program Leadership.

Importance: Since 1964, the National Institutes of Health (NIH) has funded the Medical Scientist Training Program (MSTP) MD-PhD program at medical schools across the US to support training physician-scientists. Recent studies have suggested that MSTPs have consistently matriculated more students from racial and ethnic backgrounds historically underrepresented in science than MD-PhD programs without NIH funding; however, the underlying basis for the increased diversity seen in NIH-funded MSTPs is poorly understood. Objective: To investigate how administrators and faculty perceive the impact of MSTP status on MD-PhD program matriculant racial and ethnic diversity. Design, Setting, and Participants: This qualitative study used a positive deviance approach to identify 9 high-performing and 3 low-performing MSTPs based on the percentage of students underrepresented in science who matriculated into the program between 2014 and 2018. This study, a subanalysis of a larger study to understand recruitment of students underrepresented in science at MSTPs, focused on in-depth qualitative interviews, conducted from October 26, 2020, to August 31, 2022, of 69 members of MSTP leadership, including program directors, associate and assistant program directors, and program administrators. Main Outcomes and Measures: The association of NIH funding with institutional priorities, programs, and practices related to MD-PhD program matriculant racial and ethnic diversity. Results: The study included 69 participants (mean [SD] age, 53 [10] years; 38 women [55%]; 13 African American or Black participants [19%], 6 Asian participants [9%], 12 Hispanic participants [17%], and 36 non-Hispanic White participants [52%]). A total of 51 participants (74%) were in administrative roles, and 18 (26%) were faculty involved in recruitment. Five themes emerged from the data: (1) by tying MSTP funding to diversity efforts, the NIH created a sense of urgency among MSTP leadership to bolster matriculant diversity; (2) MD-PhD program leadership leveraged the changes to MSTP grant review to secure new institutional investments to promote recruitment of students underrepresented in science; (3) MSTPs increasingly adopted holistic review to evaluate applicants to meet NIH funding requirements; (4) MSTP leadership began to systematically assess the effectiveness of their diversity initiatives and proactively identify opportunities to enhance matriculant diversity; and (5) although all MSTPs were required to respond to NIH criteria, changes made by low-performing programs generally lacked the robustness demonstrated by high-performing programs. Conclusions and Relevance: This study suggests that NIH funding requirements may be a powerful incentive to promote diversity and positively affect representation of students underrepresented in science in the biomedical scientific workforce.

Ethiopia National Food and Nutrition Survey to inform the Ethiopian National Food and Nutrition Strategy: a study protocol.

INTRODUCTION: Ethiopia has made significant progress in reducing malnutrition in the past two decades. Despite such improvements, a substantial segment of the country's population remains chronically undernourished and suffers from micronutrient deficiencies and from increasing diet-related non-communicable diseases such as diabetes, hypertension and cancer. This survey aims to assess anthropometric status, dietary intake and micronutrient status of Ethiopian children, women and adolescent girls. The study will also assess coverage of direct and indirect nutrition-related interventions and map agricultural soil nutrients. The survey will serve as a baseline for the recently developed Ethiopian Food System Transformation Plan and will inform the implementation of the National Food and Nutrition Strategy. METHODS AND ANALYSIS: As a population-based, cross-sectional survey, the study will collect data from the 10 regions and 2 city administrations of Ethiopia. The study population will be women of reproductive age, children aged 0-59 months, school-aged children and adolescent girls. A total of 16 596 households will be surveyed, allowing the generation of national and regional estimates. A two-stage stratified cluster sampling procedure will be used to select households. In the first stage, 639 enumeration areas (EAs) will be selected using probability-proportional-to-size allocation. In the second stage, 26 eligible households will be selected within each EA using systematic random selection. Primary outcomes include coverage of direct and indirect nutrition interventions, infant and young child feeding (IYCF) practices, food insecurity, dietary intakes, mental health, anthropometric status, micronutrient status and soil nutrient status. ETHICS AND DISSEMINATION: The protocol was fully reviewed and approved by the Institutional Review Board of the Ethiopian Public Health Institute (protocol no: EPHI-IRB-317-2020). The study is based on voluntary participation and written informed consent is required from study participants. The findings will be disseminated via forums and conferences and will be submitted for publication in peer-reviewed journals.

Nav1.7 is essential for nociceptor action potentials in the mouse in a manner independent of endogenous opioids.

Loss-of-function mutations in Nav1.7, a voltage-gated sodium channel, cause congenital insensitivity to pain (CIP) in humans, demonstrating that Nav1.7 is essential for the perception of pain. However, the mechanism by which loss of Nav1.7 results in insensitivity to pain is not entirely clear. It has been suggested that loss of Nav1.7 induces overexpression of enkephalin, an endogenous opioid receptor agonist, leading to opioid-dependent analgesia. Using behavioral pharmacology and single-cell RNA-seq analysis, we find that overexpression of enkephalin occurs only in cLTMR neurons, a subclass of sensory neurons involved in low-threshold touch detection, and that this overexpression does not play a role in the analgesia observed following genetic removal of Nav1.7. Furthermore, we demonstrate using laser speckle contrast imaging (LSCI) and in vivo electrophysiology that Nav1.7 function is required for the initiation of C-fiber action potentials (APs), which explains the observed insensitivity to pain following genetic removal or inhibition of Nav1.7.

Obligate role for Rock1 and Rock2 in adult stem cell viability and function.

The ability of stem cells to rapidly proliferate and differentiate is integral to the steady-state maintenance of tissues with high turnover such as the blood and intestine. Mutations that alter these processes can cause primary immunodeficiencies, malignancies and defects in barrier function. The Rho-kinases, Rock1 and Rock2, regulate cell shape and cytoskeletal rearrangement, activities essential to mitosis. Here, we use inducible gene targeting to ablate Rock1 and Rock2 in adult mice, and identify an obligate requirement for these enzymes in the preservation of the hematopoietic and gastrointestinal systems. Hematopoietic cell progenitors devoid of Rho-kinases display cell cycle arrest, blocking the differentiation to mature blood lineages. Similarly, these mice exhibit impaired epithelial cell renewal in the small intestine, which is ultimately fatal. Our data reveal a novel role for these kinases in the proliferation and viability of stem cells and their progenitors, which is vital to maintaining the steady-state integrity of these organ systems.

Cryopyrin activates the inflammasome in response to toxins and ATP.

A crucial part of the innate immune response is the assembly of the inflammasome, a cytosolic complex of proteins that activates caspase-1 to process the proinflammatory cytokines interleukin (IL)-1beta and IL-18. The adaptor protein ASC is essential for inflammasome function, binding directly to caspase-1 (refs 3, 4), but the triggers of this interaction are less clear. ASC also interacts with the adaptor cryopyrin (also known as NALP3 or CIAS1). Activating mutations in cryopyrin are associated with familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, diseases that are characterized by excessive production of IL-1beta. Here we show that cryopyrin-deficient macrophages cannot activate caspase-1 in response to Toll-like receptor agonists plus ATP, the latter activating the P2X7 receptor to decrease intracellular K+ levels. The release of IL-1beta in response to nigericin, a potassium ionophore, and maitotoxin, a potent marine toxin, was also found to be dependent on cryopyrin. In contrast to Asc-/- macrophages, cells deficient in the gene encoding cryopyrin (Cias1-/-) activated caspase-1 and secreted normal levels of IL-1beta and IL-18 when infected with Gram-negative Salmonella typhimurium or Francisella tularensis. Macrophages exposed to Gram-positive Staphylococcus aureus or Listeria monocytogenes, however, required both ASC and cryopyrin to activate caspase-1 and secrete IL-1beta. Therefore, cryopyrin is essential for inflammasome activation in response to signalling pathways triggered specifically by ATP, nigericin, maitotoxin, S. aureus or L. monocytogenes.

Determinants of time to full enteral feeding achievement among infants with birth weight 1000-2000g admitted to the neonatal intensive care unit of public hospitals in Hawassa city, Sidama region Ethiopian, 2019: A retrospective cohort study.

BACKGROUND: Nutritional care during the neonatal period is a cornerstone towards achieving optimal care. However, very limited data is available on optimizing parenteral and enteral nutrition that directly affects infant survival among Ethiopian neonates. Therefore, the objective of this study is to identify determinants of time to full enteral feeding achievement among low-birth-weight neonates admitted to neonatal intensive care units of public hospitals in Hawassa city. METHODS: A facility-based retrospective cohort study was conducted in Adare general hospital and Hawassa University's comprehensive specialized hospital from August 2018 to 2019. Charts of infants with a birth weight of 1000-2000g (n = 273) neonates who were admitted to the neonatal intensive care unit (ICU) were reviewed. The sample size for each hospital was allocated proportionally and subjects were selected by using a simple random sampling technique. Data were entered using Epi. data version 3.1, and analysis was performed using SPSS version 20. Kaplan-Meier estimator and a Cox proportional hazard model were used. RESULT: The mean (SD) age when an enteral feed (trophic feeding) was first commenced was 2.13(1.373) days. The median time to achieve full enteral feeding was 8 days with IQR (7-10 days). Gestational age reduces the time to full enteral feeding by 18.8% for each additional week of gestation (AHR = 0.812, p-value = 0.003). The time to achieve full enteral feeding was shorter by 70.4% among neonates who were small for gestational age, as compared with that appropriate for gestational age (AHR = 0.296, p-value<0.001). CONCLUSION: According to this study, the time that the neonate takes to achieve full enteral feeding was relatively short. Gestational age and weight for gestational were the determinants for time to full enteral feeding achievement. Further research needs to be conducted to explore further, in addition to current findings.

Vitamin D binding protein gene polymorphisms are associated with lower plasma 25-hydroxy-cholecalciferol concentrations in Ethiopian lactating women.

Ethiopian women have been reported to have low plasma 25-hydroxy-cholecalciferol (25(OH)D) concentrations despite an abundance of sunshine. Low dietary vitamin D intake, limited skin exposure to sun, and genetics are among factors suggested to affect vitamin D status in this population. In this study (Clinical Trial NCT02210884), we hypothesized that polymorphisms in the vitamin D binding protein (VDBP) gene (rs7041, rs4588) are associated with reduced plasma 25(OH)D concentrations in Ethiopian women. Lactating Ethiopian women (n = 110) were randomly assigned to weekly administration of vitamin D3 (15,000 IU) or a placebo. Plasma 25(OH)D was measured at baseline (within 2 weeks of delivery, before supplementation) and at 3, 6, and 12 months after delivery. Associations between VDBP polymorphism status for rs7041 and rs4588 and plasma 25(OH)D were determined by analysis of variance and multiple linear and logistic regressions. Multiple linear regression with maternal age as a covariate revealed that rs7041 is associated with reduced plasma 25(OH)D (P = .021) and more risk alleles at rs7041 and rs4588 are associated with reduced plasma 25(OH)D (P = .017). Logistic regression models for vitamin D insufficiency showed that additional risk alleles for rs7041 and rs4588 are associated with increased odds ratios (OR = 1.66; 95% CI, 1.10-2.62; P = .019) for plasma 25(OH)D below 40 nmol/L. Supplementation increased plasma 25(OH)D at 3 months in women with fewer risk alleles and across all genotypes at 6 and 12 months. VDBP polymorphisms may contribute to vitamin D insufficiency in Ethiopian lactating women. Furthermore, VDBP polymorphisms may blunt short-term responses to vitamin D supplementation and require longer periods of intervention.

TGFß2 and TGFß3 isoforms drive fibrotic disease pathogenesis.

Transforming growth factor-ß (TGFß) is a key driver of fibrogenesis. Three TGFß isoforms (TGFß1, TGFß2, and TGFß3) in mammals have distinct functions in embryonic development; however, the postnatal pathological roles and activation mechanisms of TGFß2 and TGFß3 have not been well characterized. Here, we show that the latent forms of TGFß2 and TGFß3 can be activated by integrin-independent mechanisms and have lower activation thresholds compared to TGFß1. Unlike TGFB1, TGFB2 and TGFB3 expression is increased in human lung and liver fibrotic tissues compared to healthy control tissues. Thus, TGFß2 and TGFß3 may play a pathological role in fibrosis. Inducible conditional knockout mice and anti-TGFß isoform-selective antibodies demonstrated that TGFß2 and TGFß3 are independently involved in mouse fibrosis models in vivo, and selective TGFß2 and TGFß3 inhibition does not lead to the increased inflammation observed with pan-TGFß isoform inhibition. A cocrystal structure of a TGFß2-anti-TGFß2/3 antibody complex reveals an allosteric isoform-selective inhibitory mechanism. Therefore, inhibiting TGFß2 and/or TGFß3 while sparing TGFß1 may alleviate fibrosis without toxicity concerns associated with pan-TGFß blockade.

Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf.

Specific adaptors regulate the activation of initiator caspases; for example, FADD and Apaf-1 engage caspases 8 and 9, respectively. The adaptors ASC, Ipaf and RIP2 have each been proposed to regulate caspase-1 (also called interleukin (IL)-1 converting enzyme), which is activated within the 'inflammasome', a complex comprising several adaptors. Here we show the impact of ASC-, Ipaf- or RIP2-deficiency on inflammasome function. ASC was essential for extracellular ATP-driven activation of caspase-1 in toll-like receptor (TLR)-stimulated macrophages. Accordingly, ASC-deficient macrophages exhibited defective maturation of IL-1beta and IL-18, and ASC-null mice were resistant to lipopolysaccharide-induced endotoxic shock. Furthermore, activation of caspase-1 in response to an intracellular pathogen (Salmonella typhimurium) was abrogated severely in ASC-null macrophages. Unexpectedly, Ipaf-deficient macrophages activated caspase-1 in response to TLR plus ATP stimulation but not S. typhimurium. Caspase-1 activation was not compromised by loss of RIP2. These data show that whereas ASC is key to caspase-1 activation within the inflammasome, Ipaf provides a special conduit to the inflammasome for signals triggered by intracellular pathogens. Notably, cell death triggered by stimuli that engage caspase-1 was ablated in macrophages lacking either ASC or Ipaf, suggesting a coupling between the inflammatory and cell death pathways.