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Item Impact of exposure to cooking fuels on stillbirths, perinatal, very early and late neonatal mortality - a multicenter prospective cohort study in rural communities in India, Pakistan, Kenya, Zambia and Guatemala(Springer (Biomed Central Ltd.), 2015) Patel, Archana B.; Meleth, Sreelatha; Pasha, Omrana; Goudar, Shivaprasad S.; Esamai, Fabian; Garces, Ana L.; Chomba, Elwyn; McClure, Elizabeth M.; Wright, Linda L.; Koso-Thomas, Marion; Moore, Janet L.; Saleem, Sarah; Liechty, Edward A.; Goldenberg, Robert L.; Derman, Richard J.; Hambidge, K. Michael; Carlo, Waldemar A.; Hibberd, Patricia L.; Department of Pediatrics, IU School of MedicineBACKGROUND: Consequences of exposure to household air pollution (HAP) from biomass fuels used for cooking on neonatal deaths and stillbirths is poorly understood. In a large multi-country observational study, we examined whether exposure to HAP was associated with perinatal mortality (stillbirths from gestation week 20 and deaths through day 7 of life) as well as when the deaths occurred (macerated, non-macerated stillbirths, very early neonatal mortality (day 0-2) and later neonatal mortality (day 3-28). Questions addressing household fuel use were asked at pregnancy, delivery, and neonatal follow-up visits in a prospective cohort study of pregnant women in rural communities in five low and lower middle income countries participating in the Global Network for Women and Children's Health's Maternal and Newborn Health Registry. The study was conducted between May 2011 and October 2012. Polluting fuels included kerosene, charcoal, coal, wood, straw, crop waste and dung. Clean fuels included electricity, liquefied petroleum gas (LPG), natural gas and biogas. RESULTS: We studied the outcomes of 65,912 singleton pregnancies, 18 % from households using clean fuels (59 % LPG) and 82 % from households using polluting fuels (86 % wood). Compared to households cooking with clean fuels, there was an increased risk of perinatal mortality among households using polluting fuels (adjusted relative risk (aRR) 1.44, 95 % confidence interval (CI) 1.30-1.61). Exposure to HAP increased the risk of having a macerated stillbirth (adjusted odds ratio (aOR) 1.66, 95%CI 1.23-2.25), non-macerated stillbirth (aOR 1.43, 95 % CI 1.15-1.85) and very early neonatal mortality (aOR 1.82, 95 % CI 1.47-2.22). CONCLUSIONS: Perinatal mortality was associated with exposure to HAP from week 20 of pregnancy through at least day 2 of life. Since pregnancy losses before labor and delivery are difficult to track, the effect of exposure to polluting fuels on global perinatal mortality may have previously been underestimated. TRIAL REGISTRATION: ClinicalTrials.gov NCT01073475.Item Presentation and Outcomes of Infants With Idiopathic Cholestasis: A Multicenter Prospective Study(Wolters Kluwer, 2021-10-01) Hertel, Paula M.; Hawthorne, Kieran; Kim, Sehee; Finegold, Milton J.; Shneider, Benjamin L.; Squires, James E.; Gupta, Nitika A.; Bull, Laura N.; Murray, Karen F.; Kerkar, Nanda; Ng, Vicky L.; Molleston, Jean P.; Bezerra, Jorge A.; Loomes, Kathleen M.; Taylor, Sarah A.; Schwarz, Kathleen B.; Turmelle, Yumirle P.; Rosenthal, Philip; Magee, John C.; Sokol, Ronald J.; Pediatrics, School of MedicineObjectives: The aim of the study was to determine the frequency and natural history of infantile idiopathic cholestasis (IC) in a large, prospective, multicenter cohort of infants. Methods: We studied 94 cholestatic infants enrolled up to 6 months of age in the NIDDK ChiLDReN (Childhood Liver Disease Research Network) "PROBE" protocol with a final diagnosis of IC; they were followed up to 30 months of age. Results: Male sex (66/94; 70%), preterm birth (22/90 with data; 24% born at < 37 weeks' gestational age), and low birth weight (25/89; 28% born at <2500 g) were frequent, with no significant differences between outcomes. Clinical outcomes included death (n = 1), liver transplant (n = 1), biochemical resolution (total bilirubin [TB] ≤1 mg/dL and ALT < 35 U/L; n = 51), partial resolution (TB > 1 mg/dL and/or ALT > 35 U/L; n = 7), and exited healthy (resolved disease per study site report but without documented biochemical resolution; n = 34). Biochemical resolution occurred at median of 9 months of age. GGT was <100 U/L at baseline in 34 of 83 participants (41%). Conclusions: Frequency of IC and of death or liver transplant was less common in this cohort than in previously published cohorts, likely because of recent discovery and diagnosis of genetic etiologies of severe/persistent cholestasis that previously were labeled as idiopathic. Preterm birth and other factors associated with increased vulnerability in neonates are relatively frequent and may contribute to IC. Overall outcome in IC is excellent. Low/normal GGT was common, possibly indicating a role for variants in genes associated with low-GGT cholestasis-this warrants further study.Item Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model(Elsevier, 2024) Hawley, Laura E.; Stringer, Megan; Deal, Abigail J.; Folz, Andrew; Goodlett, Charles R.; Roper, Randall J.; Biology, School of ScienceAberrant neurodevelopment in Down syndrome (DS)-caused by triplication of human chromosome 21-is commonly attributed to gene dosage imbalance, linking overexpression of trisomic genes with disrupted developmental processes, with DYRK1A particularly implicated. We hypothesized that regional brain DYRK1A protein overexpression in trisomic mice varies over development in sex-specific patterns that may be distinct from Dyrk1a transcription, and reduction of Dyrk1a copy number from 3 to 2 in otherwise trisomic mice reduces DYRK1A, independent of other trisomic genes. DYRK1A overexpression varied with age, sex, and brain region, with peak overexpression on postnatal day (P) 6 in both sexes. Sex-dependent differences were also evident from P15-P24. Reducing Dyrk1a copy number confirmed that these differences depended on Dyrk1a gene dosage and not other trisomic genes. Trisomic Dyrk1a mRNA and protein expression were not highly correlated. Sex-specific patterns of DYRK1A overexpression during trisomic neurodevelopment may provide mechanistic targets for therapeutic intervention in DS.Item Stem cell therapy in necrotizing enterocolitis: Current state and future directions(Elsevier, 2018-02) Drucker, Natalie A.; McCulloh, Christopher J.; Li, Bo; Pierro, Agostino; Besner, Gail E.; Markel, Troy A.; Surgery, School of MedicineStem cell therapy is a promising treatment modality for necrotizing enterocolitis. Among the many promising stem cells identified to date, it is likely that mesenchymal stem cells will be the most useful and practical cell-based therapies for this condition. Using acellular components such as exosomes or other paracrine mediators are promising as well. Multiple mechanisms are likely at play in the positive effects provided by these cells, and further research is underway to further elucidate these effects.Item Transient and persistent acute kidney injury phenotypes following the Norwood operation: a retrospective study(Cambridge University Press, 2022) Gist, Katja M.; Borasino, Santiago; SooHoo, Megan; Soranno, Danielle E.; Mack, Emily; Hock, Kristal M.; Rahman, A. K. M. Fazlur; Brinton, John T.; Basu, Rajit K.; Alten, Jeffrey A.; Pediatrics, School of MedicineBackground: Acute kidney injury is a common complication following the Norwood operation. Most neonatal studies report acute kidney injury peaking within the first 48 hours after cardiac surgery. The aim of this study was to evaluate if persistent acute kidney injury (>48 postoperative hours) after the Norwood operation was associated with clinically relevant outcomes. Methods: Two-centre retrospective study among neonates undergoing the Norwood operation. Acute kidney injury was initially identified as developing within the first 48 hours after cardiac surgery and stratified into transient (≤48 hours) and persistent (>48 hours) using the neonatal modification of the Kidney Disease: Improving Global Outcomes serum creatinine criteria. Severe was defined as stage ≥2. Primary and secondary outcomes were mortality and duration of ventilation and hospital length of stay. Results: One hundred sixty-eight patients were included. Transient and persistent acute kidney injuries occurred in 24 and 17%, respectively. Cardiopulmonary bypass and aortic cross clamp duration, and incidence of cardiac arrest were greater among those with persistent kidney injury. Mortality was four times higher (41 versus 12%, p < 0.001) and mechanical ventilation duration 50 hours longer in persistent acute kidney injury patients (158 versus 107 hours; p < 0.001). In multivariable analysis, persistent acute kidney injury was not associated with mortality, duration of ventilation or length of stay. Severe persistent acute kidney injury was associated with a 59% increase in expected ventilation duration (aIRR:1.59, 95% CI:1.16, 2.18; p = 0.004). Conclusions: Future large studies are needed to determine if risk factors and outcomes change by delineating acute kidney injury into discrete timing phenotypes.