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    Impact of Oxidative Stress on Risk of Death and Readmission in African Children With Severe Malaria: A Prospective Observational Study
    (Oxford University Press, 2022) Blatt, Daniel B.; Hanisch, Benjamin; Co, Katrina; Datta, Dibyadyuti; Bond, Caitlin; Opoka, Robert O.; Cusick, Sarah E.; Michelow, Ian C.; John, Chandy C.; Pediatrics, School of Medicine
    Background: We hypothesized that oxidative stress in Ugandan children with severe malaria is associated with mortality. Methods: We evaluated biomarkers of oxidative stress in children with cerebral malaria (CM, n = 77) or severe malarial anemia (SMA, n = 79), who were enrolled in a randomized clinical trial of immediate vs delayed iron therapy, compared with community children (CC, n = 83). Associations between admission biomarkers and risk of death during hospitalization or risk of readmission within 6 months were analyzed. Results: Nine children with CM and none with SMA died during hospitalization. Children with CM or SMA had higher levels of heme oxygenase-1 (HO-1) (P < .001) and lower superoxide dismutase (SOD) activity than CC (P < .02). Children with CM had a higher risk of death with increasing HO-1 concentration (odds ratio [OR], 6.07 [95% confidence interval {CI}, 1.17-31.31]; P = .03) but a lower risk of death with increasing SOD activity (OR, 0.02 [95% CI, .001-.70]; P = .03). There were no associations between oxidative stress biomarkers on admission and risk of readmission within 6 months of enrollment. Conclusions: Children with CM or SMA develop oxidative stress in response to severe malaria. Oxidative stress is associated with higher mortality in children with CM but not with SMA.
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    Broad perspectives in understanding vaccine hesitancy and vaccine confidence: an introduction to the special issue
    (Springer Nature, 2023) Baldwin, Austin S.; Tiro, Jasmin A.; Zimet, Gregory D.; Pediatrics, School of Medicine
    The World Health Organization has designated vaccine hesitancy and vaccine confidence among the most pressing issues in global health. The COVID-19 pandemic has made vaccine hesitancy and vaccine confidence particularly salient and urgent. The purpose of this special issue is to highlight a broad range of perspectives on these critical issues. We have included a total of 30 papers that address issues related to vaccine hesitancy and vaccine confidence across multiple levels of the Socio-Ecological Model. We have organized the empirical papers into the following sections: individual-level beliefs, minority health and health disparities, social media and conspiracy beliefs, and interventions. In addition to the empirical papers, three commentaries are included in this special issue.
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    156. Daily Association of Drug Use Cravings and Physical and Emotional Well-Being among Students Attending a Recovery High School during COVID-19: Results from an EMA Study
    (Elsevier, 2023) Hensel, Devon J.; Wilburn, Victoria Garcia; Pediatrics, School of Medicine
    Purpose: Ongoing COVID-19 restrictions are now well-known to increase youth substance use. Little research has addressed this vulnerability among adolescents in substance use recovery (AIR), who may be at heightened risk for relapse within ongoing pandemic management. We used ecological momentary assessment-focused (EMA) to characterize daily shifts in recovery management among adolescents attending a recovery high school. We engage the first wave of these EMA-data collected during third wave of the pandemic (January-February 2022) to: 1) document day-to-day changes in drug craving context (e.g., frequency, temporality, duration, and intensity) and; 2) examine its association with daily shifts in physical and emotional well-being. Methods: Data were from an EMA-study (ongoing through 2022-2023 school-year) intended to understand the social/emotional context of drug use cravings among a cohort of AIR attending a recovery high school in Indianapolis, IN. Our analytic-sample includes six-students (N=40 total) who were enrolled during the second pandemic wave (57.3% female, 42.5% heterosexual, 71.0% White, 52.3% 12th-grade, 57.4% had weekly urges use). Drug use context measures: any drug-use urge (no/yes), urge frequency (5-point item: once-6+ times), urge temporality/duration (6-point item: AM, aft or PM only, more than half the day, all day) and urge intensity (single item: 0-10). Physical and emotional variables: emotional pain (5-point single item: not at all-extremely), self-perceived health (5-point single item: poor to excellent), positive and negative mood (PANAS) and somatic symptoms (summed 12-point: all no/yes). Descriptive statistics and intraclass correlation coefficients (ICC) examined the prevalence and day-to-day variability of each outcome; random intercept mixed effects binary or ordinal regression assessed the impact of physical and emotional predictors on each outcome (Stata v. 18). Results: Participants contributed 81.2% (147/180) of expected EMAs, one-third of which were associated with an urge to use drugs. 6% of urge days also involved a report of drug-use (4/48; ns sample size for additional-analysis). Median within-day urge frequency was 3-5x/day (35.3% of all urge events). We observed significant day-to-day variability in reports of drug urges and the intensity of urges (ICC: 0.209-0.601), but not in temporality and duration of urges. Greater daily emotional pain nearly quadrupled the odds of reporting having drug urges (OR=3.75) and was associated with three-fold higher within-day urge frequency (OR=2.42) and urge intensity (OR=2.92). Higher positive mood was positively associated with urge to use (OR=1.36), urge frequency (OR=1.17) and urge intensity (OR=1.18). More somatic symptoms were associated with greater odds of having drug urges (OR=1.26) and urge frequency during the day (OR=1.10). Conclusions: Our research demonstrates that daily emotional valence and greater somatic symptoms are associated with daily drug urge occurrence, daily urge frequency and daily drug urge intensity among AIR. These EMA data have important clinical implications for “just in time” mental and behavioral health interventions that could focus on mood stability and physical wellness as scaffolds in adolescent recovery management.
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    Index60 Identifies Individuals at Appreciable Risk for Stage 3 Among an Autoantibody-Positive Population With Normal 2-Hour Glucose Levels: Implications for Current Staging Criteria of Type 1 Diabetes
    (American Diabetes Association, 2022) Nathan, Brandon M.; Redondo, Maria J.; Ismail, Heba; Jacobsen, Laura; Sims, Emily K.; Palmer, Jerry; Skyler, Jay; Bocchino, Laura; Geyer, Susan; Sosenko, Jay M.; Pediatrics, School of Medicine
    Objective: We assessed whether Index60, a composite measure of fasting C-peptide, 60-min C-peptide, and 60-min glucose, could improve the metabolic staging of type 1 diabetes for progression to clinical disease (stage 3) among autoantibody-positive (Ab+) individuals with normal 2-h glucose values (<140 mg/dL). Research design and methods: We analyzed 3,058 Type 1 Diabetes TrialNet Pathway to Prevention participants with 2-h glucose <140 mg/dL and Index60 <1.00 values from baseline oral glucose tolerance tests. Characteristics associated with type 1 diabetes (younger age, greater Ab+, higher HLA DR3-DQ2/DR4-DQ8 prevalence, and lower C-peptide) were compared among four mutually exclusive groups: top 2-h glucose quartile only (HI-2HGLU), top Index60 quartile only (HI-IND60), both top quartiles (HI-BOTH), and neither top quartile (LO-BOTH). Additionally, within the 2-h glucose distribution of <140 mg/dL and separately within the Index60 <1.00 distribution, comparisons were made between those above or below the medians. Results: HI-IND60 and HI-BOTH were younger, with greater frequency of more than two Ab+, and lower C-peptide levels, than either HI-2HGLU or LO-BOTH (all P < 0.001). The cumulative incidence for stage 3 was greater for HI-IND60 and HI-BOTH than for either HI-2HGLU or LO-BOTH (all P < 0.001). Those with Index60 values above the median were younger and had higher frequency of two or more Ab+ (P < 0.001) and DR3-DQ2/DR4-DQ8 prevalence (P < 0.001) and lower area under the curve (AUC) C-peptide levels (P < 0.001) than those below. Those above the 2-h glucose median had higher AUC C-peptide levels (P < 0.001), but otherwise did not differ from those below. Conclusions: Index60 identifies individuals with characteristics of type 1 diabetes at appreciable risk for progression who would otherwise be missed by 2-h glucose staging criteria.
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    Gene editing reverses arrhythmia susceptibility in humanized PLN-R14del mice: modelling a European cardiomyopathy with global impact
    (Oxford University Press, 2022) Dave, Jaydev; Raad, Nour; Mittal, Nishka; Zhang, Lu; Fargnoli, Anthony; Oh, Jae Gyun; Savoia, Maria Elisabetta; Hansen, Jens; Fava, Marika; Yin, Xiaoke; Theofilatos, Konstantinos; Ceholski, Delaine; Kohlbrenner, Erik; Jeong, Dongtak; Wills, Lauren; Nonnenmacher, Mathieu; Haghighi, Kobra; Costa, Kevin D.; Turnbull, Irene C.; Mayr, Manuel; Cai, Chen-Leng; Kranias, Evangelia G.; Akar, Fadi G.; Hajjar, Roger J.; Stillitano, Francesca; Pediatrics, School of Medicine
    Aims: A mutation in the phospholamban (PLN) gene, leading to deletion of Arg14 (R14del), has been associated with malignant arrhythmias and ventricular dilation. Identifying pre-symptomatic carriers with vulnerable myocardium is crucial because arrhythmia can result in sudden cardiac death, especially in young adults with PLN-R14del mutation. This study aimed at assessing the efficiency and efficacy of in vivo genome editing, using CRISPR/Cas9 and a cardiotropic adeno-associated virus-9 (AAV9), in improving cardiac function in young adult mice expressing the human PLN-R14del. Methods and results: Humanized mice were generated expressing human wild-type (hPLN-WT) or mutant (hPLN-R14del) PLN in the heterozygous state, mimicking human carriers. Cardiac magnetic resonance imaging at 12 weeks of age showed bi-ventricular dilation and increased stroke volume in mutant vs. WT mice, with no deficit in ejection fraction or cardiac output. Challenge of ex vivo hearts with isoproterenol and rapid pacing unmasked higher propensity for sustained ventricular tachycardia (VT) in hPLN-R14del relative to hPLN-WT. Specifically, the VT threshold was significantly reduced (20.3 ± 1.2 Hz in hPLN-R14del vs. 25.7 ± 1.3 Hz in WT, P < 0.01) reflecting higher arrhythmia burden. To inactivate the R14del allele, mice were tail-vein-injected with AAV9.CRISPR/Cas9/gRNA or AAV9 empty capsid (controls). CRISPR-Cas9 efficiency was evaluated by droplet digital polymerase chain reaction and NGS-based amplicon sequencing. In vivo gene editing significantly reduced end-diastolic and stroke volumes in hPLN-R14del CRISPR-treated mice compared to controls. Susceptibility to VT was also reduced, as the VT threshold was significantly increased relative to controls (30.9 ± 2.3 Hz vs. 21.3 ± 1.5 Hz; P < 0.01). Conclusions: This study is the first to show that disruption of hPLN-R14del allele by AAV9-CRISPR/Cas9 improves cardiac function and reduces VT susceptibility in humanized PLN-R14del mice, offering preclinical evidence for translatable approaches to therapeutically suppress the arrhythmogenic phenotype in human patients with PLN-R14del disease.
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    Breast Cancer Screening, Diagnosis, and Surgery during the Pre- and Peri-pandemic: Experience of Patients in a Statewide Health Information Exchange
    (Springer Nature, 2023) Milgrom, Zheng Z.; Milgrom, Daniel P.; Han, Yan; Hui, Siu L.; Haggstrom, David A.; Fisher, Carla S.; Mendonca, Eneida A.; Pediatrics, School of Medicine
    Background: Measures taken to address the COVID-19 pandemic interrupted routine diagnosis and care for breast cancer. The aim of this study was to characterize the effects of the pandemic on breast cancer care in a statewide cohort. Patients and methods: Using data from a large health information exchange, we retrospectively analyzed the timing of breast cancer screening, and identified a cohort of newly diagnosed patients with any stage of breast cancer to further access the information available about their surgical treatments. We compared data for four subgroups: pre-lockdown (preLD) 25 March to 16 June 2019; lockdown (LD) 23 March to 3 May 2020; reopening (RO) 4 May to 14 June 2020; and post-lockdown (postLD) 22 March to 13 June 2021. Results: During LD and RO, screening mammograms in the cohort decreased by 96.3% and 36.2%, respectively. The overall breast cancer diagnosis and surgery volumes decreased up to 38.7%, and the median time to surgery was prolonged from 1.5 months to 2.4 for LD and 1.8 months for RO. Interestingly, higher mean DCIS diagnosis (5.0 per week vs. 3.1 per week, p < 0.05) and surgery volume (14.8 vs. 10.5, p < 0.05) were found for postLD compared with preLD, while median time to surgery was shorter (1.2 months vs. 1.5 months, p < 0.0001). However, the postLD average weekly screening and diagnostic mammogram did not fully recover to preLD levels (2055.3 vs. 2326.2, p < 0.05; 574.2 vs. 624.1, p < 0.05). Conclusions: Breast cancer diagnosis and treatment patterns were interrupted during the lockdown and still altered 1 year after. Screening in primary care should be expanded to mitigate possible longer-term effects of these interruptions.
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    Examination of Adverse Reactions After COVID-19 Vaccination Among Patients With a History of Multisystem Inflammatory Syndrome in Children
    (American Medical Association, 2023-01-03) Elias, Matthew D.; Truong, Dongngan T.; Oster, Matthew E.; Trachtenberg, Felicia L.; Mu, Xiangyu; Jone, Pei-Ni; Mitchell, Elizabeth C.; Dummer, Kirsten B.; Sexson Tejtel, S. Kristen; Osakwe, Onyekachukwu; Thacker, Deepika; Su, Jennifer A.; Bradford, Tamara T.; Burns, Kristin M.; Campbell, M. Jay; Connors, Thomas J.; D'Addese, Laura; Forsha, Daniel; Frosch, Olivia H.; Giglia, Therese M.; Goodell, Lauren R.; Handler, Stephanie S.; Hasbani, Keren; Hebson, Camden; Krishnan, Anita; Lang, Sean M.; McCrindle, Brian W.; McHugh, Kimberly E.; Morgan, Lerraughn M.; Payne, R. Mark; Sabati, Arash; Sagiv, Eyal; Sanil, Yamuna; Serrano, Faridis; Newburger, Jane W.; Dionne, Audrey; Pediatric Heart Network MUSIC Study Investigators; Pediatrics, School of Medicine
    Importance: Data are limited regarding adverse reactions after COVID-19 vaccination in patients with a history of multisystem inflammatory syndrome in children (MIS-C). The lack of vaccine safety data in this unique population may cause hesitancy and concern for many families and health care professionals. Objective: To describe adverse reactions following COVID-19 vaccination in patients with a history of MIS-C. Design, setting, and participants: In this multicenter cross-sectional study including 22 North American centers participating in a National Heart, Lung, and Blood Institute, National Institutes of Health-sponsored study, Long-Term Outcomes After the Multisystem Inflammatory Syndrome in Children (MUSIC), patients with a prior diagnosis of MIS-C who were eligible for COVID-19 vaccination (age ≥5 years; ≥90 days after MIS-C diagnosis) were surveyed between December 13, 2021, and February 18, 2022, regarding COVID-19 vaccination status and adverse reactions. Exposures: COVID-19 vaccination after MIS-C diagnosis. Main outcomes and measures: The main outcome was adverse reactions following COVID-19 vaccination. Comparisons were made using the Wilcoxon rank sum test for continuous variables and the χ2 or Fisher exact test for categorical variables. Results: Of 385 vaccine-eligible patients who were surveyed, 185 (48.1%) received at least 1 vaccine dose; 136 of the vaccinated patients (73.5%) were male, and the median age was 12.2 years (IQR, 9.5-14.7 years). Among vaccinated patients, 1 (0.5%) identified as American Indian/Alaska Native, non-Hispanic; 9 (4.9%) as Asian, non-Hispanic; 45 (24.3%) as Black, non-Hispanic; 59 (31.9%) as Hispanic or Latino; 53 (28.6%) as White, non-Hispanic; 2 (1.1%) as multiracial, non-Hispanic; and 2 (1.1%) as other, non-Hispanic; 14 (7.6%) had unknown or undeclared race and ethnicity. The median time from MIS-C diagnosis to first vaccine dose was 9.0 months (IQR, 5.1-11.9 months); 31 patients (16.8%) received 1 dose, 142 (76.8%) received 2 doses, and 12 (6.5%) received 3 doses. Almost all patients received the BNT162b2 vaccine (347 of 351 vaccine doses [98.9%]). Minor adverse reactions were observed in 90 patients (48.6%) and were most often arm soreness (62 patients [33.5%]) and/or fatigue (32 [17.3%]). In 32 patients (17.3%), adverse reactions were treated with medications, most commonly acetaminophen (21 patients [11.4%]) or ibuprofen (11 [5.9%]). Four patients (2.2%) sought medical evaluation, but none required testing or hospitalization. There were no patients with any serious adverse events, including myocarditis or recurrence of MIS-C. Conclusions and relevance: In this cross-sectional study of patients with a history of MIS-C, no serious adverse events were reported after COVID-19 vaccination. These findings suggest that the safety profile of COVID-19 vaccination administered at least 90 days following MIS-C diagnosis appears to be similar to that in the general population.
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    Mineral bone disorders and kidney disease in hospitalized children with sickle cell anemia
    (Frontiers Media, 2023-02-02) Batte, Anthony; Kasirye, Philip; Baluku, Reagan; Kiguli, Sarah; Kalyesubula, Robert; John, Chandy C.; Schwaderer, Andrew L.; Imel, Erik A.; Conroy, Andrea L.; Pediatrics, School of Medicine
    Background: Mineral bone disorders (MBD) are common in sickle cell anemia (SCA). Frequent vaso-occlusive crises (VOC) further impact MBD in children with SCA. We evaluated the prevalence of markers of SCA-related MBD (sMBD) in hospitalized children and assessed the relationship between sMBD and individual mineral abnormalities with kidney disease. Methods: We prospectively recruited 185 children with SCA hospitalized with a VOC. Serum measures of mineral bone metabolism (calcium, phosphate, parathyroid hormone, 25-hydroxy vitamin D, FGF23, osteopontin) were measured at enrollment. The primary outcome was markers of sMBD defined as a composite of hypocalcemia, hyperphosphatemia, hyperparathyroidism, or deficiency in 25-OH vitamin D. Secondary outcomes included individual abnormalities in mineral metabolism. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines were used to define SCA-associated acute kidney injury (AKI). AKI was further assessed using urine NGAL as a marker of tubular injury. Acute kidney disease (AKD) was defined as a composite of AKI, an eGFR < 90 ml/min per 1.73 m2 using the Cystatin C GFR equation, or evidence of structural injury (positive biomarker test or albuminuria). Results: The mean age of children was 8.9 years and 41.6% were female. The prevalence of sMBD was 47.6%, with hypocalcemia the most frequent abnormality (29.9%, 55/184) followed by hyperphosphatemia (20.7%, 38/184), hyperparathyroidism (8.7%, 16/185), and vitamin D deficiency (5.4%, 10/185). There was no association between sMBD and sKDIGO-defined AKI using serial changes in creatinine or when incorporating biomarkers to define AKI. However, the presence of AKD was associated with a 2.01-fold increased odds of sMBD (95% CI 1.05 to 3.83) and was driven by a decrease in eGFR (OR, 2.90 95% CI: 1.59 to 5.29). When evaluating individual mineral abnormalities, hypocalcemia was associated with AKD and low eGFR while hyperparathyroidism was associated with low eGFR, AKI and structural injury. Vitamin D deficiency was associated with structural kidney injury. Vitamin D deficiency, hyperparathryoidism, and increases in FGF23 and osteopontin predicted mortality (p < 0.05 for all). Conclusion: MBD is common among children with SCA hospitalized with VOC. Biomarkers of kidney injury and bone health may help risk stratify children at risk of sMBD. Routine evaluation of sMBD in children with SCA may improve long-term bone health.
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    Serum bile acids as a prognostic biomarker in biliary atresia following Kasai portoenterostomy
    (Wolters Kluwer, 2023) Harpavat, Sanjiv; Hawthorne, Kieran; Setchell, Kenneth D. R.; Narvaez Rivas, Monica; Henn, Lisa; Beil, Charlotte A.; Karpen, Saul J.; Ng, Vicky L.; Alonso, Estella M.; Bezerra, Jorge A.; Guthery, Stephen L.; Horslen, Simon; Loomes, Kathy M.; McKiernan, Patrick; Magee, John C.; Merion, Robert M.; Molleston, Jean P.; Rosenthal, Philip; Thompson, Richard J.; Wang, Kasper S.; Sokol, Ronald J.; Shneider, Benjamin L.; Childhood Liver Disease Research Network (ChiLDReN); Pediatrics, School of Medicine
    Background and aims: In biliary atresia, serum bilirubin is commonly used to predict outcomes after Kasai portoenterostomy (KP). Infants with persistently high levels invariably need liver transplant, but those achieving normalized levels have a less certain disease course. We hypothesized that serum bile acid levels could help predict outcomes in the latter group. Approach and results: Participants with biliary atresia from the Childhood Liver Disease Research Network were included if they had normalized bilirubin levels 6 months after KP and stored serum samples from the 6-month post-KP clinic visit ( n = 137). Bile acids were measured from the stored serum samples and used to divide participants into ≤40 μmol/L ( n = 43) or >40 μmol/L ( n = 94) groups. At 2 years of age, the ≤40 μmol/L compared with >40 μmol/L group had significantly lower total bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, bile acids, and spleen size, as well as significantly higher albumin and platelet counts. Furthermore, during 734 person-years of follow-up, those in the ≤40 μmol/L group were significantly less likely to develop splenomegaly, ascites, gastrointestinal bleeding, or clinically evident portal hypertension. The ≤40 μmol/L group had a 10-year cumulative incidence of liver transplant/death of 8.5% (95% CI: 1.1%-26.1%), compared with 42.9% (95% CI: 28.6%-56.4%) for the >40 μmol/L group ( p = 0.001). Conclusions: Serum bile acid levels may be a useful prognostic biomarker for infants achieving normalized bilirubin levels after KP.
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    Innovative Designs and Logistical Considerations for Expedited Clinical Development of Combination Disease-Modifying Treatments for Type 1 Diabetes
    (American Diabetes Association, 2022) Anderson, Randy L.; DiMeglio, Linda A.; Mander, Adrian P.; Dayan, Colin M.; Linsley, Peter S.; Herold, Kevan C.; Marinac, Marjana; Ahmed, Simi T.; Pediatrics, School of Medicine
    It has been 100 years since the life-saving discovery of insulin, yet daily management of type 1 diabetes (T1D) remains challenging. Even with closed-loop systems, the prevailing need for persons with T1D to attempt to match the kinetics of insulin activity with the kinetics of carbohydrate metabolism, alongside dynamic life factors affecting insulin requirements, results in the need for frequent interventions to adjust insulin dosages or consume carbohydrates to correct mismatches. Moreover, peripheral insulin dosing leaves the liver underinsulinized and hyperglucagonemic and peripheral tissues overinsulinized relative to their normal physiologic roles in glucose homeostasis. Disease-modifying therapies (DMT) to preserve and/or restore functional β-cell mass with controlled or corrected autoimmunity would simplify exogenous insulin need, thereby reducing disease mortality, morbidity, and management burdens. However, identifying effective DMTs for T1D has proven complex. There is some consensus that combination DMTs are needed for more meaningful clinical benefit. Other complexities are addressable with more innovative trial designs and logistics. While no DMT has yet been approved for marketing, existing regulatory guidance provides opportunities to further "de-risk" development. The T1D development ecosystem can accelerate progress by using more innovative ways for testing DMTs for T1D. This perspective outlines suggestions for accelerating evaluation of candidate T1D DMTs, including combination therapies, by use of innovative trial designs, enhanced logistical coordination of efforts, and regulatory guidance for expedited development, combination therapies, and adaptive designs.