Publications by authors named "Sarah Taylor"

338 Publications

Transcriptional Analysis of Liver Tissue Identifies Distinct Phenotypes of Indeterminate Pediatric Acute Liver Failure.

Hepatol Commun 2021 Aug 6;5(8):1373-1384. Epub 2021 May 6.

Department of Pediatrics Northwestern University Feinberg School of Medicine Ann & Robert H. Lurie Children's Hospital of Chicago Chicago IL USA.

Many patients with indeterminate pediatric acute liver failure (PALF) have evidence of T-cell driven immune injury; however, the precise inflammatory pathways are not well defined. We have characterized the hepatic cytokine and transcriptional signatures of patients with PALF. A retrospective review was performed on 22 children presenting with indeterminate (IND-PALF; n = 17) or other known diagnoses (DX-PALF; n = 6) with available archived liver tissue. Specimens were stained for clusters of differentiation 8 (CD8) T cells and scored as dense, moderate, or minimal. Measurement of immune analytes and RNA sequencing (RNA-seq) was performed on whole-liver tissue. Immune analyte data were analyzed by principal component analysis, and RNA-seq was analyzed by unsupervised hierarchical clustering, differential gene expression, and gene-set enrichment analysis. Most patients with IND-PALF (94%) had dense/moderate CD8 staining and were characterized by Th1 immune analytes including tumor necrosis factor α, interferon γ (IFN-γ), interleukin (IL) 1β, IL-12, C-X-C motif chemokine ligand (CXCL) 9, and CXCL12. Transcriptional analyses identified two transcriptional PALF phenotypes. Most patients in group 1 (91%) had IND-PALF and dense/moderate CD8 staining. This group was characterized by increased expression of genes and cell subset-specific signatures related to innate inflammation, T-cell activation, and antigen stimulation. Group 1 expressed significantly higher levels of gene signatures for regulatory T cells, macrophages, Th1 cells, T effector memory cells, cytotoxic T cells, and activated dendritic cells (adjusted  < 0.05). In contrast, patients in group 2 exhibited increased expression for genes involved in metabolic processes. Patients with IND-PALF have evidence of a Th1-mediated inflammatory response driven by IFN-γ. Transcriptional analyses suggest that a complex immune network may regulate an immune-driven PALF phenotype with less evidence of metabolic processes. These findings provide insight into mechanisms of hepatic injury in PALF, areas for future research, and potential therapeutic targets.
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http://dx.doi.org/10.1002/hep4.1726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369940PMC
August 2021

Habitat patches providing south-north connectivity are under-protected in a fragmented landscape.

Proc Biol Sci 2021 Aug 25;288(1957):20211010. Epub 2021 Aug 25.

Department of Evolution, Ecology, and Behaviour, University of Liverpool, Crown Street, Liverpool, Merseyside L69 7ZB, UK.

As species' ranges shift to track climate change, conservationists increasingly recognize the need to consider connectivity when designating protected areas (PAs). In fragmented landscapes, some habitat patches are more important than others in maintaining connectivity, and methods are needed for their identification. Here, using the Condatis methodology, we model range expansion through an adaptation of circuit theory. Specifically, we map 'flow' through 16 conservation priority habitat networks in England, quantifying how patches contribute to functional South-North connectivity. We also explore how much additional connectivity could be protected via a connectivity-led protection procedure. We find high-flow patches are often left out of existing PAs; across 12 of 16 habitat networks, connectivity protection falls short of area protection by 13.6% on average. We conclude that the legacy of past protection decisions has left habitat-specialist species vulnerable to climate change. This situation may be mirrored in many countries which have similar habitat protection principles. Addressing this requires specific planning tools that can account for the directions species may shift. Our connectivity-led reserve selection procedure efficiently identifies additional PAs that prioritize connectivity, protecting a median of 40.9% more connectivity in these landscapes with just a 10% increase in area.
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http://dx.doi.org/10.1098/rspb.2021.1010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385378PMC
August 2021

Design, structure-activity relationship study and biological evaluation of the thieno[3,2-c]isoquinoline scaffold as a potential anti-cancer agent.

Bioorg Med Chem Lett 2021 Aug 17:128327. Epub 2021 Aug 17.

Department of Chemistry & Biochemistry, Concordia University, 7141 rue Sherbrooke O., Montréal, QC H4B 1R6, Canada; Department of Biology, Concordia University, 7141 rue Sherbrooke O., Montréal, QC H4B 1R6, Canada.

Several derivatives of a series that share a thienoisoquinoline scaffold have demonstrated potent anti-cancer activity against cancer cell lines A549, HeLa, HCT-116 in the submicromolar concentration range. Structure-activity relationship (SAR) studies on a range of derivatives aided in identifying key pharmacophores in the lead compound. A series of compounds have been identified as the most promising with submicromolar IC values against a lung cancer cell line (A549). Microscopy studies of cancer cells treated with the lead compound revealed that it causes mitotic arrest and disrupts microtubules. Further evaluation via an in vitro microtubule polymerization assay and competition studies indicate that the lead compound binds to tubulin via the colchicine site.
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http://dx.doi.org/10.1016/j.bmcl.2021.128327DOI Listing
August 2021

Immunohistochemical analysis of glassy cell carcinoma of the cervix reveals robust lymphocyte infiltrate and the expression of targetable inhibitory immune checkpoints.

Arch Gynecol Obstet 2021 Aug 15. Epub 2021 Aug 15.

Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Objective: To validate our previous findings of high-level EGFR expression in GCCC using an expanded cohort of specimens and to further examine the molecular and cellular features of this aggressive malignancy to identify potentially actionable therapeutic targets.

Methods: The SEER database was queried to obtain the epidemiological data regarding the current national survival trends for GCCC. Immunohistochemistry (IHC) was used to examine the expression of EGFR, PD-1, and PD-L1. CiberSort analysis was used to analyze a previously published RNA-sequencing dataset obtained from a single patient diagnosed with GCCC.

Results: In comparison to squamous cell carcinomas and adenocarcinoma/adenosquamous carcinomas, GCCC was observed in younger patients (p < 0.001) and demonstrated inferior survival (p < 0.001). All (100%) of the specimens (8/8) exhibited immunoreactivity when stained for CD3ε (T-cell marker), EGFR, PD-1, and PD-L1 whereas CTLA4 expression was not detected. Analysis of RNA-sequencing data revealed that cetuximab and erlotinib altered the chemokine profile, lymphocyte abundance, and expression of inhibitory immune checkpoints in a single patient when combined with cytotoxic chemotherapy in a single patient.

Conclusions: The data from this descriptive study suggests that immune checkpoint blockade, whether single agent or in combination, may be a suitable therapeutic option for a disease for which targeted approaches do not currently exist.
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http://dx.doi.org/10.1007/s00404-021-06164-xDOI Listing
August 2021

Using error-estimation to probe the psychological processes underlying contextual interference effects.

Hum Mov Sci 2021 Oct 7;79:102854. Epub 2021 Aug 7.

Program in Physical Therapy, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA. Electronic address:

Although the learning benefits of interleaved practice schedules relative to blocked schedules are well-reported, the mechanisms underlying these effects are not fully understood. Researchers have generally suggested that random schedules of practice increase task-related information processing which arises due to switching between variations of the same task (or switching between different tasks). Thus, one potentially useful way to both probe and manipulate contextual interference is to pair it with error estimation during practice. Forced error estimation increases task-related information processing and recording these estimates provides insight into learners' self-awareness of their errors. In the present study, 84 participants were randomly allocated to four groups. Participants practiced a timing task under blocked or random schedules, with and without error estimations prior to feedback. During the acquisition phase, three target times were trained (1500, 1700, 1900 ms), with feedback delivered after every trial. We used delayed post-tests (24 hrs later) to evaluate the retention of these target times and their transfer to two new target times (1600, 1800 ms). Participants who practiced with a random schedule performed worse (i.e., greater absolute error) than those with a blocked schedule during acquisition (p = .006); however, randomly scheduled participants also showed reduced error (p = .004) on the retention and transfer tests. Although prompting error estimations led to greater self-reported mental effort being invested on the task (p = .001), error estimation was not reliably associated with superior learning (p = .133). The accuracy of error estimations did not differ as a function of practice structure (p = .070), although the accuracy of error estimations improved during acquisition (p = .006). Findings highlight the robustness of the contextual interference effect, but we did not find evidence that error estimations moderated the effect on this task. It is in some ways surprising that we found an effect of contextual interference, as past-work suggests that interference effects are attenuated (or eliminated) when participants switch between different parameters of the same task. We speculate that this might be due to the difficulty of the task; even though participants switched between parametric variations of the same task, the distinction between parameters was subtle (i.e., tenths of a second).
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http://dx.doi.org/10.1016/j.humov.2021.102854DOI Listing
October 2021

Calcium, Magnesium, Phosphorus, and Vitamin D.

Authors:
Sarah N Taylor

World Rev Nutr Diet 2021 5;122:122-139. Epub 2021 Aug 5.

Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA.

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http://dx.doi.org/10.1159/000514742DOI Listing
August 2021

Monitoring of Growth and Body Composition: New Methodologies.

World Rev Nutr Diet 2021 5;122:32-45. Epub 2021 Aug 5.

Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.

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http://dx.doi.org/10.1159/000514741DOI Listing
August 2021

Presentation and Outcomes of Infants With Idiopathic Cholestasis: A Multicenter Prospective Study.

J Pediatr Gastroenterol Nutr 2021 Oct;73(4):478-484

University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, CO.

Objectives: 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.
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http://dx.doi.org/10.1097/MPG.0000000000003248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448404PMC
October 2021

Compatibility of Estradiol, Estriol, Estrone, Progesterone, and Testosterone Single Formulation in Fitalite, Versatile, or HRT Supreme Cream Base.

Int J Pharm Compd 2021 Jul-Aug;25(4):336-343

Fagron US, St. Paul, Minnesota.

In this work, we focus on three ready-to-use vehicles: Fitalite, Versatile, and HRT Supreme Cream Base. Fitalite is a natural, light, hydrophilic gel-cream that contains vitamin E and oil bodies from plant sources (phytosomes), providing antioxidant and skinmoisturizing properties. Versatile is a vanishing oil-inwater cream base which retains its consistency with a broad range and high concentrations of active pharmaceutical ingredients, dermaceutical ingredients, and solvents. Finally, HRT Supreme Cream Base is a paraben-free, dye-free, fragrance-free O/W emulsion base, formulated with a complex of botanical oils to soothe and provide moisture to dry and sensitive skin. In the current study, we evaluated the beyond-use date of formulations containing estradiol, estriol, estrone, progesterone, and testosterone in combination, compounded with these three vehicles. Validated, stability-indicating high-performance liquid chromatography methods were used throughout a 180-day period. A beyond-use date of 180 days was observed for all vehicles stored both at refrigerated and at room temperature. The combination of five ingredients represents a worst-case scenario since there are more possibilities of cross reactions. Therefore, we expect the same or greater stability as individual ingredients are removed from the tested formulation. The extended beyond-use dates provide convenience for both the compounding pharmacist and the patient.
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July 2021

Bivalirudin for the prevention of hepatic artery thrombosis in pediatric liver transplantation.

Pediatr Transplant 2021 Jul 13:e14068. Epub 2021 Jul 13.

Division of Transplant Surgery, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Background: Early hepatic artery thrombosis (HAT) after liver transplantation is a serious complication that frequently results in graft loss and the need for retransplantation. Although studies have reported on various operative and endovascular treatment approaches, pharmacologic strategies for the prevention or management of HAT are not well defined. Patients with blood clotting disorders, those with a contraindication to heparin, and those who have previously developed HAT represent unique challenges in management.

Methods: We present the case of a 9-month-old male with a hypercoagulable state who developed early HAT after two liver transplants, despite the use of postoperative therapeutic heparin infusion.

Results And Conclusion: The patient successfully underwent a third liver transplant using intraoperative and postoperative bivalirudin infusion, a direct thrombin inhibitor. Rotational thromboelastometry (ROTEM) was used to guide anticoagulation and blood product administration in the perioperative period. At 1.5 years post-transplant, the patient has good graft function with patent hepatic vasculature. This case demonstrates the innovative use of bivalirudin anticoagulant therapy and viscoelastic methodologies to improve outcomes in hypercoagulable liver transplant recipients.
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http://dx.doi.org/10.1111/petr.14068DOI Listing
July 2021

Spatial transcriptomics at subspot resolution with BayesSpace.

Nat Biotechnol 2021 Jun 3. Epub 2021 Jun 3.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Recent spatial gene expression technologies enable comprehensive measurement of transcriptomic profiles while retaining spatial context. However, existing analysis methods do not address the limited resolution of the technology or use the spatial information efficiently. Here, we introduce BayesSpace, a fully Bayesian statistical method that uses the information from spatial neighborhoods for resolution enhancement of spatial transcriptomic data and for clustering analysis. We benchmark BayesSpace against current methods for spatial and non-spatial clustering and show that it improves identification of distinct intra-tissue transcriptional profiles from samples of the brain, melanoma, invasive ductal carcinoma and ovarian adenocarcinoma. Using immunohistochemistry and an in silico dataset constructed from scRNA-seq data, we show that BayesSpace resolves tissue structure that is not detectable at the original resolution and identifies transcriptional heterogeneity inaccessible to histological analysis. Our results illustrate BayesSpace's utility in facilitating the discovery of biological insights from spatial transcriptomic datasets.
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http://dx.doi.org/10.1038/s41587-021-00935-2DOI Listing
June 2021

Relationships among hope, body satisfaction, wellness habits, and stress in nursing students.

J Prof Nurs 2021 May-Jun;37(3):640-647. Epub 2021 Feb 3.

Department of Counseling and Instructional Sciences, University Commons 3800, University of South Alabama, Mobile, AL 36688, United States of America.

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http://dx.doi.org/10.1016/j.profnurs.2021.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152788PMC
June 2021

Quality improvement engagement and competence: A comparison between frontline nurses and nurse leaders.

Nurs Outlook 2021 May 11. Epub 2021 May 11.

Sacred Heart University, Davis & Henley College of Nursing, Fairfield, CT.

Background: Nurses play a pivotal role in improving patient care. To maximize nurses' impact on quality, nurses must have quality improvement (QI) competence and engage fully in QI initiatives.

Purpose: To describe QI competence (knowledge, skills, and attitudes) among frontline nurses and leaders; and compare variations in competence among nursing roles, experience, and specialty areas.

Methods: A total of 681 nurses at one heath system fully completed the Nursing Quality Improvement Practice tool electronically.

Findings: Half of the respondents reported QI engagement (53.6%). Mean knowledge scores were 5.08 (SD 1.16, 7 items). Skill proficiency was low (M = 2.82, SD = 1.03; range 1-6) although QI attitudes were favorable (M = 3.76, SD = 0.63; range 1-5). Significant differences in skills and attitudes were identified by role. QI competence among nurses employed in various specialty areas were similar.

Discussion: Strategies for increasing QI competence and engagement of nurses must be created and deployed in order to improve quality and safety.
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http://dx.doi.org/10.1016/j.outlook.2021.02.008DOI Listing
May 2021

Use of Omics Data in Fracture Prediction; a Scoping and Systematic Review in Horses and Humans.

Animals (Basel) 2021 Mar 30;11(4). Epub 2021 Mar 30.

The Dick Vet Equine Hospital, The Roslin Institute, Easter Bush, Roslin, Midlothian EH25 9RG, UK.

Despite many recent advances in imaging and epidemiological data analysis, musculoskeletal injuries continue to be a welfare issue in racehorses. Peptide biomarker studies have failed to consistently predict bone injury. Molecular profiling studies provide an opportunity to study equine musculoskeletal disease. A systematic review of the literature was performed using preferred reporting items for systematic reviews and meta-analyses protocols (PRISMA-P) guidelines to assess the use of miRNA profiling studies in equine and human musculoskeletal injuries. Data were extracted from 40 papers between 2008 and 2020. Three miRNA studies profiling equine musculoskeletal disease were identified, none of which related to equine stress fractures. Eleven papers studied miRNA profiles in osteoporotic human patients with fractures, but differentially expressed miRNAs were not consistent between studies. MicroRNA target prediction programmes also produced conflicting results between studies. Exercise affected miRNA profiles in both horse and human studies (e.g., miR-21 was upregulated by endurance exercise and miR-125b was downregulated by exercise). MicroRNA profiling studies in horses continue to emerge, but as yet, no miRNA profile can reliably predict the occurrence of fractures. It is very important that future studies are well designed to mitigate the effects of variation in sample size, exercise and normalisation methods.
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http://dx.doi.org/10.3390/ani11040959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065418PMC
March 2021

Stability of Fagron's Phytobase Cream Compounded with Various Hormones.

Int J Pharm Compd 2021 Mar-Apr;25(2):156-162

Fagron North America, St. Paul, Minnesota, United States.

The objective of this study was to evaluate the stability of 5 common hormones used as active pharmaceutical ingredients in Fagron Phytobase cream. The active pharmaceutical ingredients were tested using a bracketed format, as well as individually, and in one combination: estrone 0.1%, estrone 1%, estradiol 0.05%, estradiol 2%, estriol 0.05%, estriol 2%, progesterone 0.1%, progesterone 20%, testosterone 0.1%, testosterone 20%; combination (estradiol 0.05%, estriol 0.05%, progesterone 0.5%), and combination (estradiol 2%, estriol 1%, progesterone 20%). All creams were stored at controlled room temperature (20ÆC to 25ÆC) in a Topi-CLICK container-closure. Stability was assessed by measuring the percent recovery at varying time points throughout a 180-day period. Active pharmaceutical ingredients' quantifications were performed by highperformance liquid chromatography via a stabilityindicating method. Antimicrobial effectiveness testing per United States Pharmacopeia Chapter <51> guidelines was carried out for each compounded formulation. Given the percent recovery of the active pharmaceutical ingredients within the cream base, the beyond-use date was determined to be 180 days in all samples except estrone, which was determined to be 150 days. This suggests that Phytobase cream is able to maintain the stability of various compounded hormones in the base over an extended time of storage.
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April 2021

'Spending all this time stressing and worrying and calculating': marginal food security and student life at a Diverse Urban University.

Public Health Nutr 2021 Jul 26;24(10):2788-2797. Epub 2021 Mar 26.

Department of Health Sciences, California State University, East Bay, 25800 Carlos Bee Blvd, Hayward, CA 94542, USA.

Objective: Food security status is a continuum ranging from high to very low food security. While marginal food security falls next to high food security on the spectrum, new quantitative research indicates marginal food security status is associated with negative health outcomes and poor academic performance among college students. Qualitative research focusing on college students experiencing marginal food security has not been conducted. The current study aims to qualitatively explore experiences of college students with marginal food security and to identify themes to better understand and provide context regarding how marginal food security impacts students.

Design: Students were recruited for semi-structured interviews with questions designed to study the challenges associated with students' food situations. All interviews were recorded and transcribed with themes identified via an inductive approach.

Setting: A large public university on the US west coast.

Participants: Thirty college students.

Results: Key themes that emerged: purchasing cheap unhealthy foods, insufficient time to prepare and eat meals on a regular basis, stress and anxiety around the inability to eat healthy food and future health issues, self-perception of health when eating poorly along with physical symptoms and low academic motivation by not fully participating in their courses due to few healthy food options or missing meals.

Conclusion: Marginal food security can potentially diminish students' health and their capacity to learn and succeed in their coursework. The results emphasise that students experiencing marginal food security should not be grouped with students experiencing high food security.
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http://dx.doi.org/10.1017/S1368980021001300DOI Listing
July 2021

The ADC API: A Web API for the Programmatic Query of the AIRR Data Commons.

Front Big Data 2020 17;3:22. Epub 2020 Jun 17.

Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, TX, United States.

The Adaptive Immune Receptor Repertoire (AIRR) Community is a research-driven group that is establishing a clear set of community-accepted data and metadata standards; standards-based reference implementation tools; and policies and practices for infrastructure to support the deposit, curation, storage, and use of high-throughput sequencing data from B-cell and T-cell receptor repertoires (AIRR-seq data). The AIRR Data Commons is a distributed system of data repositories that utilizes a common data model, a common query language, and common interoperability formats for storage, query, and downloading of AIRR-seq data. Here is described the principal technical standards for the AIRR Data Commons consisting of the AIRR Data Model for repertoires and rearrangements, the AIRR Data Commons (ADC) API for programmatic query of data repositories, a reference implementation for ADC API services, and tools for querying and validating data repositories that support the ADC API. AIRR-seq data repositories can become part of the AIRR Data Commons by implementing the data model and API. The AIRR Data Commons allows AIRR-seq data to be reused for novel analyses and empowers researchers to discover new biological insights about the adaptive immune system.
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http://dx.doi.org/10.3389/fdata.2020.00022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931935PMC
June 2020

Applying an Age-specific Definition to Better Characterize Etiologies and Outcomes in Neonatal Acute Liver Failure.

J Pediatr Gastroenterol Nutr 2021 07;73(1):80-85

Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL.

Objective: Neonatal acute liver failure (ALF) is a rare disease with high mortality for which no standard age-specific definition exists. To advance the understanding of neonatal ALF, we characterize the etiology, presenting features, treatment, and outcomes in infants within 1 month of life.

Methods: We performed a single-center 11-year retrospective chart review of neonates ≤30 days of life with ALF as defined by an INR of ≥2.0. Comparisons were made by etiology and survival with native liver (SNL). Estimated survival was performed using the Kaplan-Meier method.

Results: Forty-three patients met inclusion criteria for neonatal ALF. Etiologies included viral infection (23%), gestational alloimmune liver disease with neonatal hemochromatosis (GALD-NH) (21%), cardiac-associated ischemia (16%), other ischemia (14%), genetic etiologies (9%), Trisomy 21-associated myelodysplasia (TAM) (7%), hemophagocytic lymphohistiocytosis (HLH) (2%), and not identified (7%). Infants with viral etiologies had the highest alanine aminotransferase (ALT) at presentation (1179 IU/L, interquartile range [IQR] 683-1585 IU/L) in contrast to low levels in GALD-NH (23 IU/L, IQR 18-64 IU/L). Across all etiologies, only 33% were alive at 1 year. Overall median survival was 74 days; 17 days for viral infection and 74 days for GALD-NH. Among laboratory values at presentation, alpha-fetoprotein (AFP) was significantly higher in patients that survived with their native liver (P = 0.04).

Conclusions: Overall, outcome for neonatal ALF is poor. Although initial laboratory values can differentiate viral infection or GALD-NH, further studies are needed to identify laboratory parameters that predict SNL by etiology to ultimately improve patient outcomes.
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http://dx.doi.org/10.1097/MPG.0000000000003103DOI Listing
July 2021

Racial Disparities in Sustaining Breastfeeding in a Baby-Friendly Designated Southeastern United States Hospital: An Opportunity to Investigate Systemic Racism.

Breastfeed Med 2021 02 4;16(2):150-155. Epub 2021 Feb 4.

Yale School of Medicine Department of Pediatrics, New Haven, Connecticut, USA.

Racial disparities in breastfeeding rates persist in the United States with Black women having the lowest rates of initiation and continuation. A literature review attributes this to many factors-historical roles, cultural norms, lack of social support, and systemic racism in the health care and lactation support system. The Baby-Friendly Hospital Initiative (BFHI) is an evidence-based program to increase breastfeeding through standardized protocols, and, in a Southeastern U.S. academic center, it was associated with increased breastfeeding, but the effect on racial disparities in breastfeeding was unknown. Through an institutional Perinatal Information Systems database, breastfeeding rates were compared before and after BFHI implementation. Breastfeeding initiation, sustained breastfeeding 24-hours before discharge, and patient demographics were assessed. After BFHI implementation, mothers were overall 1.17 (95% confidence interval: 1.13-1.19) times more likely to initiate breastfeeding. For Black mothers, breastfeeding initiation increased significantly from 52% to 66%, but they were significantly less likely to sustain in-hospital breastfeeding compared to nonBlack mothers (69.4% versus 84.6%,  < 0.0001). Several demographic and medical comorbidities were significantly associated with failure to sustain breastfeeding to hospital discharge. When controlling for these factors, the racial disparity persisted. Since BFHI implementation, the racial gap in breastfeeding initiation decreased, but a significant disparity remained for sustained in-hospital breastfeeding. This study highlights the success of the BFHI program, but in the context of the current literature, also reveals the need for further work to ensure interventions are culturally competent and delivered equitably to support sustained breastfeeding for Black women.
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http://dx.doi.org/10.1089/bfm.2020.0306DOI Listing
February 2021

Secreted Phosphoprotein 24 is a Biomarker of Mineral Metabolism.

Calcif Tissue Int 2021 03 22;108(3):354-363. Epub 2021 Jan 22.

Department of Biomedical and Molecular Sciences, Queen's University, 3048C Etherington Hall, Kingston, ON, K7L 3V6, Canada.

The 24 kD form of secreted phosphoprotein (SPP-24), a cytokine-binding bone matrix protein with various truncated C-terminal products, is primarily synthesized by the liver. SPP-24 shares homology with fetuin-A, a potent vascular and soft tissue calcification inhibitor and SPP-24 is one component of calciprotein particles (CPPs), a circulating fetuin-mineral complex. The limited molecular evidence to date suggests that SPP-24 may also function as an inhibitor of bone formation and ectopic vascular calcification, potentially through bone morphogenic protein 2 (BMP-2) and Wnt-signaling mediated actions. The C-terminal products of SPP-24 bind to BMP-2 and attenuate BMP-2-induced bone formation. The aim of this study was to assess circulating SPP-24 in relation to kidney function and in concert with markers of mineral metabolism in humans. SPP-24 was measured in the serum of total of 192 subjects using ELISA-based measurements. Subjects were participants of one of two cohorts: (1) mGFR Cohort (n = 80) was participants of a study of measured GFR (mGFR) using inulin urinary clearance, recruited mostly from a chronic kidney disease clinic with low-range kidney function (eGFR 38.7 ± 25.0 mL/min/1.73 m) and (2) CaMOS Cohort (n = 112) was a subset of randomly selected, community-dwelling participants of year 10 of the Canadian Multicentre Osteoporosis Study with eGFR in the normal range of 75.0 ± 15.9 mL/min/1.73 m. In the combined cohort, the mean SPP-24 was 167.7 ± 101.1 ng/mL (range 33.4-633.6 ng/mL). The mean age was 66.5 ± 11.3, 57.1% female and mean eGFR (CKD-EPI) was 59.9 ± 27.0 mL/min/1.73 m (range 8-122 mL/min/1.73 m). There was a strong inverse correlation between SPP-24 and eGFR (R = - 0.58, p < 0.001) that remained after adjustment for age. Following adjustment for age, eGFR, and sex, SPP-24 was significantly associated with phosphate (R = - 0.199), PTH (R = 0.298), and the Wnt-signaling inhibitor Dickkopf-related protein 1 (R = - 0.156). The results of this study indicate that SPP-24 is significantly altered by kidney function and is the first human data linking levels of SPP-24 to other biomarkers involved in mineral metabolism. Whether there is a role for circulating SPP-24 in bone formation and ectopic mineralization requires further study.
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http://dx.doi.org/10.1007/s00223-020-00783-3DOI Listing
March 2021

Barriers and benefits to breastfeeding with gestational diabetes.

Semin Perinatol 2021 Mar 31;45(2):151385. Epub 2020 Dec 31.

Associate Professor, Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA. Electronic address:

Gestational diabetes mellitus (GDM) is a disease of glucose intolerance during pregnancy and is associated with infant macrosomia, infant hypoglycemia, and increased risk of type 2 diabetes development for both mother and infant. Although breastfeeding potentially mitigates metabolic sequelae for both mother and her offspring, women with GDM are more likely to introduce formula and, therefore, are less likely to exclusively breastfeed, and some studies show less initiation and shorter breastfeeding duration as well. Therefore, women with GDM and their infants warrant investigation of methods by which to increase breastfeeding exclusivity and duration. Exploration of the barriers to breastfeeding for women with GDM demonstrate not only biologic complications such as maternal obesity, increased prevalence of cesarean section, and infant hypoglycemia, but also maternal report of less provider support of breastfeeding and reduced breastfeeding self-efficacy. Consequently, interventions designed to optimize breastfeeding outcomes in this high-risk population should not only focus on the biology but also on provider behavior and maternal social factors.
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http://dx.doi.org/10.1016/j.semperi.2020.151385DOI Listing
March 2021

Aberrant Induction of a Mesenchymal/Stem Cell Program Engages Senescence in Normal Mammary Epithelial Cells.

Mol Cancer Res 2021 04 22;19(4):651-666. Epub 2020 Dec 22.

Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Although frequently associated with tumor progression, inflammatory cytokines initially restrain transformation by inducing senescence, a key tumor-suppressive barrier. Here, we demonstrate that the inflammatory cytokine, oncostatin M, activates a mesenchymal/stem cell (SC) program that engages cytokine-induced senescence (CIS) in normal human epithelial cells. CIS is driven by Snail induction and requires cooperation between STAT3 and the TGFβ effector, SMAD3. Importantly, as cells escape CIS, they retain the mesenchymal/SC program and are thereby bestowed with a set of cancer SC (CSC) traits. Of therapeutic importance, cells that escape CIS can be induced back into senescence by CDK4/6 inhibition, confirming that the mechanisms allowing cells to escape senescence are targetable and reversible. Moreover, by combining CDK4/6 inhibition with a senolytic therapy, mesenchymal/CSCs can be efficiently killed. Our studies provide insight into how the CIS barriers that prevent tumorigenesis can be exploited as potential therapies for highly aggressive cancers. IMPLICATIONS: These studies reveal how a normal cell's arduous escape from senescence can bestow aggressive features early in the transformation process, and how this persistent mesenchymal/SC program can create a novel potential targetability following tumor development.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-1181DOI Listing
April 2021

School-based interventions modestly increase physical activity and cardiorespiratory fitness but are least effective for youth who need them most: an individual participant pooled analysis of 20 controlled trials.

Br J Sports Med 2021 Jan 13. Epub 2021 Jan 13.

Department of Sport Science, Nottingham Trent University, Nottingham, Nottinghamshire, UK.

Objectives: To determine if subpopulations of students benefit equally from school-based physical activity interventions in terms of cardiorespiratory fitness and physical activity. To examine if physical activity intensity mediates improvements in cardiorespiratory fitness.

Design: Pooled analysis of individual participant data from controlled trials that assessed the impact of school-based physical activity interventions on cardiorespiratory fitness and device-measured physical activity.

Participants: Data for 6621 children and adolescents aged 4-18 years from 20 trials were included.

Main Outcome Measures: Peak oxygen consumption (VO mL/kg/min) and minutes of moderate and vigorous physical activity.

Results: Interventions modestly improved students' cardiorespiratory fitness by 0.47 mL/kg/min (95% CI 0.33 to 0.61), but the effects were not distributed equally across subpopulations. Girls and older students benefited less than boys and younger students, respectively. Students with lower levels of initial fitness, and those with higher levels of baseline physical activity benefitted more than those who were initially fitter and less active, respectively. Interventions had a modest positive effect on physical activity with approximately one additional minute per day of both moderate and vigorous physical activity. Changes in vigorous, but not moderate intensity, physical activity explained a small amount (~5%) of the intervention effect on cardiorespiratory fitness.

Conclusions: Future interventions should include targeted strategies to address the needs of girls and older students. Interventions may also be improved by promoting more vigorous intensity physical activity. Interventions could mitigate declining youth cardiorespiratory fitness, increase physical activity and promote cardiovascular health if they can be delivered equitably and their effects sustained at the population level.
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http://dx.doi.org/10.1136/bjsports-2020-102740DOI Listing
January 2021

The Impact of 2 Weight-Based Standard Parenteral Nutrition Formulations Compared With One Standard Formulation on the Incidence of Hyperglycemia and Hypernatremia in Low Birth-Weight Preterm Infants.

Adv Neonatal Care 2021 06;21(3):E65-E72

Department of Clinical Pharmacy and Outcome Sciences, College of Pharmacy (Dr Garner), and Department of Pharmacy Services (Dr Cox), Medical University of South Carolina, Charleston; Department of Pharmacy, Hospital of the University of Pennsylvania, Philadelphia (Dr Safirstein); Children's National Health System, Washington, District of Columbia (Dr Groat); Department of Clinical Nutrition, St Christopher's Hospital for Children, Philadelphia, Pennsylvania (Ms Breznak); and Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut (Dr Taylor).

Background: Standardized parenteral nutrition (PN) formulations are used in at-risk neonates to provide nutrition immediately following birth. However, evidence for the optimal formulation(s) to maximize growth while reducing the risks of glucose and electrolyte abnormalities is limited.

Purpose: The purpose of this study was to compare the rates of hypernatremia and hyperglycemia with 2 weight-based standardized PN formulations versus one standard PN in low birth-weight preterm neonates.

Methods: This was a single-center observational study of infants less than 1800 g birth weight and less than 37 weeks' gestation who received standardized PN in the first 48 hours of life. Patients in the weight-based PN group were compared with a historical group of patients receiving single standard PN. Rates of hypernatremia and hyperglycemia were compared by χ2 analysis.

Results: There was a nonsignificant (P = .147) reduction in hypernatremia in the weight-based PN group (9 of 87; 10.3%) compared with the single PN group (16 of 89; 18.0%). However, hyperglycemia was significantly more frequent in the weight-based group than in the single PN group (24.1% vs 12.4%, P = .035).

Implications For Practice: The 2 weight-based PN standardized formulations studied did not significantly decrease the incidence of hypernatremia or hyperglycemia.

Implications For Research: Future studies to determine optimal standardized PN to provide early nutrition in high-risk neonates are warranted.
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http://dx.doi.org/10.1097/ANC.0000000000000806DOI Listing
June 2021

Empowering mothers to realize their choice for infant feeding.

Authors:
Sarah N Taylor

Semin Perinatol 2021 Mar 2;45(2):151379. Epub 2021 Jan 2.

Yale School of Medicine, United States. Electronic address:

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http://dx.doi.org/10.1016/j.semperi.2020.151379DOI Listing
March 2021

Transcriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations.

PLoS One 2021 7;16(1):e0244743. Epub 2021 Jan 7.

Division of Rheumatology, Department of Medicine, Northwestern University, Chicago, Illinois, United States of America.

Background & Aims: Limited understanding of the role for specific macrophage subsets in the pathogenesis of cholestatic liver injury is a barrier to advancing medical therapy. Macrophages have previously been implicated in both the mal-adaptive and protective responses in obstructive cholestasis. Recently two macrophage subsets were identified in non-diseased human liver; however, no studies to date fully define the heterogeneous macrophage subsets during the pathogenesis of cholestasis. Here, we aim to further characterize the transcriptional profile of macrophages in pediatric cholestatic liver disease.

Methods: We isolated live hepatic immune cells from patients with biliary atresia (BA), Alagille syndrome (ALGS), and non-cholestatic pediatric liver by fluorescence activated cell sorting. Through single-cell RNA sequencing analysis and immunofluorescence, we characterized cholestatic macrophages. We next compared the transcriptional profile of pediatric cholestatic and non-cholestatic macrophage populations to previously published data on normal adult hepatic macrophages.

Results: We identified 3 distinct macrophage populations across cholestatic liver samples and annotated them as lipid-associated macrophages, monocyte-like macrophages, and adaptive macrophages based on their transcriptional profile. Immunofluorescence of liver tissue using markers for each subset confirmed their presence across BA (n = 6) and ALGS (n = 6) patients. Cholestatic macrophages demonstrated reduced expression of immune regulatory genes as compared to normal hepatic macrophages and were distinct from macrophage populations defined in either healthy adult or pediatric non-cholestatic liver.

Conclusions: We are the first to perform single-cell RNA sequencing on human pediatric cholestatic liver and identified three macrophage subsets with distinct transcriptional signatures from healthy liver macrophages. Further analyses will identify similarities and differences in these macrophage sub-populations across etiologies of cholestatic liver disease. Taken together, these findings may allow for future development of targeted therapeutic strategies to reprogram macrophages to an immune regulatory phenotype and reduce cholestatic liver injury.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244743PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790256PMC
May 2021

Do air gaps with image-guided vaginal cuff brachytherapy impact failure rates in patients with high-intermediate risk FIGO Stage I endometrial cancer?

Brachytherapy 2021 May-Jun;20(3):512-518. Epub 2020 Dec 29.

Department of Radiation Oncology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA. Electronic address:

Purpose: The aim of this study was to assess the impact of air gaps at the cylinder surface on the rate of vaginal cuff failure (VCF) after image-guided adjuvant vaginal cuff brachytherapy (VCBT) in the treatment of high-intermediate risk (HIR) FIGO (Fédération Internationale de Gynécologie et d'Obstétrique (International Federation of Gynecology and Obstetrics)) Stage I endometrial cancer.

Methods And Materials: A retrospective review of patients treated with image-guided VCBT from 2009 to 2016 for HIR FIGO Stage I endometrial cancer was performed. Air gaps present at the applicator surface on the first postinsertion CT were contoured. Vaginal cuff failure-free survival (VCFFS) was measured from the first fraction of VCBT to VCF.

Results: A total of 234 patients were identified. Air gaps were present on the first postinsertion CT scan in 82% of patients. The median number of air gaps was 2 (interquartile range [IQR] 1-3), median depth of the largest air gap was 2.7 mm (IQR 2.1-3.4 mm), and the median cumulative volume of air gaps was less than 0.1 cm (range < 0.1-0.7 cm). At a median followup of 56 months (IQR 41-69), 12 patients (5%) experienced VCF, of which 4 had isolated VCF and 8 had synchronous pelvic or distant failure. Five-year VCFFS and isolated VCFFS were 96% (95% confidence interval 93-98%) and 98% (95% confidence interval 96-100%), respectively. On univariate analysis, no factors, including the presence, number, maximum depth, or cumulative volume of air gaps, were predictive for VCFFS.

Conclusions: In this population, VCFFS remained high despite most patients having air gaps present on postinsertion CT scan.
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http://dx.doi.org/10.1016/j.brachy.2020.11.012DOI Listing
December 2020

Effect of Enteral Protein Amount on Growth and Health Outcomes in Very-Low-Birth-Weight Preterm Infants: Phase II of the Pre-B Project and an Evidence Analysis Center Systematic Review.

J Acad Nutr Diet 2020 Dec 22. Epub 2020 Dec 22.

Adequate protein intake by very-low-birth-weight preterm infants (≤1,500 g at birth) is essential to optimize growth and development. The estimated needs for this population are the highest of all humans, however, the recommended intake has varied greatly over the past several years. A literature search was conducted in PubMed, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and Cochrane Central databases to identify randomized controlled trials evaluating the effect of prescribed protein intake and identified outcomes. Articles were screened by 2 reviewers, risk of bias was assessed, data were synthesized quantitatively and narratively, and each outcome was separately graded for certainty of evidence. The literature search retrieved 25,384 articles and 2 trials were included in final analysis. No trials were identified that evaluated effect of protein amount on morbidities or mortality. Moderate certainty evidence found a significant difference in weight gain when protein intake of greater than 3.5 g/kg/day from preterm infant formula was compared with lower intakes. Low-certainty evidence found no evidence of effect of protein intake of 2.6 vs 3.1 vs 3.8 g/kg/day on length, head circumference, skinfold measurements, or mid-arm circumference. Low-certainty evidence found some improvement in development measures when higher protein intake of 3.8 vs 3.1 vs 2.6 g/kg/day were compared. Low-certainty evidence found no significant difference in bone mineral content when these protein intakes were compared. No studies were identified that compared protein intake greater than 4.0 g/kg/day. This systematic review found that protein intake between 3.5 and 4.0 g/kg/day promotes weight gain and improved development.
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http://dx.doi.org/10.1016/j.jand.2020.11.002DOI Listing
December 2020
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