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1.
Hosp Pediatr ; 10(11): 955-962, 2020 11.
Article in English | MEDLINE | ID: mdl-33020193

ABSTRACT

BACKGROUND: Observation care is frequently indistinguishable from inpatient care. However, the financial burden of inappropriate status assignment for hospitals and patients can be large. Increased awareness of the potential for financial hardships experienced by patients because of status designation spurred interest among physicians in this improvement project. The goal was to improve the percentage of appropriate inpatient-status assignments from 76% to 90% in 2 years and eliminate observation assignments for patients with hospitalizations >48 hours. METHODS: Our multidisciplinary team used the Model for Improvement. Interventions included securing a lead physician advisor to the use-review team, improving the process for status review and adjustment, and creating educational sessions and tools for physicians. Data collected included the percentage of appropriate inpatient assignments, percentage of observation assignments for patients with hospitalizations >48 hours, write-off dollar amount per year from denial of payment due to payer disagreement with inpatient status, and resident physician confidence in assigning status. RESULTS: Appropriate use of inpatient assignments increased from 76% to 84%. Status assignments remaining in observation >48 hours of hospital length of stay decreased by one-half, from 6% to 3%. The write-off dollar amount increased during the study period but decreased by 19% the following calendar year, 2018. Resident self-reported confidence in status designation increased after educational sessions. CONCLUSIONS: Careful selection of admission status by educated providers and a system to identify relevant cases for status changes can increase appropriate status assignment and, potentially, positively affect the economic burden placed on patients and hospitals.


Subject(s)
Hospitalization , Inpatients , Hospitals , Humans
2.
J Pediatr Gastroenterol Nutr ; 70(5): 640-644, 2020 05.
Article in English | MEDLINE | ID: mdl-31939866

ABSTRACT

Parenteral nutrition-associated cholestasis (PNAC) causes serious morbidity in the neonatal intensive care unit. Infection with gut-associated bacteria is associated with cholestasis, but the role of intestinal microbiota in PNAC is poorly understood. We examined the composition of stool microbiota from premature twins discordant for PNAC as a strategy to reduce confounding from variables associated with both microbiota and cholestasis. Eighty-four serial stool samples were included from 4 twin sets discordant for PNAC. Random Forests was utilized to determine genera most discriminatory in classifying samples from infants with and without PNAC. In infants with PNAC, we detected a significant increase in the relative abundance of Klebsiella, Veillonella, Enterobacter, and Enterococcus (P < 0.05). Bray-Curtis dissimilarities in infants with PNAC were significantly different (P < 0.05) from infants without PNAC. Our findings warrant further exploration in larger cohorts and experimental models of PNAC to determine if a microbiota signature predicts PNAC, as a basis for future interventions to mitigate liver injury.


Subject(s)
Cholestasis , Microbiota , Cholestasis/etiology , Cholestasis/therapy , Gestational Age , Humans , Infant , Infant, Newborn , Infant, Premature , Parenteral Nutrition/adverse effects
3.
Mol Oncol ; 8(8): 1379-92, 2014 Dec.
Article in English | MEDLINE | ID: mdl-24954856

ABSTRACT

Romidepsin and vorinostat are histone deacetylase inhibitors (HDACis) that have activity in T-cell lymphomas, but have not gained traction in solid tumors. To gain deeper insight into mechanisms of HDACi efficacy, we systematically surveyed 19 cell lines with different molecular phenotypes, comparing romidepsin and vorinostat at equipotent doses. Acetylation at H3K9 and H4K8 along with 22 other histone lysine acetylation and methylation modifications were measured by reverse phase proteomics array (RPPA), and compared with growth inhibition (IC50), and cell cycle arrest. These assays typically used to assess HDACi effect showed that acetylation and methylation of specific lysine residues in response to HDACis were consistent across cell lines, and not related to drug sensitivity. Using a treatment duration more reflective of the clinical exposure, cell death detected by annexin staining following a 6 h drug exposure identified a subset of cell lines, including the T-cell lymphoma line, that was markedly more sensitive to HDAC inhibition. Kinetic parameters (Km values) were determined for lysine acetylation and for cell cycle data and were themselves correlated following HDACi exposure, but neither parameter correlated with cell death. The impact on cell survival signaling varied with the molecular phenotype. This study suggests that cellular response to HDACis can be viewed as two distinct effects: a chromatin effect and a cell death effect. All cells undergo acetylation, which is necessary but not sufficient for cell death. Cells not primed for apoptosis will not respond with cell death to the impact of altered histone acetylation. The divergent apoptotic responses observed reflect the variable clinical outcome of HDACi treatment. These observations should change our approach to the development of therapeutic strategies that exploit the dual activities of HDACis.


Subject(s)
Cell Death/drug effects , Chromatin/metabolism , Histone Deacetylase Inhibitors/pharmacology , Acetylation/drug effects , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Cycle Checkpoints/drug effects , Flow Cytometry , HCT116 Cells , Humans , Immunoblotting
4.
Science ; 340(6135): 984-7, 2013 May 24.
Article in English | MEDLINE | ID: mdl-23661646

ABSTRACT

Plasmodium falciparum transmission by Anopheles gambiae mosquitoes is remarkably efficient, resulting in a very high prevalence of human malaria infection in sub-Saharan Africa. A combination of genetic mapping, linkage group selection, and functional genomics was used to identify Pfs47 as a P. falciparum gene that allows the parasite to infect A. gambiae without activating the mosquito immune system. Disruption of Pfs47 greatly reduced parasite survival in the mosquito, and this phenotype could be reverted by genetic complementation of the parasite or by disruption of the mosquito complement-like system. Pfs47 suppresses midgut nitration responses that are critical to activate the complement-like system. We provide direct experimental evidence that immune evasion mediated by Pfs47 is critical for efficient human malaria transmission by A. gambiae.


Subject(s)
Anopheles/immunology , Anopheles/parasitology , Malaria, Falciparum/parasitology , Malaria, Falciparum/transmission , Membrane Glycoproteins/physiology , Plasmodium falciparum/pathogenicity , Protozoan Proteins/physiology , Animals , Gene Knockout Techniques , Humans , Immune System , Membrane Glycoproteins/genetics , Plasmodium falciparum/genetics , Protozoan Proteins/genetics
5.
Mol Cancer Res ; 9(4): 516-27, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21357443

ABSTRACT

Histone deacetylase inhibitors (HDACI) are promising anticancer agents and their use in combination with conventional anticancer drugs is currently under investigation. We previously reported cell line-specific upregulation of ABCG2, a multidrug resistance transporter shown to control oral bioavailability and CNS penetration, by the HDACI romidepsin, although the precise mechanism in a particular cell line remains to be determined. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can be activated by numerous environmental contaminants and has been shown to be a client protein of heat shock protein 90 (Hsp90). A xenobiotic response element was defined in the ABCG2 promoter and was shown to mediate AhR signaling. Activated AhR was found to be associated with the ABCG2 promoter only in cell line models that respond to romidepsin with ABCG2 upregulation. Our data suggest that romidepsin acetylated Hsp70 and inhibited the chaperone function of Hsp90, thereby allowing the dissociation of AhR from Hsp90. The dissociation of AhR from Hsp90 may be a prerequisite for the differential upregulation of ABCG2 by romidepsin. Increasing our understanding of the mechanism(s) governing differential upregulation of ABCG2 in response to romidepsin could provide an insight into strategies needed to tackle resistance to HDACIs in cancer therapeutics.


Subject(s)
ATP-Binding Cassette Transporters/biosynthesis , Antibiotics, Antineoplastic/pharmacology , Depsipeptides/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Neoplasm Proteins/biosynthesis , Receptors, Aryl Hydrocarbon/agonists , Response Elements , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/genetics , Acetylation/drug effects , Aryl Hydrocarbon Receptor Nuclear Translocator/metabolism , Cell Line, Tumor , HSP70 Heat-Shock Proteins/metabolism , HSP90 Heat-Shock Proteins/metabolism , Humans , Metabolic Networks and Pathways/genetics , Neoplasm Proteins/genetics , Promoter Regions, Genetic/genetics , Receptors, Aryl Hydrocarbon/antagonists & inhibitors , Receptors, Aryl Hydrocarbon/metabolism , Up-Regulation/genetics
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