Impact of maternal factors, environmental factors, and race on necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a complex disease with a multifactorial etiology. As the leading cause of intestinal morbidity and mortality among premature infants, many resources are being dedicated to neonatal care and molecular targets in the newborn intestine. However, NEC is heavily influenced by maternal and perinatal factors as well.

Activation of homology-directed DNA repair plays key role in CRISPR-mediated genome correction.

Gene editing for the cure of inborn errors of metabolism (IEMs) has been limited by inefficiency of adult hepatocyte targeting. Here, we demonstrate that in utero CRISPR/Cas9-mediated gene editing in a mouse model of hereditary tyrosinemia type 1 provides stable cure of the disease. Following this, we performed an extensive gene expression analysis to explore the inherent characteristics of fetal/neonatal hepatocytes that make them more susceptible to efficient gene editing than adult hepatocytes.

In vivo lentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions.

Conventional therapy for hereditary tyrosinemia type-1 (HT1) with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) delays and in some cases fails to prevent disease progression to liver fibrosis, liver failure, and activation of tumorigenic pathways. Here we demonstrate cure of HT1 by direct, in vivo administration of a therapeutic lentiviral vector targeting the expression of a human fumarylacetoacetate hydrolase (FAH) transgene in the porcine model of HT1. This therapy is well tolerated and provides stable long-term expression of FAH in pigs with HT1.

Coronavirus 2019 (COVID-19) venovenous extracorporeal oxygenation: Single community hospital results and insights.

Background: The role of extracorporeal membrane oxygenation (ECMO) for patients with refractory respiratory failure due to coronavirus 2019 (COVID-19) is still unclear even now over a year into the pandemic. ECMO is becoming more commonplace even at smaller community hospitals. While the advantages of venovenous (VV) ECMO in acute respiratory distress syndrome (ARDS) from COVID-19 have not been fully determined, we believe the benefits outweighed the risks in our patient population.

Development of a porcine model of phenylketonuria with a humanized R408W mutation for gene editing.

Phenylketonuria (PKU) is a metabolic disorder whereby phenylalanine metabolism is deficient due to allelic variations in the gene for phenylalanine hydroxylase (PAH). There is no cure for PKU other than orthotopic liver transplantation, and the standard of care for patients is limited to dietary restrictions and key amino acid supplementation. Therefore, Pah was edited in pig fibroblasts for the generation of PKU clone piglets that harbor a common and severe human mutation, R408W.

Cell Therapy by Ectopic Hepatocyte Transplantation Treats the Porcine Tyrosinemia Model of Acute Liver Failure.

The effectiveness of cell-based therapies to treat liver failure is often limited by the diseased liver environment. Here, we provide preclinical proof of concept for hepatocyte transplantation into lymph nodes as a cure for liver failure in a large-animal model with hereditary tyrosinemia type 1 (HT1), a metabolic liver disease caused by deficiency of fumarylacetoacetate hydrolase (FAH) enzyme. Autologous porcine hepatocytes were transduced with a lentiviral vector carrying the pig gene and transplanted into mesenteric lymph nodes.

The fifth vital sign? Nurse worry predicts inpatient deterioration within 24 hours.

Introduction: Identification of hospitalized patients with suddenly unfavorable clinical course remains challenging. Models using objective data elements from the electronic health record may miss important sources of information available to nurses.

Methods: We recorded nurses' perception of patient potential for deterioration in 2 medical and 2 surgical adult hospital units using a 5-point score at the start of the shift (the Worry Factor [WF]), and any time a change or an increase was noted by the nurse.

Diffuse histology-proven mucinous cystic neoplasm of the pancreas: A case report and review of literature.

Introduction: Mucinous cystic neoplasms (MCN) are rare premalignant neoplasms of the pancreas that are typically found as single lesions in the pancreatic body and tail of women in the fifth and sixth decade of life, do not communicate with the pancreatic ductal system and are characterized by mucin-producing epithelium supported by ovarian-type stroma.

Presentation Of Case: We present here a case of diffuse pancreatic involvement by MCN in a 64-year-old woman with chronic pancreatitis. Pre-operative suspicion for MCN was low due to the multi-centric nature of the lesions and imaging/biochemical fluid analysis demonstrating connection with the pancreatic ductal architecture.

Fetoscopy-Assisted Percutaneous Decompression of the Distal Trachea and Lungs Reverses Hydrops Fetalis and Fetal Distress in a Fetus with Laryngeal Atresia.

We present a case of prenatal hydrops secondary to congenital high airway obstruction syndrome (CHAOS) that was treated with fetoscopy-assisted needle decompression. A 22-year-old G3P2 woman presented after a 21-week ultrasound demonstrated CHAOS. The fetus developed hydrops at 25 weeks, characterized by abdominal ascites, pericardial effusion, and scalp edema.

Hepatocyte Reprograming Promotes Homology-Directed DNA Repair to Correct Metabolic Disease in Mice After Transplantation.

CRISPR/Cas9-mediated gene editing in hepatocytes using homology-directed repair (HDR) is a potential alternative curative therapy to organ transplantation for metabolic liver disease. However, a major limitation of this approach in quiescent adult primary hepatocytes is that nonhomologous end-joining is the predominant DNA repair pathway for double-strand breaks (DSBs). This study explored the hypothesis that hepatocyte culture could reprogram hepatocytes to favor HDR after CRISPR/Cas9-mediated DNA DSBs.

Hepatotoxicity and Toxicology of Lentiviral Vector Administration in Healthy and Liver-Injury Mouse Models.

General safety and toxicology assessments supporting lentiviral vector-based therapeutic development are sparse. We have previously demonstrated the efficacy of a lentiviral vector expressing fumarylacetoacetate hydrolase (LV-FAH) to cure animal models of hereditary tyrosinemia type 1. Therefore, we performed a complete preclinical toxicological evaluation of LV-FAH, in a large cohort ( = 20/group) of wildtype mice and included matched groups of N-nitrosodiethylamine/carbon tetrachloride (DEN/CCl)-induced liver injury mice to assess specific toxicity in fibrotic liver tissue.

Autologous Gene and Cell Therapy Provides Safe and Long-Term Curative Therapy in A Large Pig Model of Hereditary Tyrosinemia Type 1.

Orthotopic liver transplantation remains the only curative therapy for inborn errors of metabolism. Given the tremendous success for primary immunodeficiencies using ex-vivo gene therapy with lentiviral vectors, there is great interest in developing similar curative therapies for metabolic liver diseases. We have previously generated a pig model of hereditary tyrosinemia type 1 (HT1), an autosomal recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH).

Lentiviral Vector-mediated Gene Therapy of Hepatocytes Ex Vivo for Autologous Transplantation in Swine.

Gene therapy is an ideal choice to cure many inborn errors of metabolism of the liver. Ex-vivo, lentiviral vectors have been used successfully in the treatment of many hematopoietic diseases in humans, as their use offers stable transgene expression due to the vector's ability to integrate into the host genome. This method demonstrates the application of ex vivo gene therapy of hepatocytes to a large animal model of hereditary tyrosinemia type I.

Randomized Trial of Spheroid Reservoir Bioartificial Liver in Porcine Model of Posthepatectomy Liver Failure.

Acute liver failure (ALF) is a catastrophic condition that can occur after major liver resection. The aim of this study was to determine the effects of the spheroid reservoir bio-artificial liver (SRBAL) on survival, serum chemistry, and liver regeneration in posthepatectomy ALF pigs. Wild-type large white swine (20 kg-30 kg) underwent intracranial pressure (ICP) probe placement followed by 85% hepatectomy.

Hepatocyte spheroids as an alternative to single cells for transplantation after ex vivo gene therapy in mice and pig models.

Background: Autologous hepatocyte transplantation after ex vivo gene therapy is an alternative to liver transplantation for metabolic liver disease. Here we evaluate ex vivo gene therapy followed by transplantation of single-cell or spheroid hepatocytes.

Methods: Pig and mouse hepatocytes were isolated, labeled with zirconium-89 and returned to the liver as single cells or spheroids.

Curative Ex Vivo Hepatocyte-Directed Gene Editing in a Mouse Model of Hereditary Tyrosinemia Type 1.

Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH). It has been previously shown that ex vivo hepatocyte-directed gene therapy using an integrating lentiviral vector to replace the defective Fah gene can cure liver disease in small- and large-animal models of HT1. This study hypothesized that ex vivo hepatocyte-directed gene editing using CRISPR/Cas9 could be used to correct a mouse model of HT1, in which a single point mutation results in loss of FAH function.

Recent Advances in Decellularization and Recellularization for Tissue-Engineered Liver Grafts.

Liver transplantation from deceased or living human donors remains the only proven option for patients with end-stage liver disease. However, the shortage of donor organs is a significant clinical concern that has led to the pursuit of tissue-engineered liver grafts generated from decellularized liver extracellular matrix and functional cells. Investigative efforts on optimizing both liver decellularization and recellularization protocols have been made in recent decades.

Recent Advances in Decellularization and Recellularization for Tissue-Engineered Liver Grafts.

Liver transplantation from deceased or living human donors remains the only proven option for patients with end-stage liver disease. However, the shortage of donor organs is a significant clinical concern that has led to the pursuit of tissue-engineered liver grafts generated from decellularized liver extracellular matrix and functional cells. Investigative efforts on optimizing both liver decellularization and recellularization protocols have been made in recent decades.

Liver transplantation after share 35: Impact on pretransplant and posttransplant costs and mortality.

Share 35 was implemented in 2013 to direct livers to the most urgent candidates by prioritizing Model for End-Stage Liver Disease (MELD) ≥ 35 patients. We aim to evaluate this policy's impact on costs and mortality. Our study includes 834 wait-listed patients and 338 patients who received deceased donor, solitary liver transplants at Mayo Clinic between January 2010 and December 2014.

Concise Review: Liver Regenerative Medicine: From Hepatocyte Transplantation to Bioartificial Livers and Bioengineered Grafts.

Donor organ shortage is the main limitation to liver transplantation as a treatment for end-stage liver disease and acute liver failure. Liver regenerative medicine may in the future offer an alternative form of therapy for these diseases, be it through cell transplantation, bioartificial liver (BAL) devices, or bioengineered whole organ liver transplantation. All three strategies have shown promising results in the past decade.

Cell therapy in chronic liver disease.

Purpose Of Review: To date, the only curative treatment for end-stage liver disease is liver transplantation, which is limited by the shortage of available organs. Cell therapy, in the form of cell transplantation or cell-based extracorporeal support devices, may in the future offer an alternative to transplantation, or at least provide liver function support as a bridging therapy until surgery may be performed. The purpose of this review is to highlight the most recent advances made in the field of cell therapy and regenerative medicine for the treatment of chronic liver disease.

Stem Cell Therapies for Treatment of Liver Disease.

Cell therapy is an emerging form of treatment for several liver diseases, but is limited by the availability of donor livers. Stem cells hold promise as an alternative to the use of primary hepatocytes. We performed an exhaustive review of the literature, with a focus on the latest studies involving the use of stem cells for the treatment of liver disease.

Evaluation of the degree of liver fibrosis and genetical characteristics in HIV patients with spontaneous clearance of HCV in Cartagena, Spain.

Introduction: Single-nucleotide polymorphisms (SNPs) in the region of the Interleukin 28B (IL28B) gene on chromosome 19, coding for the interferon (IFN)-λ3, are involved in hepatitis c virus (HCV), spontaneous clearance. There is little information on the degree of liver fibrosis (LF) in HIV patients, who have had spontaneous clearance of HCV. Our objective in this study is to assess the degree of liver fibrosis in this population, as well as to identify key genetic characteristics associated with spontaneous clearance.