Biliary Atresia in Adolescence and Adult Life: Medical, Surgical and Psychological Aspects.

Prior to 1955, when Morio Kasai first performed the hepatic portoenterostomy procedure which now bears his name, Biliary atresia (BA) was a uniformly fatal disease. Both the Kasai procedure and liver transplantation have markedly improved the outlook for infants with this condition. Although long-term survival with native liver occurs in the minority, survival rates post liver transplantation are high.

Impact of blood factors on endothelial cell metabolism and function in two diverse heart failure models.

Role of blood-based factors in development and progression of heart failure (HF) is poorly characterized. Blood contains factors released during pathophysiological states that may impact cellular function and provide mechanistic insights to HF management. We tested effects of blood from two distinct HF models on cardiac metabolism and identified possible cellular targets of the effects.

Multisystem Inflammatory Syndrome therapies in children (MISTIC): A randomized trial.

Background: Multisystem Inflammatory Syndrome in Children (MIS-C), which occurs 2-6 weeks after initial exposure to SARS-CoV-2, was first identified in early 2020 when patients presented with fever and significant inflammation, often requiring management in the intensive care unit. To date, there has been no clinical trial to determine the most effective treatment. This study compares anti-inflammatory treatments that were selected based on current treatments for Kawasaki disease, a coronary artery vasculitis that shares many clinical features with MIS-C.

Endosomal escape of RNA therapeutics: How do we solve this rate-limiting problem?

With over 15 FDA approved drugs on the market and numerous ongoing clinical trials, RNA therapeutics, such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs), have shown great potential to treat human disease. Their mechanism of action is based entirely on the sequence of validated disease-causing genes without the prerequisite knowledge of protein structure, activity or cellular location. In contrast to small molecule therapeutics that passively diffuse across the cell membrane's lipid bilayer, RNA therapeutics are too large, too charged, and/or too hydrophilic to passively diffuse across the cellular membrane and instead are taken up into cells by endocytosis.

Hearing rehabilitation and microbial shift after middle ear surgery with Vibrant Soundbridge in patients with chronic otitis media.

Introduction: Patients with otitis media (OM) encounter significant functional hearing impairment with conductive, or a combined hearing loss and long-term sequelae involving impaired speech/language development in children, reduced academic achievement and irreversible disorders of middle and inner ear requiring a long time therapy and/or multiple surgeries. In its persistent chronic form, Otitis media (COM) can often only be treated by undergoing ear surgery for hearing restoration. The persistent inflammatory reaction plays a major role, often caused by multi-resistant pathogens in the ear.

MIS-C: myths have been debunked, but mysteries remain.

Although elegant work has detailed the clinical presentation, immune response and disease outcome of multisystem inflammatory syndrome in children, many questions remain. Studies in 2022 have explored the nature of the vascular injury, the role of the SARS-CoV-2 spike protein and the association with the current variants of the virus.

Genomic Immune Evasion: Diagnostic and Therapeutic Opportunities in Head and Neck Squamous Cell Carcinomas.

Head and neck squamous cell cancers (HNSCCs) represent a diverse group of tumors emerging within different mucosal surfaces of the oral cavity, nasopharynx, oropharynx, larynx, and hypopharynx. HNSCCs share common clinical risk factors and genomic features, including smoking, alcohol, age, male sex, aneuploidy, and mutations. Viral initiating and contributing events are increasingly recognized in HNSCCs.

Targeting caveolae to pump bispecific antibody to TGF-β into diseased lungs enables ultra-low dose therapeutic efficacy.

The long-sought-after "magic bullet" in systemic therapy remains unrealized for disease targets existing inside most tissues, theoretically because vascular endothelium impedes passive tissue entry and full target engagement. We engineered the first "dual precision" bispecific antibody with one arm pair to precisely bind to lung endothelium and drive active delivery and the other to precisely block TGF-β effector function inside lung tissue. Targeting caveolae for transendothelial pumping proved essential for delivering most of the injected intravenous dose precisely into lungs within one hour and for enhancing therapeutic potency by >1000-fold in a rat pneumonitis model.

Changes in abdominal adipose tissue depots assessed by MRI correlate with hepatic histologic improvement in non-alcoholic steatohepatitis.

Background & Aims: Non-alcoholic steatohepatitis (NASH) is prevalent in adults with obesity and can progress to cirrhosis. In a secondary analysis of prospectively acquired data from the multicenter, randomized, placebo-controlled FLINT trial, we investigated the relationship between reduction in adipose tissue compartment volumes and hepatic histologic improvement.

Methods: Adult participants in the FLINT trial with paired liver biopsies and abdominal MRI exams at baseline and end-of-treatment (72 weeks) were included (n = 76).

Systematic discovery and functional dissection of enhancers needed for cancer cell fitness and proliferation.

A scarcity of functionally validated enhancers in the human genome presents a significant hurdle to understanding how these cis-regulatory elements contribute to human diseases. We carry out highly multiplexed CRISPR-based perturbation and sequencing to identify enhancers required for cell proliferation and fitness in 10 human cancer cell lines. Our results suggest that the cell fitness enhancers, unlike their target genes, display high cell-type specificity of chromatin features.

Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome.

Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive cancer that frequently progresses and spreads by metastasis to the liver. Cancer-associated fibroblasts, the extracellular matrix and type I collagen (Col I) support or restrain the progression of PDAC and may impede blood supply and nutrient availability. The dichotomous role of the stroma in PDAC, and the mechanisms through which it influences patient survival and enables desmoplastic cancers to escape nutrient limitation, remain poorly understood.

Axial Pain and Arthritis in Diagnosed Inflammatory Bowel Disease: US National Health and Nutrition Examination Survey Data.

Objective: To estimate the nationally representative prevalence of chronic axial pain, inflammatory back pain (IBP), axial spondyloarthritis (axSpA), and peripheral arthritis in persons diagnosed with inflammatory bowel disease (IBD).

Patients And Methods: US National Health and Nutrition Examination Survey (NHANES) data from the 1976-1980 and 2009-2010 survey cycles.

Results: In NHANES 1976-1980, the chronic axial pain prevalence in participants with diagnosed ulcerative colitis (UC) was 19.

Measuring the Frailty Phenotype and its Association with Cognition in Mid-Life and Older Age.

Background: Frailty is directly linked to physical robustness and cognitive decline in older age. The Fried Frailty phenotype (FP) is a construct composed of five core symptoms that has been studied predominately in older age. There is little research contrasting the psychometric properties of the FP in mid-life versus older age.

Practice trends for perioperative intravesical chemotherapy in upper tract urothelial carcinoma: Low but increasing utilization during minimally invasive nephroureterectomy.

Introduction: Perioperative intravesical chemotherapy (IVC) at or around the time of radical nephroureterectomy (RNU) reduces the risk of intravesical recurrence. Guidelines since 2013 have recommended its use. The objective of this study is to examine IVC utilization and determine predictors of its administration within a large international consortium.

ETS1 loss in mice impairs cardiac outflow tract septation via a cell migration defect autonomous to the neural crest.

Ets1 deletion in some mouse strains causes septal defects and has been implicated in human congenital heart defects in Jacobsen syndrome, in which one copy of the Ets1 gene is missing. Here, we demonstrate that loss of Ets1 in mice results in a decrease in neural crest (NC) cells migrating into the proximal outflow tract cushions during early heart development, with subsequent malalignment of the cushions relative to the muscular ventricular septum, resembling double outlet right ventricle (DORV) defects in humans. Consistent with this, we find that cultured cardiac NC cells from Ets1 mutant mice or derived from iPS cells from Jacobsen patients exhibit decreased migration speed and impaired cell-to-cell interactions.

Endothelial Loss of ETS1 Impairs Coronary Vascular Development and Leads to Ventricular Non-Compaction.

Rationale: Jacobsen syndrome is a rare chromosomal disorder caused by deletions in the long arm of human chromosome 11, resulting in multiple developmental defects including congenital heart defects. Combined studies in humans and genetically engineered mice implicate that loss of ETS1 (E26 transformation specific 1) is the cause of congenital heart defects in Jacobsen syndrome, but the underlying molecular and cellular mechanisms are unknown.

Objective: To determine the role of ETS1 in heart development, specifically its roles in coronary endothelium and endocardium and the mechanisms by which loss of ETS1 causes coronary vascular defects and ventricular noncompaction.

ETS1 and HLHS: Implications for the Role of the Endocardium.

We have identified the ETS1 gene as the cause of congenital heart defects, including an unprecedented high frequency of HLHS, in the chromosomal disorder Jacobsen syndrome. Studies in demonstrated a critical role for ETS1 in heart cell fate determination and cell migration, suggesting that the impairment of one or both processes can underlie the pathogenesis of HLHS. Our studies determined that ETS1 is expressed in the cardiac neural crest and endocardium in the developing murine heart, implicating one or both lineages in the development of HLHS.

Variable Eating Patterns: A Potential Novel Risk Factor for Systemic Inflammation in Women.

Background: The timing and regularity of eating patterns could play a role in systemic inflammation, as circadian clocks responsible for daily rhythms of inflammatory signaling are entrained by food intake.

Purpose: To evaluate associations of intra-weekly and weekday-weekend differences in eating timing patterns with high-sensitivity C-reactive protein (hsCRP).

Methods: A community-based sample of 103 U.

Effect of Thermoelectric Warming Therapy for the Treatment of Meibomian Gland Dysfunction.

Purpose: To evaluate the efficacy of thermoelectric warming therapy (MiBoFlo) in improving patient symptoms with standardized questionnaires and objective signs of meibomian gland dysfunction (MGD), which is an important underlying treatable factor in dry eye disease (DED), such as ocular surface staining, tear quality, and meibomian gland morphology. Multivariate analysis to identify predictors for the improvement in Ocular Surface Disease Index (OSDI) was also performed.

Design: Retrospective before-and-after study.

Constructing Taxonomies: Identifying Distinctive Class of HIV Support and Risk Networks among People Who Use Drugs (PWID) and Their Network Members in the HPTN 037 Randomized Controlled Trial.

Injection drug use is a significant mode of HIV transmission. Social networks are potential avenues for behavior change among high-risk populations. Increasing knowledge should include a classification or taxonomy system of networks' attributes, risks, and needs.