Biliary atresia.

Biliary atresia (BA) is a progressive inflammatory fibrosclerosing disease of the biliary system and a major cause of neonatal cholestasis. It affects 1:5,000-20,000 live births, with the highest incidence in Asia. The pathogenesis is still unknown, but emerging research suggests a role for ciliary dysfunction, redox stress and hypoxia. The study of the underlying mechanisms can be conceptualized along the likely prenatal timing of an initial insult and the distinction between the injury and prenatal and postnatal responses to injury. Although still speculative, these emerging concepts, new diagnostic tools and early diagnosis might enable neoadjuvant therapy (possibly aimed at oxidative stress) before a Kasai portoenterostomy (KPE). This is particularly important, as timely KPE restores bile flow in only 50-75% of patients of whom many subsequently develop cholangitis, portal hypertension and progressive fibrosis; 60-75% of patients require liver transplantation by the age of 18 years. Early diagnosis, multidisciplinary management, centralization of surgery and optimized interventions for complications after KPE lead to better survival. Postoperative corticosteroid use has shown benefits, whereas the role of other adjuvant therapies remains to be evaluated. Continued research to better understand disease mechanisms is necessary to develop innovative treatments, including adjuvant therapies targeting the immune response, regenerative medicine approaches and new clinical tests to improve patient outcomes.

Enlarged Breast Size (Macromastia) and Associated Neurologic Risks: A Scoping Review.

BACKGROUND AND OBJECTIVES: Symptomatic macromastia (enlarged breasts) is a syndrome of persistent headache, neck and shoulder pain, thoracic kyphosis, painful shoulder grooving from bra straps, inframammary rash, backache, and upper extremity paresthesias. Up to 89% of the 100,000 US women undergoing breast reduction surgery (reduction mammoplasty) annually report headache preoperatively with many endorsing postoperative headache improvement. Headache is one insurance indication to cover surgical reduction, and peak prevalence of migraine matches the average age of women with macromastia at time of surgery. Little is known about the influence of macromastia on headache. The goal of our narrative review is to understand the evidence for and potential mechanisms underlying macromastia-related headache. METHODS: A literature search was performed in PubMed Medline using concepts "breast hypertrophy," "macromastia," "headache," "migraine," "breast reduction," and "reduction mammoplasty" excluding limits on age, language, publication date, or study type. Supplemental literature searches were performed to provide a comprehensive understanding of potential mechanisms underlying macromastia-related headache. RESULTS: We identified 25 studies describing macromastia-associated headache in the setting of reduction mammoplasty, with 23 original research studies (retrospective, n = 12, prospective, n = 11) totaling 3,799 patients, 1 systematic review, and 1 meta-analysis. Most (24/25) were published in Plastic Surgery, one in Internal Medicine, and none in Neurology. Wide ranges were identified for preoperative headache prevalence (2%-89%) and postoperative headache improvement (34%-100%). Studies described headache as "myofascial" or "tension-type" without detailing headache definitions, chronicity, headache screening method, or neurologic examination. Potential pathophysiologic mechanisms of macromastia-associated headache include structural, mechanical, psychosocial, and hormonal. DISCUSSION: No studies on macromastia-associated headache and reduction mammoplasty are published in Neurology. This important women's health topic remains unexplored in fields outside Plastic Surgery. Many questions remain unanswered that are important for neurologists to understand, including which headache type(s) women with macromastia experience and which headache type(s) respond to surgical intervention.

Biliary atresia: insights into mechanisms using a toxic model of the disease including Wnt and Hippo signaling pathways and microtubules.

BACKGROUND: Mechanisms underlying bile duct injury in biliary atresia (BA) remain unclear and mechanisms of bile duct repair are unknown. This study aimed to explore the roles of microtubule instability and Wnt and Hippo signaling pathways in a biliatresone-induced BA model. METHODS: Using primary murine neonatal cholangiocytes in both 2D and 3D cultures, and ex-vivo extra hepatic bile ducts (EHBD) which also has peri-cholangiocyte area, we analyzed injury and recovery processes. Injury was induced by the toxin biliatresone and recovery was induced by toxin wash-out. RESULTS: Microtubule stabilizer paclitaxel prevented biliatresone-induced injury, both to cholangiocytes as well as reduced periductal αSMA stain, this process is mediated by decreased glutathione levels. RhoU and Wnt11 (Wnt signaling) and Pard6g and Amotl1 (Hippo signaling) are involved in both injury and recovery processes, with the latter acting upstream to Wnt signaling. CONCLUSIONS: Early stages of biliatresone-induced EHBD injury in cholangiocytes and periductal structures are reversible. Wnt and Hippo signaling pathways play crucial roles in injury and recovery, providing insights into BA injury mechanisms and potential recovery avenues. IMPACT: Microtubule stabilization prevents cholangiocyte injury and lumen obstruction in a toxic model of biliary atresia (biliatresone induced). Early stages of biliatresone-induced injury, affecting both cholangiocytes and periductal structures, are reversible. Both Wnt and Hippo signaling pathways play a crucial role in bile duct injury and recovery, with a noted interplay between the two. Understanding mechanisms of cholangiocyte recovery is imperative to unveil potential therapeutic avenues.

On the relationship between viscoelasticity and water diffusion in soft biological tissues.

Magnetic resonance elastography (MRE) and diffusion-weighted imaging (DWI) are complementary imaging techniques that detect disease based on viscoelasticity and water mobility, respectively. However, the relationship between viscoelasticity and water diffusion is still poorly understood, hindering the clinical translation of combined DWI-MRE markers. We used DWI-MRE to study 129 biomaterial samples including native and cross-linked collagen, glycosaminoglycans (GAGs) with different sulfation levels, and decellularized specimens of pancreas and liver, all with different proportions of solid tissue, or solid fractions. We developed a theoretical framework of the relationship between mechanical loss and tissue-water mobility based on two parameters, solid and fluid viscosity. These parameters revealed distinct DWI-MRE property clusters characterizing weak, moderate, and strong water-network interactions. Sparse networks interacting weakly with water, such as collagen or diluted decellularized tissue, resulted in marginal changes in water diffusion over increasing solid viscosity. In contrast, dense networks with larger solid fractions exhibited both free and hindered water diffusion depending on the polarity of the solid components. For example, polar and highly sulfated GAGs as well as native soft tissues hindered water diffusion despite relatively low solid viscosity. Our results suggest that two fundamental properties of tissue networks, solid fraction and network polarity, critically influence solid and fluid viscosity in biological tissues. Since clinical DWI and MRE are sensitive to these viscosity parameters, the framework we present here can be used to detect tissue remodeling and architectural changes in the setting of diagnostic imaging. STATEMENT OF SIGNIFICANCE: The viscoelastic properties of biological tissues provide a wealth of information on the vital state of cells and host matrix. Combined measurement of viscoelasticity and water diffusion by medical imaging is sensitive to tissue microarchitecture. However, the relationship between viscoelasticity and water diffusion is still poorly understood, hindering full exploitation of these properties as a combined clinical biomarker. Therefore, we analyzed the parameter space accessible by diffusion-weighted imaging (DWI) and magnetic resonance elastography (MRE) and developed a theoretical framework for the relationship between water mobility and mechanical parameters in biomaterials. Our theory of solid material properties related to particle motion can be translated to clinical radiology using clinically established MRE and DWI.

In Utero Extrahepatic Bile Duct Damage and Repair: Implications for Biliary Atresia.

Biliary atresia (BA) is a cholangiopathy affecting the extrahepatic bile duct (EHBD) of newborns. The etiology and pathophysiology of BA are not fully understood; however, multiple causes of damage and obstruction of the neonatal EHBD have been identified. Initial damage to the EHBD likely occurs before birth. We discuss how different developmental stages in utero and birth itself could influence the susceptibility of the fetal EHBD to damage and a damaging wound-healing response. We propose that a damage-repair response of the fetal and neonatal EHBD involving redox stress and a program of fetal wound healing could-regardless of the cause of the initial damage-lead to either obstruction and BA or repair of the duct and recovery. This overarching concept should guide future research targeted toward identification of factors that contribute to recovery as opposed to progression of injury and fibrosis. Viewing BA through the lens of an in utero damage-repair response could open up new avenues for research and suggests exciting new therapeutic targets.

The ß-Secretase BACE1 Drives Fibroblast Activation in Systemic Sclerosis through the APP/ß-Catenin/Notch Signaling Axis.

BACE1 is well-known for its role in the development of Alzheimer's disease. Recent publications, including our own, have demonstrated a role for this enzyme in other chronic diseases. The aim of this study was to investigate the role of BACE1 in the autoimmune disease systemic sclerosis (SSc). BACE1 protein levels were elevated in the skin of patients with SSc. Inhibition of BACE1 with small-molecule inhibitors or small interfering RNA blocked SSc and fibrotic stimuli-mediated fibroblast activation. Furthermore, we show that BACE1 regulation of dermal fibroblast activation is dependent on ß-catenin and Notch signaling. The neurotropic factor brain-derived neurotrophic factor negatively regulates BACE1 expression and activity in dermal fibroblasts. Finally, sera from patients with SSc show higher ß-amyloid and lower brain-derived neurotrophic factor levels than healthy controls. The ability of BACE1 to regulate SSc fibroblast activation reveals a therapeutic target in SSc. Several BACE1 inhibitors have been shown to be safe in clinical trials for Alzheimer's disease and could be repurposed to ameliorate fibrosis progression.

Low-dose biliatresone treatment of pregnant mice causes subclinical biliary disease in their offspring: Evidence for a spectrum of neonatal injury.

Biliary atresia is a neonatal disease characterized by damage, inflammation, and fibrosis of the liver and bile ducts and by abnormal bile metabolism. It likely results from a prenatal environmental exposure that spares the mother and affects the fetus. Our aim was to develop a model of fetal injury by exposing pregnant mice to low-dose biliatresone, a plant toxin implicated in biliary atresia in livestock, and then to determine whether there was a hepatobiliary phenotype in their pups. Pregnant mice were treated orally with 15 mg/kg/d biliatresone for 2 days. Histology of the liver and bile ducts, serum bile acids, and liver immune cells of pups from treated mothers were analyzed at P5 and P21. Pups had no evidence of histological liver or bile duct injury or fibrosis at either timepoint. In addition, growth was normal. However, serum levels of glycocholic acid were elevated at P5, suggesting altered bile metabolism, and the serum bile acid profile became increasingly abnormal through P21, with enhanced glycine conjugation of bile acids. There was also immune cell activation observed in the liver at P21. These results suggest that prenatal exposure to low doses of an environmental toxin can cause subclinical disease including liver inflammation and aberrant bile metabolism even in the absence of histological changes. This finding suggests a wide potential spectrum of disease after fetal biliary injury.

Metabolically intact nuclei are fluidized by the activity of the chromatin remodeling motor BRG1.

The structure and dynamics of the cell nucleus regulate nearly every facet of the cell. Changes in nuclear shape limit cell motility and gene expression. Although the nucleus is generally seen as the stiffest organelle in the cell, cells can nevertheless deform the nucleus to large strains by small mechanical stresses. Here, we show that the mechanical response of the cell nucleus exhibits active fluidization that is driven by the BRG 1 motor of the SWI/SNF/BAF chromatin-remodeling complex. Atomic force microscopy measurements show that the nucleus alters stiffness in response to the cell substrate stiffness, which is retained after the nucleus is isolated and that the work of nuclear compression is mostly dissipated rather than elastically stored. Inhibiting BRG 1 stiffens the nucleus and eliminates dissipation and nuclear remodeling both in isolated nuclei and in intact cells. These findings demonstrate a novel link between nuclear motor activity and global nuclear mechanics.

Toxins and Biliary Atresia: Is Karenia Brevis (Red Tide) The Culprit?

OBJECTIVE: The study objective was to evaluate the association between Karenia brevis (K. brevis) exposure during pregnancy and the prevalence of biliary atresia (BA) in offspring. STUDY DESIGN: This was a hospital-based, case-control study in which cases were infants diagnosed with BA at Johns Hopkins All Children's Hospital from October 2001 to December 2019. Cases were matched 1:4 by age to controls who were randomly selected from a pool of healthy infants hospitalized during the study period for common pediatric diagnoses. Infants were excluded if they had congenital anomalies and/or were non-Florida residents. Gestational K. brevis exposure levels (cells/liter) were determined from Florida Fish and Wildlife Conservation Commission exposure data at 10- and 50 mile radii from the mother's zip code of residence. Multivariable conditional logistic regression determined odds of BA in offspring in relation to maternal gestational K. brevis exposure adjusted for infant sex, race/ethnicity, coastal residence, and seasonality. RESULTS: Of 38 cases and 152 controls, no significant inter-group differences were observed for infant race/ethnicity, season of birth, or coastal residence. Median gestational exposure at the 10 mile radius was 0 cells/liter in both groups. A greater proportion of cases had no gestational K. brevis exposure (63.2 %, n = 24) in comparison to controls (37.5 %, n = 57; p = .04) at a 10 mile radius. At a 50 mile radius, cases had a peak median exposure at 6 months of gestation compared to controls' peak at 9 months. After adjustment for sex, seasonality, race/ethnicity, and coastal residence, there was no significant association between BA and maximum K. brevis exposure per trimester of pregnancy observed at a 10- or 50 mile radius. CONCLUSION: In this matched case-control study, we observed no association between gestational K. brevis (cells/liter) exposure at a 10- or 50 mile radius from maternal zip code of residence and BA in offspring.

Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver.

Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development1,2, and increased stiffness is known to promote HCC progression in cirrhotic conditions3,4. Type 2 diabetes mellitus is characterized by an accumulation of advanced glycation end-products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here we find that, in patients and animal models, AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic ß-catenin signalling promote HCC induction, whereas inhibiting AGE production, reconstituting the AGE clearance receptor AGER1 or breaking AGE-mediated collagen cross-links reduces viscoelasticity and HCC growth. Matrix analysis and computational modelling demonstrate that lower interconnectivity of AGE-bundled collagen matrix, marked by shorter fibre length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin-ß1-tensin-1-YAP mechanotransductive pathway. These results reveal that AGE-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.

Usual Source of Care and Contraceptive Use.

BACKGROUND: A high proportion of people in the United States at risk of unintended pregnancy also have limited primary care access. STUDY DESIGN: We pooled data for analyses from separate 2015-2017 and 2017-2019 waves of the National Survey of Family Growth. Multivariable logistic regression was used to estimate associations between the usual source of health care and self-reported use of a comprehensive range of contraceptive options, as well as alignment between patient preference and the current method. RESULTS: Compared with having a private doctor or Health Maintenance Organization, not having a usual source of care was associated with lower odds of using short-term hormonal methods (OR=0.54, 95% CI: 0.40-0.73, for an 11 percentage point lower rate); higher odds of using time-based methods (OR=1.47, 95% CI: 1.10-1.97, for a 6 percentage point higher rate); and higher odds of preferring a contraceptive method other than the one most recently used (OR=1.39, 95% CI: 1.01-1.90, for a 6 percentage point higher probability). Reliance on an emergency department as a usual source of care was not associated with contraceptive use or satisfaction with the method used. Reliance on urgent care was associated only with higher odds of using time-based methods (OR=1.60, 95% CI: 1.03-2.50, for a 7 percentage point higher rate). Clinic-based usual care was not associated with any differences in contraceptive use but was associated with preferring a contraceptive method other than the one most recently used (OR=1.65, 95% CI: 1.21-2.25, for an 8 percentage point higher probability). CONCLUSIONS: All sources of usual care can improve contraceptive access.

Contraception Use by Title X Clients and Clients of Other Providers, 2015-2019.

INTRODUCTION: Title X clinics provide access to a wide range of contraceptive options for individuals of all income levels and documentation statuses. As Title X continues to face political uncertainties, it is important to provide up-to-date information about its clients' use of contraception. This study used recent nationally representative data to compare contraception received by Title X clients with that received by clients of other providers. METHODS: This article draws on 2015-2017 and 2017-2019 waves of the National Survey of Family Growth. The sample was restricted to 15- to 44-year-old women needing contraception. Logistic regressions estimated associations between receiving services at Title X clinics versus at other providers (including private) and use of a range of contraceptive options, as well as number of months' supply for those using oral contraceptives. RESULTS: In 2015-2017, Title X was associated with using any contraception (adjusted odds ratio [AOR], 4.11; p = .004). In both waves, Title X clients were more likely to use long-acting reversible contraceptives (AOR, 1.78 in 2015-2017 [p = .023] and AOR, 2.59 in 2017-2019 [p = .003]) and hormonal methods other than oral contraceptives (AOR, 2.31 in 2015-2017 [p = .007] and AOR, 3.04 in 2017-2019 [p = .001]). In both waves, Title X clients using oral contraceptives were also more likely than non-Title X clients to receive more than a 3-month supply (AOR, 3.54 in 2015-2017 [p = .008] and AOR, 2.61 in 2017-2019 [p = .043]). Title X was not associated in either wave with use of barrier or time-based methods, such as periodic abstinence or withdrawal. CONCLUSIONS: Patterns of contraceptive use by Title X clients compared with those of clients of other providers indicate that the Title X program has allowed access to a wide range of contraceptive methods. Ongoing research is necessary to see whether these patterns change over time.

Conjugated hyperbilirubinemia is associated with increased morbidity and mortality after neonatal heart surgery.

BACKGROUND: Cholestasis characterised by conjugated hyperbilirubinemia is a marker of hepatobiliary dysfunction following neonatal cardiac surgery. We aimed to characterise the incidence of conjugated hyperbilirubinemia following neonatal heart surgery and examine the effect of conjugated hyperbilirubinemia on post-operative morbidity and mortality. METHODS: This was a retrospective study of all neonates who underwent surgery for congenital heart disease (CHD) at our institution between 1/1/2010 and 12/31/2020. Patient- and surgery-specific data were abstracted from local registry data and review of the medical record. Conjugated hyperbilirubinemia was defined as perioperative maximum conjugated bilirubin level > 1 mg/dL. The primary outcome was in-hospital mortality. Survival analysis was conducted using the Kaplan-Meier survival function. RESULTS: Conjugated hyperbilirubinemia occurred in 8.5% of patients during the study period. Neonates with conjugated hyperbilirubinemia were more likely to be of younger gestational age, lower birth weight, and non-Caucasian race (all p < 0.001). Patients with conjugated hyperbilirubinemia were more likely to have chromosomal and non-cardiac anomalies and require ECMO pre-operatively. In-hospital mortality among patients with conjugated hyperbilirubinemia was increased compared to those without (odds ratio 5.4). Post-operative complications including mechanical circulatory support, reoperation, prolonged ventilator dependence, and multi-system organ failure were more common with conjugated hyperbilirubinemia (all p < 0.04). Patients with higher levels of conjugated bilirubin had worst intermediate-term survival, with patients in the highest conjugated bilirubin group (>10 mg/dL) having a 1-year survival of only 6%. CONCLUSIONS: Conjugated hyperbilirubinemia is associated with post-operative complications and worse survival following neonatal heart surgery. Cholestasis is more common in patients with chromosomal abnormalities and non-cardiac anomalies, but the underlying mechanisms have not been delineated.

Understanding the use of media analysis in public health research through food tax debates (HEALTHEI Project): a scoping review.

BACKGROUND: Poor diet is a major public health concern. In 2021, 63·8% of adults and 22·2% of reception-age children were either overweight or obese in England. Fiscal interventions have become a popular policy measure to reduce obesity and encourage healthy eating. Such measures are highly controversial, leading to media debate promoting pro-tax and anti-tax arguments. To better understand food tax debates and the use of media analysis in public health research, we conducted a scoping review of media analyses using food taxes as a case study. METHODS: In this scoping review, we searched SCOPUS, PubMed, and EBSCOhost databases on Feb 14-22, 2023, using keyword variations for "food", "tax", and "media analysis". Results were restricted to English-only, peer-reviewed journal articles. The initial results were manually screened through an iterative process to exclude articles that did not analyse a food tax, were non-English language, were not peer-reviewed, or did not use media analysis as the primary method. Modelled on Arksey and O'Malley's (2005) five-stage review protocol, two researchers used a coding framework to independently code all articles and checked result quality through regular discussion. Extracted data included article title, author, year, country, tax type, media sources used, identified media frames, and research aims, methods, results, and conclusions. Results are reported according to PRISMA guidelines and data files submitted to FigShare Repository (non-accessible). FINDINGS: Of 1087 articles reviewed, 19 were eligible to be included in the study. Articles were published between 2013 and 2023, with 2021 having the highest concentration of studies carried out mainly in UK and USA. Despite search terms encompassing a range of food products, the retrieved media analyses focused on three types of food product taxes: sugar-sweetened beverages, meat, and groceries. Most articles explored arguments for and against policy implementation, with some investigating stakeholder representation. Results demonstrate that stakeholders' arguments, both positive and negative, are consistent across countries and food products. INTERPRETATION: The consistency of how both pro-tax and anti-tax arguments are presented in the media demonstrates the importance of coordination between stakeholder groups to influence policy adoption. To our knowledge, this is the first study to investigate media analysis across a diverse range of food products. FUNDING: National Institute for Health and Care Research (NIHR).

Human vascularized bile duct-on-a chip: a multi-cellular micro-physiological system for studying cholestatic liver disease.

Exploring the pathogenesis of and developing therapies for cholestatic liver diseases such as primary sclerosing cholangitis (PSC) remains challenging, partly due to a paucity ofin vitromodels that capture the complex environments contributing to disease progression and partly due to difficulty in obtaining cholangiocytes. Here we report the development of a human vascularized bile duct-on-a-chip (VBDOC) that uses cholangiocyte organoids derived from normal bile duct tissue and human vascular endothelial cells to model bile ducts and blood vessels structurally and functionally in three dimensions. Cholangiocytes in the duct polarized, formed mature tight junctions and had permeability properties comparable to those measured inex vivosystems. The flow of blood and bile was modeled by perfusion of the cell-lined channels, and cholangiocytes and endothelial cells displayed differential responses to flow. We also showed that the device can be constructed with biliary organoids from cells isolated from both bile duct tissue and the bile of PSC patients. Cholangiocytes in the duct became more inflammatory under the stimulation of IL-17A, which induced peripheral blood mononuclear cells and differentiated Th17 cells to transmigrate across the vascular channel. In sum, this human VBDOC recapitulated the vascular-biliary interface structurally and functionally and represents a novel multicellular platform to study inflammatory and fibrotic cholestatic liver diseases.