Biliary Disorders, Anomalies, and Malignancies in Children.

Biliary abnormalities in children are uncommon, and the spectrum of biliary disorders is broader than in adult patients. Unlike in adults, biliary disorders in children are rarely neoplastic and are more commonly rhabdomyosarcoma rather than cholangiocarcinoma. Pediatric biliary disorders may be embryologic or congenital, such as anatomic gallbladder anomalies, anomalous pancreaticobiliary tracts, various cholestatic processes, congenital cystic lesions, or genetic conditions. They may also be benign, such as biliary filling anomalies, biliary motility disorders, and biliary inflammatory and infectious disorders. Distinguishing these entities with a single imaging modality is challenging. US is the primary imaging modality for initial evaluation of biliary abnormalities in children, due to its wide availability, lack of ionizing radiation, and low cost and because it requires no sedation. Other examinations such as MRI, CT, and nuclear medicine examinations may provide anatomic and functional information to narrow the diagnosis further. Hepatobiliary-specific contrast material with MRI can provide better assessment of biliary anatomy on delayed images than can traditional MRI contrast material. MR cholangiopancreatography (MRCP) allows visualization of the intra- and extrahepatic biliary ducts, which may not be possible with endoscopic retrograde cholangiopancreatography (ERCP). Suspected biliary atresia requires multiple modalities for diagnosis and timely treatment. Determining the type of choledochal cyst calls for a combination of initial US and MRCP. Many benign and malignant biliary masses require biopsy for definitive diagnosis. Knowledge of the imaging appearances of different pediatric biliary abnormalities is necessary for appropriate imaging workup, providing a diagnosis or differential diagnosis, and guiding appropriate management. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

Beliefs About the Causes of Alzheimer's Disease Among Latinos in New York City.

Latinos face health disparities in Alzheimer's disease (AD), with high disease prevalence relative to non-Latino whites and barriers to healthcare access. Several studies have found misconceptions about AD among Latinos that were linked to reduced preventative or help-seeking behavior. To improve understanding of illness perceptions among Latinos, we examined beliefs about the causes of AD, one of the five dimensions of illness representations from Leventhal's Self-Regulation Theory, among a sample of N = 216 Latinos. We conducted in-depth, semi-structured interviews with participants aged 40 to 64 (average age 53 years) living in northern Manhattan. Seven distinct causes of AD were identified, though participants demonstrated a general understanding of AD as a multifactorial disease. Genetics was found to be the most endorsed cause of AD, followed by unhealthy lifestyle factors. Most Latinos who believed psychosocial factors played a critical role in AD development were first-generation immigrants. No participants attributed AD to a normal process of aging, and few ascribed the disease to brain damage from stroke or head injuries. Several participants expressed the belief that environmental contaminants can cause AD, which has received little mention in prior studies. Though only a small number thought AD could occur by chance, most participants remained uncertain about the exact causes of the disease and used lay knowledge to explain their beliefs. Our findings help identify areas where educational interventions would be beneficial in improving community knowledge and offer perspectives that can foster cultural competency in healthcare.

Clinical impact of diagnostic image-guided injections for musculoskeletal pain work-up in adolescent and adult patients at a children's hospital: initial results.

OBJECTIVE: To assess the clinical impact of diagnostic musculoskeletal (MSK) injections on treatment decision-making in adolescent and adult patients at a children's hospital. MATERIALS AND METHODS: Retrospective study in patients who underwent diagnostic MSK injections by fluoroscopy or ultrasound (US) between 8/2020 and 3/2023 at a children's hospital. Patients received ropivacaine and triamcinolone acetonide at pain site, reporting quantitative FACES pain score prior to, immediately following, and 2-3 days following injection. Impact on patient care was subsequently assessed. RESULTS: A total of 109 diagnostic fluoroscopic or US MSK injection referrals (mean: 17.6 years old) were included, most commonly hip (76.2%), ankle (9.2%), and iliopsoas tendon sheath (8.3%). Pain improvement occurred in 89.0% immediately and 67.9% 2-3 days after MSK injection, with net 84.4% exhibiting improvement based on pain scores and clinical exams. When there was pain improvement at the site of injection, there was a statistically higher incidence of operative intervention or additional therapeutic injections compared with the cohort that did not have symptom improvement (88% versus 35.3%, P < 0.0001). For the 15.6% (N = 17) of referrals that did not have pain improvement, 17.6% (n = 3) ultimately had an operative intervention at a separate site from the diagnostic injection, as an alternative etiology for the pain was found. CONCLUSION: Image-guided MSK injections play an important role in the management of musculoskeletal disorders. 84.4% of referrals experienced symptom relief, improving confidence for treatment decision-making. Importantly, 15.6% of patients were found to have an alternative etiology for symptoms, altering management altogether.

Hospital admission as a deprescribing triage point for patients discharged to Residential Aged Care Facilities.

BACKGROUND: Deprescribing may benefit older frail patients experiencing polypharmacy. We investigated the scope for deprescribing in acutely hospitalised patients and the long-term implications of continuation of medications that could potentially be deprescribed. METHODS: Acutely hospitalised patients (n = 170) discharged to Residential Aged Care Facilities, ≥75 years and receiving ≥5 regular medications were assessed during admission to determine eligibility for deprescribing of key drug classes, along with the actual incidence of deprescribing. The impact of continuation of nominated drug classes (anticoagulants, antidiabetics, antiplatelets, antipsychotics, benzodiazepines, proton pump inhibitors (PPIs), statins) on a combined endpoint (death/readmission) was determined. RESULTS: Hyperpolypharmacy (>10 regular medications) was common (49.4%) at admission. Varying rates of deprescribing occurred during hospitalisation for the nominated drug classes (8-53%), with considerable potential for further deprescribing (34-90%). PPI use was prevalent (56%) and 89.5% of these had no clear indication. Of the drug classes studied, only continued PPI use at discharge was associated with increased mortality/readmission at 1 year (hazard ratio 1.54, 95% confidence interval (1.06-2.26), P = 0.025), driven largely by readmission. CONCLUSION: There is considerable scope for acute hospitalisation to act as a triage point for deprescribing in older patients. PPIs in particular appeared overprescribed in this susceptible patient group, and this was associated with earlier readmission. Polypharmacy in older hospitalised patients should be targeted for possible deprescribing during hospitalisation, especially PPIs.

Cross-Species Transcriptome Profiling Identifies New Alveolar Epithelial Type I Cell-Specific Genes.

Diseases involving the distal lung alveolar epithelium include chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung adenocarcinoma. Accurate labeling of specific cell types is critical for determining the contribution of each to the pathogenesis of these diseases. The distal lung alveolar epithelium is composed of two cell types, alveolar epithelial type 1 (AT1) and type 2 (AT2) cells. Although cell type-specific markers, most prominently surfactant protein C, have allowed detailed lineage tracing studies of AT2 cell differentiation and the cells' roles in disease, studies of AT1 cells have been hampered by a lack of genes with expression unique to AT1 cells. In this study, we performed genome-wide expression profiling of multiple rat organs together with purified rat AT2, AT1, and in vitro differentiated AT1-like cells, resulting in the identification of 54 candidate AT1 cell markers. Cross-referencing with genes up-regulated in human in vitro differentiated AT1-like cells narrowed the potential list to 18 candidate genes. Testing the top four candidate genes at RNA and protein levels revealed GRAM domain 2 (GRAMD2), a protein of unknown function, as highly specific to AT1 cells. RNA sequencing (RNAseq) confirmed that GRAMD2 is transcriptionally silent in human AT2 cells. Immunofluorescence verified that GRAMD2 expression is restricted to the plasma membrane of AT1 cells and is not expressed in bronchial epithelial cells, whereas reverse transcription-polymerase chain reaction confirmed that it is not expressed in endothelial cells. Using GRAMD2 as a new AT1 cell-specific gene will enhance AT1 cell isolation, the investigation of alveolar epithelial cell differentiation potential, and the contribution of AT1 cells to distal lung diseases.

Epidermal growth factor augments the self-renewal capacity of aged hematopoietic stem cells.

Hematopoietic aging is associated with decreased hematopoietic stem cell (HSC) self-renewal capacity and myeloid skewing. We report that culture of bone marrow (BM) HSCs from aged mice with epidermal growth factor (EGF) suppressed myeloid skewing, increased multipotent colony formation, and increased HSC repopulation in primary and secondary transplantation assays. Mice transplanted with aged, EGF-treated HSCs displayed increased donor cell engraftment within BM HSCs and systemic administration of EGF to aged mice increased HSC self-renewal capacity in primary and secondary transplantation assays. Expression of a dominant negative EGFR in Scl/Tal1+ hematopoietic cells caused increased myeloid skewing and depletion of long term-HSCs in 15-month-old mice. EGF treatment decreased DNA damage in aged HSCs and shifted the transcriptome of aged HSCs from genes regulating cell death to genes involved in HSC self-renewal and DNA repair but had no effect on HSC senescence. These data suggest that EGFR signaling regulates the repopulating capacity of aged HSCs.

Analysis of protein-RNA complexes involving a RNA recognition motif engineered to bind hairpins with seven- and eight-nucleotide loops.

U1A binds U1hpII, a hairpin RNA with a 10-nucleotide loop. A U1A mutant (ΔK50ΔM51) binds U1hpII-derived hairpins with shorter loops, making it an interesting scaffold for engineering or evolving proteins that bind similarly sized disease-related hairpin RNAs. However, a more detailed understanding of complexes involving ΔK50ΔM51 is likely a prerequisite to generating such proteins. Toward this end, we measured mutational effects for complexes involving U1A ΔK50ΔM51 and U1hpII-derived hairpin RNAs with seven- or eight-nucleotide loops and identified contacts that are critical to the stabilization of these complexes. Our data provide valuable insight into sequence-selective recognition of seven- or eight-nucleotide loop hairpins by an engineered RNA binding protein.

Decoding the IGF1 signaling gene regulatory network behind alveologenesis from a mouse model of bronchopulmonary dysplasia.

Lung development is precisely controlled by underlying gene regulatory networks (GRN). Disruption of genes in the network can interrupt normal development and cause diseases such as bronchopulmonary dysplasia (BPD) - a chronic lung disease in preterm infants with morbid and sometimes lethal consequences characterized by lung immaturity and reduced alveolarization. Here, we generated a transgenic mouse exhibiting a moderate severity BPD phenotype by blocking IGF1 signaling in secondary crest myofibroblasts (SCMF) at the onset of alveologenesis. Using approaches mirroring the construction of the model GRN in sea urchin's development, we constructed the IGF1 signaling network underlying alveologenesis using this mouse model that phenocopies BPD. The constructed GRN, consisting of 43 genes, provides a bird's eye view of how the genes downstream of IGF1 are regulatorily connected. The GRN also reveals a mechanistic interpretation of how the effects of IGF1 signaling are transduced within SCMF from its specification genes to its effector genes and then from SCMF to its neighboring alveolar epithelial cells with WNT5A and FGF10 signaling as the bridge. Consistently, blocking WNT5A signaling in mice phenocopies BPD as inferred by the network. A comparative study on human samples suggests that a GRN of similar components and wiring underlies human BPD. Our network view of alveologenesis is transforming our perspective to understand and treat BPD. This new perspective calls for the construction of the full signaling GRN underlying alveologenesis, upon which targeted therapies for this neonatal chronic lung disease can be viably developed.

Educational intervention to adopt selective laser trabeculoplasty as first-line glaucoma treatment: Randomized controlled trial: Educational intervention on selective laser trabeculoplasty.

PURPOSE: To determine the efficacy of an educational intervention on patient adoption and attitudes toward selective laser trabeculoplasty (SLT) as first-line treatment for glaucoma. METHODS: This study is a randomized controlled trial. Subjects include 33 patients within 1-year diagnosis of either primary open-angle glaucoma, ocular hypertension, or pseudoexfoliation syndrome. After informed consent, subjects were randomly assigned to a Usual Care or Educational Intervention group. All subjects completed a pre-intervention questionnaire. The Educational Intervention group was shown a slideshow presentation and a 3-min video and given a post-intervention questionnaire. Follow-up examinations were reviewed for 6 months to determine subject completion of SLT, the primary outcome. Secondary outcomes include assessment of attitude toward SLT before and after intervention. RESULTS: Age, gender, and baseline characteristics between the groups did not differ. The Usual Care group had a higher proportion of African Americans (77% vs 31%, p = 0.04). At 6 months following the intervention, 63% of subjects underwent SLT compared to 35% of Usual Care subjects (p = 0.12). Older age was associated with decreased SLT uptake (OR 0.90, 95% CI 0.82-0.99, p = 0.03). Prior to the intervention, there were no differences in attitudes of both groups regarding SLT therapy. Nineteen percent of Educational Intervention subjects changed positively toward SLT (p = 0.08) and 50% scheduled an SLT appointment after intervention (p = 0.005). CONCLUSIONS: A slideshow and video-based educational intervention may positively enhance patient adoption of SLT.Clinical trial registration name, number, URL: Educational Intervention to Adopt SLT as First-Line Glaucoma Treatment, NCT03365778, https://clinicaltrials.gov/ct2/show/NCT03365778.

Development of human alveolar epithelial cell models to study distal lung biology and disease.

Many acute and chronic diseases affect the distal lung alveoli. Alveolar epithelial cell (AEC) lines are needed to better model these diseases. We used de-identified human remnant transplant lungs to develop a method to establish AEC lines. The lines grow well in 2-dimensional (2D) culture as epithelial monolayers expressing lung progenitor markers. In 3-dimensional (3D) culture with fibroblasts, Matrigel, and specific media conditions, the cells form alveolar-like organoids expressing mature AEC markers including aquaporin 5 (AQP5), G-protein-coupled receptor class C group 5 member A (GPRC5A), and surface marker HTII280. Single-cell RNA sequencing of an AEC line in 2D versus 3D culture revealed increased cellular heterogeneity and induction of cytokine and lipoprotein signaling in 3D organoids. Our approach yields lung progenitor lines that retain the ability to differentiate along the alveolar cell lineage despite long-term expansion and provides a valuable system to model and study the distal lung in vitro.

Single Cell Sequencing Analysis of Lizard Phagocytic Cell Populations and Their Role in Tail Regeneration.

Lizards are the closest relatives of mammals capable of tail regeneration, but the specific determinants of amniote regenerative capabilities are currently unknown. Macrophages are phagocytic immune cells that play a critical role in wound healing and tissue regeneration in a wide range of species. We hypothesize that macrophages regulate the process of lizard tail regeneration, and that comparisons with mammalian cell populations will yield insight into the role phagocytes play in determining an organism's regenerative potential. Single cell RNA sequencing (scRNAseq) was used to profile lizard immune cells and compare with mouse counterparts to contrast cell types between the two species. Treatment with clodronate liposomes effectively inhibited lizard tail stump tissue ablation and subsequent regeneration, and scRNAseq was used to profile changes in lizard immune cell populations resulting from tail amputation as well as identifying specific cell types affected by clodronate treatment. ScRNAseq analysis of lizard bone marrow, peripheral blood, and tissue-resident phagocyte cell populations was used to trace marker progression during macrophage differentiation and activation. These results indicated that lizard macrophages are recruited to tail amputation injuries faster than mouse populations and express high levels of matrix metalloproteinases (MMPs). In turn, treatment with MMP inhibitors inhibited lizard tail regeneration. These results provide single cell sequencing data sets for evaluating and comparing lizard and mammalian immune cell populations, and identifying macrophage populations that are critical regulators of lizard tail regrowth.

Beliefs and Attitudes of Ophthalmologists Regarding SLT as First Line Therapy for Glaucoma.

PRECIS: Targeted educational interventions for physicians may be useful in increasing adoption of selective laser trabeculoplasty (SLT) as first line therapy for the treatment of glaucoma. PURPOSE: SLT is a safe and effective first line treatment for glaucoma, however, it is underutilized. To evaluate barriers for the widespread adoption of this procedure, we assessed the beliefs and attitudes of ophthalmologists. We developed an educational intervention directed to physicians to increase the consideration of SLT earlier in the glaucoma treatment paradigm. SUBJECTS AND METHODS: In this prospective study, an online survey and educational slide presentation was sent to a group of comprehensive ophthalmologists, ophthalmology residents, and glaucoma specialists. Subjects were asked to respond to questions regarding their beliefs and attitudes towards SLT before and after watching the educational slide presentation. RESULTS: A total of 53 subjects were enrolled. Before watching the slide presentation, 85% of subjects stated they offer SLT to newly diagnosed patients, although only 28% preferred it over medications. While 52% of physicians reported between 0% and 10% of their newly diagnosed patients receive laser therapy, 47% said they would use it as a first line therapy for all or most newly diagnosed glaucoma patients. Most subjects (94%) stated the educational slide presentation convinced them that SLT is appropriate as a first line therapy for treatment of open angle glaucoma. CONCLUSIONS: A better understanding of the barriers for utilizing SLT as a first line therapy provides valuable information to help increase the adoption of this safe and effective procedure. A targeted educational intervention may improve acceptance of SLT as first line therapy for open angle glaucoma.

RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and highly resistant to available chemotherapies. Mammalian target of rapamycin (mTOR) functions to regulate protein translation, angiogenesis and cell cycle progression in many cancers including HCC. In the present study, subcutaneous patient-derived HCC xenografts were used to study the effects of an mTOR inhibitor, RAD001 (everolimus), on tumour growth, apoptosis and angiogenesis. We report that oral administration of RAD001 to mice bearing patient-derived HCC xenografts resulted in a dose-dependent inhibition of tumour growth. RAD001-induced growth suppression was associated with inactivation of downstream targets of mTOR, reduction in VEGF expression and microvessel density, inhibition of cell proliferation, up-regulation of p27(Kip1) and down-regulation of p21(Cip1/Waf1), Cdk-6, Cdk-2, Cdk-4, cdc-25C, cyclin B1 and c-Myc. Our data indicate that the mTOR pathway plays an important role in angiogenesis, cell cycle progression and proliferation of liver cancer cells. Our study provides a strong rationale for clinical investigation of mTOR inhibitor RAD001 in patients with HCC.

Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) is the fifth most common primary neoplasm; surgery is the only curative option but 5-year survival rates are only 25% to 50%. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are known to be involved in growth and neovascularization of HCC. Therefore, agents that target these pathways may be effective in the treatment of HCC. The aim of this study was to determine the antineoplastic activity of brivanib alaninate, a dual inhibitor of VEGF receptor (VEGFR) and FGF receptor (FGFR) signaling pathways. EXPERIMENTAL DESIGN: Six different s.c. patient-derived HCC xenografts were implanted into mice. Tumor growth was evaluated in mice treated with brivanib compared with control. The effects of brivanib on apoptosis and cell proliferation were evaluated by immunohistochemistry. The SK-HEP1 and HepG2 cells were used to investigate the effects of brivanib on the VEGFR-2 and FGFR-1 signaling pathways in vitro. Western blotting was used to determine changes in proteins in these xenografts and cell lines. RESULTS: Brivanib significantly suppressed tumor growth in five of six xenograft lines. Furthermore, brivanib-induced growth inhibition was associated with a decrease in phosphorylated VEGFR-2 at Tyr(1054/1059), increased apoptosis, reduced microvessel density, inhibition of cell proliferation, and down-regulation of cell cycle regulators. The levels of FGFR-1 and FGFR-2 expression in these xenograft lines were positively correlated with its sensitivity to brivanib-induced growth inhibition. In VEGF-stimulated and basic FGF stimulated SK-HEP1 cells, brivanib significantly inhibited VEGFR-2, FGFR-1, extracellular signal-regulated kinase 1/2, and Akt phosphorylation. CONCLUSION: This study provides a strong rationale for clinical investigation of brivanib in patients with HCC.

Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignancy in Asia and Africa. We previously reported that overexpression of extracellular signal-regulated kinase (ERK) kinase 1/2 (MEK1/2) and ERK1/2 was detected in HCC, and that their activation was required for liver cancer cell proliferation and survival. In the present study, we determined the efficacy of a specific MEK1/2 inhibitor AZD6244 (ARRAY-142886) in treatment of HCC. Treatment of primary HCC cells with AZD6244 led to growth inhibition, elevation of the cleavage of caspase-3 and caspase-7, and cleaved poly(ADP)ribose polymerase, but inhibition of ERK1/2 and p90RSK phosphorylation. Studying the protein expression profile of seven HCC xenografts revealed that their growth rate was positively correlated with the levels of phosphorylated MEK. AZD6244, when given p.o. to mice bearing these xenografts, resulted in a dose-dependent inhibition of tumor growth. AZD6244-induced growth suppression was associated with inactivation of ERK1/2 and p90RSK, and up-regulation of activated caspase-3 and caspase-7, and cleaved poly(ADP)ribose polymerase. Our data suggest that the MEK-ERK pathway plays an important role in the growth and survival of liver cancer cells and that the HCC xenograft models are excellent tools for screening preclinical drugs. Targeted inhibition of the MEK-ERK pathway with AZD6244 may represent an alternative approach for the treatment of this disease.

Efficacy and outcomes of a summer-based pediatric vision screening program.

PURPOSE: To investigate the prevalence of decreased visual acuity and uncorrected refractive error in school-aged children participating in summer programs. METHODS: During the summers of 2014-2016, Wills Eye Hospital collaborated with summer programs in Philadelphia to provide vision screenings for underserved children. Parental consent was obtained prior to vision screening. Fail criteria included children in grades K-1 (ages 5-6) with visual acuity worse than 20/40 in either eye, children in grades 2-6 (ages 7-13) with visual acuity worse than 20/30 in either eye, or children with ≥2 lines of interocular difference. If decreased visual acuity was correctable to ≥20/30 by the onsite optometrist, two pairs of free eyeglasses were provided. Children with other ocular abnormalities were referred to pediatric ophthalmology. RESULTS: Of 1,627 children screened, 360 children (22.1%) did not pass vision screening, and 64 (3.9%) were referred. The prevalence of decreased distance visual was 34.1%. Younger children were more likely to have worse visual acuity than older children (OR = 0.943; P = 0.023; 95% CI, 0.896-0.992). Myopia (73%), astigmatism (56.8%), hyperopia (15.5%), spherical anisometropia (12.5%), and cylindrical anisometropia (11.9%) presented in the 303 children who underwent a manifest refraction. Myopia increased with age (OR = 0.818; P = 0.001; 95% CI, 0.724-0.922), whereas astigmatism decreased (OR = 0.817; P < 0.001; 95% CI, 0.728-0.913) with age. Two pairs of glasses were provided to 301 children. CONCLUSIONS: Partnership with summer programs and other community initiatives to provide vision screenings facilitates access to eye care ultimately aimed at improving social functioning and academic performance.