Diagnostic Role of Oral Fluorescein Angiography in Pediatric Ambulatory Clinics.

Oral ingestion of fluorescein can be done in ambulatory pediatric clinics. We show that oral ultra-widefield fluorescein angiography is a non-invasive approach to rapidly diagnose and manage a diverse set of pediatric retinal vascular diseases.

Validity of an Automated Algorithm to Identify Cirrhosis Using Electronic Health Records in Patients with Primary Biliary Cholangitis.

BACKGROUND: Biopsy remains the gold standard for determining fibrosis stage in patients with primary biliary cholangitis (PBC), but it is unavailable for most patients. We used data from the 11 US health systems in the FibrOtic Liver Disease Consortium to explore a combination of biochemical markers and electronic health record (EHR)-based diagnosis/procedure codes (DPCs) to identify the presence of cirrhosis in PBC patients. METHODS: Histological fibrosis staging data were obtained from liver biopsies. Variables considered for the model included demographics (age, gender, race, ethnicity), total bilirubin, alkaline phosphatase, albumin, aspartate aminotransferase (AST) to platelet ratio index (APRI), Fibrosis 4 (FIB4) index, AST to alanine aminotransferase (ALT) ratio, and >100 DPCs associated with cirrhosis/decompensated cirrhosis, categorized into ten clusters. Using least absolute shrinkage and selection operator regression (LASSO), we derived and validated cutoffs for identifying cirrhosis. RESULTS: Among 4328 PBC patients, 1350 (32%) had biopsy data; 121 (9%) were staged F4 (cirrhosis). DPC clusters (including codes related to cirrhosis and hepatocellular carcinoma diagnoses/procedures), Hispanic ethnicity, ALP, AST/ALT ratio, and total bilirubin were retained in the final model (AUROC=0.86 and 0.83 on learning and testing data, respectively); this model with two cutoffs divided patients into three categories (no cirrhosis, indeterminate, and cirrhosis) with specificities of 81.8% (for no cirrhosis) and 80.3% (for cirrhosis). A model excluding DPCs retained ALP, AST/ALT ratio, total bilirubin, Hispanic ethnicity, and gender (AUROC=0.81 and 0.78 on learning and testing data, respectively). CONCLUSION: An algorithm using laboratory results and DPCs can categorize a majority of PBC patients as cirrhotic or noncirrhotic with high accuracy (with a small remaining group of patients' cirrhosis status indeterminate). In the absence of biopsy data, this EHR-based model can be used to identify cirrhosis in cohorts of PBC patients for research and/or clinical follow-up.

Orally Bioavailable and Blood-Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice.

Inhibition of ataxia-telangiectasia mutated (ATM) during radiotherapy of glioblastoma multiforme (GBM) may improve tumor control by short-circuiting the response to radiation-induced DNA damage. A major impediment for clinical implementation is that current inhibitors have limited central nervous system (CNS) bioavailability; thus, the goal was to identify ATM inhibitors (ATMi) with improved CNS penetration. Drug screens and refinement of lead compounds identified AZ31 and AZ32. The compounds were then tested in vivo for efficacy and impact on tumor and healthy brain. Both AZ31 and AZ32 blocked the DNA damage response and radiosensitized GBM cells in vitro AZ32, with enhanced blood-brain barrier (BBB) penetration, was highly efficient in vivo as radiosensitizer in syngeneic and human, orthotopic mouse glioma model compared with AZ31. Furthermore, human glioma cell lines expressing mutant p53 or having checkpoint-defective mutations were particularly sensitive to ATMi radiosensitization. The mechanism for this p53 effect involves a propensity to undergo mitotic catastrophe relative to cells with wild-type p53. In vivo, apoptosis was >6-fold higher in tumor relative to healthy brain after exposure to AZ32 and low-dose radiation. AZ32 is the first ATMi with oral bioavailability shown to radiosensitize glioma and improve survival in orthotopic mouse models. These findings support the development of a clinical-grade, BBB-penetrating ATMi for the treatment of GBM. Importantly, because many GBMs have defective p53 signaling, the use of an ATMi concurrent with standard radiotherapy is expected to be cancer-specific, increase the therapeutic ratio, and maintain full therapeutic effect at lower radiation doses. Mol Cancer Ther; 17(8); 1637-47. ©2018 AACR.

Laparoscopic versus open pyloromyotomy in infants: a systematic review and meta-analysis.

PURPOSE: To determine whether open or laparoscopic pyloromyotomy is superior for the treatment of hypertrophic pyloric stenosis in infants. METHODS: We searched MEDLINE, EMBASE, and CENTRAL for articles comparing laparoscopic and open procedures. We conducted meta-analyses when possible and described other results narratively. RESULTS: Our meta-analyses revealed no significant difference in our primary outcome of major complications [risk difference (RD) 0.03, 95% confidence interval (CI) -0.03 to 0.08, P = 0.35, I 2 = 55%], or in our secondary outcomes of all perioperative complications (RD -0.01, 95% CI -0.06 to 0.04, P = 0.74, I 2 = 0%), operative time [mean difference (MD) 0.68, 95% CI -3.60 to 4.79, P = 0.76, I 2 = 86%], and length of stay (MD -2.60, 95% CI -6.05 to 0.86, P = 0.14, I 2 = 0%). Laparoscopy was associated with a shorter time to full feeds (standardized mean difference -0.25, 95% CI -0.43 to -0.06, P = 0.009, I 2 = 8%) and a slightly higher rate of inadequate pyloromyotomy (RD 0.04, 95% CI 0.00-0.08, P = 0.03, I 2 = 0%). Results from one randomized controlled trial indicate a better cosmetic outcome after laparoscopy compared to open procedure. CONCLUSION: There is no strong evidence to support a recommendation of one procedure over the other; therefore, the choice of laparoscopic or open procedure should be left to the discretion of the surgeon.

Management of a Complex Excoriation Disorder-induced Wound with a Viable Cryopreserved Placental Membrane.

Excoriation disorder (ED), also known as dermatotillomania, is a condition characterized by repeated "skin picking" that leads to the formation of skin lesions. Because of the similarity of its symptoms to obsessive compulsive disorder, ED is classified as a subcategory of obsessive compulsive disorder by Diagnostic and Statistical Manual of Mental Disorders Fifth Edition. Although the majority of the self-inflicted wounds are not clinically significant, many wounds lead to social and occupational dysfunction by becoming infected, chronic, and life threatening. This report describes the successful use of a viable intact cryopreserved human amniotic membrane in conjunction with selective serotonin re-uptake inhibitors in treating an ED patient who presented with a large calvarial wound of 3-year duration that had failed previous extensive medical and surgical interventions.

Phytic Acid and Inorganic Phosphate Composition in Soybean Lines with Independent IPK1 Mutations.

Soybean seeds contain a large amount of P, which is stored as phytic acid (PA). Phytic acid is indigestible by nonruminant livestock and considered an antinutritional factor in soybean meal. Several low PA soybean lines have been discovered, but many of these lines have either minor reductions in PA or inadequate germination and emergence. The reduced PA phenotype of soybean line Gm-lpa-ZC-2 was previously shown to be the result of a mutation in a gene encoding an inositol pentakisphosphate 2-kinase on chromosome 14 (14IPK1). While the 14IPK1 mutation was shown to have no impact on germination and emergence, the reduction in PA was modest (up to 50%). Our objective was to determine the effect on seed P partitioning for a novel mutation of an independent IPK1 gene on chromosome six (06IPK1) on its own and in combination with mutant alleles of the 14IPK1. We developed soybean populations and conducted genotype and phenotype association analyses based on the genotype of the 06IPK1 and 14IPK1 genes and the seed P partitioning profile. The lines with both mutant IPK1 genes had very low PA levels, moderate accumulation of inorganic phosphate (Pi), and accumulation of high amounts of P in lower inositols. The developed lines did not have significant reductions in germination or field emergence. In addition, characterization of the lower inositols produced in the mutant lines suggests that IPK1 is a polyphosphate kinase and provides some insight into the PA biosynthesis pathway in soybean seeds.

Survey respondents planning to have screening colonoscopy report unique barriers.

Tailoring colorectal cancer screening interventions to address the needs of individuals for whom screening is recommended requires accurate identification of the barriers experienced by each targeted group. The primary purpose of this survey study was to test differences in the barriers to undergoing screening colonoscopy reported by men and women. In addition, we were interested in differences in barriers reported by 1) 50-year-olds versus those age 51 to 80 years, 2) persons reporting readiness for colonoscopy versus those not reporting readiness, and 3) persons who had had a primary care encounter in the preceding 12 months versus those who had not. Four thousand members of a health maintenance organization (Scott & White Health Plan) were surveyed. Response rate overall was 30.85%. No differences in barriers to screening colonoscopy were identified for men versus women. We did identify differences in barriers reported by persons reporting readiness versus those not reporting readiness. Findings suggest that interventions to increase rates of screening colonoscopy require addressing different sets of barriers depending on whether persons report readiness to have a colonoscopy within 6 months.

Novel 4-anilinoquinazolines with C-6 carbon-linked side chains: synthesis and structure-activity relationship of a series of potent, orally active, EGF receptor tyrosine kinase inhibitors.

The structure-activity relationship of a novel subseries of 4-anilinoquinazoline EGFR inhibitors substituted at the C-6 position with carbon-linked side chains has been investigated. This exploration has led to the discovery of novel aminomethyl carboxamides with good biological, pharmacokinetic and physical properties.