Opportunities in Assessing and Regulating Organohalogen Flame Retardants (OFRs) as a Class in Consumer Products.

BACKGROUND: In 2015, the U.S. Consumer Product Safety Commission (CPSC) received and then, in 2017, granted a petition under the Federal Hazardous Substances Act to declare certain groups of consumer products as banned hazardous substances if they contain nonpolymeric, additive organohalogen flame retardants (OFRs). The petitioners asked the CPSC to regulate OFRs as a single chemical class with similar health effects. The CPSC later sponsored a National Academy of Sciences, Engineering, and Medicine (NASEM) report in 2019, which ultimately identified 161 OFRs and grouped them into 14 subclasses based on chemical structural similarity. In 2021, a follow-up discussion was held among a group of scientists from both inside and outside of the CPSC for current research on OFRs and to promote collaboration that could increase public awareness of CPSC work and support the class-based approach for the CPSC's required risk assessment of OFRs. OBJECTIVES: Given the extensive data collected to date, there is a need to synthesize what is known about OFR and how class-based regulations have previously managed this information. This commentary discusses both OFR exposure and OFR toxicity and fills some gaps for OFR exposure that were not within the scope of the NASEM report. The objective of this commentary is therefore to provide an overview of the OFR research presented at SOT 2021, explore opportunities and challenges associated with OFR risk assessment, and inform CPSC's work on an OFR class-based approach. DISCUSSION: A class-based approach for regulating OFRs can be successful. Expanding the use of read-across and the use of New Approach Methodologies (NAMs) in assessing and regulating existing chemicals was considered as a necessary part of the class-based process. Recommendations for OFR class-based risk assessment include the need to balance fire and chemical safety and to protect vulnerable populations, including children and pregnant women. The authors also suggest the CPSC should consider global, federal, and state OFR regulations. The lack of data or lack of concordance in toxicity data could present significant hurdles for some OFR subclasses. The potential for cumulative risks within or between subclasses, OFR mixtures, and metabolites common to more than one OFR all add extra complexity for class-based risk assessment. This commentary discusses scientific and regulatory challenges for a class-based approach suggested by NASEM. This commentary is offered as a resource for anyone performing class-based assessments and to provide potential collaboration opportunities for OFR stakeholders. https://doi.org/10.1289/EHP12725.

Topology and adenocarcinoma cell localization dataset on the labyrinthin diapeutic biomarker.

OBJECTIVE: The discovery and characterization of tumor associated antigens is increasingly important to advance the field of immuno-oncology. In this regard, labyrinthin has been implicated as a neoantigen found on the cell surface of adenocarcinomas. Data on the (1) topology, (2) amino acid (a.a.) homology analyses and (3) cell surface localization of labyrinthin by fluorescent activated cell sorter (FACS) are studied in support of labyrinthin as a novel, pan-adenocarcinoma marker. RESULTS: Bioinformatics analyses predict labyrinthin as a type II protein with calcium binding domain(s), N-myristoylation sites, and kinase II phosphorylation sites. Sequence homologies for labyrinthin (255 a.a.) were found vs. the intracellular aspartyl/asparaginyl beta-hydroxylase (ASPH; 758 a.a.) and the ASPH-gene related protein junctate (299 a.a.), which are both type II proteins. Labyrinthin was detected by FACS on only non-permeablized A549 human lung adenocarcinoma cells, but not on normal WI-38 human lung fibroblasts nor primary cultures of normal human glandular-related cells. Microscopic images of immunofluorescent labelled MCA 44-3A6 binding to A549 cells at random cell cycle stages complement the FACS results by further showing that labyrinthin persisted on the cell surfaces along with some cell internalization for greater than 20 min.

Labyrinthin Expression Is Associated with Poor Prognosis in Patients with Non-Small-Cell Lung Cancer.

To determine Labyrinthin (LAB) expression in non-small-cell lung cancer (NSCLC), we immunostained and scored for LAB immunohistochemistry (IHC) expression on sections of tissue microarrays (TMAs) prepared from 256 archival tissue blocks of NSCLC. Propensity-score-weighted Kaplan-Meier curves and weighted Cox models were used to associate LAB expression with overall survival. LAB mRNA expression was assessed in The Cancer Genome Atlas (TCGA) and correlated with clinical phenotype and outcome. Positive LAB IHC expression (>5% of tumor cells) was detected in 208/256 (81.3%) of NSCLC samples, and found in both lung adenocarcinomas (LUAD) and lung squamous cell cancer (LUSC). LAB positivity was associated with poor overall survival (HR = 3.56, 95% CI: 2.3-5.4; p < 0.0001) and high tumor differentiation grade or metastasis compared with negative LAB expression. Univariant and multivariate survival analyses demonstrated LAB expression as an independent prognostic factor for NSCLC patients. LAB RNA expression in TCGA-LUAD was higher in primary and advanced-stage tumors than in normal tissue, and was associated with poorer overall survival. No significant differences or associations were found with LAB RNA expression in TCGA-LUSC. The LAB IHC assay is being used to identify candidate cancer patients for the first-in-human phase I trial evaluating the LAB vaccines (UCDCC#296, NCT051013560).

Predictors and Outcomes of Palliative Care Consultations for Patients With Liver Disease: Results of a Cohort Study of 75 Million Medical Records.

Background: Liver transplant is the only cure for cirrhosis. We studied the impact of palliative care on patient care by conducting a population-based cohort study. Methods: We queried the Explorys database (IBM, New York) database for a diagnosis of 'cirrhosis' followed by 'palliative care consultation' and collected demographic and clinical data. Results: We identified 316,970 patients with cirrhosis. Palliative care was consulted for 10.9% (n = 34,600) of patients. Patients aged >65 [OR 1.33 (1.30-1.36), P < .0001], men [OR 1.13 (1.11-1.16), P < .0001], a diagnosis of hepatocellular carcinoma (HCC) [OR 2.53 (2.45-2.60), P < .0001] were more likely to receive a palliative care consultation. Patients for whom palliative care were consulted were less likely to undergo surgical procedures [OR .49 (.47-.50)]. Conclusion: Only about 1 in 10 cirrhotics received a palliative care consultation. Older patients, males, and patients with a diagnosis of HCC are more likely to receive palliative care.

Labyrinthin: A distinct pan-adenocarcinoma diagnostic and immunotherapeutic tumor specific antigen.

Structural analysis and detection of optimal cell surface localization of labyrinthin, a pan-adenocarcinoma target, was studied with respect to adenocarcinoma specificity vs. normal and non-adenocarcinoma cells. Patient-derived tissue microarray immunohistochemistry (IHC) was performed on 729 commercially prepared tissue blocks of lung, colon, breast, pancreas, prostate, and ovary cancers combined, plus a National Cancer Institute (NCI) tissue microarray derived from another 236 cases. The results confirmed that anti-labyrinthin mouse monoclonal MCA 44-3A6 antibody recognized adenocarcinomas, but not normal or non-adenocarcinoma cancer cells. The consensus of multiple topology analysis programs on labyrinthin (255 amino acids) estimate a type II cell membrane associated protein with an N-terminus signal peptide. However, because the labyrinthin sequence is enveloped within the 758 amino acids of the intracellular aspartyl/asparaginyl beta-hydroxylase (ASPH), a purported tumor associated antigen, standard IHC methods that permeabilize cells can expose common epitopes. To circumvent antibody cross-reactivity, cell surface labyrinthin was distinguished from intracellular ASPH by FACS analysis of permeabilized vs non-permeabilized cells. All permeabilized normal, adeno-and non-adenocarcinoma cells produced a strong MCA 44-3A6 binding signal, likely reflecting co-recognition of intracellular ASPH proteins along with internalized labyrinthin, but in non-permeabilized cells only adenocarcinoma cells were positive for labyrinthin. Confocal microscopy confirmed the FACS results. Labyrinthin as a functional cell-surface marker was suggested when: 1) WI-38 normal lung fibroblasts transfected with labyrinthin sense cDNA displayed a cancerous phenotype; 2) antisense transfection of A549 human lung adenocarcinoma cells appeared more normal; and 3) MCA44-3A6 suppressed A549 cell proliferation. Collectively, the data indicate that labyrinthin is a unique, promising adenocarcinoma tumor-specific antigen and therapeutic target. The study also raises a controversial issue on the extent, specificity, and usefulness of ASPH as an adenocarcinoma tumor-associated antigen.

Gastroenterology Fellowship Applicants' Perspectives on GI Program Preferences.

Gastroenterology fellowship continues to be highly competitive among internal medicine subspecialties. Recruiting excellent applicants is also important for GI fellowship program directors. We aim to examine factors that influence GI fellowship applicants' perspectives about a fellowship program. The authors conducted an anonymous online survey of applicants focusing on program characteristics including location, faculty, research/clinical opportunities, website, and interview day experience. Anonymous survey responses were recorded regarding program characteristics, and subsequent candidate preferences were evaluated for factors influencing their decision. Candidates were also asked to evaluate their interview experience and share other comments about the program. Though GI fellowship applicants have varying preferences regarding the ideal training program, some opinions converged. The study of these trends can inform program directors regarding areas for improvement that in turn can help attract the best applicants.

Plasticizer migration from children's toys, child care articles, art materials, and school supplies.

Dialkyl phthalates, including diisononyl phthalate (DINP), have been used as plasticizers in children's products made from polyvinyl chloride (PVC), such as teethers and toys. Children may be exposed to phthalates when handling or mouthing PVC products because plasticizers are not covalently bound. The Consumer Product Safety Improvement Act of 2008 prohibited certain phthalates from use in child care articles and children's toys. Thus, manufacturers have changed to other plasticizers or non-PVC plastics and there is interest in evaluating the potential health risks of alternative plasticizers. In 2008, CPSC staff purchased 63 children's products comprising 129 individual pieces (articles). Plastics identified FTIR included PVC, polypropylene, polyethylene, and acrylonitrile butadiene styrene. Plasticizers identified by in the 38 PVC articles included acetyltributyl citrate (ATBC) (20); di (2-ethylhexyl) terephthalate (DEHT) (14); 1,2-cyclohexanedicarboxylic acid diisononyl ester (DINX) (13); 2,2,4-trimethyl-1,3-pentanediol diisobutyrate (TPIB) (9); di (2 ethyhexyl) phthalate (DEHP) (1); and DINP (1). Half of the tested articles contained multiple plasticizers. CPSC measured migration rates using the Joint Research Centre method. Migration rates correlated roughly with plasticizer concentration and inversely with the molecular mass of the plasticizer. We then combined the migration rates with data on mouthing duration to estimate children's exposure to plasticizers in toys and child care articles, and estimated margins of exposure. All margins of exposure were >1,000, suggesting a low risk potential. However, the plasticizers in this study have multiple uses. Exposure from other sources and routes of exposure will be considered in future work.

Drug-Induced Liver Injury Resources and Reporting for the Clinician.

Although many risk factors for developing drug-induced liver injury (DILI) have been identified and more than 1000 medications and herbal and dietary supplements are known to cause liver dysfunction, idiosyncratic drug reactions remain unpredictable and erratic. Varying effects of individual drugs on the event cascade and patient genetic polymorphisms lead to different clinical presentations. Mechanisms and causality scales have been developed to guide the clinician in diagnosis, and several databases and registries are available for reference and reporting. We identify and summarize the resources available to clinicians to help diagnose, manage, and report DILI and to identify hepatotoxic drugs.

Labyrinthin, The Tumor Marker Recognized By MCA 44-3A6: A Case For Pan-Tumor Markers As Targets To Treat Cancer.

A paradigm shift is currently underway on the relationship between cancer treatment markers and therapies. Labyrinthin is a prime example of such a marker because it is a pan-cancer target for adenocarcinomas. This movement supports the idea that we must change our thinking from various cancer types (eg, lung, breast, colon) to "cancer arising" in a given tissue or organ. In doing so, this would further support the efforts toward pan-treatments rather than organ-specific treatments.

Adherence to Two Large-Bore Intravenous Lines in Acute Gastrointestinal Bleeding Is Low.

BACKGROUND: While the available literature recommends placement of two large-bore intravenous (2LBIV) lines in every patient presenting with acute GIB, the adherence and impact of this recommendation have never before been reported. AIMS: We designed a quality improvement project to assess whether the patients presenting to our institution with acute GIB have appropriate intravenous (IV) access or not. METHODS: We conducted a prospective, observational study, of all patients presenting to our emergency department with overt GIB over a 2-month period. Data analysis was performed, and based on the results, an intervention plan was developed and executed. Post-intervention data collection was done over a 3-month period. Our interventions included physician and nursing education, placing posters in the emergency department, and creation of an order set in the electronic medical record system. RESULTS: A total of 46 patients were in the pre-intervention group, and 71 patients were in the post-intervention group. The presence of 2LBIV lines in the pre-intervention group was only 19.5%, which improved to 36.6% in the post-intervention group (p = 0.049). Factors associated with placement of 2LBIV lines were being in the post-intervention group and admission to the intensive care unit. CONCLUSION: The relatively simple and cost-effective intervention of placing 2LBIV lines is not often executed. We suggest that specific mention of 2LBIV placement in guidelines from national gastroenterology societies might improve compliance in this aspect.

Differences between morning and afternoon colonoscopies for adenoma detection in female and male patients.

BACKGROUND: Colonoscopies performed in the afternoon (PM) have been shown to have lower adenoma detection rates (ADR) compared to those in the morning (AM). Endoscopist fatigue has been suggested as a possible reason. Colonoscopies tend to be technically more challenging in female patients. Furthermore, women have a lower incidence of adenomas then men. The impact of the timing of colonoscopy based on sex has not been studied. We hypothesized that any decrease in ADR in PM colonoscopies would be more pronounced in female patients when compared to male patients. METHODS: We retrospectively reviewed colonoscopies performed for screening or surveillance in our outpatient endoscopy center from January 2008 to December 2011. Complete colonoscopies with a documented cecal intubation were included. All patients with a history of colorectal cancer or colonic resection, inadequate bowel preparation, or incomplete data were excluded. RESULTS: A total of 2305 patients (1207 female) were included. Overall, ADR was significantly higher in AM than in PM procedures. Multivariate analysis demonstrated that ADR for females was lower in PM than in AM colonoscopies (odds ratio [OR] 0.63, 95% confidence interval [CI] 0.44-0.91, P=0.015). There was a non-significant trend towards a lower ADR for males in PM (OR 0.84, 95% CI 0.62-1.15, P=0.28). Females had a prolonged intubation time and a longer procedure time. CONCLUSION: The difference in ADR between AM and PM procedures seems to apply mainly to female patients. No significant change in ADR was noted in male patients in the afternoon.

Idiopathic Adulthood Ductopenia: 'It Is Out There'.

Idiopathic adulthood ductopenia (IAD) is a chronic cholestatic entity of unknown origin characterized by loss of inter-lobular bile ducts that was first described two decades ago. Although the diagnostic criteria have been described in detail, IAD continues to be a rare diagnosis. Our thorough literature search revealed less than a hundred cases of IAD reported. Here we present a 34-year-old female with no significant past history who was evaluated for persistent elevation of serum alkaline phosphate levels. Serology was negative for all viral hepatitides, and a chronic liver disease workup was unremarkable. Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography did not reveal any abnormalities in the biliary tree. Finally, a liver biopsy demonstrated ductopenia involving greater than 50% of the portal triads, making a diagnosis of IAD. Since the disease can progress rapidly, close follow-up is warranted, so liver transplantation can be pursued if deemed necessary.

Linoleic Acid Induced Acute Hepatitis: A Case Report and Review of the Literature.

Several dietary supplements used for weight loss have been reported to cause hepatotoxicity. Conjugated Linoleic Acid (CLA) is a dietary supplement that has been shown to cause reduction in body fat mass. Here, we present the first case of CLA induced acute hepatitis in the United States and only the third case in the worldwide literature along with a brief review of the literature.

Intense pruritus in Epstein-Barr virus (EBV) hepatitis treated with naloxone drip.

Pruritus is a manifestation of chronic liver disease. Epstein-Barr virus (EBV) infection often presents as infectious mononucleosis and mild hepatitis. Severe pruritus in the setting of infectious mononucleosis and persistent marked hyperbilirubinaemia is exceedingly uncommon. To the best of our knowledge, we present the first case of a patient with EBV hepatitis and severe pruritus that was successfully treated with an ultra-low dose of intravenous naltraxone.

Hepatitis C variability, patterns of resistance, and impact on therapy.

Hepatitis C (HCV), a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma, is the most common indication for liver transplantation in the United States. Although annual incidence of infection has declined since the 1980s, aging of the currently infected population is expected to result in an increase in HCV burden. HCV is prone to develop resistance to antiviral drugs, and despite considerable efforts to understand the virus for effective treatments, our knowledge remains incomplete. This paper reviews HCV resistance mechanisms, the traditional treatment with and the new standard of care for hepatitis C treatment. Although these new treatments remain PEG-IFN-α- and ribavirin-based, they add one of the newly FDA approved direct antiviral agents, telaprevir or boceprevir. This new "triple therapy" has resulted in greater viral cure rates, although treatment failure remains a possibility. The future may belong to nucleoside/nucleotide analogues, non-nucleoside RNA-dependent RNA polymerase inhibitors, or cyclophilin inhibitors, and the treatment of HCV may ultimately parallel that of HIV. However, research should focus not only on effective treatments, but also on the development of a HCV vaccine, as this may prove to be the most cost-effective method of eradicating this disease.

Fundamentals of antibody-related therapy and diagnostics.

Antibodies for therapy and diagnostics form one of the fastest growing segments of the pharmaceutical market. The combination of hybridoma and recombinant DNA technologies have led to an increased production of monoclonal antibodies (MAbs), including fully human MAbs, that can be tailored for specific applications. With advances in imaging methods, MAbs are increasingly used as in vivo diagnostic tools. Therapeutic MAbs, used to treat cancer and autoimmune diseases, have proven beneficial in the clinic. An overview is presented of the history, current state and future perspectives of this emergent field.