bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interference with the HNF4-dependent gene regulatory network diminishes endoplasmic reticulum stress in hepatocytes
Authors: Shah Anit , Huck Ian , Duncan Kaylia , Gansemer Erica R. , Liu Kaihua , Adajar Reed C. , Apte Udayan , Stamnes Mark A. , Rutkowski D. Thomas 
Published: October 2023

Background:
In all eukaryotic cell types, the unfolded protein response (UPR) upregulates factors that promote protein folding and misfolded protein clearance to help alleviate endoplasmic reticulum (ER) stress. Yet, ER stress in the liver is uniquely accompanied by the suppression of metabolic genes, the coordination and purpose of which are largely unknown.

Methods:
Here, we combined in silico machine learning, in vivo liver-specific deletion of the master regulator of hepatocyte differentiation HNF4α, and in vitro manipulation of hepatocyte differentiation state to determine how the UPR regulates hepatocyte identity and toward what end.

Results:
Machine learning identified a cluster of correlated genes that were profoundly suppressed by persistent ER stress in the liver. These genes, which encode diverse functions including metabolism, coagulation, drug detoxification, and bile synthesis, are likely targets of the master regulator of hepatocyte differentiation HNF4α. The response of these genes to ER stress was phenocopied by liver-specific deletion of HNF4α. Strikingly, while deletion of HNF4α exacerbated liver injury in response to an ER stress challenge, it also diminished UPR activation and partially preserved ER ultrastructure, suggesting attenuated ER stress. Conversely, pharmacological maintenance of hepatocyte identity in vitro enhanced sensitivity to stress.

Conclusions:
Together, our findings suggest that the UPR regulates hepatocyte identity through HNF4α to protect ER homeostasis even at the expense of liver function.
HBV suppresses macrophage immune responses by impairing the TCA cycle through the induction of CS/PDHC hyperacetylation
Authors: Bei Jiaxin , Chen Ye , Zhang Qianbing , Wang Xiaobin , Lin Liteng , Huang Jingjun , Huang Wensou , Cai Mingyue , Cai Weiguo , Guo Yongjian , Zhu Kangshun 
Published: October 2023

Background:
It is now understood that HBV can induce innate and adaptive immune response disorders by affecting immunosuppressive macrophages, resulting in chronic HBV infection. However, the underlying mechanism is not fully understood. Dysregulated protein acetylation can reportedly influence the differentiation and functions of innate immune cells by coordinating metabolic signaling. This study aims to assess whether HBV suppresses macrophage-mediated innate immune responses by affecting protein acetylation and to elucidate the underlying mechanisms of HBV immune escape.

Methods:
We investigated the effect of HBV on the acetylation levels of human THP-1 macrophages and identified potential targets of acetylation that play a role in glucose metabolism. Metabolic and immune phenotypes of macrophages were analyzed using metabolomic and flow cytometry techniques. Western blot, immunoprecipitation, and immunofluorescence were performed to measure the interactions between deacetylase and acetylated targets. Chronic HBV persistent infected mice were established to evaluate the role of activating the tricarboxylic acid (TCA) cycle in macrophages for HBV clearance.

Results:
Citrate synthase/pyruvate dehydrogenase complex hyperacetylation in macrophages after HBV stimulation inhibited their enzymatic activities and was associated with impaired TCA cycle and M2-like polarization. HBV downregulated Sirtuin 3 (SIRT3) expression in macrophages by means of the toll-like receptor 2 (TLR2)-NF-κB- peroxisome proliferatoractivated receptor γ coactivator 1α (PGC-1α) axis, resulting in citrate synthase/pyruvate dehydrogenase complex hyperacetylation. In vivo administration of the TCA cycle agonist dichloroacetate inhibited macrophage M2-like polarization and effectively reduced the number of serum HBV DNA copies.

Conclusions:
HBV-induced citrate synthase/pyruvate dehydrogenase complex hyperacetylation negatively modulates the innate immune response by impairing the TCA cycle of macrophages. This mechanism represents a potential therapeutic target for controlling HBV infection.
A specialized HE testing clinic improves rational decision-making for therapy in cirrhosis
Authors: Nadeem Mahum , Tafader Asiya , Park Dan , Fagan Andrew , Wade James B. , Bajaj Jasmohan S. 
Published: October 2023

Background:
Cognitive complaints in cirrhosis are often attributed to HE with reflexive therapy if specialized tests are not performed. The aim was to determine the utility of a specialized HE clinic for management decisions.

Methods:
Cirrhosis patients with cognitive complaints were referred through a dedicated consult pathway to a specialized clinic and followed for 6 months. This clinic included detailed history, medication review, standardized tests [Mini-Mental Status Exam (MMSE), Psychometric HE Score, and others], and obstructive sleep apnea screening. Results were communicated with patients and referring providers. A subset was offered repeat testing.

Results:
A total of 286 patients were tested between 2012 and 2022. Of the 286 patients, 4 patients who showed a Mini-Mental State Exam <25 were referred to neurology. Thirty-nine percent had normal Psychometric HE Score (higher in younger patients, without prior HE, depression, and lower Model for End-Stage Liver Disease-Sodium), while 172 (61%) patients had cognitive impairment. Of the 172 patients, 51 did not want management change, 84 were started on HE therapy, and 37 were considered impaired due to other causes. In 51 without management change, 32 refused lactulose, while the remaining were counseled regarding lactulose titration. Of the 84 patients with HE-therapy initiation, lactulose was initiated in 56 and rifaximin in 28; most therapies continued over 6 months. The ones who were retested improved their Psychometric HE Score. The 37 with other causes (obstructive sleep apnea, mood disorders, substance use, and mild cognitive impairment) led to specialized referrals. No overt HE was found over 6 months in those without HE-related impairment. The clinic was billed for.

Conclusions:
A specialized HE clinic for patients with cirrhosis and cognitive complaints established through a dedicated consult pathway showed that 39% of referred patients had normal cognitive performance, while the results guided management changes, including for HE and other causes in the remaining patients.
Radiofrequency lesion formation prediction with contact force versus local impedance
Authors: Issa Ziad F. 
Published: October 2023

Purpose of review
Safe and effective radiofrequency (RF) myocardial ablation requires real-time monitoring of lesion formation. Here, we review conventional and novel approaches proposed to guide titration of RF energy application.

Recent findings
Conventional monitoring modalities, such as ablation electrode temperature, generator impedance, and tissue electrophysiological properties have been of limited value in predicting efficacy and safety of ablation. Therefore, several input-driven indices have been proposed to improve the quality and durability of RF ablation lesion while maintaining safety. These metrics predominantly incorporate RF power output, duration of RF application, and firmness and stability of electrode-tissue contact. More recently, novel catheters have enabled measuring local impedance at the catheter-tissue interface, which has been found valuable for real-time monitoring of RF lesion formation.

Summary
It is likely that using the combination of multiple metrics would be required to improve the quality and safety of RF lesions, but further investigation is still required.
An entropy weight method to integrate big omics and mechanistically evaluate DILI
Authors: Jin Yuan , Shou Yingqing , Lei Qinkai , Du Chenlong , Xu Lin , Chen Ningning , Ma Wanli , Zhu Xiaoxiao , Zhou Shuya , Zheng Yuxin , Yu Dianke 
Published: October 2023

Background and Aims:
DILI accounts for more than half of acute liver failure cases in the United States and is a major health care issue for the public worldwide. As investigative toxicology is playing an evolving role in the pharmaceutical industry, mechanistic insights into drug hepatotoxicity can facilitate drug development and clinical medication.

Methods:
By integrating multisource datasets including gene expression profiles of rat livers from open TG-GATE database and DrugMatrix, drug labels from FDA Liver Toxicity Knowledge Base, and clinical reports from LiverTox, and with the employment of bioinformatic and computational tools, this study developed an approach to characterize and predict DILI based on the molecular understanding of the processes (toxicity pathways).

Results:
A panel of 11 pathways widely covering biological processes and stress responses was established using a training set of six positive and one negative DILI drugs from open TG-GATEs. An entropy weight method-based model was developed to weight responsive genes within a pathway, and an interpretable machine-learning (ML) model XGBoot-SHAP was trained to rank the importance of pathways to the panel activity. The panel activity was proven to differentiate between injured and noninjured sample points and characterize DILI manifestation using six training drugs. Next, the model was tested using an additional 89 drugs (61 positives + 28 negatives), and a precision of 86% and higher can be achieved.

Conclusions:
This study provides a novel approach to mechanisms-driven prediction modeling, as well as big data integration for insights into pharmacology and other human biology areas.
Keratitis Fugax Hereditaria Associated With a Novel NLRP3 Mutation in a Non-Finnish Patient
Authors: Jatavallabhula Kavya , Onyia Onyinye , Chung Doug D. , Williams Dominic , Wang Kaidi , Aldave Anthony J. 
Published: October 2023

Purpose:
The aim of this study was to report a novel heterozygous variant c.1712G>T (p.Gly571Val) in the nucleotide-binding domain, leucine-rich repeat family, pyrin domain–containing 3 gene (NLRP3) in a previously unreported non-Finnish individual with keratitis fugax hereditaria (KFH).

Methods:
Ophthalmologic examination of the proband was performed with slit-lamp biomicroscopy and anterior segment optical coherence tomography. Saliva was collected as a source of DNA, after which targeted exome sequencing of candidate genes was performed using a commercially available panel. Identified presumed pathogenic variants were confirmed by Sanger sequencing.

Results:
Slit-lamp examination of the 52-year-old female proband revealed peripheral arcus-like degeneration and bilateral central corneal opacification, observed on anterior segment optical coherence tomography to involve the anterior half of the corneal stroma. Examination of the proband's parents revealed clear corneas in each eye. Genetic testing of the proband identified the presence of a novel heterozygous NLRP3 missense mutation (c.1712G>T, p.Gly571Val), which was confirmed by Sanger sequencing. This mutation was absent in the proband's parents.

Conclusions:
Although KFH has been reported only in individuals of Finnish descent and only in association with a missense mutation in exon 1 of NLRP3, we report an individual of non-Finnish descent with KFH associated with a novel heterozygous variant in exon 2 of NLRP3. Thus, ophthalmologists should be aware of the ethnic and genetic heterogeneity associated with KFH.
An update on intraocular lens power calculations in eyes with previous laser refractive surgery
Authors: Savage Daniel E. , Pantanelli Seth M. 
Published: October 2023

Purpose of reviewThere is an ever-growing body of research regarding intraocular lens (IOL) power calculations following photorefractive keratectomy (PRK), laser-assisted in-situ keratomileusis (LASIK), and small-incision lenticule extraction (SMILE). This review intends to summarize recent data and offer updated recommendations.Recent findingsPostmyopic LASIK/PRK eyes have the best refractive outcomes when multiple methods are averaged, or when Barrett True-K is used. Posthyperopic LASIK/PRK eyes also seem to do best when Barrett True-K is used, but with more variable results. With both aforementioned methods, using measured total corneal power incrementally improves results. For post-SMILE eyes, the first nontheoretical data favors raytracing.SummaryRefractive outcomes after cataract surgery in eyes with prior laser refractive surgery are less accurate and more variable compared to virgin eyes. Surgeons may simplify their approach to IOL power calculations in postmyopic and posthyperopic LASIK/PRK by using Barrett True-K, and employing measured total corneal power when available. For post-SMILE eyes, ray tracing seems to work well, but lack of accessibility may hamper its adoption.
Carcinogenic Effects of Nitrosodimethylamine (NDMA) Contamination in Ranitidine: Defining the Relationship With Renal Malignancies
Authors: Gold Samuel A. , Margulis Vitaly 
Published: October 2023

Purpose:
Ranitidine, a medication used to treat gastric ulcers and reflux, was once the highest selling drug in the world with over $1 billion in annual sales. However, in 2020, ranitidine, known more commonly by the brand name Zantac, virtually vanished from the market after multiple regulatory bodies including the US Food and Drug Administration recommended withdrawal. Their concern was based on detection of nitrosodimethylamine (NDMA), a known animal carcinogen, in ranitidine samples. NDMA has been shown to induce multiple tumor types, including renal tumors. The effects of human exposure, however, are not completely understood. This review aims to clarify what is known about NDMA contamination in ranitidine, the carcinogenic mechanisms of NDMA, and possible associations between ranitidine consumption and renal cancers.

Materials and Methods:
A comprehensive literature review was performed regarding ranitidine and NDMA, carcinogenesis, and associations with malignancy. Data were considered from environmental, preclinical, and clinical studies from various disciplines. Publications from governmental bodies, including the Food and Drug Administration and International Agency for Research on Cancer, were reviewed and included for analysis.

Results:
Multiple preclinical studies have demonstrated the carcinogenic effects of NDMA in animals with high rates of renal tumor development. NDMA has been detected in industrial, dietary, and pharmacologic sources. Regarding NDMA levels in ranitidine, evidence points to associations with storage conditions at elevated temperatures and/or prolonged duration as well as endogenous production facilitated by physiologic gastric conditions. Once metabolized, NDMA by-products form DNA adducts with established roles in carcinogenesis. Human data on ranitidine consumption and cancer development are derived from large population studies limited by their observational nature and inconsistent measure of NDMA exposure. To date, NDMA associations with renal malignancies—although evident in animal studies—is not clearly delineated in humans.

Conclusions:
Detection of NDMA in ranitidine has prompted governmental regulatory bodies to recommend withdrawal of ranitidine from US markets. Classification of NDMA as a “probable human carcinogen” is based on decades of animal studies with a notable rate of renal malignancies. Human observational studies do not clearly demonstrate an association with renal malignancies, but the available data have significant limitations and any conclusions drawn from these observational studies, whether supporting or challenging associations between ranitidine use and renal cancer, should be interpreted with caution.
Laryngeal verrucous cell carcinoma
Authors: Lechien Jerome R. , Vaira Luigi A. , Chiesa-Estomba Carlos M. 
Published: October 2023

Purpose of review
To summarize the recent literature on epidemiology, clinical findings, treatment, and survival of laryngeal verrucous cell carcinoma (LVC).

Recent findings
Epidemiological studies report that LVC accounts for 1–3% of all laryngeal cancers. The incidence is decreasing, while most patients are male individuals and smokers. LVC are commonly detected in early stages because they are more frequently located in the glottic region. Tobacco, alcohol overuse, and, possibly, human papilloma virus are the main contributing factors. Recent studies confirm that surgery is the primary therapeutic approach with better prognosis when compared with other treatment modalities. Surgery alone is associated with 86.8% disease-free and 80.3% overall survival rates, while metastases are anecdotal.

Summary
LVC presents different clinical, pathological, and survival outcomes when compared with the classic laryngeal squamous cell carcinoma. Biopsies need often to be repeated before getting the most appropriate diagnosis; this supports the need of large-sample biopsy during the tumor diagnosis and staging. The glottic location of most LVC leads to detection of this lesion in its early stages, with ensuing better survival and outcomes after surgery compared with the classic form of squamous cell carcinoma. Future studies are needed to understand the biology of LVC and its related better prognostic outcomes when compared to other laryngeal malignancies.
Esophageal motility disorder – has Chicago classification v4.0 simplified our management?
Authors: Edeani Francis , Massey Benson 
Published: October 2023

Review purpose
Addressing dysphagia is vital due to its prevalence and impact on healthcare expenditure. While high resolution manometry (HRM) effectively evaluates esophageal dysphagia, its role in oropharyngeal dysphagia and upper esophageal sphincter (UES) dysfunction remains debated. The fourth iteration of the Chicago classification (CC) offers an algorithmic approach for diagnosing abnormal motor patterns via HRM. This review assesses the CC's impact on dysphagia management.

Recent insights
The Chicago classification version 4.0 emphasizes auxiliary and provocative techniques when the algorithm falls short of a conclusive diagnosis. It introduces stricter criteria for previously ambiguous conditions like ineffective motility and esophagogastric junction outflow obstruction. This version also introduces the concept of conclusive and inconclusive classifications based on symptoms, provocation maneuvers, and supportive testing minimizing ambiguity.

Summary
The Chicago classification v4.0 remains a useful tool for the diagnosis of well characterized esophageal motility disorders. However, major limitations include reliance on HRM and a focus on distal esophagus contractile characteristics without considering proximal esophagus or upper esophageal sphincter, both of which can sometimes be the only evident abnormality in patients with dysphagia. Despite efforts to reduce ambiguity, diagnostic challenges persist. These limitations can be addressed in future updates
Evaluation of the Impact and Outcomes of a Rapid Transition to Telehealth PrEP Delivery at a Sexual Health Clinic During the COVID-19 Pandemic
Authors: Higgins David M. , Riba Adrean , Alderton Lucy , Wendel Karen A. , Scanlon Jennifer , Weise Julia , Gibson Nathan , Obafemi Oluyomi 
Published: October 2023

ABSTRACT

Background
Increasing HIV pre-exposure prophylaxis (PrEP) use is a critical part of ending the HIV epidemic. In response to the COVID-19 pandemic, many PrEP services transitioned to a telehealth model (telePrEP). This report evaluates the effect of COVID-19 and the addition of telePrEP on delivery of PrEP services at the Denver Sexual Health Clinic (DSHC), a regional sexual health clinic in Denver, CO.

Methods
Prior to COVID-19, DSHC PrEP services were offered exclusively in-clinic. In response to the pandemic, after March 15, 2020, most PrEP initiation and follow up visits were converted to telePrEP. A retrospective analysis of DSHC PrEP visits compared pre-COVID-19 (September 1, 2019 to March 15, 2020) to post-COVID-19 (March 16, 2020 to September 30, 2020) visit volume, demographics, and outcomes.

Results
The DSHC completed 689 PrEP visits pre-COVID-19 and maintained 96.8% (n = 667) of this volume post-COVID-19. There were no differences in client demographics between pre-COVID-19 (n = 341) and post-COVID-19 PrEP start visits (n = 283) or between post-COVID-19 in-clinic (n = 140) vs telePrEP start visits (n = 143). There were no differences in 3-4-month retention rates pre-COVID-19 (n = 17/43) and post-COVID-19 (n = 21/43) (P = 0.52) or between in-clinic (n = 12/21) and telePrEP clients (n = 9/22) in the post-COVID-19 window (P = 0.37). Also, there were no significant differences in lab completion rates between in-clinic (n = 140/140) and telePrEP clients (n = 138/143) (P = 0.06) and prescription fill rates between in-clinic (n = 115/136) and telePrEP clients (n = 116/135) in the post-COVID-19 window (P = 0.86).

Conclusions
Implementation of TelePrEP enabled the DSHC to sustain PrEP services during the COVID-19 pandemic without significant differences in demographics, engagement, or retention in PrEP services.
Choosing Wisely and Promoting High-Value Care and Staff Safety During the COVID-19 Pandemic in a Large Safety Net System
Authors: Krouss Mona , Israilov Sigal , Mestari Nessreen , Talledo Joseph , Alaiev Daniel , Moskovitz Joshua B. , Faillace Robert T. , Uppal Amit , Fagan Ian , Curcio Joan , Scott Jinel , Bouton Michael , Ford Kenra , Cohen Victor , Wei Eric K. , Cho Hyung J. 
Published: October 2023

Background and Objectives:
As the COVID-19 pandemic brought surges of hospitalized patients, it was important to focus on reducing overuse of tests and procedures to not only reduce potential harm to patients but also reduce unnecessary exposure to staff. The objective of this study was to create a Choosing Wisely in COVID-19 list to guide clinicians in practicing high-value care at our health system.

Methods:
A Choosing Wisely in COVID-19 list was developed in October 2020 by an interdisciplinary High Value Care Council at New York City Health + Hospitals, the largest public health system in the United States. The first phase involved gathering areas of overuse from interdisciplinary staff across the system. The second phase used a modified Delphi scoring process asking participants to rate recommendations on a 5-point Likert scale based on criteria of degree of evidence, potential to prevent patient harm, and potential to prevent staff harm.

Results:
The top 5 recommendations included avoiding tracheal intubation without trial of noninvasive ventilation (4.4); not placing routine central venous catheters (4.33); avoiding routine daily laboratory tests and batching laboratory draws (4.19); not ordering daily chest radiographs (4.17); and not using bronchodilators in the absence of reactive airway disease (4.13).

Conclusion:
We successfully developed Choosing Wisely in COVID-19 recommendations that focus on evidence and preventing patient and staff harm in a large safety net system to reduce overuse.