bluuebunny/crossref_metadata_2025 huggingface dataset:
NeoTCR: an immunoinformatic database of experimentally-supported functional neoantigen-specific TCR sequences
Authors: Zhou Weijun , Xiang Wenting , Yu Jinyi , Ruan Zhihan , Pan Yichen , Wang Kankan , Liu Jian
Published: February 2024

Neoantigen-based immunotherapy has demonstrated long-lasting antitumor activity. The recognition of neoantigens by T cell receptors (TCRs) is considered a trigger for antitumor responses. Due to the overwhelming number of TCR repertoires in the human genome, pinpointing neoantigen-specific TCRs is a formidable challenge. Recent studies have identified a number of functional neoantigen-specific TCRs, but the corresponding information is scattered across published literature and is difficult to retrieve. To improve access to these data, we developed an immunoinformatic database (NeoTCR) containing a unified description of publicly available neoantigen-specific TCR sequences, as well as relevant information on targeted neoantigens, from experimentally supported studies across 18 cancer subtypes. A user-friendly web interface allows interactive browsing and running of complex database queries. To facilitate rapid identification of neoantigen-specific TCRs from raw sequencing data, NeoTCR offers a one-stop analysis for annotation and visualization of TCR clonotypes, discovery of existing neoantigen-specific TCRs, and exclusion of bystander viral-associated TCRs. NeoTCR represents a unique tool to expedite future studies of neoantigen-specific TCRs and the development of neoantigen-based immunotherapy. NeoTCR is available at http://neotcrdb.bioaimed.com/ and https://github.com/lyotvincent/NeoTCR.
HCCDB v2.0: Decompose Expression Variations by Single-cell RNA-seq and Spatial Transcriptomics in HCC
Authors: Jiang Ziming , Wu Yanhong , Miao Yuxin , Deng Kaige , Yang Fan , Xu Shuhuan , Wang Yupeng , You Renke , Zhang Lei , Fan Yuhan , Guo Wenbo , Lian Qiuyu , Chen Lei , Zhang Xuegong , Zheng Yongchang , Gu Jin
Published: February 2024

Large-scale transcriptomic data are crucial for understanding the molecular features of hepatocellular carcinoma (HCC). Integrated 15 transcriptomic datasets of HCC clinical samples, the first version of HCC database (HCCDB v1.0) was released in 2018. Through the meta-analysis of differentially expressed genes and prognosis-related genes across multiple datasets, it provides a systematic view of the altered biological processes and the inter-patient heterogeneities of HCC with high reproducibility and robustness. With four years having passed, the database now needs integration of recently published datasets. Furthermore, the latest single-cell and spatial transcriptomics have provided a great opportunity to decipher complex gene expression variations at the cellular level with spatial architecture. Here, we present HCCDB v2.0, an updated version that combines bulk, single-cell, and spatial transcriptomic data of HCC clinical samples. It dramatically expands the bulk sample size by adding 1656 new samples from 11 datasets to the existing 3917 samples, thereby enhancing the reliability of transcriptomic meta-analysis. A total of 182,832 cells and 69,352 spatial spots are added to the single-cell and spatial transcriptomics sections, respectively. A novel single-cell level and 2-dimension (sc-2D) metric is proposed as well to summarize cell type-specific and dysregulated gene expression patterns. Results are all graphically visualized in our online portal, allowing users to easily retrieve data through a user-friendly interface and navigate between different views. With extensive clinical phenotypes and transcriptomic data in the database, we show two applications for identifying prognosis-associated cells and tumor microenvironment. HCCDB v2.0 is available at http://lifeome.net/database/hccdb2.
Diagnostic Performance of a Fecal Calprotectin Assay as a Biomarker for Mayo Endoscopic Subscore in Ulcerative Colitis: Result From a Tertiary Referral Center
Authors: Suttichaimongkol Tanita , Coelho-Prabhu Nayantara , Bruining David H , Tariq Raseen , Snyder Melissa R , Loftus Edward V
Published: February 2024

Background

Fecal calprotectin (FC) is a promising biomarker for assessing ulcerative colitis (UC) endoscopic activity. However, the optimal FC cutoff to identify each Mayo endoscopic subscore (MES) remains inconclusive.

Methods

The electronic medical records of 177 adult UC patients evaluated at Mayo Clinic Rochester from January 2017 to March 2023 were retrospectively reviewed, obtaining clinical data and US-based Werfen Diagnostics FC levels collected within 30 days before colonoscopy or flexible sigmoidoscopy. Three independent inflammatory bowel disease specialist endoscopists blindly reviewed the most severe endoscopic images for grading MES.

Results

The median interval between FC collection and endoscopy was 2 days. Fecal calprotectin showed strong positive correlations with MES (Spearman’s r = 0.709; P < .01) and other clinical parameters. Fecal calprotectin cutoff of 60 mcg/g effectively distinguished MES 0 from MES 1-3 (sensitivity, 0.78; specificity, 0.97; area under the receiver operating characteristic curve [AUC], 0.901) and predicted clinical remission (Total Mayo Score ≤2 and no subscore >1; sensitivity, 0.83; specificity, 0.98; AUC, 0.921). Fecal calprotectin cutoff of 110 mcg/g effectively differentiated MES 0-1 from MES 2-3 (sensitivity, 0.86; specificity, 0.87; AUC, 0.915), while a cutoff of 310 mcg/g distinguished MES 0-2 from MES 3 (sensitivity, 0.80; specificity, 0.76; AUC, 0.820).

Conclusions

This study supports the reliability and applicability of FC as a valuable marker of endoscopic inflammation, particularly in distinguishing MES 0 from MES 1-3 using the FC cutoff of 60 mcg/g. Sensitivity analysis demonstrated robust results.
Monitoring-Based Model for Personalizing Fecal Incontinence in Patients With Crohn’s Disease: A Multicenter Inception Cohort Study
Authors: Wang Can , Yang Fan , Qiao Lichao , Wang Xiaoxiao , Chen Qi , Chen Hongjin , Li Yi , Zhang Xiaoqi , Liao Xiujun , Cao Lei , Xu Haixia , Xiang Yu , Yang Bolin
Published: February 2024

Background and Aims

Fecal incontinence (FI) is a common complaint that greatly affects the quality of life of patients with Crohn’s disease (CD) and is associated with the clinical characteristics of CD. We aimed to identify risk factors related to FI and construct a risk prediction model for FI in patients with CD.

Methods

This retrospective study included 600 Chinese patients with CD from 4 IBD centers between June 2016 and October 2021. The patients were assigned to the training (n = 480) and testing cohorts (n = 120). Two nomograms were developed based on the logistic regression and Cox regression models to predict the risk factors for FI in patients with CD. The discriminatory ability and accuracy of the nomograms were evaluated using the receiver operating characteristic (ROC) curves and the area under the ROC curves (AUCs). Additionally, the Kaplan-Meier survival curve was also used further to validate the clinical efficacy of the Cox regression model.

Results

The overall prevalence of FI was 22.3% (n = 134 of 600). In the logistic regression model, age at diagnosis (odds ratio [OR], 1.032; P = .033), penetrating behavior of disease (OR, 3.529; P = .008) and Perianal Disease Activity Index score >4 (OR, 3.068; P < .001) were independent risk factors for FI. In the Cox regression model, age at diagnosis (hazard ratio [HR], 1.027; P = .018), Montreal P classification (HR, 2.608; P = .011), and Perianal Disease Activity Index score >4 (HR, 2.190; P = .001) were independent predictors of the prevalence of FI over time. Two nomograms were developed to facilitate risk score calculation, and they showed good discrimination ability according to AUCs.

Conclusions

In this study, we identified 4 risk factors related to the prevalence of FI and developed 2 models to effectively predict the risk scores of FI in CD patients, helping to delay the course of FI and improve the prognosis with timely intervention.
Plasma concentrations of histidine-rich glycoprotein in primary graft dysfunction after lung transplantation
Authors: Shiotani Toshio , Sugimoto Seiichiro , Tomioka Yasuaki , Tanaka Shin , Mitsuhashi Toshiharu , Suzawa Ken , Shien Kazuhiko , Miyoshi Kentaroh , Yamamoto Hiromasa , Okazaki Mikio , Toyooka Shinichi
Published: February 2024

OBJECTIVES

Histidine-rich glycoprotein has been reported as an anti-inflammatory glycoprotein that inhibits acute lung injury in mice with sepsis and as a prognostic biomarker in patients with sepsis. We investigated the relationship between plasma concentrations of histidine-rich glycoprotein and the risk of occurrence of primary graft dysfunction.

METHODS

According to the primary graft dysfunction grade at post-transplant 72 h, patients who underwent lung transplantation were divided into three groups: non-primary graft dysfunction group (grade 0–1), moderate primary graft dysfunction group (grade 2), and severe primary graft dysfunction group (grade 3). The plasma concentrations of histidine-rich glycoprotein measured daily during the first post-transplant 7 days were compared among the three groups. Appropriate cutoff values of the concentrations were set for survival analyses after lung transplantation.

RESULTS

A total of 68 patients were included. The plasma histidine-rich glycoprotein concentration at post-transplant 72 h was significantly lower in the severe primary graft dysfunction group (n = 7) than in the other two groups [non-primary graft dysfunction group (n = 43), P = 0.042; moderate primary graft dysfunction group (n = 18), P = 0.040]. Patients with plasma histidine-rich glycoprotein concentration ≥34.4 µg/ml at post-transplant 72 h had significantly better chronic lung allograft dysfunction-free survival (P = 0.012) and overall survival (P = 0.037) than those with the concentration <34.4 µg/ml.

CONCLUSIONS

Plasma histidine-rich glycoprotein concentrations at post-transplant 72 h might be associated with the risk of development of primary graft dysfunction.
Agricultural paraquat dichloride use and Parkinson’s disease in California’s Central Valley
Authors: Paul Kimberly C , Cockburn Myles , Gong Yufan , Bronstein Jeff , Ritz Beate
Published: February 2024

Background

Paraquat dichloride is currently among the most widely used commercial herbicides in the USA. In the present study, we provide epidemiological assessment of ambient paraquat exposure and Parkinson’s disease (PD) risk in a population-based study of PD in agricultural regions of Central California.

Methods

Based on 829 PD patients and 824 community controls, we assessed associations between ambient paraquat dichloride exposure and PD. We estimated residential and workplace proximity to commercial agricultural applications in three California counties since 1974 using the CA pesticide use reporting (PUR) data and land use maps. We evaluated any, duration and average intensity [pounds (0.45 kilograms) per acre per year] of exposure for paraquat in four time windows.

Results

Ambient paraquat exposure assessed at both residence and workplace was associated with PD, based on several different exposure measures. The PD patients both lived and worked near agricultural facilities applying greater amounts of the herbicide than community controls. For workplace proximity to commercial applications since 1974, working near paraquat applications every year in the window [odds ratio (OR) = 2.15, 95% confidence interval (CI) = 1.46, 3.19] and a higher average intensity of exposure [per 10 pounds (4.54 kilograms), OR = 2.08, 95% CI = 1.31, 3.38] were both associated with an increased odds of PD. Similar associations were observed for residential proximity (duration: OR = 1.91, 95% CI = 1.30, 2.83; average intensity: OR = 1.72, 95% CI = 0.99, 3.04). Risk estimates were comparable for men and women, and the strongest odds were observed for those diagnosed at ≤60 years of age.

Conclusion

This study provides further indication that paraquat dichloride exposure increases the risk of Parkinson’s disease.
Infectious Diseases Training in the 21st Century: A Glass Half Full or Half Empty?
Authors: Arias Cesar A , Pirofski Liise-anne
Published: February 2024

The percentage of infectious diseases (ID) fellowship positions filled has declined in the last years despite a relatively stable number of applicants. The data are concerning since this could impact an already strained workforce. A recent survey of ID fellowship program directors provides insight into the perceptions of program directors about factors that might have affected the match rate in 2023 and could also be applicable to the recent 2024 match. Here, we discuss the results of this survey and discuss the complex factors that might influence the choice of ID as an specialty. Although concerning, recent fellowship match results provide new opportunities to reassess current models of ID training and design innovative strategies for ID fellowship and education.
Eco-Friendly Stability-Indicating HPLC Method for Related Compounds in Pemetrexed Ditromethamine (Antineoplastic Agent) for Injection
Authors: Nekkalapudi Arjuna Rao , Navuluri Srinivasu , Pippalla Sreenivas
Published: February 2024

Background

An eco-friendly analytical technique was developed with the intention of preserving the environment by using green chemistry principles. Pemetrexed is a folate analogue indicated for the treatment of advanced lung cancer.

Objective

Development of a green stability-indicating HPLC method for the quantification of pemetrexed ditromethamine (PDT) impurities in Active Pharmaceutical Ingredient (API) and parenteral dosage form.

Methods

Chromatographic separation was achieved using a Zorbax SB C18 column (150 mm × 4.6 mm i.d., 3.5 µ particle size) with perchlorate buffer (pH 3.0 ± 0.1, 50 mM) as mobile phase A and acetonitrile–perchlorate (90 + 10, v/v) buffer as mobile phase B at a flow rate of 0.8 mL/min with a column temperature of 40°C ± 0.5°C. All analytes were well resolved by gradient elution with a total run time of 75 min. The UV detection wavelength was 230 nm.

Results

The RP-HPLC method is capable of resolving all the degradation and process impurities for PDT API and parenteral dosage form. The related compounds method was validated in accordance with International conference on harmonization (ICH) Q2(R1) and United states of Pharmacopoeia (USP) <1225> guidelines, and found to be accurate, specific, precise, linear, robust and stability-indicating. The precision and intermediate results were <5% CV for all the impurities. The accuracy for all the impurities was found to be between 90 and 110%. The linearity of regression co-efficient values for all the impurities were found to be more than 0.999.

Conclusion

The proposed related compounds method is found suitable for the determination of process and degradation impurities of commercial formulations, stability samples in QC analysis for PDT API, and drug product.

Highlights

The developed liquid chromatographic method greenness and eco-friendliness were assessed using the green analytical procedure index (GAPI) and the analytical greenness (AGREE) tool, and found to be green. A PDT detoxification procedure was also developed to reduce environmental pollution.
Risk factors for hip and vertebral fractures in chronic kidney disease: the CRIC study
Authors: Hsu Simon , Bansal Nisha , Denburg Michelle , Ginsberg Charles , Hoofnagle Andrew N , Isakova Tamara , Ix Joachim H , Robinson-Cohen Cassianne , Wolf Myles , Kestenbaum Bryan R , de Boer Ian H , Zelnick Leila R
Published: February 2024

Fracture risk is high in chronic kidney disease (CKD) and underlying pathophysiology and risk factors may differ from the general population. In a cohort study of 3939 participants in the chronic renal insufficiency cohort (CRIC), we used Cox regression to test associations of putative risk factors with the composite of first hip or vertebral fracture assessed using hospital discharge codes. Mean age was 58 years, 45% were female, 42% were Black, and 13% were Hispanic. There were 82 hip and 24 vertebral fractures over a mean (SD) 11.1 (4.8) years (2.4 events per 1000 person-years [95% CI: 2.0, 2.9]). Measured at baseline, diabetes, lower body mass index (BMI), steroid use, proteinuria, and elevated parathyroid hormone (PTH) were each associated with fracture risk after adjusting for covariates. Lower time-updated estimated glomerular filtration rate (eGFR) was associated with fractures (HR 1.20 per 10 mL/min/1.73m2 lower eGFR; 95% CI: 1.04, 1.38) as were lower time-updated serum calcium and bicarbonate concentrations. Among time-updated categories of kidney function, hazard ratios (95% CI) for incident fracture were 4.53 (1.77, 11.60) for kidney failure treated with dialysis and 2.48 (0.86, 7.14) for post-kidney transplantation, compared with eGFR ≥60. Proton pump inhibitor use, dietary calcium intake, measures of vitamin D status, serum phosphate, urine calcium and phosphate, and plasma fibroblast growth factor-23 were not associated with fracture risk. In conclusion, lower eGFR in CKD is associated with higher fracture risk, which was highest in kidney failure. Diabetes, lower BMI, steroid use, proteinuria, higher serum concentrations of PTH, and lower calcium and bicarbonate concentrations were associated with fractures and may be modifiable risk factors.
Association between BMD and coronary artery calcification: an observational and Mendelian randomization study
Authors: Lu Haojie , Lary Christine W , Hodonsky Chani J , Peyser Patricia A , Bos Daniel , van der Laan Sander W , Miller Clint L , Rivadeneira Fernando , Kiel Douglas P , Kavousi Maryam , Medina-Gomez Carolina
Published: February 2024

Observational studies have reported inconsistent associations between bone mineral density (BMD) and coronary artery calcification (CAC). We examined the observational association of BMD with CAC in 2 large population-based studies and evaluated the evidence for a potential causal relation between BMD and CAC using polygenic risk scores (PRS), 1- and 2-sample Mendelian randomization (MR) approaches. Our study populations comprised 1414 individuals (mean age 69.9 yr, 52.0% women) from the Rotterdam Study and 2233 individuals (mean age 56.5 yr, 50.9% women) from the Framingham Heart Study with complete information on CAC and BMD measurements at the total body (TB-), lumbar spine (LS-), and femoral neck (FN-). We used linear regression models to evaluate the observational association between BMD and CAC. Subsequently, we compared the mean CAC across PRSBMD quintile groups at different skeletal sites. In addition, we used the 2-stage least squares regression and the inverse variance weighted (IVW) model as primary methods for 1- and 2-sample MR to test evidence for a potentially causal association. We did not observe robust associations between measured BMD levels and CAC. These results were consistent with a uniform random distribution of mean CAC across PRSBMD quintile groups (P-value > .05). Moreover, neither 1- nor 2-sample MR supported the possible causal association between BMD and CAC. Our results do not support the contention that lower BMD is (causally) associated with an increased CAC risk. These findings suggest that previously reported epidemiological associations of BMD with CAC are likely explained by unmeasured confounders or shared etiology, rather than by causal pathways underlying both osteoporosis and vascular calcification processes.
Temporal patterns of osteoclast formation and activity following withdrawal of RANKL inhibition
Authors: Kim Albert S , Taylor Victoria E , Castro-Martinez Ariel , Dhakal Suraj , Zamerli Amjad , Mohanty Sindhu , Xiao Ya , Simic Marija K , Wen Jinchen , Chai Ryan , Croucher Peter I , Center Jacqueline R , Girgis Christian M , McDonald Michelle M
Published: February 2024

Rebound bone loss following denosumab discontinuation is an important clinical challenge. Current treatment strategies to prevent this fail to suppress the rise and overshoot in osteoclast-mediated bone resorption. In this study, we use a murine model of denosumab treatment and discontinuation to show the temporal changes in osteoclast formation and activity during RANKL inhibition and withdrawal. We show that the cellular processes that drive the formation of osteoclasts and subsequent bone resorption following withdrawal of RANKL inhibition precede the rebound bone loss. Furthermore, a rise in serum TRAP and RANKL levels is detected before markers of bone turnover used in current clinical practice. These mechanistic advances may provide insight into a more defined window of opportunity to intervene with sequential therapy following denosumab discontinuation.
Maximizing scarce colonoscopy resources: the crucial role of stool-based tests
Authors: Coronado Gloria D , Bienen Leslie , Burnett-Hartman Andrea , Lee Jeffrey K , Rutter Carolyn M
Published: February 2024

During the COVID-19 pandemic, health systems, including federally qualified health centers, experienced disruptions in colorectal cancer (CRC) screening. National organizations called for greater use of at-home stool-based testing followed by colonoscopy for those with abnormal test results to limit (in-person) colonoscopy exams to people with acute symptoms or who were high risk. This stool-test-first strategy may also be useful for adults with low-risk adenomas who are due for surveillance colonoscopy. We argue that colonoscopy is overused as a first-line screening method in low- and average-risk adults and as a surveillance tool among adults with small adenomas. Yet, simultaneously, many people do not receive much-needed colonoscopies. Delivering the right screening tests at intervals that reduce the risk of CRC, while minimizing patient inconvenience and procedural risks, can strengthen health-care systems. Risk stratification could improve efficiency of CRC screening, but because models that adequately predict risk are years away from clinical use, we need to optimize use of currently available technology—that is, low-cost fecal testing followed by colonoscopy for those with abnormal test results. The COVID-19 pandemic highlighted the urgent need to adapt to resource constraints around colonoscopies and showed that increased use of stool-based testing was possible. Learning how to adapt to such constraints without sacrificing patients’ health, particularly for patients who receive care at federally qualified health centers, should be a priority for CRC prevention research.
Effect of surgery versus chemotherapy in pancreatic cancer patients: a target trial emulation
Authors: Kirkegård Jakob , Gaber Charles , Heide-Jørgensen Uffe , Fristrup Claus Wilki , Lund Jennifer L , Cronin-Fenton Deirdre , Mortensen Frank Viborg
Published: February 2024

Background

To estimate the causal effect of surgery vs chemotherapy on survival in patients with T1-3NxM0 pancreatic cancer in a rigorous framework addressing selection bias and immortal time bias.

Methods

We used population-based Danish health-care registries to conduct a cohort study emulating a hypothetical randomized trial to estimate the absolute difference in survival, comparing surgery with chemotherapy. We included pancreatic cancer patients diagnosed during 2008-2021. Exposure was surgery or chemotherapy initiated within a 16-week grace period after diagnosis. At the time of diagnosis, data of each patient were duplicated; one copy was assigned to the surgery protocol, and one copy to the chemotherapy protocol of the hypothetical trial. Copies were censored when the assigned treatment deviated from the observed treatment. To account for informative censoring, uncensored patients were weighted according to confounders. For comparison, we also applied a more conventional analysis using propensity score-based inverse probability weighting.

Results

We included 1744 patients with a median age of 68 years: 73.6% underwent surgery, and 18.6% had chemotherapy without surgery; 7.8% received no treatment. The 3-year survival was 39.7% (95% confidence interval [CI] = 36.7% to 42.6%) after surgery and 22.7% (95% CI = 17.7% to 28.4%) after chemotherapy, corresponding to an absolute difference of 17.0% (95% CI = 10.8% to 23.1%). In the conventional survival analysis, this difference was 23.0% (95% CI = 17.0% to 29.0%).

Conclusion

Surgery was superior to chemotherapy in achieving long-term survival for pancreatic cancer. The difference comparing surgery and chemotherapy was substantially smaller when using the clone-censor-weight approach than conventional survival analysis.
Dysregulation of mucosal-associated invariant T cells correlates with altered placental microenvironment in preterm birth
Authors: Wu Mi , Li Fei , Zhou Ting , Zhao Juan , Jiang Lang , Zhang Haoquan , Wang Wei , Cheng Xue , Wu Xiongwen , Xiong Min , Weng Xiufang
Published: February 2024

Preterm birth (PTB) is a major problem affecting perinatal health, directly increasing the mortality risk of mother and infant that often results from the breakdown of the maternal–fetal immune balance. Increasing evidence shows the essential role of mucosal-associated invariant T (MAIT) cells to balance antibacterial function and immune tolerance function during pregnancy. However, the phenotype and function of placental MAIT cells and their specific mechanisms in PTB remain unclear. Here, we report that MAIT cells in placentas from PTBs show increased activation levels and decreased IFN-γ secretion capacity compared with those from normal pregnancies. Moreover, our data indicate gravidity is a factor affecting placental MAIT cells during pregnancies. Multi-omics analysis indicated aberrant immune activation and abnormal increase of lipids and lipid-like metabolites in the PTB placental microenvironment. Moreover, the proportion and activation of MAIT cells were positively correlated with the abnormal increase of lipids and lipid-like metabolites. Together, our work revealed that abnormal activation and impaired function of MAIT cells may be related to abnormal elevation of lipids and lipid-like metabolites in PTB.
E-Cigarette “Tobacco Flavor,” How Do I Name Thee? Let Me Count the Ways…
Authors: Zhang Ying , Kennedy Ryan David , Czaplicki Lauren , Moran Meghan Bridgid
Published: February 2024

Introduction

In recent years, hundreds of jurisdictions around the world have enacted policies that prohibit sales of flavored e-cigarettes. In most cases, these jurisdictions permit the sale of tobacco flavored e-cigarettes. We sought to understand how tobacco flavor in e-cigarette advertisements were presented.

Aims and Methods

Our sample included 2966 U.S. English-language e-cigarette ads compiled by a market research firm, Numerator, that ran from January 2018 to December 2020. We describe the prevalence of different tobacco flavor names in our sample and classified each name into one of the following thematic categories: Traditional Tobacco, Pipe/Cigar Tobacco, Sensory Expectancies, Color, Physical Attribute, Place, and non-characterizing Concept flavor.

Results

In our sample, 28% (n = 832/2966) of ads promoted at least one tobacco flavored e-cigarette product (e-cigarette device or liquid). Across the 832 ads, we counted 1019 tobacco flavored products and identified 51 unique tobacco flavor names. The most common tobacco flavor names were Traditional Tobacco names like “Tobacco” (n = 393), “Classic tobacco” (n = 107) and ‘Original’ (n = 59). Some names were associated with Color (eg, ‘Golden tobacco’; n = 153), Sensory Expectancy (eg, ‘Rich tobacco’; n = 148), Place where tobacco cultivation takes place (eg, ‘Carolina tobacco’; n = 83), Physical Attributes of tobacco (eg, ‘Cut tobacco’; n = 17) and non-characterizing Concept flavor (eg, ‘Freedom juice’; n = 14). Few tobacco flavors suggested a type of Pipe/Cigar Tobacco (eg, “Cavendish”; n = 4).

Conclusions

We identified 51 different tobacco flavor names, highlighting the practice describing the flavor beyond “tobacco.” Future research can investigate whether these flavor names and descriptors influence consumers’ perceptions, including perceived risks, of e-cigarette products.

Implications

Flavors are used to market e-cigarettes. Globally, many jurisdictions restrict flavored e-cigarette sales, but few restrict tobacco flavor. This study identified 51 unique ways tobacco flavored e-cigarettes have been named in a sample of U.S. English-language ads, suggesting diversified ways to market “tobacco.” We identified several sub-categories of tobacco flavor names that rely on Color, Sensory Expectancies, and non-characterizing Concept flavor attributes. As e-cigarette flavor restrictions that exempt tobacco flavor are still prevalent, this study highlights the need for continued monitoring of naming conventions of tobacco flavored products and examination of how nuanced flavor names influence perceptions and expectations.
Comparison of Large Language Models in Answering Immuno-Oncology Questions: A Cross-Sectional Study
Authors: Iannantuono Giovanni Maria , Bracken-Clarke Dara , Karzai Fatima , Choo-Wosoba Hyoyoung , Gulley James L , Floudas Charalampos S
Published: February 2024

Background

The capability of large language models (LLMs) to understand and generate human-readable text has prompted the investigation of their potential as educational and management tools for patients with cancer and healthcare providers.

Materials and Methods

We conducted a cross-sectional study aimed at evaluating the ability of ChatGPT-4, ChatGPT-3.5, and Google Bard to answer questions related to 4 domains of immuno-oncology (Mechanisms, Indications, Toxicities, and Prognosis). We generated 60 open-ended questions (15 for each section). Questions were manually submitted to LLMs, and responses were collected on June 30, 2023. Two reviewers evaluated the answers independently.

Results

ChatGPT-4 and ChatGPT-3.5 answered all questions, whereas Google Bard answered only 53.3% (P < .0001). The number of questions with reproducible answers was higher for ChatGPT-4 (95%) and ChatGPT3.5 (88.3%) than for Google Bard (50%) (P < .0001). In terms of accuracy, the number of answers deemed fully correct were 75.4%, 58.5%, and 43.8% for ChatGPT-4, ChatGPT-3.5, and Google Bard, respectively (P = .03). Furthermore, the number of responses deemed highly relevant was 71.9%, 77.4%, and 43.8% for ChatGPT-4, ChatGPT-3.5, and Google Bard, respectively (P = .04). Regarding readability, the number of highly readable was higher for ChatGPT-4 and ChatGPT-3.5 (98.1%) and (100%) compared to Google Bard (87.5%) (P = .02).

Conclusion

ChatGPT-4 and ChatGPT-3.5 are potentially powerful tools in immuno-oncology, whereas Google Bard demonstrated relatively poorer performance. However, the risk of inaccuracy or incompleteness in the responses was evident in all 3 LLMs, highlighting the importance of expert-driven verification of the outputs returned by these technologies.
Linker histone H1 drives heterochromatin condensation via phase separation in Arabidopsis
Authors: He Shengbo , Yu Yiming , Wang Liang , Zhang Jingyi , Bai Zhengyong , Li Guohong , Li Pilong , Feng Xiaoqi
Published: February 2024

In the eukaryotic nucleus, heterochromatin forms highly condensed, visible foci known as heterochromatin foci (HF). These HF are enriched with linker histone H1, a key player in heterochromatin condensation and silencing. However, it is unknown how H1 aggregates HF and condenses heterochromatin. In this study, we established that H1 facilitates heterochromatin condensation by enhancing inter- and intrachromosomal interactions between and within heterochromatic regions of the Arabidopsis (Arabidopsis thaliana) genome. We demonstrated that H1 drives HF formation via phase separation, which requires its C-terminal intrinsically disordered region (C-IDR). A truncated H1 lacking the C-IDR fails to form foci or recover HF in the h1 mutant background, whereas C-IDR with a short stretch of the globular domain (18 out of 71 amino acids) is sufficient to rescue both defects. In addition, C-IDR is essential for H1's roles in regulating nucleosome repeat length and DNA methylation in Arabidopsis, indicating that phase separation capability is required for chromatin functions of H1. Our data suggest that bacterial H1-like proteins, which have been shown to condense DNA, are intrinsically disordered and capable of mediating phase separation. Therefore, we propose that phase separation mediated by H1 or H1-like proteins may represent an ancient mechanism for condensing chromatin and DNA.
CAMTA3 repressor destabilization triggers TIR domain protein TN2-mediated autoimmunity in the Arabidopsis exo70B1 mutant
Authors: Liu Na , Jiang Xiyuan , Zhong Guitao , Wang Wei , Hake Katharina , Matschi Susanne , Lederer Sarah , Hoehenwarter Wolfgang , Sun Qianqian , Lee Justin , Romeis Tina , Tang Dingzhong
Published: February 2024

Calcium-dependent protein kinases (CPKs) can decode and translate intracellular calcium signals to induce plant immunity. Mutation of the exocyst subunit gene EXO70B1 causes autoimmunity that depends on CPK5 and the Toll/interleukin-1 receptor (TIR) domain resistance protein TIR-NBS2 (TN2), where direct interaction with TN2 stabilizes CPK5 kinase activity. However, how the CPK5–TN2 interaction initiates downstream immune responses remains unclear. Here, we show that, besides CPK5 activity, the physical interaction between CPK5 and functional TN2 triggers immune activation in exo70B1 and may represent reciprocal regulation between CPK5 and the TIR domain functions of TN2 in Arabidopsis (Arabidopsis thaliana). Moreover, we detected differential phosphorylation of the calmodulin-binding transcription activator 3 (CAMTA3) in the cpk5 background. CPK5 directly phosphorylates CAMTA3 at S964, contributing to its destabilization. The gain-of-function CAMTA3A855V variant that resists CPK5-induced degradation rescues immunity activated through CPK5 overexpression or exo70B1 mutation. Thus, CPK5-mediated immunity is executed through CAMTA3 repressor degradation via phosphorylation-induced and/or calmodulin-regulated processes. Conversely, autoimmunity in camta3 also partially requires functional CPK5. While the TIR domain activity of TN2 remains to be tested, our study uncovers a TN2–CPK5–CAMTA3 signaling module for exo70B1-mediated autoimmunity, highlighting the direct embedding of a calcium-sensing decoder element within resistance signalosomes.
Psychologically based interventions for adults with chronic neuropathic pain: a scoping review
Authors: Oguchi Mayumi , Nicholas Michael K , Asghari Ali , Sanders Duncan , Wrigley Paul J
Published: February 2024

Objective

As psychologically based interventions have been shown to have clinical utility for adults with chronic pain generally, a similar benefit might be expected in the management of chronic neuropathic pain (NeuP). However, to date, this has not been established, with existing systematic reviews on this topic being hampered by the scarcity of randomized controlled trials (RCTs). This review aimed to identify the type of psychologically based interventions studied for adults with chronic NeuP. It also aimed to assess whether there are enough RCTs to justify undertaking an updated systematic review.

Methods

Seven databases and 2 clinical trial registries were searched for NeuP and psychologically based interventions from database inception to December 2021, and the search was updated in February 2023. The search was broadened by reviewing the reference list of included studies and contacting field experts. Predetermined study characteristics were extracted.

Results

Of 4682 records screened, 33 articles (less than 1%) met the eligibility criteria. Four broad intervention approaches were observed, including cognitive-behavioral approaches (n = 16), mindfulness/meditation (n = 10), trauma-focused therapy (n = 4), and hypnosis (n = 3). Thirteen RCTs were identified, and of these, 9 retained 20 participants in each arm after treatment.

Conclusions

Cognitive-behavioral therapy was the most common therapeutic approach identified, whereas mindfulness/meditation was the most frequently used technique. Almost half to two-thirds of the studies reported significant improvements in pain, disability, or distress, which suggests that psychologically based interventions are potentially beneficial for adults with chronic NeuP. An updated systematic review seems warranted.

Study registration

Open Science Framework (https://osf.io) (December 6, 2021; DOI: 10.17605/OSF.IO/WNSTM).
From populations to networks: Relating diversity indices and frustration in signed graphs
Authors: Fontan Angela , Ratta Marco , Altafini Claudio
Published: February 2024

Diversity indices of quadratic type, such as fractionalization and Simpson index, are measures of heterogeneity in a population. Even though they are univariate, they have an intrinsic bivariate interpretation as encounters among the elements of the population. In the paper, it is shown that this leads naturally to associate populations to weakly balanced signed networks. In particular, the frustration of such signed networks is shown to be related to fractionalization by a closed-form expression. This expression allows to simplify drastically the calculation of frustration for weakly balanced signed graphs.
Decomposing Uncertainty in Macro-Finance Term Structure Models
Authors: Byrne Joseph P , Cao Shuo
Published: February 2024

This paper studies the extent to which macro-finance term structure models are susceptible to predictive uncertainty. We propose a general form of arbitrage-free models and quantify the relative importance of unpredictable priced risk variance, as well as macro-finance model uncertainty and learning uncertainty in predictability. Predictive performance and relative contributions of uncertainty sources are dynamically measured based on Bayesian methods, revealing dominating priced risk variance and other important uncertainty sources at different points in time. Macro-finance model uncertainty is high for near-term forward spread forecasts and contributes up to 87% of predictive uncertainty prior to recessions, implying strong dispersion in the information content of macro variables when forming near-term monetary policy expectations. (JEL C1, C3, C5, D8, E4, G1)
Very-low-dose glucocorticoid therapy in rheumatoid arthritis: impact of b/tsDMARDs initiation timing on glucocorticoid withdrawal
Authors: Giollo Alessandro , Salvato Mariangela , Frizzera Francesca , Zen Margherita , Doria Andrea
Published: February 2024

Objectives

We investigated the effectiveness and safety of very-low-dose (<5 mg/day) glucocorticoids (GCs) in patients with RA treated with biologic and targeted synthetic DMARDs (b/tsDMARDs).

Methods

In this prospective cohort study, we included all RA patients who started their first b/tsDMARDs at our institution between 2015 and 2020 and were monitored every 6 months for 3 years. Relationships between exposure to very-low-dose GCs and disease activity were examined through multivariable logistic regression and repeated-measures analysis of variance. The impact of very-low-dose GCs on safety was also evaluated.

Results

We enrolled 229 RA patients, of whom 68% were prescribed very-low-dose GCs and 32% received no GCs. After 3 years on b/tsDMARDs, 32% had never abandoned, 20% had gone on and off and 23% had permanently discontinued very-low-dose GCs, while 25% had never taken GCs. Shorter disease duration at b/tsDMARD initiation was the single modifiable predictor of very-low-dose GC cessation [odds ratio 1.1 (95% CI 1.03, 1.14) for any 1-year decrease; P = 0.001]. A significant association existed between ongoing utilization of very-low-dose GCs and persistent moderate disease activity. Use of very-low-dose GCs was associated with hypertension (20% vs 11%) and myocardial infarction (2.3% vs 0%).

Conclusion

A substantial proportion of RA patients treated with b/tsDMARDs continue to receive very-low-dose GCs without significantly improving disease control. However, this appears to increase cardiovascular morbidity.
Improving adolescent sleep in long-term Juvenile correctional settings: case examples with clinical, research, and policy implications
Authors: Robles-Ramamurthy Barbara , Zaki Saadia , Sandoval Jessica F , Dube Anish R , Hlozek Steven , Fortuna Lisa R , Williamson Ariel A
Published: February 2024

Poor sleep during adolescence is a public health concern that may be especially important to address among youth in juvenile correctional facilities, who tend to experience greater mental health challenges, substance use disorders, and traumatic stress exposure. However, evidence for addressing sleep in correctional settings is limited. Using de-identified composite clinical cases, this paper describes challenges and opportunities for addressing sleep disorders (i.e. insomnia) and promoting sleep health (i.e. improving duration, regularity, and behaviors) among adolescents in long-term juvenile correctional facilities. These clinical cases highlight common presenting problems and underscore the need for integrated sleep and mental health interventions as well as adaptations to enhance feasibility and efficacy of behavioral sleep treatment and sleep health promotion in juvenile correctional contexts. We conclude by summarizing clinical, research, and policy implications for addressing adolescent sleep problems and promoting sleep health and well-being in these contexts.
Technical evaluation and standardization of the human thyroid microtissue assay
Authors: Foley Briana , Hopperstad Kristen , Gamble John , Lynn Scott G , Thomas Russell S , Deisenroth Chad
Published: February 2024

The success and sustainability of U.S. EPA efforts to reduce, refine, and replace in vivo animal testing depends on the ability to translate toxicokinetic and toxicodynamic data from in vitro and in silico new approach methods (NAMs) to human-relevant exposures and health outcomes. Organotypic culture models employing primary human cells enable consideration of human health effects and inter-individual variability but present significant challenges for test method standardization, transferability, and validation. Increasing confidence in the information provided by these in vitro NAMs requires setting appropriate performance standards and benchmarks, defined by the context of use, to consider human biology and mechanistic relevance without animal data. The human thyroid microtissue (hTMT) assay utilizes primary human thyrocytes to reproduce structural and functional features of the thyroid gland that enable testing for potential thyroid-disrupting chemicals. As a variable-donor assay platform, conventional principles for assay performance standardization need to be balanced with the ability to predict a range of human responses. The objectives of this study were to (1) define the technical parameters for optimal donor procurement, primary thyrocyte qualification, and performance in the hTMT assay, and (2) set benchmark ranges for reference chemical responses. Thyrocytes derived from a cohort of 32 demographically diverse euthyroid donors were characterized across a battery of endpoints to evaluate morphological and functional variability. Reference chemical responses were profiled to evaluate the range and chemical-specific variability of donor-dependent effects within the cohort. The data-informed minimum acceptance criteria for donor qualification and set benchmark parameters for method transfer proficiency testing and validation of assay performance.
Comparative cardiotoxicity assessment of bisphenol chemicals and estradiol using human induced pluripotent stem cell-derived cardiomyocytes
Authors: Cooper Blake L , Salameh Shatha , Posnack Nikki Gillum
Published: February 2024

Bisphenol A (BPA) is commonly used to manufacture consumer and medical-grade plastics. Due to health concerns, BPA substitutes are being incorporated—including bisphenol S (BPS) and bisphenol F (BPF)—without a comprehensive understanding of their toxicological profile. Previous studies suggest that bisphenol chemicals perturb cardiac electrophysiology in a manner that is similar to 17β-estradiol (E2). We aimed to compare the effects of E2 with BPA, BPF, and BPS using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Cardiac parameters were evaluated using microelectrode array (MEA) technology and live-cell fluorescent imaging. Cardiac metrics remained relatively stable after exposure to nanomolar concentrations (1–1000 nM) of E2, BPA, BPF, or BPS. At higher micromolar concentrations, chemical exposures decreased the depolarization spike amplitude, and shortened the field potential, action potential duration, and calcium transient duration (E2 ≥ BPA ≥ BPF ≫ BPS). Cardiomyocyte physiology was largely undisturbed by BPS. BPA-induced effects were exaggerated when coadministered with an L-type calcium channel (LTCC) antagonist or E2, and reduced when coadministered with an LTCC agonist or an estrogen receptor alpha antagonist. E2-induced effects were not exaggerated by coadministration with an LTCC antagonist. Although the observed cardiac effects of E2 and BPA were similar, a few distinct differences suggest that these chemicals may act (in part) through different mechanisms. hiPSC-CM are a useful model for screening cardiotoxic chemicals, nevertheless, the described findings should be validated using a more complex ex vivo and/or in vivo model.
Chronic arsenic exposure affects stromal cells and signaling in the small intestine in a sex-specific manner
Authors: Ventrello Scott W , McMurry Nicholas R , Edwards Nicholas M , Bain Lisa J
Published: February 2024

Arsenic is a toxicant that is ingested through drinking water and food, exposing nearly 140 million people to levels above the 10 ppb guideline concentration. Studies have shown that arsenic affects intestinal stem cells (ISCs), but the mechanisms by which arsenic alters the formation of adult cells in the small intestine are not well understood. Signals derived from intestinal stromal cells initiate and maintain differentiation. The goal of this study is to evaluate arsenic’s effect on intestinal stromal cells, including PdgfrαLo trophocytes, located proximal to the ISCs, and PdgfrαHi telocytes, located proximal to the transit-amplifying region and up the villi. Adult Sox9tm2Crm−EGFP mice were exposed to 0, 33, and 100 ppb sodium arsenite in their drinking water for 13 weeks, and sections of duodenum were examined. Flow cytometry indicated that arsenic exposure dose-responsively reduced Sox9+ epithelial cells and trended toward increased Pdgfrα+ cells. The trophocyte marker, CD81, was reduced by 10-fold and 9.0-fold in the 100 ppb exposure group in male and female mice, respectively. Additionally, a significant 2.2- to 3.1-fold increase in PdgfrαLo expression was found in male mice in trophocytes and Igfbp5+ cells. PdgfrαHi protein expression, a telocyte marker, was more prevalent along the villus/crypt structure in females, whereas Gli1 expression (telocytes) was reduced in male mice exposed to arsenic. Principle coordinate analysis confirmed the sex-dependent response to arsenic exposure, with an increase in trophocyte and decrease in telocyte marker expression observed in male mice. These results imply that arsenic alters intestinal mesenchymal cells in a sex-dependent manner.