bluuebunny/crossref_metadata_2025_split huggingface dataset:
Infectious Diseases Training in the 21st Century: A Glass Half Full or Half Empty?
Authors: Arias Cesar A , Pirofski Liise-anne 
Published: February 2024

Abstract
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

Abstract

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) &lt;1225&gt; guidelines, and found to be accurate, specific, precise, linear, robust and stability-indicating. The precision and intermediate results were &lt;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

Abstract
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

Abstract
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 &gt; .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

Abstract
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

Abstract
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

Abstract

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

Abstract
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

Abstract

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

Abstract

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 &lt; .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 &lt; .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

Abstract
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

Abstract
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.