bluuebunny/crossref_metadata_2025_split huggingface dataset:
Downregulation of TCF7 and LEF1 is a key determinant of tumor-infiltrating regulatory T-cell function
Authors: Kidani Yujiro , Kitagawa Yohko , Hagiwara Masaki , Kawashima Atsunari , Kanazawa Takayuki , Wada Hisashi , Uemura Motohide , Nonomura Norio , Motooka Daisuke , Nakamura Shota , Ohkura Naganari , Sakaguchi Shimon 
Published: January 2024

Abstract
Forkhead box P3 (Foxp3)-expressing regulatory T (Treg) cells play essential roles in immune homeostasis but also contribute to establish a favorable environment for tumor growth by suppressing anti-tumor immune responses. It is thus necessary to specifically target tumor-infiltrating Treg cells to minimize effects on immune homeostasis in cancer immunotherapy. However, molecular features that distinguish tumor-infiltrating Treg cells from those in secondary lymphoid organs remain unknown. Here we characterize distinct features of tumor-infiltrating Treg cells by global analyses of the transcriptome and chromatin landscape. They exhibited activated phenotypes with enhanced Foxp3-dependent transcriptional regulation, yet being distinct from activated Treg cells in secondary lymphoid organs. Such differences may be attributed to the extensive clonal expansion of tumor-infiltrating Treg cells. Moreover, we found that TCF7 and LEF1 were specifically downregulated in tumor-infiltrating Treg cells both in mice and humans. These factors and Foxp3 co-occupied Treg suppressive function-related gene loci in secondary lymphoid organ Treg cells, whereas the absence of TCF7 and LEF1 accompanied altered gene expression and chromatin status at these gene loci in tumor-infiltrating Treg cells. Functionally, overexpression of TCF7 and LEF1 in Treg cells inhibited the enhancement of Treg suppressive function upon activation. Our results thus show the downregulation of TCF7 and LEF1 as markers of highly suppressive Treg cells in tumors and suggest that their absence controls the augmentation of Treg suppressive function in tumors. These molecules may be potential targets for novel cancer immunotherapy with minimum effects on immune homeostasis.
P03 Amikacin drug levels and efficacy—a 3 month remissive study
Authors: Coutinho Ana 
Published: January 2024

Abstract

Background
The therapeutic drug monitoring (TDM) of toxic drugs is a routine practice in our 200-bed hospital. Amikacin is not often used except in MDR bacteria. TDM is based on trough and peak levels of aminoglycosides, although AUC TDM may be the way forward, as discussed in the conclusions. According to the literature, measurement of serum amikacin levels is indicated in cases when prolonged aminoglycoside therapy is expected or in patients with compromised renal function and is not recommended for aminoglycoside use for less than 5–7 days or for treatment of mild infections in patients with no risk factors for drug toxicity.

Objectives
This study delivers some controversy on not to recommend monitoring for aminoglycoside use for less than 5–7 days, or for treatment of mild infections in patients with no risk factors for drug toxicity.

Methods
A retrospective study was conducted in our hospital between May and June 2023. Five patients aged 62–82 years on amikacin therapy for 5 to 10 days were included, all with Klebsiella pneumoniae OXA-48 UTI. At least two peak and trough samples were collected, and data were submitted to the Precise PK© software for precision dosing. The software is designed to predict population-based levels and patient-based levels. Interpretation of these values by pharmacists delivers optimized/viable amikacin intervals and dose individualized recommendations.

Results
Results are shown in Table 1.

Conclusions
Serum amikacin monitoring should guide therapy to ensure adequate levels, especially in Gram-negative resistant bacterial infections. According to these results, with Gram-negative resistant bacteria, it is worth monitoring even the short treatments—as seen in Patient 3. AUC TDM instead of peak TDM might be the way forward— this obviates distribution phase underdosing and delivers more accurate correlation to efficacy after changing intervals.
Diagnostic Test Utilization Management Strategies as an Opportunity for Equitable Access to Molecularly Informed Clinical Care
Authors: Hou Helen X , Li Annie , Thierauf Julia C , Lennerz Jochen K 
Published: January 2024

Abstract

Background
Companion diagnostics are an essential component of oncology. Timing, cost, and adaptability to new drug/biomarker approvals represent challenges in assuring value-based care. Overcoming these challenges requires strategies for equitable access and efficient integration.

Methods
Based on prior laboratory improvements and payor policy implementations, we define equitable access in laboratory testing and conceptualized a framework for initiatives that optimize diagnostic performance.

Results
We define equitable access as an imperative goal seeking to remove disparities that may arise due to financial hardships, geographical isolation, cultural differences, or other social determinants of health. We distinguish (a) utilization, as the practice pattern of ordered tests, (b) utilization management, as the evidence-based guidance of the utilization decisions, and (c) utilization management strategies, defined as the tools and techniques used to influence decision-making. These 3 dimensions establish a standardized vocabulary to clarify equitable alignment of strategies in specific care pathways. Alignment of logistic, administrative, and financial incentive structures is paramount when creating sustainable personalized care pathway programs.

Conclusions
Strategies to accomplish equitable and meaningful use of diagnostic tests can help enhance access to timely and accurate diagnoses, ultimately leading to improved patient outcomes.
Interrogating Pharmacogenetics Using Next-Generation Sequencing
Authors: Ji Yuan , Shaaban Sherin 
Published: January 2024

Abstract

Background
Pharmacogenetics or pharmacogenomics (PGx) is the study of the role of inherited or acquired sequence change in drug response. With the rapid evolution of molecular techniques, bioinformatic tools, and increased throughput of functional genomic studies, the discovery of PGx associations and clinical implementation of PGx test results have now moved beyond a handful variants in single pharmacogenes and multi-gene panels that interrogate a few pharmacogenes to whole-exome and whole-genome scales. Although some laboratories have adopted next-generation sequencing (NGS) as a testing platform for PGx and other molecular tests, most clinical laboratories that offer PGx tests still use targeted genotyping approaches.

Content
This article discusses primarily the technical considerations for clinical laboratories to develop NGS-based PGx tests including whole-genome and whole-exome sequencing analyses and highlights the challenges and opportunities in test design, content selection, bioinformatic pipeline for PGx allele and diplotype assignment, rare variant classification, reporting, and briefly touches a few additional areas that are important for successful clinical implementation of PGx results.

Summary
The accelerated speed of technology development associated with continuous cost reduction and enhanced ability to interrogate complex genome regions makes it inevitable for most, if not all, clinical laboratories to transition PGx testing to an NGS-based platform in the near future. It is important for laboratories and relevant professional societies to recognize both the potential and limitations of NGS-based PGx profiling, and to work together to develop a standard and consistent practice to maximize the variant or allele detection rate and utility of PGx testing.
Benefits of Implementing Reflex Genomic Analysis for Nonsmall Cell Lung Cancer
Authors: Smith Benjamin F , Hampel Ken J , Sidiropoulos Nikoletta 
Published: January 2024

Abstract

Background
Molecular biomarker analysis is standard of care in advanced nonsmall cell lung cancer (NSCLC). Pathologist-driven reflex testing protocols are one approach to initiating this analysis. Two years after insourcing genomic analysis at our institution, a reflex testing protocol for advanced NSCLC was initiated.

Methods
A retrospective review of the records of 578 NSCLC biopsies was performed to assess the impact of 3 genomic testing workflows (send-out, in-house clinician-ordered, and in-house reflex) on time to initiation of molecular testing [initiation time (IT)], reporting time (RT), proportion of test failures, and test ordering practices. The proportion of test failures by test methodology was also assessed.

Results
IT was lowest for reflex protocol orders (mean weekdays: 30.0 send-out, 27.4 in-house clinician-ordered, 0.95 reflex). Test failure was highest for send-out testing (31.7% vs. 10% each for in-house clinician-ordered and reflex). RT remained consistent across the 3 workflows (mean weekdays: 11.1 send-out, 11.9 in-house clinician-ordered, and 11.4 reflex). Guideline-congruent molecular testing increased upon insourcing genomic analysis and again upon implementing reflex testing with a reduction in nonbiomarker informed care (58.8% send-out, 19.5% in-house clinician-ordered, 11.5% reflex).

Conclusions
Implementation of reflex in-house genomic analysis for advanced NSCLC ensured consistency in RT and significantly decreased IT and proportion of test failures. Insourcing genomic analysis and thoughtful care pathway design improve equitable access to molecular biomarker analysis and mitigate nonbiomarker informed cancer care in NSCLC.
Establishing Population Values for Chlorine Exposure in the United States (2015–2016) Using 2 Chlorine Biomarkers, 3-Chlorotyrosine and 3,5-Dichlorotyrosine
Authors: Boles Stephanie L , Pantazides Brooke G , Perez Jonas W , Sternberg Maya R , Crow Brian S , Blake Thomas A 
Published: January 2024

Abstract

Background
In the United States, 12 million short tons of chlorine are manufactured and transported each year. Due to the volume of this volatile chemical, large- and small-scale chemical exposures occur frequently. To diagnose and treat potentially exposed individuals, reference range values for confirmatory biomarkers are required to differentiate between normal and abnormal exposure levels.

Methods
Serum surplus samples (n = 1780) from the National Health and Nutrition Examination Survey (NHANES) 2015–2016 were measured for 2 chlorine biomarkers, 3-chlorotyrosine (Cl-Tyr) and 3,5-dichlorotyrosine (Cl2-Tyr), by liquid chromatography coupled to a triple quadrupole mass spectrometer. We evaluated demographic factors associated with elevated biomarker levels.

Results
Participant samples were analyzed for the chlorine biomarkers Cl-Tyr and Cl2-Tyr. In the unweighted analysis of these samples, 1349 (75.8%) were under the limit of detection (&lt; LOD) of 2.50 ng/mL for Cl-Tyr and 1773 (99.6%) were &lt; LOD for Cl2-Tyr. Samples within the method reportable range were 2.50 to 35.6 ng/mL for Cl-Tyr and 2.69 to 11.2 ng/mL for Cl2-Tyr. Since only 7 of the 1780 participants had detectable Cl2-Tyr, statistical analysis was limited to Cl-Tyr. Of the demographic characteristics examined, age, body mass index (BMI), estimated glomerular filtration rate (eGFR), and sex exhibited statistically significant differences in the weighted prevalence of detectable Cl-Tyr.

Conclusions
This is the first reported set of Cl-Tyr and Cl2-Tyr population values for the United States. This population range coupled with NHANES demographic information could help healthcare professionals distinguish between normal and abnormal chlorine biomarker levels in an emergency. With this information, an inference could be made when determining acute chlorine exposure in individuals.
Perturbed collagen metabolism underlies lymphatic recanalization failure in Gata2 heterozygous deficient mice
Authors: Watanabe-Asaka Tomomi , Hayashi Moyuru , Harada Takuya , Uemura Satoshi , Takai Jun , Nakamura Yasuhiro , Moriguchi Takashi , Kawai Yoshiko 
Published: January 2024

Abstract
Lymphedema has become a global health issue following the growing number of cancer surgeries. Curative or supportive therapeutics have long been awaited for this refractory condition. Transcription factor GATA2 is crucial in lymphatic development and maintenance, as GATA2 haploinsufficient disease often manifests as lymphedema. We recently demonstrated that Gata2 heterozygous deficient mice displayed delayed lymphatic recanalization upon lymph node resection. However, whether GATA2 contributes to lymphatic regeneration by functioning in the damaged lymph vessels' microenvironment remains explored. In this study, our integrated analysis demonstrated that dermal collagen fibers were more densely accumulated in the Gata2 heterozygous deficient mice. The collagen metabolism-related transcriptome was perturbed, and collagen matrix contractile activity was aberrantly increased in Gata2 heterozygous embryonic fibroblasts. Notably, soluble collagen placement ameliorated delayed lymphatic recanalization, presumably by modulating the stiffness of the extracellular matrix around the resection site of Gata2 heterozygous deficient mice. Our results provide valuable insights into mechanisms underlying GATA2-haploinsufficiency-mediated lymphedema and shed light on potential therapeutic avenues for this intractable disease.
Point-of-care neutrophil and monocyte surface markers differentiate bacterial from viral infections at the emergency department within 30 min
Authors: Jukema Bernard N , de Hond Titus A P , Kroon Martijn , Maranus Anna E , Koenderman Leo , Kaasjager Karin A H 
Published: January 2024

Abstract
Rapid discrimination between viral and bacterial infections in a point-of-care setting will improve clinical outcome. Expression of CD64 on neutrophils (neuCD64) increases during bacterial infections, whereas expression of CD169 on classical monocytes (cmCD169) increases during viral infections. The diagnostic value of automated point-of-care neuCD64 and cmCD169 analysis was assessed for detecting bacterial and viral infections at the emergency department. Additionally, their value as input for machine learning models was studied. A prospective observational cohort study in patients suspected of infection was performed at an emergency department. A fully automated point-of-care flow cytometer measured neuCD64, cmCD169, and additional leukocyte surface markers. Flow cytometry data were gated using the FlowSOM algorithm. Bacterial and viral infections were assessed in standardized clinical care. The sole and combined diagnostic value of the markers was investigated. Clustering based on unsupervised machine learning identified unique patient clusters. Eighty-six patients were included. Thirty-five had a bacterial infection, 30 had a viral infection, and 21 had no infection. neuCD64 was increased in bacterial infections (P &lt; 0.001), with an area under the receiver operating characteristic curve (AUROC) of 0.73. cmCD169 was higher in virally infected patients (P &lt; 0.001; AUROC 0.79). Multivariate analyses incorporating additional markers increased the AUROC for bacterial and viral infections to 0.86 and 0.93, respectively. The additional clustering identified 4 distinctive patient clusters based on infection type and outcome. Automated neuCD64 and cmCD169 determination can discriminate between bacterial and viral infections. These markers can be determined within 30 min, allowing fast infection diagnostics in the acute clinical setting.
The jet composition of GRB 230307A: Poynting-flux-dominated outflow?
Authors: Du Zhao-Wei , Lü HouJun , Liu Xiaoxuan , Liang EnWei 
Published: January 2024

ABSTRACT
The jet composition of GRB plays an important role in understanding the energy dissipation and radiation mechanisms in GRB physics, but it is poorly constrained from the observational data. Recently, an interesting long-duration GRB 230307A with redshift z = 0.065 has attracted great attention. The lack of detected thermal emission and mini-structure of prompt emission light curve of this burst suggest that the outflow is Poynting-flux-dominated and point towards the ICMART model. In this paper, we invoke two independent methods to investigate the jet composition of GRB 230307A. The high magnetization parameter (σ &gt; 7 or ever large) for R0 = 1010 cm that is used to suppress thermal component, strongly suggests that a significant fraction of the outflow energy is likely in a Poynting flux entrained with the baryonic matter. Moreover, it is found that the radiation efficiency of this burst for typical values ϵe = 0.1 and ϵB = 0.01 can reach as high as $~50{{\ \rm per\ cent}}$ which disfavours the internal shock model, but is consistent with ICMART model. Finally, a possible unified picture to produce GRB 230307A originated from a compact star merger is also discussed.
Risk factor analysis for a rapid progression of chronic kidney disease
Authors: Vestergaard Anne H S , Jensen Simon K , Heide-Jørgensen Uffe , Frederiksen Line E , Birn Henrik , Jarbøl Dorte E , Søndergaard Jens , Persson Frederik , Thomsen Reimar W , Christiansen Christian F 
Published: January 2024

ABSTRACT

Background
Chronic kidney disease (CKD) is a growing global health concern. Identifying individuals in routine clinical care with new-onset CKD at high risk of rapid progression of the disease is imperative to guide allocation of prophylactic interventions, but community-based data are limited. We aimed to examine the risk of rapid progression, kidney failure, hospitalization and death among adults with incident CKD stage G3 and to clarify the association between predefined risk markers and rapid CKD progression.

Methods
Using plasma creatinine measurements for the entire Danish population from both hospitals and primary care, we conducted a nationwide, population-based cohort study, including adults in Denmark with incident CKD stage G3 in 2017–2020. We estimated 3-year risks of rapid progression (defined by a confirmed decline in estimated glomerular filtration rate of ≥5 mL/min/1.73 m2/year), kidney failure, all-cause hospitalization and death. To examine risk markers, we constructed a heat map showing the risk of rapid progression based on predefined markers: albuminuria, sex, diabetes and hypertension/cardiovascular disease.

Results
Among 133 443 individuals with incident CKD stage G3, the 3-year risk of rapid progression was 14.6% [95% confidence interval (CI) 14.4–14.8]. The 3-year risks of kidney failure, hospitalization and death were 0.3% (95% CI 0.3–0.4), 53.3% (95% CI 53.0–53.6) and 18.1% (95% CI 17.9–18.4), respectively. In the heat map, the 3-year risk of rapid progression ranged from 7% in females without albuminuria, hypertension/cardiovascular disease or diabetes, to 46%–47% in males and females with severe albuminuria, diabetes and hypertension/cardiovascular disease.

Conclusion
This population-based study shows that CKD stage G3 is associated with considerable morbidity in a community-based setting and underscores the need for optimized prophylactic interventions among such patients. Moreover, our data highlight the potential of using easily accessible markers in routine clinical care to identify individuals who are at high risk of rapid progression.
Bioinspired polysaccharide-based nanocomposite membranes with robust wet mechanical properties for guided bone regeneration
Authors: Xiao Jian-Hong , Zhang Zhen-Bang , Li JiaHao , Chen Si-Ming , Gao Huai-Ling , Liao YinXiu , Chen Lu , Wang ZiShuo , Lu YiFan , Hou YuanZhen , Wu HengAn , Zou DuoHong , Yu Shu-Hong 
Published: January 2024

ABSTRACT
Polysaccharide-based membranes with excellent mechanical properties are highly desired. However, severe mechanical deterioration under wet conditions limits their biomedical applications. Here, inspired by the structural heterogeneity of strong yet hydrated biological materials, we propose a strategy based on heterogeneous crosslink-and-hydration (HCH) of a molecule/nano dual-scale network to fabricate polysaccharide-based nanocomposites with robust wet mechanical properties. The heterogeneity lies in that the crosslink-and-hydration occurs in the molecule-network while the stress-bearing nanofiber-network remains unaffected. As one demonstration, a membrane assembled by bacterial cellulose nanofiber-network and Ca2+-crosslinked and hydrated sodium alginate molecule-network is designed. Studies show that the crosslinked-and-hydrated molecule-network restricts water invasion and boosts stress transfer of the nanofiber-network by serving as interfibrous bridge. Overall, the molecule-network makes the membrane hydrated and flexible; the nanofiber-network as stress-bearing component provides strength and toughness. The HCH dual-scale network featuring a cooperative effect stimulates the design of advanced biomaterials applied under wet conditions such as guided bone regeneration membranes.
Early Prediction of Poststroke Rehabilitation Outcomes Using Wearable Sensors
Authors: O’Brien Megan K , Lanotte Francesco , Khazanchi Rushmin , Shin Sung Yul , Lieber Richard L , Ghaffari Roozbeh , Rogers John A , Jayaraman Arun 
Published: January 2024

AbstractObjectiveInpatient rehabilitation represents a critical setting for stroke treatment, providing intensive, targeted therapy and task-specific practice to minimize a patient’s functional deficits and facilitate their reintegration into the community. However, impairment and recovery vary greatly after stroke, making it difficult to predict a patient’s future outcomes or response to treatment. In this study, the authors examined the value of early-stage wearable sensor data to predict 3 functional outcomes (ambulation, independence, and risk of falling) at rehabilitation discharge.MethodsFifty-five individuals undergoing inpatient stroke rehabilitation participated in this study. Supervised machine learning classifiers were retrospectively trained to predict discharge outcomes using data collected at hospital admission, including patient information, functional assessment scores, and inertial sensor data from the lower limbs during gait and/or balance tasks. Model performance was compared across different data combinations and was benchmarked against a traditional model trained without sensor data.ResultsFor patients who were ambulatory at admission, sensor data improved the predictions of ambulation and risk of falling (with weighted F1 scores increasing by 19.6% and 23.4%, respectively) and maintained similar performance for predictions of independence, compared to a benchmark model without sensor data. The best-performing sensor-based models predicted discharge ambulation (community vs household), independence (high vs low), and risk of falling (normal vs high) with accuracies of 84.4%, 68.8%, and 65.9%, respectively. Most misclassifications occurred with admission or discharge scores near the classification boundary. For patients who were nonambulatory at admission, sensor data recorded during simple balance tasks did not offer predictive value over the benchmark models.ConclusionThese findings support the continued investigation of wearable sensors as an accessible, easy-to-use tool to predict the functional recovery after stroke.ImpactAccurate, early prediction of poststroke rehabilitation outcomes from wearable sensors would improve our ability to deliver personalized, effective care and discharge planning in the inpatient setting and beyond.