bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient-derived reference intervals for alkaline phosphatase to support appropriate utility for isoenzymes determinations and hypophosphatasia
Authors: Joseph Jonathan , Hashim Ibrahim A
Published: May 2024

Background

Appropriate age- and sex-specific reference intervals for alkaline phosphatase (ALP) are essential to identify patients with hypophosphatasia (low ALP) and to avoid unnecessary ALP isoenzymes analysis (elevated ALP). This study used patient ALP historical data to statistically derive sex- and age-specific reference intervals.

Methods

The ALP values reported as part of clinical management during an 18 month period (from July 2021 to March 2023) were obtained. Following logarithmic transformation of ALP data and repeated removal of outliers, cumulative frequency plots were generated using a modified Hoffmann approach to derive age- and sex-specific reference intervals.

Results

Age-specific ALP reference intervals ranged from 110 to 250 and 120 to 295 U/L for males and females <15 days old, 80 to 400 and 90 to 380 U/L for males and females 15 days to 1 year old, 105 to 280 and 90 to 290 U/L for males and females 1 to 10 years old, 75 to 300 and 90 to 300 U/L for males and females 10 to 13 years old, 80 to 300 and 60 to 175 U/L for males and females 13 to 15 years old, 55 to 150 and 60 to 180 U/L for males and females 15 to 18 years old, and 55 to 140 and 60 to 147 U/L for male and female adults, respectively (>18 years old).

Conclusion

By applying derived ranges, a retrospective review of ALP isoenzymes would eliminate 24.5% of requests. Additionally, 9 neonates would have required investigation for possible hypophosphatasia.
90 years of Gödel’s incompleteness theorems: Logic and computation
Authors: Baaz Matthias , Ertel Marcel , Kahle Reinhard , Piecha Thomas , von Plato Jan
Published: May 2024

This volume is one of two special issues collecting articles by invited speakers of the conference ‘Celebrating 90 Years of Gödel’s Incompleteness Theorems’ held in Nürtingen (Germany) in July 2021. The conference was organized by the Carl Friedrich von Weizsäcker Center at the University of Tübingen with support by the ERC-funded project Gödel Enigma: Rediscovering Kurt Gödel through his unpublished works at the University of Helsinki and by the Kurt Gödel Society in Vienna.
Management of disseminated histoplasmosis in a high-complexity clinic in Cali, Colombia
Authors: Ramos-Ospina Natalia , Carolina Lambertinez-Álvarez Indira , Johanna Hurtado-Bermúdez Leidy , Patricia Muñoz-Lombo Jenny , Diego Vélez-Londoño Juan , Andrés Valencia-Montagut Jorge , Andrés Moncada-Vallejo Pablo
Published: May 2024

Histoplasmosis presents a substantial clinical challenge globally, with a particular prevalence in South America, especially among patients with concurrent Human Immunodeficiency Virus (HIV) infection. Despite itraconazole's established efficacy, investigating alternative therapeutic approaches remains imperative. This is the largest study in our region to date, assessing the effectiveness of the less explored posaconazole treatment. This observational study, conducted at Fundación Valle del Lili (FVL) from 2016 to 2022, encompassed adults with disseminated histoplasmosis. Patients (n = 31) were treated with liposomal amphotericin B as an initial treatment, followed by consolidation treatment with posaconazole or itraconazole. Patients with single-organ cases, those lacking microbiological diagnosis, those who received initial treatment with antifungals other than liposomal Amphotericin B and those with < 6 months follow-up were excluded (Figure 1). Analyses considered population characteristics, treatments, and outcomes. Patients (average age: 45.6; 58.1% female) had common comorbidities (HIV 38.7%, solid organ transplantation 29% and oncologic disease 12.9%). Lungs (48.4%) and lymph nodes (16.1%) were commonly affected. Biopsy (64.5%) was the primary diagnostic method. Initial treatment with liposomal amphotericin B (100%) was given for 14 days on average. Follow-up indicated 71% completion with 19.4% requiring treatment modifications. Notably, 70.9% completed a posaconazole consolidation regimen over 350 days on average. Drug interactions during consolidation (80.6%) were common. No relapses occurred, and three deaths unrelated to histoplasmosis were reported. Traditionally, itraconazole has been the prevalent initial treatment; however, in our cohort, 55.9% of patients received posaconazole as the primary option. Encouragingly, posaconazole showed favorable tolerance and infection resolution, suggesting its potential as an effective and well-tolerated alternative for consolidation treatment. This finding prompts further exploration of posaconazole, potentially leading to more effective patient care and better outcomes.
Deciphering the association between biopsy-confirmed systemic small vessel vasculitis and Epstein–Barr virus-positive polymorphic B-cell lymphoproliferation
Authors: Sunaga Atsuhiko , Seno Takahiro , Omura Satoshi , Inoue Takuya , Miyagawa-Hayashino Aya , Omatsu Ikoi , Wada Makoto , Kohno Masataka , Kawahito Yutaka
Published: May 2024

The Epstein-Barr virus (EBV) is associated with various lymphoproliferative disorders (LPDs). Additionally, EBV infection has correlated with diverse autoimmune diseases. However, the association between EBV and systemic small vessel vasculitis (SVV) remains controversial. Here, we report a case of SVV with pauci-immune glomerulonephritis accompanied by an EBV-positive polymorphic B-cell LPD, not otherwise specified. The intricate distinction between EBV-positive B-cell LPD and SVV was difficult, as both diseases demonstrated similar clinical presentations. Lymph node and kidney biopsies facilitated the accurate diagnosis of these two conditions. The administration of high-dose prednisolone, combined with rituximab, proved efficacious, with no instances of relapse over the subsequent 2-year period. This case indicates an association between EBV-positive B-cell LPD and SVV. The diligent execution of biopsies is a crucial diagnostic and interpretive strategy, generating precise comprehension of this condition and guiding its appropriate therapeutic management.
Dysregulated DnaB unwinding induces replisome decoupling and daughter strand gaps that are countered by RecA polymerization
Authors: Behrmann Megan S , Perera Himasha M , Welikala Malisha U , Matthews Jacquelynn E , Butterworth Lauren J , Trakselis Michael A
Published: May 2024

The replicative helicase, DnaB, is a central component of the replisome and unwinds duplex DNA coupled with immediate template-dependent DNA synthesis by the polymerase, Pol III. The rate of helicase unwinding is dynamically regulated through structural transitions in the DnaB hexamer between dilated and constricted states. Site-specific mutations in DnaB enforce a faster more constricted conformation that dysregulates unwinding dynamics, causing replisome decoupling that generates excess ssDNA and induces severe cellular stress. This surplus ssDNA can stimulate RecA recruitment to initiate recombinational repair, restart, or activation of the transcriptional SOS response. To better understand the consequences of dysregulated unwinding, we combined targeted genomic dnaB mutations with an inducible RecA filament inhibition strategy to examine the dependencies on RecA in mitigating replisome decoupling phenotypes. Without RecA filamentation, dnaB:mut strains had reduced growth rates, decreased mutagenesis, but a greater burden from endogenous damage. Interestingly, disruption of RecA filamentation in these dnaB:mut strains also reduced cellular filamentation but increased markers of double strand breaks and ssDNA gaps as detected by in situ fluorescence microscopy and FACS assays, TUNEL and PLUG, respectively. Overall, RecA plays a critical role in strain survival by protecting and processing ssDNA gaps caused by dysregulated helicase activity in vivo.
PHF2 regulates genome topology and DNA replication in neural stem cells via cohesin
Authors: Feng Jia , Chuah You Heng , Liang Yajing , Cipta Nadia Omega , Zeng Yingying , Warrier Tushar , Elfar Gamal Ahmed Rashed Elsayed , Yoon Jeehyun , Grinchuk Oleg V , Tay Emmy Xue Yun , Lok Ker-Zhing , Zheng Zong-Qing , Khong Zi Jian , Chong Zheng-Shan , Teo Jackie , Sanford Emma May , Neo Cheryl Jia Yi , Chiu Hsin Yao , Leung Jia Yu , Wang Loo Chien , Lim Yan Ting , Zhao Tianyun , Sobota Radoslaw M , Crasta Karen Carmelina , Tergaonkar Vinay , Taneja Reshma , Ng Shi-Yan , Cheok Chit Fang , Ling Shuo-Chien , Loh Yuin-Han , Ong Derrick Sek Tong
Published: May 2024

Cohesin plays a crucial role in the organization of topologically-associated domains (TADs), which influence gene expression and DNA replication timing. Whether epigenetic regulators may affect TADs via cohesin to mediate DNA replication remains elusive. Here, we discover that the histone demethylase PHF2 associates with RAD21, a core subunit of cohesin, to regulate DNA replication in mouse neural stem cells (NSC). PHF2 loss impairs DNA replication due to the activation of dormant replication origins in NSC. Notably, the PHF2/RAD21 co-bound genomic regions are characterized by CTCF enrichment and epigenomic features that resemble efficient, active replication origins, and can act as boundaries to separate adjacent domains. Accordingly, PHF2 loss weakens TADs and chromatin loops at the co-bound loci due to reduced RAD21 occupancy. The observed topological and DNA replication defects in PHF2 KO NSC support a cohesin-dependent mechanism. Furthermore, we demonstrate that the PHF2/RAD21 complex exerts little effect on gene regulation, and that PHF2’s histone-demethylase activity is dispensable for normal DNA replication and proliferation of NSC. We propose that PHF2 may serve as a topological accessory to cohesin for cohesin localization to TADs and chromatin loops, where cohesin represses dormant replication origins directly or indirectly, to sustain DNA replication in NSC.
Imaging meningioma biology: Machine learning predicts integrated risk score in WHO grade 2/3 meningioma
Authors: Kertels Olivia , Delbridge Claire , Sahm Felix , Ehret Felix , Acker Güliz , Capper David , Peeken Jan C , Diehl Christian , Griessmair Michael , Metz Marie-Christin , Negwer Chiara , Krieg Sandro M , Onken Julia , Yakushev Igor , Vajkoczy Peter , Meyer Bernhard , Zips Daniel , Combs Stephanie E , Zimmer Claus , Kaul David , Bernhardt Denise , Wiestler Benedikt
Published: May 2024

Background

Meningiomas are the most common primary brain tumors. While most are benign (WHO grade 1) and have a favorable prognosis, up to one-fourth are classified as higher-grade, falling into WHO grade 2 or 3 categories. Recently, an integrated risk score (IRS) pertaining to tumor biology was developed and its prognostic relevance was validated in a large, multicenter study. We hypothesized imaging data to be reflective of the IRS. Thus, we assessed the potential of a machine learning classifier for its noninvasive prediction using preoperative magnetic resonance imaging (MRI).

Methods

In total, 160 WHO grade 2 and 3 meningioma patients from 2 university centers were included in this study. All patients underwent surgery with histopathological workup including methylation analysis. Preoperative MRI scans were automatically segmented, and radiomic parameters were extracted. Using a random forest classifier, 3 machine learning classifiers (1 multiclass classifier for IRS and 2 binary classifiers for low-risk and high-risk prediction, respectively) were developed in a training set (120 patients) and independently tested in a hold-out test set (40 patients).

Results

Multiclass IRS classification had a test set area under the curve (AUC) of 0.7, mostly driven by the difficulties in clearly separating medium-risk from high-risk patients. Consequently, a classifier predicting low-risk IRS versus medium-/high-risk showed a very high test accuracy of 90% (AUC 0.88). In particular, “sphericity” was associated with low-risk IRS classification.

Conclusion

The IRS, in particular molecular low-risk, can be predicted from imaging data with high accuracy, making this important prognostic classification accessible by imaging.
Childhood dyslipidemia: Clinician management practices in the primary care setting
Authors: Tom Katherine N , Polack Alicia M , De Silva Natasha D , Wong Jonathan P , Keown-Stoneman Charles D G , Maguire Jonathon L , Birken Catherine S , Wong Peter D
Published: May 2024

Objectives

To describe clinician management practices for childhood dyslipidemia in the community setting.

Methods

A descriptive study was conducted for children aged 2 to 10 years with dyslipidemia as defined by the National Cholesterol Education Program Expert Panel on Cholesterol in Children criteria. A convenience sample of participants from the TARGet Kids! cohort study (Toronto, Canada) was used. Trained research assistants reviewed participant medical records to document clinician management practices of abnormal lipid levels. The study outcome was the proportion of clinicians engaging in each management practice. Descriptive statistics were completed, reporting the proportion of clinician engagement in management practices.

Results

All 768 children were seen by primary paediatric care providers after lipid levels identified dyslipidemia. Medical history regarding lifestyle behaviours and cardiovascular risk factors were frequently obtained (n = 565, 73.6%). Physicians rarely informed families about abnormal lipid levels (n = 11, 1.43%). Management plans for abnormal lipid levels were rarely documented (n = 4, 0.5%). Clinicians did not refer to paediatric lipid specialists or initiate statin therapy.

Conclusions

Paediatric care providers rarely identified and initiated early management for abnormal lipid levels. Our results may inform the need for improved knowledge translation of the recently published Canadian clinical practice update for the detection and management of childhood dyslipidemia.
ContinUNet: fast deep radio image segmentation in the Square Kilometre Array era with U-Net
Authors: Stewart Hattie , Birkinshaw Mark , Yeung Siu-Lun , Maddox Natasha , Maughan Ben , Thiyagalingam Jeyan
Published: May 2024

We present a new machine learning (ML)-driven source-finding tool for next-generation radio surveys that performs fast source extraction on a range of source morphologies at large dynamic ranges with minimal parameter tuning and post-processing. The construction of the Square Kilometre Array (SKA) radio telescope will revolutionize the field of radio astronomy. However, accurate and automated source-finding techniques are required to reach SKA science goals. We have developed a novel source-finding method, ContinUNet, powered by an ML segmentation algorithm, U-Net, that has proven highly effective and efficient when tested on SKA precursor data sets. Our model was trained and tested on simulated radio continuum data from SKA Science Data Challenge 1 and proved comparable with the state-of-the-art source-finding methods, PyBDSF and ProFound. ContinUNet was then tested on the MeerKAT International GHz Tiered Extragalactic Exploration Early Science data without retraining and was able to extract point-like and extended sources with equal ease; processing a 1.6 deg$^2$ field in $\lt $13 s on a supercomputer and $\approx$2 min on a personal laptop. We were able to associate components of extended sources without manual intervention with the powerful inference capabilities learnt within the network, making ContinUNet a promising tool for enabling science in the upcoming SKA era.
Evaluation of information accuracy and clarity: ChatGPT responses to the most frequently asked questions about premature ejaculation
Authors: Şahin Mehmet Fatih , Keleş Anil , Özcan Rıdvan , Doğan Çağrı , Topkaç Erdem Can , Akgül Murat , Yazıci Cenk Murat
Published: May 2024

Background

Premature ejaculation (PE) is the most prevalent sexual dysfunction in men, and like many diseases and conditions, patients use Internet sources like ChatGPT, which is a popular artificial intelligence–based language model, for queries about this andrological disorder.

Aim

The objective of this research was to evaluate the quality, readability, and understanding of texts produced by ChatGPT in response to frequently requested inquiries on PE.

Methods

In this study we used Google Trends to identify the most frequently searched phrases related to PE. Subsequently, the discovered keywords were methodically entered into ChatGPT, and the resulting replies were assessed for quality using the Ensuring Quality Information for Patients (EQIP) program. The produced texts were assessed for readability using the Flesch–Kincaid Grade Level (FKGL), Flesch Reading Ease Score (FRES), and DISCERN metrics.

Outcomes

This investigation has identified substantial concerns about the quality of texts produced by ChatGPT, highlighting severe problems with reading and understanding.

Results

The mean EQIP score for the texts was determined to be 45.93 ± 4.34, while the FRES was 15.8 ± 8.73. Additionally, the FKGL score was computed to be 15.68 ± 1.67 and the DISCERN score was 38.1 ± 3.78. The comparatively low average EQIP and DISCERN scores suggest that improvements are required to increase the quality and dependability of the presented information. In addition, the FKGL scores indicate a significant degree of linguistic intricacy, requiring a level of knowledge comparable to about 14 to 15 years of formal schooling in order to understand. The texts about treatment, which are the most frequently searched items, are more difficult to understand compared to other texts about other categories.

Clinical Implications

The results of this research suggest that compared to texts on other topics the PE texts produced by ChatGPT exhibit a higher degree of complexity, which exceeds the recommended reading threshold for effective health communication. Currently, ChatGPT is cannot be considered a substitute for comprehensive medical consultations.

Strengths and Limitations

This study is to our knowledge the first reported research investigating the quality and comprehensibility of information generated by ChatGPT in relation to frequently requested queries about PE. The main limitation is that the investigation included only the first 25 popular keywords in English.

Conclusion

ChatGPT is incapable of replacing the need for thorough medical consultations.
The Role of Roman Law in the Formation of the State and Modern Law
Authors: Pejo Erida , Kolaneci Esmeralda
Published: May 2024

The research aims to determine the role that Roman law played in the development of modern jurisprudence. Several methods of theoretical cognition were used in the course of the study, such as analysis, synthesis, comparison, specification, and generalization. As a result, some conclusions have been reached, in particular, that the mechanisms and principles of the Roman legal order, which have existed for many centuries, remain relevant in the modern legal context, and have influenced the formation of political and institutional structures, especially in the field of market relations and economic development. In addition, the study identifies how different branches of Roman law have influenced the further development of jurisprudence. Roman public law (ius publicum) influenced the development of constitutional law in modern countries by regulating relations between the state and citizens. Roman private law (ius privatum) defined the foundations of modern civil law systems, regulating the rights and obligations of citizens among themselves. Also, with the development of trade in Rome, the concept of ius gentium or “law of nations” emerged, which became the basis of modern international law through the formalization of rules and regulations governing the international exchange and circulation of goods.
Decreasing Stigma Toward People Who Inject Drugs: Harm Reduction Training for First-Year Medical Students
Authors: Avra Tucker , Cowan Amanda , Friedman Joseph , Fukushima Jack , Nelson Andrew , Truman Kyla , Stevens Autumn , Bourgois Philippe , Hansen Helena , Shover Chelsea , Goodman-Meza David
Published: May 2024

Problem

Stigma in health care toward people who inject drugs (PWID) is a well-described, significant barrier to quality care, resulting in poor health outcomes. Harm reduction offers a person-centered counter-framework for minimizing harm for people who use drugs. Despite the evidence in support of harm reduction, medical students typically receive minimal training on harm reduction and the care of PWID.

Approach

To fill this gap, medical students at the University of California, Los Angeles organized around the principles of harm reduction to improve the medical school curriculum related to PWID. Students screened lectures for stigmatizing language and collaborated with faculty to improve lecture materials. They partnered with a community organizer and hosted a mandatory 1-hour lecture and 30-minute discussion introducing the principles of harm reduction within an overdose prevention, recognition, and response training for first-year medical students during medical school orientation in August 2022. An anonymous online pretest and posttest survey, assessing student attitudes toward PWID, was used to evaluate the effects of the training.

Outcomes

A total of 156 students completed the pretest survey, and 107 students completed the pretest and posttest survey (68.5% response rate). The overall posttest mean stigma score was 1.8 (standard deviation [SD] = 0.5) and was significantly lower than the pretest mean of 2.1 (SD = 0.7;P< .0001), indicating a reduction in stigma among medical student attitudes after the course. There was statistically significant improvement in attitudes for 7 of 13 component measures.

Next Steps

This analysis demonstrated that the mandatory class has the capacity to improve medical student attitudes toward PWID. The authors plan to further evaluate the program’s effectiveness through measuring and reporting outcomes for future student cohorts. The authors are working with curriculum directors to further incorporate harm reduction principles into other lectures and problem-based learning exercises.
Preoperative Physical Therapy is Associated With Decreased Length of Stay and Improved Postoperative Mobility in Patients With Sarcopenia Undergoing Adult Spinal Deformity Surgery
Authors: Hirase Takashi , Lovecchio Francis C. , Allen Myles R.J. , Achebe Chukwuebuka C. , Mazzucco Michael , Uzzo Robert N. , Kazarian Gregory S. , Asada Tomoyuki , Nakarai Hiroyuki , Subramanian Tejas , Simon Chad Z. , Durbas Atahan , Kaidi Austin C. , Araghi Kasra , Samuel Justin T. , Kwas Cole , Albert Todd J. , Kim Han Jo
Published: May 2024

Study Design.

Retrospective cohort study.

Objective.

To determine the relationship between preoperative physical therapy (PT) and postoperative mobility, adverse events (AEs), and length of stay (LOS) among patients with low normalized total psoas area (NTPA) undergoing adult spinal deformity (ASD) surgery.

Background.

Sarcopenia, as defined by low NTPA, has been shown to predict poor perioperative outcomes of ASD surgery. However, there is limited evidence correlating the benefits of PT within the patient population with sarcopenic.

Materials and Methods.

NTPA was analyzed at the L3 and L4 mid-vertebral bodies on preoperative magnetic resonance imaging. Receiver operating characteristic curve analysis was used to determine sex-specific NTPA cutoff values for predicting perioperative AEs. Patients were categorized as having low NTPA if both L3 and L4 NTPA were below these cutoff values. Perioperative outcomes were compared between patients with low NTPA who underwent documented formal PT within 6 months before ASD surgery with those who did not.

Results.

A total of 103 patients (42 males, 61 females) met the criteria for low NTPA for inclusion in the study, of which 42 underwent preoperative PT and 61 did not. The preoperative PT group had a shorter LOS (111.2 ± 37.5 vs. 162.1 ± 97.0 h, P < 0.001), higher ambulation distances (feet) on postoperative day (POD) 1 (61.7 ± 50.3 vs. 26.1 ± 69.0, P < 0.001), POD 2 (113.2 ± 81.8 vs. 62.1 ± 73.1, P = 0.003), and POD 3 (126.0 ± 61.2 vs. 91.2 ± 72.6, P = 0.029), and lower rates of total AEs (31.0% vs. 54.1%, P = 0.003) when excluding anemia requiring transfusion. Multivariable analysis found preoperative PT to be the most significant predictor of decreased LOS (odds ratio: 0.32, P = 0.013).

Conclusion.

Patients with sarcopenia may benefit from formal preoperative PT before undergoing ASD surgery to improve early postoperative mobility, decrease adverse eveents, and reduce length of stay.

Level of Evidence.

Level III.
Chinese Guidelines for the Diagnosis and Management of Atrial Fibrillation
Authors:   Chinese Society of Cardiology, Chinese Medical Association; Heart Rhythm Committee of Chinese Society of Biomedical Engineering
Published: May 2024

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, significantly impacting patients’ quality of life and increasing the risk of death, stroke, heart failure, and dementia. Over the past 2 decades, there have been significant breakthroughs in AF risk prediction and screening, stroke prevention, rhythm control, catheter ablation, and integrated management. During this period, the scale, quality, and experience of AF management in China have greatly improved, providing a solid foundation for the development of guidelines for the diagnosis and management of AF. To further promote standardized AF management, and apply new technologies and concepts to clinical practice in a timely and comprehensive manner, the Chinese Society of Cardiology of the Chinese Medical Association and the Heart Rhythm Committee of the Chinese Society of Biomedical Engineering have jointly developed the Chinese Guidelines for the Diagnosis and Management of Atrial Fibrillation. The guidelines have comprehensively elaborated on various aspects of AF management and proposed the CHA2DS2-VASc-60 stroke risk score based on the characteristics of AF in the Asian population. The guidelines have also reevaluated the clinical application of AF screening, emphasized the significance of early rhythm control, and highlighted the central role of catheter ablation in rhythm control.
Identification of the CD8+ T-cell Related Signature for Predicting the Prognosis of Gastric Cancer Based on Integrated Analysis of Bulk and Single-cell RNA Sequencing Data
Authors: Zhu Zhi-gang , Wang Zheng , Wu Qiong , Miao Dong-liu , Jin Yi-qi , Chen Lei
Published: May 2024

The infiltration of CD8+ T cells in the tumor microenvironment is associated with better survival and immunotherapy response. However, their roles in gastric cancer have not been explored so far. In here, the profiles of GC gene expression were collected from The Cancer Genome Atlas database. Single-cell transcriptomic data originated from GSE134520. Cell clustering, annotation, and CD8+ T-cell differential genes were from the TISCH database. We determined 896 CD8+ T-cell differential genes by scRNA-seq analysis. After integrating immune-related genes, 174 overlapping genes were obtained and a novel risk model was subsequently built. The performance of CD8+ T-cell–associated gene signature was assessed in the training and external validation sets. The gene signature showed independent risk factors of overall survival for GC. A quantitative nomogram was built to enhance the clinical efficacy of this signature. Furthermore, low-risk individuals showed higher mutation status, higher immune checkpoint expression, low Tumour Immune Dysfunction and Exclusion (TIDE) scores, and higher IPS-PD-1 combined IPS-CTLA4 scores, indicating a greater response to immunotherapy. In addition, analysis of IMvigor210 immunotherapy cohort demonstrated that low-risk individuals had a favorable response to prognosis and immunotherapy. In conclusion, we generated a CD8+ T-cell–related signature that can serve as a promising tool for personalized prognosis prediction and guiding decisions regarding immunotherapy in GC patients.
Evaluating the Accuracy of Off-Label Placement of Pulse Oximetry Sensors in Comparison to On-Label Placement in the Adult Cardiac Intensive Care Unit Patient Population
Authors: Hlavin Danielle , Bosma Grace N. , Bolt Matthew A. , Sammel Mary D. , Seyller Nicole , Varty Maureen
Published: May 2024

Background

Continuous pulse oximetry (Spo
2) is a commonly utilized tool to obtain an indirect, noninvasive measurement of hemoglobin oxygen saturation. Difficulty obtaining measurement with Spo
2 sensors can lead nurses to try off-label sites until they find placement that provides a signal. Currently, there is limited evidence to support this application.

Purpose

The purpose of this study was to evaluate the accuracy of off-label placement of pulse oximetry sensors in comparison to on-label placement in adult cardiac intensive care patients.

Methods

Data were collected on 24 participants. At the time of a medically necessary arterial blood gas laboratory draws, 4 Spo
2 measurements were gathered from an on-label finger sensor, an off-label finger sensor, an on-label ear sensor, and an off-label ear sensor. Results were analyzed using 4 Pearson correlation coefficients, Bland-Altman plots, and 2 linear mixed-effect models.

Results

Our study found that while both our on-label finger and off-label finger pulse oximetry sensor overestimated when compared to the arterial hemoglobin saturation (gold standard), there was greater overestimation found with the off-label placement. Though there was not a significant difference observed between the ear probe on the nose and the gold standard, figures examining off-label ear probe and gold standard measures show that, in lower ranges of oxygen saturation, the off-site probe substantially overestimates true oxygen saturation, while in higher ranges of oxygen saturation, the off-site ear probe underestimates true oxygen saturation.

Conclusions

No changes should be made to the current practice of using pulse oximetry sensor placement.
Care of the Patient With an Artificial Airway
Authors: Evers Julianne M. , Minton Lori A. , Webb Chris , Taylor Rachel M. , York Nancy L.
Published: May 2024

Background

Artificial airways are essential in various clinical settings to maintain a patient's airway and provide necessary support for ventilation and oxygenation. These devices are commonly temporary and come in several types, each serving specific purposes. Understanding the indications, types, and proper care of artificial airways is crucial for health care professionals to ensure patients receive optimal care and prevent complications.

Objective

This article aims to review the indications for using artificial airways and discuss the most commonly used types, including supraglottic airway devices, endotracheal tubes, tracheostomy tubes, and laryngectomy tubes. It also provides insights into the procedures involved in intubation and percutaneous tracheostomy and offers guidance on patient management, emphasizing assessment, oral care, suctioning, and humidification for patients with these airway devices.

Conclusion

This article underscores the significance of understanding artificial airways, not just as a set of skills but as a commitment to patient welfare. Health care professionals who master the knowledge and care of these devices can significantly contribute to their patients' well-being and quality of life.
Optimizing thiopurine therapy in autoimmune hepatitis: A multicenter study on monitoring metabolite profiles and co-therapy with allopurinol
Authors: Weltzsch Jan Philipp , Bartel Claudius F. , Waldmann Moritz , Renné Thomas , Schulze Stephanie , Terziroli Beretta-Piccoli Benedetta , Papp Maria , Oo Ye H. , Ronca Vincenzo , Sebode Marcial , Lohse Ansgar W. , Schramm Christoph , Hartl Johannes
Published: May 2024

Background and Aims:

In autoimmune hepatitis, achieving complete biochemical remission (CBR) with current weight-based thiopurine dosing is challenging. We investigated whether patients could be stratified regarding CBR according to a target range of thiopurine metabolites. Moreover, we explored the effects of azathioprine dosage increases and co-therapy of allopurinol with low-dose thiopurines on metabolite profiles and treatment response.

Approach and Results:

The relation between metabolites and treatment response was assessed in 337 individuals from 4 European centers. In a global, cross-sectional analysis, active metabolites 6-thioguanine nucleotides (6TGN) were similar in those with and without CBR. However, analyzing patients with sequential measurements over 4 years (N = 146) revealed higher average 6TGN levels in those with stable CBR (260 pmol/0.2 mL) compared to those failing to maintain CBR (181 pmol/0.2 mL; p = 0.0014) or never achieving CBR (153 pmol/0.2 mL; p < 0.0001), with an optimal 6TGN cutoff of ≥223 pmol/0.2 mL (sensitivity: 76% and specificity: 78%). Only 42% exhibited 6TGN ≥223 pmol/0.2 mL following weight-based dosing, as doses weakly correlated with 6TGN but with 6-methylmercaptopurine (6MMP), a metabolite associated with toxicity. Azathioprine dose increases led to preferential 6MMP formation (+127% vs. 6TGN +34%; p < 0.0001). Conversely, adding allopurinol to thiopurines in difficult-to-treat patients (N = 36) raised 6TGN (168→321 pmol/0.2 mL; p < 0.0001) and lowered 6MMP (2125→184 pmol/0.2 mL; p < 0.0001), resulting in improved transaminases in all patients and long-term CBR in 75%.

Conclusions:

Maintaining CBR in autoimmune hepatitis was associated with 6TGN ≥223 pmol/0.2 mL. For patients who fail to achieve CBR and therapeutic 6TGN levels despite thiopurine dose increase due to preferential 6MMP formation, comedication of allopurinol alongside low-dose thiopurines represents an efficient alternative.
Elucidating the mechanism of hepatotoxicity in Euodia rutaecarpa: insights from QSAR toxicity prediction and metabolomics
Authors: Yang Chunqi , Lai Chengcai , Ru Yi , Shen Baoying , Wu Xiangjun , Cui Jialu , Li Fangyang , Zhang Cheng , Shi Zhuo , Qian Qingyuan , Xiao Chengrong , Wang Yuguang , Zhang Boli , Gao Yue
Published: May 2024

Objective:

Euodia rutaecarpa, (Wu Zhu Yu) a Chinese medicine clinically used to treat gastrointestinal disorders, has been widely employed. However, Euodia rutaecarpa is regarded as a small toxic traditional Chinese medicine in the Chinese Pharmacopoeia and other herbal works. Using toxicity predictions combined with in vitro and in vivo studies, this study aimed to identify the toxic components and toxic target organs of Euodia rutaecarpa, and explore its toxic mechanism from a metabolic perspective.

Methods:

The toxic target organs of Euodia rutaecarpa were identified through in vitro and in vivo studies. In vitro toxicity screening was performed by alkaloid enrichment and isolation. The potential toxicity of compounds was predicted by Absorption, Distribution, Metabolism, Excretion, and Toxicity Predictor (ADMET Predictor) based on Quantitative Structure–Activity Relationship (QSAR) construction. In addition, the study integrated the serum metabolomic analysis after the administration of potentially toxic components to clarify the effect of potentially toxic substances on metabolism in mice.

Results:

Comparing the acute toxicity in mice of different extraction methods and before and after processing, it was evident that Euodia rutaecarpa alcoholic extract had the highest toxicity, and the target organ of Euodia rutaecarpa toxicity was the liver. The alkaloid fraction of alcoholic extract of Euodia showed strong cytotoxicity. The potential toxicity of Euodia rutaecarpa was calculated and predicted by ADMET Predictor, and alkaloids are suspected to be responsible for the toxicity of Euodia rutaecarpa. Evodiamine significantly reduced the number of cells and increased the mitochondrial membrane potential in vitro. Different metabolites were significantly identified by serum metabolomics, of which bile acid metabolism and steroid hormone biosynthesis are the key pathways of hepatotoxicity.

Conclusions:

Clarify the scientific significance of clinical use of processed products by comparing the acute toxicity of different extraction methods before and after processing. Combining the toxicity prediction based on QSAR with the toxicity screening in vitro and in vivo, the potential toxic target organs and toxic components of Euodia rutaecarpa can be identified. Through metabolomics, we preliminarily revealed that the hepatotoxicity of Euodia rutaecarpa may be related to bile acid metabolism and steroid hormone biosynthesis. This study lays the foundation for elucidating the mechanism of Euodia rutaecarpa and evaluating its safety and quality.
Chemical nature of metabolic activation of natural products in traditional Chinese medicines possibly associated with toxicities
Authors: Liu Yuyang , Wang Xu , Liu Minglu , Hao Xialing , Peng Ying , Zheng Jiang
Published: May 2024

Ensuring the safety of traditional Chinese medicines (TCM) has perennially presented a universal challenge in the healthcare realm. Meticulous investigations into the toxicological intricacies of natural products are of paramount significance, particularly regarding the metabolic transformation of these substances and the subsequent generation of reactive intermediates. This biochemical process underlies the genesis of diverse toxic manifestations, including hepatotoxicity, nephrotoxicity, pulmonary toxicity, and genotoxicity. Compounds sorted within TCM, including pyrrolizidine alkaloids, anthraquinones, furanoterpenoids, alkenylbenzenes, bisbenzylisoquinoline alkaloids, flavonoids, and methylenedioxyphenyl derivatives, evince a spectrum of deleterious mechanisms upon metabolic activation. This review provides a comprehensive delineation of the pathways through which these compounds induce toxicity via metabolic activation. This review emphasizes the chemical mechanisms involved in the metabolic activation of natural products that may trigger a toxic cascade, rather than a superficial phenomenon. Furthermore, this study enriches the extant literature by delving into advancements in elucidating the mechanisms of toxicity engendered by metabolic activation. In conclusion, this review highlights the importance of scrutinizing the mechanisms of toxicity and provides insights into the judicious and safe use of TCM.
FACTORS ASSOCIATED WITH DELAYED DIAGNOSIS IN PATIENTS WITH PRIMARY VITREORETINAL LYMPHOMA
Authors: Wang Kenny Y. , Xu Timothy T. , Mogil Rachel S. , Song Allisa J. , White Launia J. , Hodge David O. , Dalvin Lauren A.
Published: May 2024

Purpose:

To identify demographic and clinical factors associated with delayed diagnosis in patients with primary vitreoretinal lymphoma (VRL).

Methods:

Retrospective, tertiary referral center-based cohort study of all patients at Mayo Clinic in Rochester, Minnesota, with a biopsy-proven diagnosis of VRL from January 1, 2000, to October 31, 2022.

Results:

There were 87 patients included during the 22-year study period with 73 patients (83.9%) diagnosed with VRL upon initial evaluation at the tertiary center, with the other 14 patients (16.1%) diagnosed later. The median referral time was 4.8 months (range: 0–113 months). Patients who received an initial diagnosis of inflammatory uveitis or another incorrect diagnosis elsewhere were referred slower than those initially diagnosed with VRL (P = 0.04). The most common incorrect initial diagnosis from an outside institution was inflammatory uveitis (n = 35, 40.2%). When patients were split into four groups based on referral time, prior use of corticosteroids was associated with a significant delay in referral (P = 0.03).

Conclusion:

Diagnosing VRL continues to be challenging, as months-long delays from initial evaluation to expert referral center evaluation are common. Prior use of corticosteroids was associated with delay in diagnosis and referral time, underscoring the need to increase awareness regarding differences between VRL and uveitis.
Widefield Swept-Source OCTA Findings in HELLP Syndrome: Choroidal Infarcts
Authors: Martinez-Velazquez Luis , Begaj Tedi , Garg Itika , Zhou Paul , Hoyek Sandra , Wai Karen M. , Miller John B. , Patel Nimesh A.
Published: May 2024

Purpose:

Pre-eclampsia, eclampsia, and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome have been previously implicated with ophthalmic complications including serous retinal detachments and disorders of the choroidal vasculature. Herein, we report a case of macular serous detachment associated with HELLP syndrome in which wide field swept-source optical coherence tomography angiography (WF SS-OCTA) was used.

Methods:

Retrospective case report of a patient who developed HELLP syndrome. The patient underwent multimodal retinal imaging and wide field swept-source OCT angiography (WF SS-OCTA) (PLEX® Elite 9000, Carl Zeiss Meditec Inc.).

Results:

A 36-year-old female patient diagnosed with HELLP syndrome presented with bilateral blurry vision. At presentation, dilated fundus exam revealed localized subretinal fluid in the macula. WF SS-OCTA showed areas of peripapillary and subfoveal flow signal attenuation in the choroid OD, consistent with choroidal infarction.

Conclusions:

These findings support the hypothesis that HELLP syndrome is associated with vascular changes that lead to choroidal dysfunction and subsequent serous retinal detachments. Furthermore, this case highlights a role for the non-invasive WF SS-OCTA technology in diagnosing and further characterizing the pathophysiology without the use of dye-based angiography.
Glaucoma and the Human Microbiome
Authors: Chang Chih-Chiun J. , Liu Benjamin , Liebmann Jeffrey M. , Cioffi George A. , Winn Bryan J.
Published: May 2024

Purpose of Review:

To explore a view of the human microbiome as an interconnected, functional, dynamic system that may be linked to the pathogenesis and progression of glaucoma.

Methods:

A literature review was undertaken that included publications from 1966 to 2023.

Results:

Bacterial lipopolysaccharides (LPS) activate toll-like receptors (TLR) and mediate the human immune response. The LPS-TLR4 pathway is a potential avenue for the ocular, gut, and oral microbiomes to interface and/or influence ocular disease. Studies of gut dysbiosis have shown that alterations in the healthy microbiota can predispose the host to immune-mediated inflammatory and neurodegenerative conditions, while oral and ocular surface dysbiosis has been correlated with glaucoma. While developmental exposure to commensal microflora has shown to be necessary for the autoimmune and neurodegenerative responses to elevated intraocular pressure to take place, commensal bacterial products like short-chain fatty acids have regulatory effects protective against glaucoma.

Alterations to human microbiotas have been associated with changes in intestinal permeability, gene regulation, immune cell differentiation, and neural functioning, which may predispose the host to glaucoma. Select microbes have been highlighted for their potential contributions to glaucoma disease progression or protection, raising the potential for microbiota-based treatment modalities. Current topical glaucoma treatments may disrupt the ocular surface microbiota, potentially having ramifications on host health. Further study of the relationships between human microbiome and glaucoma is needed.
Vancomycin Dosing and Its Association With Acute Kidney Injury in Pediatric Cardiac Intensive Care Patients Under 3 Months of Age
Authors: Ashkenazi-Hoffnung Liat , Schiller Ofer , Krubiner Mor , Dagan Ovadia , Haskin Orly , Manor-Shulman Orit , Feinstein Yael , Shochat Tzippy , Shostak Eran , Yarden-Bilavsky Havatzelet
Published: May 2024

Background:

The standard vancomycin regimen for term neonates is 45 mg/kg/day. However, the optimal starting vancomycin dosing for achieving therapeutic levels in young infants in cardiac intensive care units remains unknown. Moreover, data on the association of supratherapeutic vancomycin levels with acute kidney injury (AKI) are limited.

Methods:

Retrospective study of infants ≤3 months old, receiving vancomycin following congenital heart surgery at postoperative intensive care unit admission. Assessed were vancomycin dosing, achievement of therapeutic trough concentration of 10–20 mg/L and development of AKI, based on the modified Kidney Disease Improving Global Outcomes criteria.

Results:

Inclusion criteria were met by 109 patients with a median age of 8 days (IQR: 6–16). The mean (SD) vancomycin dose required for achieving therapeutic concentration was 28.9 (9.1) mg/kg at the first postoperative day. Multivariate logistic regression identified higher preoperative creatinine levels and shorter cardiopulmonary bypass time as predictors of supratherapeutic vancomycin concentrations (c-index 0.788). During the treatment course, 62 (56.9%) developed AKI. Length of stay and mortality were higher in those who developed AKI as compared with those who did not. Multivariate logistic regression identified higher vancomycin concentration as a predictor for postoperative AKI, OR, 3.391 (95% CI: 1.257–9.151), P = 0.016 (c-index 0.896).

Conclusion:

Our results support a lower starting vancomycin dose of ~30 mg/kg/day followed by an early personalized therapeutic approach, to achieve therapeutic trough concentrations of 10–20 mg/L in cardiac postoperative term infants. Supratherapeutic concentrations are associated with an increased risk for AKI, which is prevalent in this population and associated with adverse outcomes.
RNA isoform expression landscape of the human dorsal root ganglion generated from long-read sequencing
Authors: Arendt-Tranholm Asta , Mwirigi Juliet M. , Price Theodore J.
Published: May 2024

Splicing is a posttranscriptional RNA processing mechanism that enhances genomic complexity by creating multiple isoforms from the same gene. We aimed to characterize the isoforms expressed in the human peripheral nervous system, with the goal of creating a resource to identify novel isoforms of functionally relevant genes associated with somatosensation and nociception. We used long-read sequencing to document isoform expression in the human dorsal root ganglia from 3 organ donors and validated in silico by confirming expression in short-read sequencing from 3 independent organ donors. Nineteen thousand five hundred forty-seven isoforms of protein-coding genes were detected and validated. We identified 763 isoforms with at least one previously undescribed splice junction. Previously unannotated isoforms of multiple pain-associated genes, including ASIC3, MRGPRX1, and HNRNPK, were identified. In the novel isoforms of ASIC3, a region comprising approximately 35% of the 5'UTR was excised. By contrast, a novel splice junction was used in isoforms of MRGPRX1 to include an additional exon upstream of the start codon, consequently adding a region to the 5'UTR. Novel isoforms of HNRNPK were identified, which used previously unannotated splice sites to both excise exon 14 and include a sequence in the 3' end of exon 13. This novel insertion is predicted to introduce a tyrosine phosphorylation site potentially phosphorylated by SRC. We also independently confirm a recently reported DRG-specific splicing event in WNK1 that gives insight into how painless peripheral neuropathy occurs when this gene is mutated. Our findings give a clear overview of mRNA isoform diversity in the human dorsal root ganglia obtained using long-read sequencing.