bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of isavuconazole at different target sites in healthy volunteers after single and multiple intravenous infusions
Authors: Bergmann Felix , Wölfl-Duchek Michael , Jorda Anselm , Al Jalali Valentin , Leutzendorff Amelie , Sanz-Codina Maria , Gompelmann Daniela , Trimmel Karin , Weber Maria , Eberl Sabine , Van Os Wisse , Minichmayr Iris K , Reiter Birgit , Stimpfl Thomas , Idzko Marco , Zeitlinger Markus 
Published: March 2024

Abstract

Background
Invasive aspergillosis is a severe fungal infection that affects multiple organ systems including the CNS and the lungs. Isavuconazole, a novel triazole antifungal agent, has demonstrated promising activity against Aspergillus spp. However, data on the penetration of isavuconazole into the CNS and ELF and intracellular accumulation remain limited.

Materials and methods
We conducted a prospective single-centre pharmacokinetic (PK) study in 12 healthy volunteers. Subjects received seven doses of 200 mg isavuconazole to achieve an assumed steady-state. After the first and final infusion, plasma sampling was conducted over 8 and 12 h, respectively. All subjects underwent one lumbar puncture and bronchoalveolar lavage, at either 2, 6 or 12 h post-infusion of the final dose. PBMCs were collected in six subjects from blood to determine intracellular isavuconazole concentrations at 6, 8 or 12 h. The AUC/MIC was calculated for an MIC value of 1 mg/L, which marks the EUCAST susceptibility breakpoint for Aspergillus fumigatus and Aspergillus flavus.

Results
C max and AUC0-24h of isavuconazole in plasma under assumed steady-state conditions were 6.57 ± 1.68 mg/L (mean ± SD) and 106 ± 32.1 h·mg/L, respectively. The average concentrations measured in CSF, ELF and in PBMCs were 0.07 ± 0.03, 0.94 ± 0.46 and 27.1 ± 17.8 mg/L, respectively. The AUC/MIC in plasma, CSF, ELF and in PBMCs under steady-state conditions were 106 ± 32.1, 1.68 ± 0.72, 22.6 ± 11.0 and 650 ± 426 mg·h/L, respectively.

Conclusion
Isavuconazole demonstrated moderate penetration into ELF, low penetrability into CSF and high accumulation in PBMCs. Current dosing regimens resulted in sufficient plasma exposure in all subjects to treat isolates with MICs ≤ 1 mg/L.
Ceftazidime/avibactam serum concentration in patients on ECMO
Authors: Curtiaud Anaïs , Petit Matthieu , Chommeloux Juliette , Pineton de Chambrun Marc , Hekimian Guillaume , Schmidt Matthieu , Combes Alain , Luyt Charles-Edouard 
Published: March 2024

Abstract

Objectives
The use of extracorporeal membrane oxygenation (ECMO) may alter blood levels of several drugs, including antibiotics, leading to under dosing of these drugs and thus to potential treatment failure. No data exist on pharmacokinetics of new antimicrobial, in particular ceftazidime/avibactam. We therefore perform this study to evaluate ceftazidime/avibactam blood levels in ECMO patients and find factors associated with underdosing.

Methods
Retrospective observational study of patients on ECMO having received ceftazidime/avibactam and in whom trough blood levels of ceftazidime and avibactam were available. Main outcome measurement was the number of patients with ceftazidime and avibactam blood levels above predefined cut-off values, derived from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints for Enterobacteriaceae and Pseudomonas aeruginosa, namely 8 mg/L for ceftazidime and 4 mg/L for avibactam, and explored factors associated with underdosing.

Results
Twenty-three ceftazidime/avibactam trough levels were available in 14 ECMO patients, all of them having received veno-venous ECMO for SARS-CoV-2-associated pneumonia. Although ceftazidime levels were above 8 mg/L in all except one patient, nine (39%) of the avibactam dosages were below 4 mg/L. Increased renal clearance (creatinine clearance &gt; 130 mL/min) was the main factor associated with under dosing, since 7 out of the 10 dosages below the predefined cut-offs were measured in patients with this condition.

Conclusions
In ECMO patients receiving ceftazidime/avibactam, ceftazidime and avibactam serum levels are above EUCAST breakpoints in most cases, justifying the use of normal dosing in ECMO patients. Increased renal clearance may lead to ceftazidime and avibactam under dosing.
Expanding the Use of Continuous Sedation Until Death and Physician-Assisted Suicide
Authors: LiPuma Samuel H , Demarco Joseph P 
Published: March 2024

Abstract
The controversy over the equivalence of continuous sedation until death (CSD) and physician-assisted suicide/euthanasia (PAS/E) provides an opportunity to focus on a significant extended use of CSD. This extension, suggested by the equivalence of PAS/E and CSD, is designed to promote additional patient autonomy at the end-of-life. Samuel LiPuma, in his article, “Continuous Sedation Until Death as Physician-Assisted Suicide/Euthanasia: A Conceptual Analysis” claims equivalence between CSD and death; his paper is seminal in the equivalency debate. Critics contend that sedation follows proportionality protocols for which LiPuma’s thesis does not adequately account. Furthermore, sedation may not eliminate consciousness, and as such LiPuma’s contention that CSD is equivalent to neocortical death is suspect. We not only defend the equivalence thesis, but also expand it to include additional moral considerations. First, we explain the equivalence thesis. This is followed by a defense of the thesis against five criticisms. The third section critiques the current use of CSD. Finally, we offer two proposals that, if adopted, would broaden the use of PAS/E and CSD and thereby expand options at the end-of-life.
Molecular and genetic regulation of petal number variation
Authors: Wang Dan , Dong Xue , Zhong Mi-Cai , Jiang Xiao-Dong , Cui Wei-Hua , Bendahmane Mohammed , Hu Jin-Yong 
Published: March 2024

Abstract
Floral forms with an increased number of petals, also known as double-flower phenotypes, have been selected and conserved in many domesticated plants, particularly in ornamentals, because of their great economic value. The molecular and genetic mechanisms that control this trait are therefore of great interest, not only for scientists, but also for breeders. In this review, we summarize current knowledge of the gene regulatory networks of flower initiation and development and known mutations that lead to variation of petal number in many species. In addition to the well-accepted miR172/AP2-like module, for which many questions remain unanswered, we also discuss other pathways in which mutations also lead to the formation of extra petals, such as those involved in meristem maintenance, hormone signalling, epigenetic regulation, and responses to environmental signals. We discuss how the concept of ‘natural mutants’ and recent advances in genomics and genome editing make it possible to explore the molecular mechanisms underlying double-flower formation, and how such knowledge could contribute to the future breeding and selection of this trait in more crops.
Commentary: Special Issue - Current Understanding of Colorectal and Pancreatic Cancers
Authors: Vodicka Pavel , Vodickova Ludmila 
Published: March 2024

Abstract
The Commentary on Special Issue- Current Understanding of Colorectal and Pancreatic Cancers provides the reasoning for the selection of the contributions on pancreatic and colorectal cancer, and summarizes in brief the individual topics and comments upon the main outcomes. The current knowledge, contribution of the individual articles within this Special Issue, and arising priorities in the research on pancreatic ductal adenocarcinoma and colorectal cancer are highlighted.
Reconstructing human history from ancient genomes: an interview with Nobel laureate Svante Pääbo
Authors: Zhao Weijie 
Published: March 2024

ABSTRACT
Professor Svante Pääbo, Director of the Max Planck Institute for Evolutionary Anthropology, won the Nobel Prize in Physiology or Medicine in 2022 for his discoveries in ancient hominine genomes and human evolution. His pioneering work in sequencing and interpreting the paleo genomes of Neanderthals and Denisovans, as well as their relationship with the modern human genome, was groundbreaking in terms of our understanding of human origins. Nowadays, we can even use commercial kits to easily detect the proportion of Neanderthal genes in our own genomes.
Recently, NSR conducted an interview with Professor Pääbo to learn about his interesting work chasing the ancient genomes and reconstructing human evolutionary and migration history from the DNA evidence, as well as his perspective on paleo genome studies and his advice to young researchers: follow your interests and be ready to try some crazy things.
Long-Term Risk of Reintervention After Surgical Leiomyoma Treatment in an Integrated Health Care System
Authors: Mitro Susanna D. , Xu Fei , Lee Catherine , Zaritsky Eve , Waetjen L. Elaine , Wise Lauren A. , Hedderson Monique M. 
Published: March 2024

OBJECTIVE:
To compare long-term risk of reintervention across four uterus-preserving surgical treatments for leiomyomas and to assess effect modification by sociodemographic factors in a prospective cohort study in an integrated health care delivery system.

METHODS:
We studied a cohort of 10,324 patients aged 18–50 (19.9% Asian, 21.2% Black, 21.3% Hispanic, 32.5% White, 5.2% additional races and ethnicities) who had a first uterus-preserving procedure (abdominal, laparoscopic, or vaginal myomectomy [referred to as myomectomy]; hysteroscopic myomectomy; endometrial ablation; uterine artery embolization) after leiomyoma diagnosis in the 2009–2021 electronic health records of Kaiser Permanente Northern California. We followed up patients until reintervention (second uterus-preserving procedure or hysterectomy) or censoring. We used a Kaplan–Meier estimator to calculate the cumulative incidence of reintervention and Cox regression models to estimate hazard ratios and 95% CIs comparing rates of reintervention across procedures, adjusting for age, parity, race and ethnicity, body mass index (BMI), Neighborhood Deprivation Index, and year. We also assessed effect modification by demographic characteristics.

RESULTS:
Median follow-up was 3.8 years (interquartile range 1.8–7.4 years). Index procedures were 18.0% (1,857) hysteroscopic myomectomies, 16.2% (1,669) uterine artery embolizations, 21.4% (2,211) endometrial ablations, and 44.4% (4,587) myomectomies. Accounting for censoring, the 7-year reintervention risk was 20.6% for myomectomy, 26.0% for uterine artery embolization, 35.5% for endometrial ablation, and 37.0% for hysteroscopic myomectomy; 63.2% of reinterventions were hysterectomies. Within each procedure type, reintervention rates did not vary by BMI, race and ethnicity, or Neighborhood Deprivation Index. However, rates of reintervention after uterine artery embolization, endometrial ablation, and hysteroscopic myomectomy decreased with age, and reintervention rates for hysteroscopic myomectomy were higher for parous than nulliparous patients.

CONCLUSION:
Long-term reintervention risks for uterine artery embolization, endometrial ablation, and hysteroscopic myomectomy are greater than for myomectomy, with potential variation by patient age and parity but not BMI, race and ethnicity, or Neighborhood Deprivation Index.
Obstetric Racial Disparities in the Era of the ARRIVE (A Randomized Trial of Induction Versus Expectant Management) Trial and the Coronavirus Disease 2019 (COVID-19) Pandemic
Authors: Wheeler Sarahn M. , Truong Tracy , Unnithan Shakthi , Hong Hwanhee , Myers Evan , Swamy Geeta K. 
Published: March 2024

OBJECTIVE:
To evaluate the influence of the ARRIVE (A Randomized Trial of Induction Versus Expectant Management) trial and the coronavirus disease 2019 (COVID-19) pandemic on racial and ethnic differences in labor induction, pregnancy-associated hypertension, and cesarean delivery among non-Hispanic Black and non-Hispanic White low-risk, first-time pregnancies.

METHODS:
We conducted an interrupted time series analysis of U.S. birth certificate data from maternal non-Hispanic Black and non-Hispanic White race and ethnicity, first pregnancy, 39 or more weeks of gestation, with no documented contraindication to vaginal delivery or expectant management beyond 39 weeks. We compared the rate of labor induction (primary outcome), pregnancy-associated hypertension, and cesarean delivery during three time periods: pre-ARRIVE (January 1, 2015–July 31, 2018), post-ARRIVE (November 1, 2018–February 29, 2020), and post-COVID-19 (March 1, 2020–December 31, 2021).

RESULTS:
In the post-ARRIVE period, the rate of labor induction increased in both non-Hispanic White and non-Hispanic Black patients, with no statistically significant difference in the magnitude of increase between the two groups (rate ratio for race [RRrace] 0.98, 95% CI, 0.95–1.02, P=.289). Post-COVID-19, the rate of labor induction increased in non-Hispanic White but not non-Hispanic Black patients. The magnitude of the rate change between non-Hispanic White and non-Hispanic Black patients was significant (RRrace 0.95, 95% CI, 0.92–0.99, P=.009). Non-Hispanic Black pregnant people were more likely to have pregnancy-associated hypertension and more often delivered by cesarean at all time periods.

CONCLUSION:
Changes in obstetric practice after both the ARRIVE trial and the COVID-19 pandemic were not associated with changes in Black–White racial differences in labor induction, cesarean delivery, and pregnancy-associated hypertension.
Time-varying associations of gestational and childhood triclosan with pubertal and adrenarchal outcomes in early adolescence
Authors: Laue Hannah E. , Lanphear Bruce P. , Calafat Antonia M. , Cecil Kim M. , Chen Aimin , Xu Yingying , Kalkwarf Heidi J. , Madan Juliette C. , Karagas Margaret R. , Yolton Kimberly , Fleisch Abby F. , Braun Joseph M. 
Published: March 2024

Background:
Triclosan is an endocrine-disrupting chemical, but associations with pubertal outcomes remain unclear. We examined associations of gestational and childhood triclosan with adolescent hormone concentrations and pubertal stage.

Methods:
We quantified urinary triclosan concentrations twice during pregnancy and seven times between birth and 12 years in participants recruited from Cincinnati, OH (2003–2006). We averaged concentrations across pregnancy and childhood and separately considered individual exposure periods in multiple informant models. At 12 years, we measured serum hormone concentrations (males [n = 72] and females [n = 84]—dehydroepiandrosterone-sulfate, luteinizing hormone, follicle-stimulating hormone; males—testosterone; females—estradiol). Also at age 12 years, participants self-reported physical development and menarchal timing. We estimated associations (95% confidence interval) of triclosan with hormone concentrations, more advanced physical development, and age at menarche.

Results:
For females, each doubling of childhood triclosan was associated with 16% lower estradiol concentrations (−29%, 0%), with stronger associations for measures closer to adolescence. We found suggestive evidence that higher triclosan at any age was associated with ~10% (for gestational triclosan: −18%, −2%) lower follicle-stimulating hormone concentrations among males and early postnatal (1–3 years) triclosan was associated with 63% (5%, 96%) lower odds of advanced pubic hair development in females. In multiple informant models, each doubling of gestational triclosan concentrations was associated with 5% (0%, 9%) earlier age at menarche, equivalent to 5.5 months.

Conclusion:
Gestational and childhood triclosan concentrations were related to some pubertal outcomes including hormone concentrations and age at menarche. Our findings highlight the relevance of elucidating potential sex-specific and time-dependent actions of triclosan.
Recognition of Glaucomatous Fundus Images Using Machine Learning Methods Based on Optic Nerve Head Topographic Features
Authors: Wu Chao-Wei , Huang Tzu-Yu , Liou Yeong-Cheng , Chen Shih-Hsin , Wu Kwou-Yeung , Tseng Han-Yi 
Published: March 2024

Précis:
Machine learning classifiers are an effective approach to detecting glaucomatous fundus images based on optic disc topographic features making it a straightforward and effective approach.

Study Design:
Retrospective case-control study.

Objective:
The aim was to compare the effectiveness of clinical discriminant rules and machine learning classifiers in identifying glaucomatous fundus images based on optic disc topographic features.

Methods:
The study used a total of 800 fundus images, half of which were glaucomatous cases and the other half non-glaucomatous cases obtained from an open database and clinical work. The images were randomly divided into training and testing sets with equal numbers of glaucomatous and non-glaucomatous images. An ophthalmologist framed the edge of the optic cup and disc, and the program calculated five features, including the vertical cup-to-disc ratio and the width of the optic rim in four quadrants in pixels, used to create machine learning classifiers. The discriminative ability of these classifiers was compared with clinical discriminant rules.

Results:
The machine learning classifiers outperformed clinical discriminant rules, with the extreme gradient boosting method showing the best performance in identifying glaucomatous fundus images. Decision tree analysis revealed that the cup-to-disc ratio was the most important feature for identifying glaucoma fundus images. At the same time, the temporal width of the optic rim was the least important feature.

Conclusions:
Machine learning classifiers are an effective approach to detecting glaucomatous fundus images based on optic disc topographic features and integration with an automated program for framing and calculating the required parameters would make it a straightforward and effective approach.
Using the Electronic Medical Record to Address Code Status Documentation: A Quality Improvement Project
Authors: Sorge John , Szpunar Susan , Daniel Theodore , Saravolatz Louis 
Published: March 2024

ABSTRACT
Code status (CS) is often overlooked while admitting patients to the hospital. This is important for patients with end-stage disease. This quality improvement project investigated whether a CS pop-up alert in the electronic medical record, combined with provider education, improved addressing CS. The project consisted of a baseline chart review, implementation of the alert and physician education, and a postintervention chart review. We reviewed 1828 charts at baseline and 1,775 at postintervention. From univariable analysis, there were improvements in addressing CS, being full code, cardiopulmonary resuscitation, intubation, use of vasopressors, and cardioversion technique categories (all p < .001). Documentation of do not resuscitate did not change. From logistic regression, after controlling for age, race, end-stage liver disease, stroke, cancer, hospital unit, and sepsis, patients in the postintervention period were two times more likely to have CS addressed (odds ratio [OR] = 2.04, p < .001). There was a significant improvement in CS documentation from our interventions.
Patient-Specific Factors for Deformity after Upper Blepharoplasty in an Asian Population
Authors: Liu Jiaxi , Wu Junzheng , Zeng Xianhui , Liang Zhen , Fan Xiao , Song Baoqiang 
Published: March 2024

Background:
The success of upper blepharoplasty depends on both surgeon experience and skill and on patient factors. Therefore, the authors aimed to identify patient-specific characteristics that may contribute to poor prognoses by analyzing data derived from patients with various deformities after undergoing upper blepharoplasty.

Methods:
This study included 202 patients who underwent revision surgery for upper blepharoplasty. The authors explored relationships between types of deformities before revisions and relevant patient factors before initial surgery using statistical analyses.

Results:
Age older than 30 years, thick upper lid skin, medial epicanthus, and other patient factors were significantly associated with the deformities. Asymmetric crease, crease disappearance, shallow crease, and low crease were the most prevalent deformities. For these 4 most prevalent deformities, the concordance indices and 95% confidence intervals (95% CI) of the risk prediction models were 0.654 (95% CI, 0.575 to 0.734), 0.724 (95% CI, 0.637 to 0.810), 0.783 (95% CI, 0.702 to 0.863), and 0.750 (95% CI, 0.655 to 0.844), respectively.

Conclusions:
Among the 4 most prevalent prognostic deformities, significant patient factors included medial epicanthus, thick upper eyelid skin, weak levator palpebrae superioris, age older than 30 years, and a short gap between eyes and brows. The authors also attempted to clarify the clinical importance of these patient factors. The authors’ findings provide a guide and reference for future investigations into upper blepharoplasty.

CLINICAL QUESTION/LEVEL OF EVIDENCE:
Risk, III.
Increasing Catecholamine Secretion Through NPY in Pheochromocytomas With False-Negative 123I-MIBG Scintigraphy
Authors: Ruike Yutaro , Suzuki Sawako , Yokote Koutaro 
Published: March 2024

Introduction

123I-MIBG has been well established as a functional imaging tool, and 131I-MIBG therapy is being considered for catecholamine-secreting tumors. Tumors with the characteristics of a noradrenergic biochemical phenotype, small, malignant, metastatic, extra-adrenal, bilateral, and hereditary, especially SDHx-related tumors, are reported to correlate with reduced MIBG uptake. However, the potential molecular mechanisms influencing MIBG uptake have been poorly studied.

Patients and Methods
To identify critical genes that may enhance MIBG accumulation in pheochromocytomas (PCCs), we performed RNA-seq analyses for 16 operated patients with PCCs (6 MIBG-negative and 10 MIBG-positive) combined with RT-qPCR for 27 PCCs (5 MIBG-negative and 22 MIBG-positive) and examined primary cultures of the surgical tissues.

Results
In the present study, 6 adrenal nodules of 66 nodules surgically removed from 63 patients with PCCs (9%) were MIBG negative. MIBG, a guanethidine analog of norepinephrine, can enter chromaffin cells through active uptake via the cellular membrane, be deposited in chromaffin granules, and be released via Ca2+-triggered exocytosis from adrenal chromaffin cells. When we compared expression of several catecholamine biosynthesis and secretion-associated genes between MIBG-negative and MIBG-positive tumors using transcriptome analyses, we found that neuropeptide Y, which is contained in chromaffin granules, was significantly increased in MIBG-negative tumors. NPY stimulated norepinephrine secretion dose-dependently in primary cell culture derived from MIBG-positive PCC. In our study, MIBG-negative PCCs were all norepinephrine-hypersecreting tumors.

Conclusions
These data indicate that NPY upregulation in PCCs may stimulate chromaffin granule catecholamine secretion, which is associated with false-negative 123I-MIBG scintigraphy.