bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world experience of therapeutic drug monitoring and PK/PD achievement of ceftaroline administered by different infusion regimens in patients with confirmed infections caused by Gram-positive bacteria
Authors: Fresán Daniel , Luque Sonia , Benítez-Cano Adela , Sorlí Luisa , Montero María Milagro , De-Antonio Marta , Vega Victoria , Roberts Jason A , Horcajada Juan P , Grau Santiago 
Published: October 2023

Abstract

Background
Ceftaroline is a novel cephalosporin active against MDR Gram-positive (GP) bacteria. For β-lactam antibiotics, such as ceftaroline, prolonged infusions and therapeutic drug monitoring (TDM) are used for dosage optimization based on their pharmacokinetics/pharmacodynamics (PK/PD).

Objectives
To describe our experience with TDM and PK/PD target attainment of ceftaroline administered by intermittent and prolonged infusion in a cohort of patients with MDR-GP bacterial infections.

Methods
Patients treated with ceftaroline administered by continuous (24 h), extended (3 h/6 h) and intermittent infusion (1 h) and undergoing TDM of plasma concentrations were included. A 100%fT&gt;4×MIC was the pre-specified PK/PD target and 100%fT&gt;10×MIC was considered overexposure. Dose recommendations were made based on TDM results and each patient’s clinical condition.

Results
Twelve patients [83.3% male, median age of 73 (38–83) years] were included. Nine patients (75%) achieved 100%fT&gt;4×MIC, all under prolonged infusions. In one patient, the 100%fT was &gt;10×MIC but no toxicity was observed. Based on TDM results, initial doses were recommended to be maintained in eight patients, decreased in three and increased in one.

Conclusions
The administration of ceftaroline by prolonged infusion together with TDM may be a useful strategy for achieving the desired PK/PD target in these patients. However, more studies evaluating the relationship between PK/PD attainment and clinical outcomes are needed.
Rifampicin reduces plasma concentration of linezolid in patients with infective endocarditis
Authors: Bock Magnus , Van Hasselt Johan G C , Schwartz Franziska , Wang Hengzhuang , Høiby Niels , Fuursted Kurt , Ihlemann Nikolaj , Gill Sabine , Christiansen Ulrik , Bruun Niels Eske , Elming Hanne , Povlsen Jonas A , Køber Lars , Høfsten Dan E , Fosbøl Emil L , Pries-Heje Mia M , Christensen Jens Jørgen , Rosenvinge Flemming S , Torp-Pedersen Christian , Helweg-Larsen Jannik , Tønder Niels , Iversen Kasper , Bundgaard Henning , Moser Claus 
Published: October 2023

Abstract

Background
Linezolid in combination with rifampicin has been used in treatment of infective endocarditis especially for patients infected with staphylococci.

Objectives
Because rifampicin has been reported to reduce the plasma concentration of linezolid, the present study aimed to characterize the population pharmacokinetics of linezolid for the purpose of quantifying an effect of rifampicin cotreatment. In addition, the possibility of compensation by dosage adjustments was evaluated.

Patients and methods
Pharmacokinetic measurements were performed in 62 patients treated with linezolid for left-sided infective endocarditis in the Partial Oral Endocarditis Treatment (POET) trial. Fifteen patients were cotreated with rifampicin. A total of 437 linezolid plasma concentrations were obtained. The pharmacokinetic data were adequately described by a one-compartment model with first-order absorption and first-order elimination.

Results
We demonstrated a substantial increase of linezolid clearance by 150% (95% CI: 78%–251%), when combined with rifampicin. The final model was evaluated by goodness-of-fit plots showing an acceptable fit, and a visual predictive check validated the model. Model-based dosing simulations showed that rifampicin cotreatment decreased the PTA of linezolid from 94.3% to 34.9% and from 52.7% to 3.5% for MICs of 2 mg/L and 4 mg/L, respectively.

Conclusions
A substantial interaction between linezolid and rifampicin was detected in patients with infective endocarditis, and the interaction was stronger than previously reported. Model-based simulations showed that increasing the linezolid dose might compensate without increasing the risk of adverse effects to the same degree.
Ancestry testing of “Old Tom,” a killer whale central to mutualistic interactions with human whalers
Authors: Reeves Isabella M , Totterdell John A , Betty Emma L , Donnelly David M , George Angela , Holmes Steven , Moller Luciana , Stockin Karen A , Wellard Rebecca , White Charlie , Foote Andrew D 
Published: October 2023

Abstract
Cooperative hunting between humans and killer whales (Orcinus orca) targeting baleen whales was reported in Eden, New South Wales, Australia, for almost a century. By 1928, whaling operations had ceased, and local killer whale sightings became scarce. A killer whale from the group, known as “Old Tom,” washed up dead in 1930 and his skeleton was preserved. How these killer whales from Eden relate to other populations globally and whether their genetic descendants persist today remains unknown. We extracted and sequenced DNA from Old Tom using ancient DNA techniques. Genomic sequences were then compared with a global dataset of mitochondrial and nuclear genomes. Old Tom shared a most recent common ancestor with killer whales from Australasia, the North Atlantic, and the North Pacific, having the highest genetic similarity with contemporary New Zealand killer whales. However, much of the variation found in Old Tom’s genome was not shared with these widespread populations, suggesting ancestral rather than ongoing gene flow. Our genetic comparisons also failed to find any clear descendants of Tom, raising the possibility of local extinction of this group. We integrated Traditional Custodian knowledge to recapture the events in Eden and recognize that Indigenous Australians initiated the relationship with the killer whales before European colonization and the advent of commercial whaling locally. This study rectifies discrepancies in local records and provides new insight into the origins of the killer whales in Eden and the history of Australasian killer whales.
Clinical benefit, development, innovation, trials, epidemiology, and price for cancer drugs and indications with multiple special FDA designations
Authors: Michaeli Daniel Tobias , Michaeli Thomas , Albers Sebastian , Michaeli Julia Caroline 
Published: October 2023

Abstract

Background
This study analyzes the development, US Food and Drug Administration (FDA) approval, benefits, innovation, trials, epidemiology, and price of cancer drugs with multiple special designations: orphan, fast track, accelerated approval, priority review, and breakthrough therapy.

Methods
In total, 355 FDA-approved cancer drug indications with 841 special designations were identified (2012-2022). Trial, epidemiology, and price data were collected from FDA labels, the Global Burden of Disease study, and Medicare and Medicaid. The association between efficacy outcomes and indications’ number of special designations were compared in meta-analyses.

Results
Median development times were 7.3, 7.8, and 5.4 months (P = .027) for drugs with 0 to 1, 2 to 3, and 4 to 5 special designations, respectively. Multiple special designations were associated with higher biotechnological and clinical innovation. Median patient enrollment in trials were 615, 471, 398, 168, 104, and 120 (P &lt; .001) for indications with 0 to 5 special designations. Drugs for rare diseases supported by open-label phase 1/2 trials of single-arm design were granted more special designations. Hazard ratios for overall survival (0.80 vs 0.73 vs 0.73 vs 0.69 vs 0.56 vs 0.52; P = .003) and progression-free survival (0.70 vs 0.61 vs 0.59 vs 0.44 vs 0.37 vs 0.67; P &lt; .001) substantially declined while tumor response increased with more special designations. Mean monthly prices increased for drugs with 0 to 4 but not 5 special designations ($21 596 vs $14 753 vs $32 410 vs $41 240 vs $38 703 vs $19 184).

Conclusions
Multiple special designations are associated with faster clinical development and greater benefits for patients with unmet needs but also with nonrobust trial evidence and a tendency toward higher drug prices.
Phylogenomics Reveals High Levels of Incomplete Lineage Sorting at the Ancestral Nodes of the Macaque Radiation
Authors: Tan Xinxin , Qi Jiwei , Liu Zhijin , Fan Pengfei , Liu Gaoming , Zhang Liye , Shen Ying , Li Jing , Roos Christian , Zhou Xuming , Li Ming 
Published: October 2023

Abstract
The genus Macaca includes 23 species assigned into 4 to 7 groups. It exhibits the largest geographic range and represents the most successful example of adaptive radiation of nonhuman primates. However, intrageneric phylogenetic relationships among species remain controversial and have not been resolved so far. In this study, we conducted a phylogenomic analysis on 16 newly generated and 8 published macaque genomes. We found strong evidence supporting the division of this genus into 7 species groups. Incomplete lineage sorting (ILS) was the primary factor contributing to the discordance observed among gene trees; however, we also found evidence of hybridization events, specifically between the ancestral arctoides/sinica and silenus/nigra lineages that resulted in the hybrid formation of the fascicularis/mulatta group. Combined with fossil data, our phylogenomic data were used to establish a scenario for macaque radiation. These findings provide insights into ILS and potential ancient introgression events that were involved in the radiation of macaques, which will lead to a better understanding of the rapid speciation occurring in nonhuman primates.
The landscape of human SVA retrotransposons
Authors: Chu Chong , Lin Eric W , Tran Antuan , Jin Hu , Ho Natalie I , Veit Alexander , Cortes-Ciriano Isidro , Burns Kathleen H , Ting David T , Park Peter J 
Published: October 2023

Abstract
SINE-VNTR-Alu (SVA) retrotransposons are evolutionarily young and still-active transposable elements (TEs) in the human genome. Several pathogenic SVA insertions have been identified that directly mutate host genes to cause neurodegenerative and other types of diseases. However, due to their sequence heterogeneity and complex structures as well as limitations in sequencing techniques and analysis, SVA insertions have been less well studied compared to other mobile element insertions. Here, we identified polymorphic SVA insertions from 3646 whole-genome sequencing (WGS) samples of &gt;150 diverse populations and constructed a polymorphic SVA insertion reference catalog. Using 20 long-read samples, we also assembled reference and polymorphic SVA sequences and characterized the internal hexamer/variable-number-tandem-repeat (VNTR) expansions as well as differing SVA activity for SVA subfamilies and human populations. In addition, we developed a module to annotate both reference and polymorphic SVA copies. By characterizing the landscape of both reference and polymorphic SVA retrotransposons, our study enables more accurate genotyping of these elements and facilitate the discovery of pathogenic SVA insertions.
Phosphate starvation regulates cellulose synthesis to modify root growth
Authors: Khan Ghazanfar Abbas , Dutta Arka , van de Meene Allison , Frandsen Kristian E H , Ogden Michael , Whelan James , Persson Staffan 
Published: October 2023

Abstract
In the model plant Arabidopsis (Arabidopsis thaliana), the absence of the essential macro-nutrient phosphate reduces primary root growth through decreased cell division and elongation, requiring alterations to the polysaccharide-rich cell wall surrounding the cells. Despite its importance, the regulation of cell wall synthesis in response to low phosphate levels is not well understood. In this study, we show that plants increase cellulose synthesis in roots under limiting phosphate conditions, which leads to changes in the thickness and structure of the cell wall. These changes contribute to the reduced growth of primary roots in low-phosphate conditions. Furthermore, we found that the cellulose synthase complex (CSC) activity at the plasma membrane increases during phosphate deficiency. Moreover, we show that this increase in the activity of the CSC is likely due to alterations in the phosphorylation status of cellulose synthases in low-phosphate conditions. Specifically, phosphorylation of CELLULOSE SYNTHASE 1 (CESA1) at the S688 site decreases in low-phosphate conditions. Phosphomimic versions of CESA1 with an S688E mutation showed significantly reduced cellulose induction and primary root length changes in low-phosphate conditions. Protein structure modeling suggests that the phosphorylation status of S688 in CESA1 could play a role in stabilizing and activating the CSC. This mechanistic understanding of root growth regulation under limiting phosphate conditions provides potential strategies for changing root responses to soil phosphate content.
Analgesic prescribing in patients with inflammatory arthritis in England: observational studies in the Clinical Practice Research Datalink
Authors: Scott Ian C , Whittle Rebecca , Bailey James , Twohig Helen , Hider Samantha L , Mallen Christian D , Muller Sara , Jordan Kelvin P 
Published: October 2023

Abstract

Objectives
Despite little evidence that analgesics are effective in inflammatory arthritis (IA), studies report substantial opioid prescribing. The extent this applies to other analgesics is uncertain. We undertook a comprehensive evaluation of analgesic prescribing in patients with IA in the Clinical Practice Research Datalink Aurum to evaluate this.

Methods
From 2004 to 2020, cross-sectional analyses evaluated analgesic prescription annual prevalence in RA, PsA and axial spondyloarthritis (axSpA), stratified by age, sex, ethnicity, deprivation and geography. Joinpoint regression evaluated temporal prescribing trends. Cohort studies determined prognostic factors at diagnosis for chronic analgesic prescriptions using Cox proportional hazards models.

Results
Analgesic prescribing declined over time but remained common: 2004 and 2020 IA prescription prevalence was 84.2/100 person-years (PY) (95% CI 83.9, 84.5) and 64.5/100 PY (64.2, 64.8), respectively. In 2004, NSAIDs were most prescribed (56.1/100 PY; 55.8, 56.5), falling over time. Opioids were most prescribed in 2020 (39.0/100 PY; 38.7, 39.2). Gabapentinoid prescribing increased: 2004 prevalence 1.1/100 PY (1.0, 1.2); 2020 prevalence 9.9/100 PY (9.7, 10.0). Most opioid prescriptions were chronic (2020 prevalence 23.4/100 PY [23.2, 23.6]). Non-NSAID analgesic prescribing was commoner in RA, older people, females and deprived areas/northern England. Conversely, NSAID prescribing was commoner in axSpA/males, varying little by deprivation/geography. Peri-diagnosis was high-risk for starting chronic opioid/NSAID prescriptions. Prognostic factors for chronic opioid/gabapentinoid and NSAID prescriptions differed, with NSAIDs having no consistently significant association with deprivation (unlike opioids/gabapentinoids).

Conclusion
IA analgesic prescribing of all classes is widespread. This is neither evidence-based nor in line with guidelines. Peri-diagnosis is an opportune moment to reduce chronic analgesic prescribing.
Fluid shear stress stimulates ATP release without regulating purinergic gene expression in the renal inner medullary collecting duct
Authors: van Megen Wouter H. , Canki Esra , Wagenaar Vera H. A. , van Waes Charlotte R. M. M. , Peters Dorien J. M. , Van Asbeck‐Van der Wijst Jenny , Hoenderop Joost G. J. 
Published: October 2023

AbstractIn the kidney, the flow rate of the pro‐urine through the renal tubules is highly variable. The tubular epithelial cells sense these variations in pro‐urinary flow rate in order to regulate various physiological processes, including electrolyte reabsorption. One of the mechanosensitive pathways activated by flow is the release of ATP, which can then act as a autocrine or paracrine factor. Increased ATP release is observed in various kidney diseases, among others autosomal dominant polycystic kidney disease (ADPKD). However, the mechanisms underlying flow‐induced ATP release in the collecting duct, especially in the inner medullary collecting duct, remain understudied. Using inner medullary collecting duct 3 (IMCD3) cells in a microfluidic setup, we show here that administration of a high flow rate for 1 min results in an increased ATP release compared to a lower flow rate. Although the ATP release channel pannexin‐1 contributed to flow‐induced ATP release in Pkd1−/− IMCD3 cells, it did not in wildtype IMCD3 cells. In addition, flow application increased the expression of the putative ATP release channel connexin‐30.3 (CX30.3) in wildtype and Pkd1−/− IMCD3 cells. However, CX30.3 knockout IMCD3 cells exhibited a similar flow‐induced ATP release as wildtype IMCD3 cells, suggesting that CX30.3 does not drive flow‐induced ATP release in wildtype IMDC3 cells. Collectively, our results show differential mechanisms underlying flow‐induced ATP release in wildtype and Pkd1−/− IMCD3 cells and further strengthen the link between ADPKD and pannexin‐1‐dependent ATP release.
Incorporating Omics and Precision Health in a Nursing PhD Program: The Perspectives of Student Nurse Scientists
Authors: Flaherty Christine Noelle , Rattan Jesse , Melson Lindsay , O’Neal Pamela V. 
Published: October 2023

Abstract
To engage in innovative and novel precision health and omics research, nurse scientists need to be knowledgeable about the genetic, behavioral, and environmental factors that impact health outcomes. This article illustrates the benefits of a nursing omics PhD curriculum at a state university. The purpose is to provide students’ perspectives and research interests that were inspired by the omics and precision health curriculum. Exposing these early-career PhD nursing student scientists to omics and precision health engaged them to think broadly about the potential to generate original nurse-led research.
Relationship between Nociplastic Pain Involvement and Medication use, Symptom Relief, and Adverse effects Among People using Medical Cannabis for Chronic Pain
Authors: Scott J. Ryan , Williams David A. , Harte Steven E. , Harris Richard E. , Litinas Evangelos , Sisley Suzanne , Clauw Daniel J. , Boehnke Kevin F. 
Published: October 2023

Objectives:
Cannabis is commonly used for chronic pain management, but cannabis’ effects remain poorly characterized in chronic nociplastic pain (NPP), which is posited to be caused by disturbances in nervous system pain processing. In this cross-sectional study (n=1,213), we used the 2011 Fibromyalgia (FM) Survey Criteria as a surrogate measure for degree of NPP among individuals using medical cannabis for chronic pain.

Methods:
Using a quartile-split, we investigated associations between degree of NPP and medication use, cannabis use characteristics, and symptom relief. Continuous variables were assessed using one-way analysis of variance (ANOVA) and categorical variables with Pearson’s Chi-square test (2) and binomial logistic regression for calculation of odds ratios (OR).

Results:
Participants were predominately female (59%), with mean ±SD age 49.4±13.6 years. Higher FM scores were associated with less self-reported improvement in pain and health since initiating medical cannabis use, as well as more cannabis-related side effects. Paradoxically, higher FM scores were also associated with higher usage of concomitant medication use (including opioids and benzodiazepines) but also with substituting cannabis for significantly more medication classes, including opioids and benzodiazepines.

Discussion:
This article presents evidence that individuals in higher NPP quartiles have higher analgesic intake, higher odds of substituting cannabis for medications, higher side effect burden, and lower therapeutic effect from cannabis. These seemingly contradictory findings may reflect higher symptom burden, polypharmacy at baseline, or that NPP may be challenging to treat with cannabis. Further research is necessary to further explain cannabinoid effects in NPP.
Comparison of Labor Curves Between Spontaneous and Induced Labor
Authors: Onishi Kazuma , Huang Jim C. , Kawakita Tetsuya 
Published: October 2023

OBJECTIVE:
To compare the labor curve between individuals with induced labor and those undergoing spontaneous labor.

METHODS:
This was a secondary analysis of the Consortium on Safe Labor database, including nulliparous and multiparous individuals with singleton vertex pregnancy who delivered vaginally after spontaneous labor or induction of labor at term. Labor that resulted in uterine rupture and neonates with a 5-minute Apgar scores less than 7, birth injury, or neonatal intensive care unit admission was excluded. We modeled the course of cervical dilation using repeated-measures analysis with a polynomial function. We compared traverse time, defined as the elapsed time between two given dilation measures, between induced and spontaneous labor using interval-censored regression.

RESULTS:
Of 46,835 nulliparous individuals, 18,576 and 28,259 underwent induced and spontaneous labor, respectively. Of 77,503 multiparous individuals, 29,684 and 47,819 underwent induced and spontaneous labor, respectively. The start of the active phase on the labor curve was 6 cm in induced labor, regardless of parity. In nulliparous individuals, induced labor compared with spontaneous labor had a significantly shorter traverse time from 6 to 10 cm (median 1.8 hours [5th–95th percentile 0.4–8.6 hours] vs 2.3 hours [5th–95th percentile 0.6–9.4 hours]; P<.01). In multiparous individuals, induced labor compared with spontaneous labor had a significantly shorter traverse time from 6 to 10 cm (median 0.9 hours [5th–95th percentile 0.1–6.0 hours] vs 1.4 hours [5th–95th percentile 0.3–7.9 hours]; P<.01).

CONCLUSION:
Similar to spontaneous labor, the start of the active phase of induced labor was at 6 cm of dilation. Comparatively, induced labor had a shorter active phase than spontaneous labor. These findings suggest that the current criteria for active phase arrest provided by the American College of Obstetricians and Gynecologists do not need to be lengthened for individuals in induced labor.
Caregiver Perspectives on the Health Care System for Tic Disorders: Utilization and Barriers
Authors: Wellen Brianna C. M. , Bootes Kirsten R. , Braley Emily I. , Conelea Christine A. , Woods Douglas W. , Himle Michael B. 
Published: October 2023

Abstract:
Tic disorders (TDs) can cause considerable functional impairment and are often associated with comorbid conditions, resulting in difficulty managing symptoms. Although several effective evidence-based interventions are available, previous research has found that caregivers of children with TDs often experience substantial burden navigating the health care system to address their child's tics.

Objective:
This study aimed to understand health care experiences among a sample of caregivers of children with TDs to inform future directions for improving the health care system.

Methods:
We conducted a survey of caregivers of youth with TDs and used descriptive statistics and quantitative analyses to characterize the health care utilization practices of the sample.

Results:
The majority (70%) of families first consulted their pediatrician/primary care provider, and caregivers reported receiving care in line with current best practice guidelines. However, caregivers in the current sample perceived a lack of knowledgeability on the part of their first providers, which significantly predicted more providers seen and also reported difficulty finding specialty providers (63% of the sample reported difficulty finding a treatment provider who understood tics).

Conclusion:
Results suggest that improving caregiver satisfaction with early health care experiences for their child's TD may help to relieve the burden on families and the health care system more broadly, along with continued efforts to increase the number of specialty providers available.