bluuebunny/crossref_metadata_2025_split huggingface dataset:
Examining Whole Blood, Total and Free Plasma Tacrolimus in Elderly Kidney Transplant Recipients
Authors: Cossart Amelia R. , Isbel Nicole M. , Campbell Scott B. , McWhinney Brett , Staatz Christine E. 
Published: November 2024

Background:
Therapeutic monitoring is routinely performed to ensure tacrolimus whole-blood concentrations fall within a predefined target. Despite this, patients still experience inefficacy and toxicity that could be related to variability in free (unbound) tacrolimus exposure. Therefore, the aim of this study was to compare tacrolimus-free plasma (Cu), total plasma (Cp), and whole-blood (Cwb) concentrations in adult kidney transplant recipients and to characterize tacrolimus disposition across different matrices.

Methods:
Twelve-hour concentration–time profiling was performed in 15 recipients, allowing simultaneous measurement of Cu, Cp, and Cwb. Pharmacokinetic parameters were estimated using noncompartmental analysis. The relationship between Cwb and Cp were examined using a capacity-limited binding model, incorporating the hematocrit fraction (f
HCT) to estimate maximum binding concentration (B
max) and dissociation constant (K

d
). The relationship between Cp and Cu was evaluated using a linear binding model to estimate the nonspecific binding parameter (N

plasma
). Nonlinear regression analysis was used to obtain estimates of B
max, K

d
, and N

plasma
.

Results:
A total of 195 paired Cwb, Cp, and Cu values were collected. The median ratios of Cwb:Cp, Cp:Cu, and Cwb:Cu were 9:1, 20:1, and 138:1, respectively. Variability in free plasma exposure was large; free trough values ranged from 8 to 51 ng/L and free area-under-the-concentration–time-curve values ranged from 424 to 7160 ng·h/L. Median (range) estimates of B
max, K

d
, and N

plasma
were 90.4 µg/L (22.4–752.5 µg/L), 2.36 µg/L (0–69.2 µg/L), and 0.05 (0.035–0.085), respectively. The interindividual variability (CV%) in binding parameters was considerable (B
max 117.2%; N

plasma
32.5%).

Conclusions:
Large variability was observed in tacrolimus-free plasma exposure and binding parameters. Future research to characterize the relationship between tacrolimus Cu and patient outcomes may be of benefit.
Hemodynamic effects of carvedilol plus simvastatin in cirrhosis with severe portal hypertension and suboptimal response to β-blockers: A double-blind, placebo-controlled, randomized trial
Authors: Alvarado-Tapias Edilmar , Brujats Anna , Puente Angela , Ardevol Alba , Rodriguez-Arias Ainhoa , Fajardo Javier , Pavel Oana , Garcia-Guix Marta , Aracil Carles , Poca Maria , Cuyàs Berta , Cantó Elisabet , Montañés Rosa , Garcia-Osuna Alvaro , Escorsell Àngels , Torras Xavier , Villanueva Càndid 
Published: November 2024

Background and Aims:
Carvedilol is a nonselective β-blocker (NSBB) with anti-α1-adrenergic activity, more effective than traditional NSBBs in reducing portal pressure hepatic venous pressure gradient (HVPG). However, 35%–45% of patients still have insufficient HVPG decrease. Statins ameliorate endothelial dysfunction, reduce hepatic vascular resistance, and have pleiotropic effects. We investigated whether the addition of simvastatin improves the efficacy of carvedilol on HVPG in cirrhosis with severe portal hypertension and suboptimal response to traditional NSBBs.

Methods:
Patients with cirrhosis and high-risk varices referred for primary prophylaxis were consecutively included. HVPG was measured at baseline and again after i.v. propranolol. Suboptimal responders (HVPG decrease <20%) were treated with carvedilol and were randomized to double-blind administration of placebo or simvastatin. Chronic HVPG response was assessed after 4–6 weeks, repeating HVPG measurements after a standard liquid meal to estimate endothelial dysfunction. Plasma samples were obtained before each study to investigate inflammatory parameters.

Results:
Of 184 eligible patients, 82 were randomized to carvedilol + simvastatin (N = 41) or carvedilol + placebo (N = 41). Baseline characteristics were similar. HVPG significantly decreased with both, carvedilol + simvastatin (18.6 ± 4 to 15.7 ± 4 mm Hg, p < 0.001) and carvedilol + placebo (18.9 ± 3 to 16.9 ± 3 mm Hg, p < 0.001). The decrease was greater with carvedilol + simvastatin (2.97 ± 2.5 vs. 2.05 ± 1.6 mm Hg, p = 0.031). An HVPG decrease ≥20% occurred in 37% versus 15% of patients, respectively (OR: 3.37, 95% CI = 1.15–9.85; p = 0.021). With test meal, HVPG increased in both groups (p < 0.01), although carvedilol + simvastatin attenuated such increment (12 ± 8% vs. 23 ± 16%, p < 0.001). Cytokine levels (Interleukine-6, monocyte-chemoattractant protein-1, and malondialdehyde) decreased significantly more with carvedilol + simvastatin (p < 0.01). The incidence of adverse events was similar.

Conclusions:
In patients with severe portal hypertension (all with high-risk varices) and suboptimal hemodynamic response to traditional NSBBs, combined therapy with carvedilol plus simvastatin significantly enhances the portal pressure reduction achieved with carvedilol monotherapy, improves endothelial dysfunction, and reduces proinflammatory cytokines.
Operational Radiation Safety Considerations During Equine Superficial Radiation Treatment Using Portable X-Ray Devices
Authors: Singh Ashutosh , Johnson Thomas , Wotman Kathryn , Leary Del 
Published: November 2024

Abstract
Veterinary personnel exposure due to scattered x rays, when present during superficial radiation treatment (SRT), was evaluated. Veterinary personnel presence is needed during SRT to minimize the degree of required aesthesia to horses. Animal treatment was simulated, and exposure rates determined for 50, 70, and 100 kV x rays using eight different SRT applicators. Exposure rates at the surface of a solid water phantom (SWP) phantom ranged from 3.9 mR h−1 to 396 mR h−1 for 50 kV, from 41 mR h−1 to 2,880 mR h−1 for 70 kV, and from 235 mR h−1 to 7,500 mR h−1, for 100 kV, respectively. A horse phantom was used to mimic SRT equine ocular treatment creating a spatial exposure field where the directional scatter was measured at 1 m. The minimum distance away from the source to reach < 2 mR h−1 varied with angular position and energy and was lowest for all energies directly behind the x-ray tube. The closest distance before exceeding 2 mR h−1 at 50 kVp was determined to 1.96 m. A worker could stand 1 m behind the x-ray tube at 50 kVp with 0.25 mm lead for 15,106 hours. Typical SRT treatment times for horse eyelid squamous cell carcinoma are less than 5 minutes, and radiation doses to practitioners are expected to be well below local administrative ALARA limits.
Platelets and circulating (tumor) cells: partners in promoting metastatic cancer
Authors: Gautam Deepa , Clarke Emily M. , Roweth Harvey G. , Smith Margaret R. , Battinelli Elisabeth M. 
Published: November 2024

Purpose of review
Despite being discovered decades ago, metastasis remains a formidable challenge in cancer treatment. During the intermediate phase of metastasis, tumor cells detach from primary tumor or metastatic sites and travel through the bloodstream and lymphatic system to distant tissues. These tumor cells in the circulation are known as circulating tumor cells (CTCs), and a higher number of CTCs has been linked to poor prognoses in various cancers. The blood is an inhospitable environment for any foreign cells, including CTCs, as they face numerous challenges, such as the shear stress within blood vessels and their interactions with blood and immune cells. However, the exact mechanisms by which CTCs survive the hostile conditions of the bloodstream remain enigmatic. Platelets have been studied for their interactions with tumor cells, promoting their survival, growth, and metastasis. This review explores the latest clinical methods for enumerating CTCs, recent findings on platelet-CTC crosstalk, and current research on antiplatelet therapy as a potential strategy to inhibit metastasis, offering new therapeutic insights.

Recent findings
Laboratory and clinical data have provided insights into the role of platelets in promoting CTC survival, while clinical advancements in CTC enumeration offer improved prognostic tools.

Summary
CTCs play a critical role in metastasis, and their interactions with platelets aid their survival in the hostile environment of the bloodstream. Understanding this crosstalk offers insights into potential therapeutic strategies, including antiplatelet therapy, to inhibit metastasis and improve cancer treatment outcomes.
An unexpected cause of intractable dysphagia after 20 years following cervical spine instrumentation using bone cement alone: a case report
Authors: Bohara Sandeep , Thapa Bikas , Regmi Prakash , Shilpakar Sushil K. 
Published: November 2024

Introduction and Importance:
Postoperative dysphagia following anterior cervical discectomy fusion (ACDF) for cervical disc herniation is still poorly understood. Dysphagia after anterior spinal cervical approach is mild and transient. Here, the authors present a rare case suffering with severe progressive dysphagia for over 1 year after 20 years of ACDF due to expulsed bone cement abutting the esophagus which was successfully removed after reoperation.

Case Presentation:
A 59-year-old homemaker female presented to us with a foreign body sensation in the throat ‘globus pharyngeus’ and progressive difficulty in swallowing for 1 year. She was previously operated for C5-C6 cervical intervertebral disc prolapse via ACDF using bone cement at another center. On examination, power in the left upper limb was MRC grade 3, and the left-hand grip was 25% only. MRI of the cervical spine showed increased prevertebral soft tissue space and a notable rectangular-shaped black prevertebral shadow at the C5-C6 level, causing esophageal compression. The patient underwent an exploration of previous ACDF surgery. Intraoperative findings revealed an extruded piece of bone cement of size ~2×1.5×1 cm3 at C5-C6 disc space level, compressing the esophagus. The yellowish extruded piece was removed and C5-C6 was reinforced with an anterior cervical plate with screws. The postoperative course was uneventful.

Clinical Discussion:
The exact pathophysiology of dysphagia after ACF surgery remains unknown. In our case, there was an expulsion of the graft. The graft used was polymethyl methacrylate, commonly known as bone cement, which was placed 20 years back. Since polymethyl methacrylate is bioinert material, the graft may have expulsed from its site of placement and thus compressed the esophagus. Taking into consideration of the cost-effectiveness and maintenance of spinal mobility, few neurosurgeons believe that the application of bone cement in ACF surgery as a spacer is a safe and very cost-effective modality compared to modern expensive artificial disc.

Conclusion:
Dysphagia after ACDF surgery is usually underrecognized. Although the serious complications after ACDF surgery are rare, dysphagia can cause prolonged morbidity to patients. Using bone cement alone for ACDF surgery may carry the risk of its anterior expulsion even after a long period of surgery.
Prenatal Diagnosis and Management of Generalized Arterial Calcification of Infancy
Authors: Kuppuswami Narmadha , Vijayaraghavan Boopathy 
Published: November 2024

BACKGROUND:
Generalized arterial calcification of infancy is a rare genetic disorder that was first reported in 1899. Since then, slightly more than 200 cases have been documented. This rare autosomal recessive disorder occurs when the homozygous ENPP1 gene mutation is associated with abnormal calcification in the medium and large arteries in the fetus. Overall mortality in individuals with generalized arterial calcification of infancy is high (55%) before the age of 6 months, with 24.4% dying in utero. Due to the high mortality rate, there is a critical need for additional reports and research regarding generalized arterial calcification of infancy.

CASE:
We submit a case report of a child with generalized arterial calcification of infancy—a unique instance in which the diagnosis was established prenatally and treatment was initiated in utero. Patient care was continued through a multidisciplinary approach coordinated between specialists across India, Australia, and the United States. There was an almost complete resolution of the calcification, with near-normal development and intellectual capacity of the child for age.

CONCLUSION:
Clear guidelines are needed regarding prenatal use of bisphosphonate therapy, timing, dosage, and duration of treatment for fetuses with ENPP1 gene mutations to minimize disease progression and improve neonatal health at birth. This case further illustrates how involving well-informed parents in decision making can help tailor the appropriate treatment. Our report also describes the possibility of new, ongoing clinical trials that may pave the way for a cure for this child and others.
Abbe Flap for Upper Lip Reconstruction
Authors: Giugliano Carlos , Echenique Patricia 
Published: November 2024

Introduction:
Lips are complex structures that are part of the facial esthetics. Their integrity may be affected by congenital diseases, trauma, burns, and cancers, among other pathologies. The reconstruction of the upper lip subunit can be a challenge for the surgeon. The purpose of this paper is to review the Abbe flap technique with the help of tips from the primary surgeon (surgical tips) and present a series of cases as experience in upper lip reconstruction.

Methods:
A retrospective study at Chilean centers Fundación Gantz and Clínica Alemana de Santiago from 2003 to 2023. The surgical technique was described, and different variables were assessed. The Strasser scale was used as an objective method for assessing the results.

Results:
Sixteen surgery patients, 50% female and 50% male. Fourteen patients (87.5%) with cleft lip and palate. In total, 85.71% of the total number of patients with follow-up had a good score of 1 to 4 on the Strasser scale. There were no mediocre results comparable to results described in other series. There were no complications relating to the technique.

Conclusions:
The Abbe flap technique continues to be an excellent option in upper lip reconstruction, especially in patients with a condition of the middle third of the lip. Knowledge of the anatomy, the surgical technique, the function of the lip, and facial esthetics leads to acceptable results for the patient and their environment with this technique.
Protective Strategies for Pituitary Function During Endoscopic Transnasal Pituitary Adenoma Surgery: A Single-center Experience
Authors: Yang Jihu , Zhang Fengmin , Chen Sihao , Zhang Xiejun , Liu Yufei , Zheng Wenjian , Chen Fanfan , Chen Lei , Huang Guodong 
Published: November 2024

Objective:
This study investigated the impact of endoscopic transnasal pituitary adenoidectomy on function and discussed the factors that contribute to postoperative pituitary function. To provide a foundation for protecting pituitary function and improving the curative effect of pituitary adenoma neuroendoscope resection.

Methods:
From January 2019 to January 2022, in the Neurosurgery Pituitary Tumor Diagnosis and Treatment Research Center, the First Affiliated Hospital of Shenzhen University, the clinical data of 306 patients who underwent endoscopic transnasal pituitary adenoma surgery were analyzed retrospectively. The surgical treatment strategy was discussed and explored, while the factors related to pituitary function were examined based on tumor size and Knosp grade.

Results:
There were 40 cases (67.8%) of pituitary-thyroid axis, 18 cases (60%) of pituitary-adrenal axis, 25 cases (45.4%) of pituitary-gonad axis, 5 cases (62.5%) of pituitary-growth hormone axis, and 8 cases (72.7%) of diabetes insipidus with postoperative improves of hypopituitarism. Postoperative newly developed hypopituitarism occurred in 20 cases (8.1%) of pituitary-thyroid axis, 15 cases (5.4%) of pituitary-adrenal axis, 10 cases (4.0%) of pituitary-gonad axis, 5 cases (1.7%) of pituitary-growth hormone axis, and 8 cases (2.7%) of new diabetes insipidus. The incidence of pituitary-adrenal axis hypofunction in giant pituitary adenomas was significantly higher than that in microadenomas and macroadenomas (P<0.05). The incidence of hypopituitarism of Knosp grade 4 pituitary adenoma before operation was higher than that of other groups (P<0.05), but there was no significant difference in the incidence of new hypopituitarism after operation (P>0.05).

Conclusions:
In endoscopic transnasal pituitary adenoma surgery, the incidence of hypothyroidism and adrenal gland dysfunction is higher than in other hormone axes, but the recovery rate is also higher, and the recovery rate of sex hormones is lower. The incidence of postoperative hypothyroidism increases dramatically with tumor size and tumor invasiveness.
EXOSOMES FROM CYCLIC MICE MODULATE LIVER TRANSCRIPTOME IN ESTROUPAUSE MICE INDEPENDENT OF AGE
Authors: Zanini Bianka M. , Ávila Bianca M. , Hense Jéssica D. , Garcia Driele N. , Ashiqueali Sarah , Alves Pâmela I. C. , Oliveira Thais L. , Collares Tiago V. , Brieño-Enríquez Miguel A. , Mason Jeffrey B. , Masternak Michal M. , Schneider Augusto 
Published: November 2024

AbstractBackgroundExosomes are extracellular vesicles secreted by cells that contain microRNAs (miRNAs). These miRNAs can induce changes in gene expression and function of recipient cells. In different cells exosome content can change with age and physiological state affecting tissues function and health.AimsTherefore, the aim of this study was to characterize the miRNA content and role of exosomes from cyclic female mice in the modulation of liver transcriptome in estropausal mice.Main MethodsTwo-month-old female mice were induced to estropause using 4-vinylcyclohexene diepoxide (VCD). At six months of age VCD-treated mice were divided in control group (VCD) and exosome treated group (VCD+EXO), which received 10 injections at 3-day intervals of exosomes extracted from serum of cyclic female mice (CTL).Key findingsExosome injection in estropausal mice had no effect on body mass, insulin sensitivity or organ weight. We observed ten miRNAs differentially regulated in serum exosomes of VCD compared to CTL mice. In the liver we observed 931 genes differentially expressed in VCD+EXO compared to VCD mice. Interestingly, eight pathways were up-regulated in liver by VCD treatment and down-regulated by exosome treatment, indicating that exosomes from cyclic mice can reverse changes promoted by estropause in liver.Cyp4a12aexpression which is male-specific was increased in VCD females and not reversed by exosome treatment.SignificanceOur findings indicate that miRNAs content in exosomes is regulated by estropause in mice independent of age. Additionally, treatment of estropausal mice with exosomes from cyclic mice can partially reverse changes in liver transcriptome.
Actin turnover and myosin contractility determine emergent Thickness Robustness of Cell-Mimicking Cortex
Authors: Gat S. , Amit Y. , Livne G. , Sanchez Daniel Sevilla , Porat N. , Yochelis A. , Gov N.S. , Bernheim-Groswasser A. 
Published: November 2024

AbstractCell shape deformation is primarily determined by the actin cortex, a thin network of actin filaments and myosin motors, that lies beneath and attached to the plasma membrane of cells and endows cells with their mechanical stability and structural integrity. Since inside the cells there are hundreds of proteins associated with the actin cortex, it is very difficult to identify the role of each component and the mechanisms that maintain a functional cortex. Here, using a minimal set of components we recreate dynamic treadmilling in an actomyosin cortex on a bilayer membrane with cell-mimicking characteristics, in the absence and presence of myosin-II molecular motors. We reveal how treadmilling is regulated by actin network disassembly factors and myosin contractility, and how this drives the robustness of the cortical thickness to concentration fluctuations in cytoskeletal components.One-Sentence SummaryRecreating the cellular skeleton network that determines cell shape and integrity using a minimal set of cellular building-blocks.
pH-dependent structural dynamics of the neuropeptide Y in aqueous solution
Authors: Nguyen Thi Hoa , Spehr Marc , Ana-Nicoleta  , Carloni Paolo 
Published: November 2024

AbstractNeuropeptide Y regulates key molecular processes in the brain. Its interaction with the cell membrane, fundamental for its function, is likely pH-dependent. Here, we perform constant pH simulations on the peptide in solution to investigate the impact of acidification on its protonation states and on its intra-molecular H-bond network. Our simulations point to a quite complex scenario at neutral or mildly acidic pH, where ionizable residues such as Asp, Glu, and His may exhibit fractional protonation states, affecting the conformational dynamics of the peptide in a non-trivial manner. Unanticipated structural dynamics emerge at low pH, where carboxyl groups are all neutral and histidine is di-protonated. Moreover, changes in protonation influence intra-molecular hydrogen bonding. Thus, using constant pH simulations could prove important to describe the structural peptide / protein dynamics at pH values that deviate from neutral.
Structuring Role of Tau-Tubulin Co-Condensates in Early Microtubule Organization
Authors: Lee-Eom Chaelin , Jung Jaehun , Park Celine , Shon Min Ju 
Published: November 2024

AbstractTau protein, a key microtubule-associated protein in neurons, is traditionally known for stabilizing microtubules. However, its recently discovered ability to undergo liquid-liquid phase separation (LLPS) reveals a broader, dynamic role in nucleating and organizing microtubule networks. Here, using a combination of real-time imaging and a geometric approach based on Voronoi tessellation, we examined how tau condensation leads to clustering and local tubulin enrichment, supporting microtubule organization. Our observations show that tau-tubulin co-condensates not only initiate nucleation and branching of microtubules but also drive the network’s gradual evolution through a “dynamic weaving” process. By generating Voronoi diagrams from super-resolution and confocal microscopy images of the stabilized network, we quantitatively mapped tubulin enrichment as a function of tau density, revealing that high-density tau clusters, approximately 0.2 μm in size, correlate with tubulin-rich spots at equilibrium. Overall, these findings provide new insights into tau-tubulin co-condensates as dynamic structuring elements, whose liquid-like properties continuously reshape the microtubule network, creating a flexible and adaptive architecture essential for cellular function.