bluuebunny/crossref_metadata_2025_split huggingface dataset:
FLASH dose rate calculation based on log files in proton pencil beam scanning therapy
Authors: Jeon Chanil , Ahn Sunghwan , Amano Daizo , Kamiguchi Nagaaki , Cho Sungkoo , Sheen Heesoon , Park Hee Chul , Han Youngyih 
Published: July 2023

AbstractBackgroundIn radiation therapy, irradiating healthy normal tissues in the beam trajectories is inevitable. This unnecessary dose means that patients undergoing treatment risk developing side effects. Recently, FLASH radiotherapy delivering ultra‐high‐dose‐rate beams has been re‐examined because of its normal‐tissue‐sparing effect. To confirm the mean and instantaneous dose rates of the FLASH beam, stable and accurate dosimetry is required.PurposeDetailed verification of the FLASH effect requires dosimeters and a method to measure the average and instantaneous dose rate stably for 2‐ or 3‐dimensional dose distributions. To verify the delivered FLASH beam, we utilized machine log files from the built‐in monitor chamber to develop a dosimetry method to calculate the dose and average/instantaneous dose rate distributions in two or three dimensions in a phantom.MethodsTo create a spread‐out Bragg peak (SOBP) and deliver a uniform dose in a target, a mini‐ridge filter was created with a 3D printer. Proton pencil beam line scanning plans of 2 × 2 cm2, 3 × 3 cm2, 4 × 4 cm2, and round shapes with 2.3 cm diameter patterns delivering 230 MeV energy protons were created. The absorbed dose in the solid water phantom of each plan was measured using a PPC05 ionization chamber (IBA Dosimetry, Virginia, USA) in the SOBP region, and the log files for each plan were exported from the treatment control system console. Using these log files, the delivered dose and average dose rate were calculated using two methods: a direct method and a Monte Carlo (MC) simulation method that uses log file information. The computed and average dose rates were compared with the ionization chamber measurements. Additionally, instantaneous dose rates in user‐defined volumes were calculated using the MC simulation method with a temporal resolution of 5 ms.ResultsCompared to ionization chamber dosimetry, 10 of 12 cases using the direct calculation method and 9 of 11 cases using the MC method had a dose difference below ±3%. Nine of 12 cases using the direct calculation method and 8 of 11 cases using the MC method had dose rate differences below ±3%. The average and maximum dose differences for the direct calculation and MC method were–0.17, +0.72%, and −3.15, +3.32%, respectively. For the dose rate difference, the average and maximum for the direct calculation and MC method were +1.26, +1.12%, and +3.75, +3.15%, respectively. In the instantaneous dose rate calculation with the MC simulation, a large fluctuation with a maximum of 163 Gy/s and a minimum of 4.29 Gy/s instantaneous dose rate was observed in a specific position, whereas the mean dose rate was 62 Gy/s.ConclusionsWe successfully developed methods in which machine log files are used to calculate the dose and the average and instantaneous dose rates for FLASH radiotherapy and demonstrated the feasibility of verifying the delivered FLASH beams.
Selective inhibition of neurogenic, but not agonist‐induced contractions by phospholipase A2 inhibitors points to presynaptic phospholipase A2 functions in contractile neurotransmission to human prostate smooth muscle
Authors: Hu Sheng , Huang Ru , Keller Patrick , Götz Melanie , Tamalunas Alexander , Weinhold Philipp , Waidelich Raphaela , Stief Christian G. , Hennenberg Martin 
Published: July 2023

AbstractBackgroundPhospholipases A2 (PLA2) may be involved in α1‐adrenergic contraction by formation of thromboxane A2 in different smooth muscle types. However, whether this mechanism occurs with α1‐adrenergic contractions of the prostate, is still unknown. While α1‐adrenoceptor antagonists are the first line option for medical treatment of voiding symptoms in benign prostatic hyperplasia (BPH), improvements are limited, probably by nonadrenergic contractions including thromboxane A2. Here, we examined effects of PLA2 inhibitors on contractions of human prostate tissues.MethodsProstate tissues were obtained from radical prostatectomy. Contractions were induced by electric field stimulation (EFS) and by α1‐adrenergic agonists in an organ bath, after application of the cytosolic PLA2 inhibitors ASB14780 and AACOCF3, the secretory PLA2 inhibitor YM26734, the leukotriene receptor antagonist montelukast, or of solvent to controls.ResultsFrequency‐dependent contractions of human prostate tissues induced by EFS were inhibited by 25% at 8 Hz, 38% at 16 Hz and 37% at 32 Hz by ASB14780 (1 µM), and by 32% at 16 Hz and 22% at 32 Hz by AACOCF3 (10 µM). None of both inhibitors affected contractions induced by noradrenaline, phenylephrine or methoxamine. YM26734 (3 µM) and montelukast (0.3 and 1 µM) neither affected EFS‐induced contractions, nor contractions by α1‐adrenergic agonists, while all contractions were substantially inhibited by silodosin (100 nM).ConclusionsOur findings suggest presynaptic PLA2 functions in prostate smooth muscle contraction, while contractions induced by α1‐adrenergic agonists occur PLA2‐independent. Lacking sensitivity to montelukast excludes an involvement of PLA2‐derived leukotrienes in promotion of contractile neurotransmission.
Reflex voiding in rat occurs at consistent bladder volume regardless of pressure or infusion rate
Authors: Jaskowak Daniel J. , Danziger Zachary C. 
Published: July 2023

AbstractAimsThe central nervous system (CNS) regulates lower urinary tract reflexes using information from sensory afferents; however, the mechanisms of this process are not well known. Pressure and volume were measured at the onset of the guarding and micturition reflexes across a range of infusion rates to provide insight into what the CNS is gauging to activate reflexes.MethodsFemale Sprague Dawley rats were anesthetized with urethane for open outlet cystometry. A set of 10 infusion rates (ranging 0.92–65.5 mL/h) were pseudo‐randomly distributed across 30 single‐fill cystometrograms. Bladder pressure and external urethral sphincter electromyography were used for the determination of the onset of the micturition and guarding reflexes, respectively. The bladder volume at the onset of both reflexes was estimated from the total infusion rate during a single fill.ResultsIn response to many single‐fill cystometrograms, there was an increased volume the bladder could store without a significant increase in pressure. Volume was adjusted for this effect for the analysis of how pressure and volume varied with infusion rate at the onset of the micturition and guarding reflexes. In 25 rats, the micturition reflex was evoked at similar volumes across all infusion rates, whereas the pressure at micturition reflex onset increased with increasing infusion rates. In 11 rats, the guarding reflex was evoked at similar pressures across infusion rates, but the volume decreased with increasing infusion rates.ConclusionsThese results suggest that the CNS is interpreting volume from the bladder to activate the micturition reflex and pressure from the bladder to activate the guarding reflex.
Socioeconomic Influence on Speech Rehabilitation After Total Laryngectomy
Authors: Stanisce Luke , McGlone Mick , Koshkareva Yekaterina , Swendseid Brian , Lawrence Ian , Kubicek Gregory J. , Gaughan John P. , Solomon Donald H. , Ahmad Nadir 
Published: July 2023

AbstractObjectiveSpeech rehabilitation following a total laryngectomy significantly impacts the quality of life. Indwelling prosthetic voice restoration provides optimal outcomes; however, the long‐term maintenance of these devices carries considerable financial costs, which are not universally covered by insurance. This investigation aimed to analyze associations between socioeconomic factors and outcomes in postlaryngectomy speech rehabilitation.Study DesignRetrospective cohort analysis.SettingAcademic tertiary‐care center from May 2014 to September 2021.MethodsIn patients undergoing total laryngectomy, the incidence of tracheoesophageal puncture with indwelling vocal prostheses (TEP‐VP) placement within the first postoperative year was compared among household income, demographic factors, and disease characteristics. Functional and maintenance outcomes served as secondary endpoints.ResultsSeventy‐seven patients were included. Forty‐five (58%) underwent indwelling TEP‐VP (41 primaries). Eighty‐nine percent of patients with annual incomes greater than $50k underwent TEP‐VP compared to only 35% with incomes less than $50k/year. TEP‐VP was performed in 85% of patients with commercial insurance, 70% with Medicare, 42% with Medicaid, and 0% with no insurance. On multivariate analysis, annual household incomes greater than $50k were predicted for TEP‐VP placement (odds ratio: 12.7 [2.45‐65.8], p = .002). The utilization of postoperative speech therapy and functional communication outcomes were similar among socioeconomic groups. Twelve patients were unable to afford supplies within the first year, with differences noted among insurance (p = .015) and income status (p = .003).ConclusionDisparities in vocal and speech rehabilitation following laryngectomy may disproportionally affect underserved patients.
Bicyclic peptides: Paving the road for therapeutics of the future
Authors: Ullrich Sven , Nitsche Christoph 
Published: July 2023

AbstractBicyclic peptides have emerged as one of the driving forces within the constrained peptide family. Due to their unique pharmaceutical attributes, peptide bicycles have garnered a reputation as promising therapeutics of the future. Combining advantages of small molecule therapeutics and biologics, the target binding qualities of this highly constrained class of molecules have been likened to those of antibodies. Over the past 5 years, the field of bicyclic peptides has advanced significantly. New bicyclic secondary peptide metabolites have been discovered in aquatic organisms and, importantly, a diverse assortment of bicyclic peptides has been synthesized de novo, exploring new chemical scaffolds. Biocompatible synthetic strategies that are suitable for large library screening platforms have helped to progress bicyclic peptides into clinical trials. This review aims to provide a comprehensive overview of the most recent progress in the field.
Heparanase—A single protein with multiple enzymatic and nonenzymatic functions
Authors: Vlodavsky Israel , Kayal Yasmin , Hilwi Maram , Soboh Soaad , Sanderson Ralph D. , Ilan Neta 
Published: July 2023

AbstractHeparanase (Hpa1) is expressed by tumor cells and cells of the tumor microenvironment and functions extracellularly to remodel the extracellular matrix (ECM) and regulate the bioavailability of ECM‐bound factors, augmenting, among other effects, gene transcription, autophagy, exosome formation, and heparan sulfate (HS) turnover. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor‐host crosstalk, priming the tumor microenvironment to better support tumor growth, metastasis, and chemoresistance. The enzyme appears to fulfill some normal functions associated, for example, with vesicular traffic, lysosomal‐based secretion, autophagy, HS turnover, and gene transcription. It activates cells of the innate immune system, promotes the formation of exosomes and autophagosomes, and stimulates signal transduction pathways via enzymatic and nonenzymatic activities. These effects dynamically impact multiple regulatory pathways that together drive tumor growth, dissemination, and drug resistance as well as inflammatory responses. The emerging premise is that heparanase expressed by tumor cells, immune cells, endothelial cells, and other cells of the tumor microenvironment is a key regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a valid target for therapy. So far, however, antiheparanase‐based therapy has not been implemented in the clinic. Unlike heparanase, heparanase‐2 (Hpa2), a close homolog of heparanase (Hpa1), does not undergo proteolytic processing and hence lacks intrinsic HS‐degrading activity, the hallmark of heparanase. Hpa2 retains the capacity to bind heparin/HS and exhibits an even higher affinity towards HS than heparanase, thus competing for HS binding and inhibiting heparanase enzymatic activity. It appears that Hpa2 functions as a natural inhibitor of Hpa1 regulates the expression of selected genes that maintain tissue hemostasis and normal function, and plays a protective role against cancer and inflammation, together emphasizing the significance of maintaining a proper balance between Hpa1 and Hpa2.
Taming Multiscale Structural Complexity in Porous Skeletons: From Open Framework Materials to Micro/Nanoscaffold Architectures
Authors: Liu Hao , Yao Yifan , Samorì Paolo 
Published: July 2023

AbstractRecent developments in the design and synthesis of more and more sophisticated organic building blocks with controlled structures and physical properties, combined with the emergence of novel assembly modes and nanofabrication methods, make it possible to tailor unprecedented structurally complex porous systems with precise multiscale control over their architectures and functions. By tuning their porosity from the nanoscale to microscale, a wide range of functional materials can be assembled, including open frameworks and micro/nanoscaffold architectures. During the last two decades, significant progress is made on the generation and optimization of advanced porous systems, resulting in high‐performance multifunctional scaffold materials and novel device configurations. In this perspective, a critical analysis is provided of the most effective methods for imparting controlled physical and chemical properties to multifunctional porous skeletons. The future research directions that underscore the role of skeleton structures with varying physical dimensions, from molecular‐level open frameworks (<10 nm) to supramolecular scaffolds (10–100 nm) and micro/nano scaffolds (>100 nm), are discussed. The limitations, challenges, and opportunities for potential applications of these multifunctional and multidimensional material systems are also evaluated in particular by addressing the greatest challenges that the society has to face.
On monohedral tilings of a regular polygon
Authors: Basit Bushra , Lángi Zsolt 
Published: July 2023

AbstractA tiling of a topological disc by topological discs is called monohedral if all tiles are congruent. Maltby (J Comb Theory Ser A 66:40–52, 1994) characterized the monohedral tilings of a square by three topological discs. Kurusa et al. (Mediterr J Math 17:156, 2020) characterized the monohedral tilings of a circular disc by three topological discs. The aim of this note is to connect these two results by characterizing the monohedral tilings of any regular n-gon with at most three tiles for any $$n \ge 5$$

n
≥
5

.
Estimating the time of human decomposition based on skeletal muscle biopsy samples utilizing an untargeted LC–MS/MS-based proteomics approach
Authors: Brockbals Lana , Garrett-Rickman Samara , Fu Shanlin , Ueland Maiken , McNevin Dennis , Padula Matthew P. 
Published: July 2023

AbstractAccurate estimation of the postmortem interval (PMI) is crucial in forensic medico-legal investigations to understand case circumstances (e.g. narrowing down list of missing persons or include/exclude suspects). Due to the complex decomposition chemistry, estimation of PMI remains challenging and currently often relies on the subjective visual assessment of gross morphological/taphonomic changes of a body during decomposition or entomological data. The aim of the current study was to investigate the human decomposition process up to 3 months after death and propose novel time-dependent biomarkers (peptide ratios) for the estimation of decomposition time. An untargeted liquid chromatography tandem mass spectrometry–based bottom-up proteomics workflow (ion mobility separated) was utilized to analyse skeletal muscle, collected repeatedly from nine body donors decomposing in an open eucalypt woodland environment in Australia. Additionally, general analytical considerations for large-scale proteomics studies for PMI determination are raised and discussed. Multiple peptide ratios (human origin) were successfully proposed (subgroups < 200 accumulated degree days (ADD), < 655 ADD and < 1535 ADD) as a first step towards generalised, objective biochemical estimation of decomposition time. Furthermore, peptide ratios for donor-specific intrinsic factors (sex and body mass) were found. Search of peptide data against a bacterial database did not yield any results most likely due to the low abundance of bacterial proteins within the collected human biopsy samples. For comprehensive time-dependent modelling, increased donor number would be necessary along with targeted confirmation of proposed peptides. Overall, the presented results provide valuable information that aid in the understanding and estimation of the human decomposition processes.
Graphical Abstract
Risk Factors and Management of Blunt Inferior Vena Cava Injury: A Retrospective Study
Authors: Choi Donghwan , Kang Byung Hee , Jung Kyoungwon , Lim Sang‐Hyun , Moon Jonghwan 
Published: July 2023

AbstractBackgroundTraumatic inferior vena cava (IVC) injuries are uncommon, but the mortality rate remains high at 38–70%. To date, most studies on traumatic IVC injuries have evaluated blunt rather than penetrating injuries. We aimed to identify the clinical features and risk factors that affect the prognosis of patients with blunt IVC injuries to improve treatment strategies for these patients.MethodsWe retrospectively analyzed patients diagnosed with blunt IVC injury over 8 years at a single trauma center. Clinical and biochemical parameters; transfusion, surgical, and resuscitation methods; associated injuries; intensive care unit stay; and complications data were compared between survival and death groups to identify clinical features and risk factors of blunt IVC injury‐related mortality.ResultsTwenty‐eight patients with blunt IVC injury were included during the study periods. Twenty‐five (89%) patients underwent surgical treatment, and the mortality was 54%. The mortality rate according to the IVC injury location was the lowest for supra‐hepatic IVC injury (25%, n = 2/8), whereas it was the highest for retrohepatic IVC injury (80%, n = 4/5). In the logistic regression analysis, Glasgow Coma Scale (GCS) (odds ratio [OR] = 0.566, 95% confidence interval [CI] [0.322–0.993], p = 0.047) and red blood cell (RBC) transfusion for 24 h (OR = 1.132, 95% CI [0.996–1.287], p = 0.058) were independent predictors for mortality.ConclusionsLow GCS score and high‐volume packed RBC transfusion requirements for 24 h were significant predictors of mortality in patients with blunt IVC injuries. Unlike IVC injuries caused by penetrating trauma, supra‐hepatic IVC injuries caused by blunt trauma have a good prognosis.
High interindividual variability in LDL-cholesterol reductions after inclisiran administration in a real-world multicenter setting in Germany
Authors: Makhmudova U. , Schatz U. , Perakakis N. , Kassner U. , Schumann F. , Axthelm C. , Stürzebecher P. , Sinning D. L. , Doevelaar A. , Rohn B. , Westhoff T. , Vogt A. , Scholl M. , Kästner U. , Geiling J.-A. , Stach K. , Mensch J. , Lorenz E. , Paitazoglou C. , Eitel I. , Baessler A. , Steinhagen-Thiessen E. , Koenig W. , Schulze P. C. , Landmesser U. , Laufs U. , Weingärtner Oliver ,   for the German Inclisiran Network (GIN), Makhmudova U. , Schatz U. , Perakakis N. , Kassner U. , Schumann F. , Axthelm C. , Stürzebecher P. , Sinning D. L. , Doevelaar A. , Rohn B. , Westhoff T. , Vogt A. , Scholl M. , Kästner U. , Geiling J.-A. , Stach K. , Mensch J. , Lorenz E. , Paitazoglou C. , Eitel I. , Baessler A. , Steinhagen-Thiessen E. , Koenig W. , Schulze P. C. , Landmesser U. , Laufs U. , Weingärtner Oliver 
Published: July 2023

Abstract
Background and aims
Low-density lipoprotein cholesterol (LDL-C) is the main therapeutic target in the treatment of hypercholesterolemia. Small interfering RNA (siRNA) inclisiran is a new drug, which targets PCSK9 mRNA in the liver, reducing concentrations of circulating LDL-C. In randomized trials, inclisiran demonstrated a substantial reduction in LDL-C. The German Inclisiran Network (GIN) aims to evaluate LDL-C reductions in a real-world cohort of patients treated with inclisiran in Germany.

Methods
Patients who received inclisiran in 14 lipid clinics in Germany for elevated LDL-C levels between February 2021 and July 2022 were included in this analysis. We described baseline characteristics, individual LDL-C changes (%) and side effects in 153 patients 3 months (n = 153) and 9 months (n = 79) after inclisiran administration.

Results
Since all patients were referred to specialized lipid clinics, only one-third were on statin therapy due to statin intolerance. The median LDL-C reduction was 35.5% at 3 months and 26.5% at 9 months. In patients previously treated with PCSK9 antibody (PCSK9-mAb), LDL-C reductions were less effective than in PCSK9-mAb-naïve patients (23.6% vs. 41.1% at 3 months). Concomitant statin treatment was associated with more effective LDL-C lowering. There was a high interindividual variability in LDL-C changes from baseline. Altogether, inclisiran was well-tolerated, and side effects were rare (5.9%).

Conclusion
In this real-world patient population referred to German lipid clinics for elevated LDL-C levels, inclisiran demonstrated a high interindividual variability in LDL-C reductions. Further research is warranted to elucidate reasons for the interindividual variability in drug efficacy.

Graphical abstract
Heart rate variability: reference values and role for clinical profile and mortality in individuals with heart failure
Authors: Zeid Silav , Buch Gregor , Velmeden David , Söhne Jakob , Schulz Andreas , Schuch Alexander , Tröbs Sven-Oliver , Heidorn Marc William , Müller Felix , Strauch Konstantin , Coboeken Katrin , Lackner Karl J. , Gori Tommaso , Münzel Thomas , Prochaska Jürgen H. , Wild Philipp S. 
Published: July 2023

Abstract
Aims
To establish reference values and clinically relevant determinants for measures of heart rate variability (HRV) and to assess their relevance for clinical outcome prediction in individuals with heart failure.

Methods
Data from the MyoVasc study (NCT04064450; N = 3289), a prospective cohort on chronic heart failure with a highly standardized, 5 h examination, and Holter ECG recording were investigated. HRV markers were selected using a systematic literature screen and a data-driven approach. Reference values were determined from a healthy subsample. Clinical determinants of HRV were investigated via multivariable linear regression analyses, while their relationship with mortality was investigated by multivariable Cox regression analyses.

Results
Holter ECG recordings were available for analysis in 1001 study participants (mean age 64.5 ± 10.5 years; female sex 35.4%). While the most frequently reported HRV markers in literature were from time and frequency domains, the data-driven approach revealed predominantly non-linear HRV measures. Age, sex, dyslipidemia, family history of myocardial infarction or stroke, peripheral artery disease, and heart failure were strongly related to HRV in multivariable models. In a follow-up period of 6.5 years, acceleration capacity [HRperSD 1.53 (95% CI 1.21/1.93), p = 0.0004], deceleration capacity [HRperSD: 0.70 (95% CI 0.55/0.88), p = 0.002], and time lag [HRperSD 1.22 (95% CI 1.03/1.44), p = 0.018] were the strongest predictors of all-cause mortality in individuals with heart failure independently of cardiovascular risk factors, comorbidities, and medication.

Conclusion
HRV markers are associated with the cardiovascular clinical profile and are strong and independent predictors of survival in heart failure. This underscores clinical relevance and interventional potential for individuals with heart failure.

ClinicalTrials.gov identifier
NCT04064450.