bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating the optical degradation of InAs quantum dot lasers on silicon through combined electro-optical characterization and gain measurements
Authors: Zenari Michele , Novarese Marco , Buffolo Matteo , De Santi Carlo , Norman Justin , Hughes Eamonn T , Bowers John E , Herrick Robert W , Gioannini Mariangela , Meneghesso Gaudenzio , Zanoni Enrico , Meneghini Matteo
Published: February 2025

We evaluate the degradation of 1.3 µm InAs quantum-dot laser diodes epitaxially grown on silicon. For the first time, the optical degradation mechanisms are investigated by evaluating the variations in the gain spectra measured during a constant-current stress test. Remarkably, the gain spectra showed that the reduction in the peak modal gain is dominant compared to the increase in internal absorption losses. Moreover, the increase in threshold current (I
th) induced by stress was found to be correlated to the gain peak reduction. This experimental evidence was investigated by modeling the peak modal gain variation through a rate equation model. The outcome of this activity confirms that the variation of both I
th and modal gain can be explained solely by the reduction in injection efficiency, caused by the stress-induced increase in non-radiative recombination centers (NRRCs). This result supports previous findings on the optical degradation of 1.3 µm InAs quantum dot lasers, which is ultimately ascribed to the increase in concentration of NRRCs within the active region.
Boundary dynamics in unbounded Fatou components
Authors: Jové Anna , Fagella Núria
Published: February 2025

We study the behaviour of a transcendental entire map

f
:

C

→

C

f\colon \mathbb {C}\to \mathbb {C}

on an unbounded invariant Fatou component

U
U

, assuming that infinity is accessible from

U
U

. It is well-known that

U
U

is simply connected. Hence, by means of a Riemann map

φ
:

D

→
U

\varphi \colon \mathbb {D}\to U

and the associated inner function

g
≔

φ

−
1

∘
f
∘
φ

g≔\varphi ^{-1}\circ f\circ \varphi

, the boundary of

U
U

is described topologically in terms of the disjoint union of clusters sets, each of them consisting of one or two connected components in

C

\mathbb {C}

, improving the results in (see Baker and Domínguez [Ann. Acad. Sci. Fenn. Math. 24 (1999), pp. 437–464]; Bargmann [Cambridge Univ. Press, Cambridge, 2008]).

Moreover, under mild assumptions on the location of singular values in

U
U

(allowing them even to accumulate at infinity, as long as they accumulate through accesses to

∞
\infty

), we show that periodic and escaping boundary points are dense in

∂
U

\partial U

, and that all periodic boundary points accessible from

U
U

. Finally, under similar conditions, the set of singularities of

g
g

is shown to have zero Lebesgue measure, strengthening substantially the results (see Evdoridou et al. [J. Math. Anal. Appl. 477 (2019), pp. 536–550; Arnold Math. J. 6 (2020), pp. 459–493]).
The Spices of Different Cuisines: The Imitation of God between Philosophy and Sufism
Authors: Vasalou Sophia
Published: February 2025

This chapter selectively introduces the viewpoints of a number of ancient philosophers and the different interpretations they invite. We may notably distinguish between moral and intellectual interpretations of the idea of godlikeness. It then offers a broad-brush survey of various contexts in which the idea was developed in the Islamic world. We find expressions of the idea in the works of prominent philosophers, including Abū Bakr al-Rāzī, al-Fārābī, Avicenna, and Miskawayh. It also appears in a range of affiliated genres, such as scriptural reworkings of the virtues (al-Rāghib al-Iṣfahānī) and mirrors for princes (pseudo-Māwardī). It assumes a vivid form in Sufi literature, where it is focused by the beautiful names of God as attested by scriptural texts. God’s names are not simply objects for abstract understanding; they make moral and spiritual demands. Al-Qushayrī provides an important set of foundations for this line of thinking.
Skin in the Game: Theological Risks and Semantic Strategies
Authors: Vasalou Sophia
Published: February 2025

This chapter explores the theological qualms aroused by the idea of imitating God. A number of the key methodological principles that al-Ghazālī adopts in the Beautiful Names can be seen as an attempt to address these qualms. This includes his basic distinction between the semantic content of the beautiful names when applied to God and when applied to human beings. The chapter illustrates al-Ghazālī’s methodology through discussion of a range of specific names. The gap between human and divine applications is sharper in some cases than others. In certain cases, the human application appears stipulative. Similarly, some of God’s names can be fitted into standard lists of the virtues more easily than others. “Just” is a good example, which also illustrates the important role played by empirical investigation in the understanding of God’s character.
Where Morality Stops: Cognitive Education, Moral Plenitude, and the Importance of Lists
Authors: Vasalou Sophia
Published: February 2025

This chapter explores the resources available in the Islamic tradition, and in al-Ghazālī’s work more specifically, for responding to the practical challenge outlined in Chapter 11. What we count as a “relevant” similarity is open to change; exponents of the idea of godlikeness commonly invite a reappraisal of our self-understanding. The problem of excessive moral superiority can be linked to the oft-discussed problem of the demandingness of morality. While al-Ghazālī appears to endorse a maximalist model of morality, he demonstrates a clear concern with the need to place boundaries around the pursuit of virtue. Important evidence includes his adoption of a threshold theory of virtue. It also includes some of the practical devices he recommends as tools for moral improvement.
Fast and reliable confidence intervals for a variance component
Authors: Zhang Yiqiao , Ekvall Karl Oskar , Molstad Aaron J
Published: February 2025

We show that in a variance component model, confidence intervals with asymptotically correct uniform coverage probability can be obtained by inverting certain test-statistics based on the score for the restricted likelihood. The results apply in settings where the variance component is near or at the boundary of the parameter set. Simulations indicate the proposed test statistics are approximately pivotal and lead to confidence intervals with near-nominal coverage even in small samples. We illustrate our methods’ application in spatially resolved transcriptomics where we compute approximately 15000 confidence intervals, used for gene ranking, in less than 4 minutes. In the settings we consider, the proposed method is between two and 28000 times faster than popular alternatives, depending on how many confidence intervals are computed.
Head and neck manifestations of extramedullary plasmacytomas and their differential diagnoses: a pictorial review
Authors: Wilkinson S , Jawad S , Kowa X
Published: February 2025

Solitary plasmacytoma and multiple myeloma are plasma cell dyscrasias that typically present as bone tumour(s) due to abnormal and unregulated proliferation of plasma cells in the skeletal marrow. Both can manifest as soft tissue lesions within the head and neck region, and they may pose a diagnostic challenge given their relative rarity. This review aims to highlight the key multimodality imaging features of plasma cell neoplasms with an emphasis on extraosseous/extramedullary presentations in the anatomically complex head and neck region, as well as the relevant anatomy of various head and neck subsites and the main differential diagnoses that the radiologist should consider. Familiarity with these entities is crucial and will help the radiologist facilitate the timely diagnosis of plasma cell neoplasia using the arsenal of increasingly available and sensitive imaging techniques.
Successful implantation of an EVOQUE-tricuspid valve replacement system in a patient with two right ventricular implantable cardioverter-defibrillator leads: a case report
Authors: Genske Florian , Marquetand Christoph , Eitel Ingo , Frerker Christian , Schmidt Tobias
Published: February 2025

Background

Tricuspid regurgitation (TR) is a disease with significant morbidity and mortality rates. Besides surgery and transcatheter edge-to-edge repair (TEER), transcatheter tricuspid valve replacement has evolved as a possible treatment option in high-risk patients with an unfavourable anatomy for TEER.

Case summary

We present a case of an 82-year-old patient with torrential TR due to an annulus dilation and subsequent central gap of >8 mm. Echocardiographic guiding was impeded by the presence of two permanent right ventricular implantable cardioverter-defibrillator (ICD) leads and previous surgical aortic valve implantation and mitral valve reconstruction. An EVOQUE prosthesis (Edwards Lifesciences; Irvine, USA) was successfully implanted without impairment of the ICD function or significant paravalvular leakage.

Conclusion

Transcatheter tricuspid valve replacement with the EVOQUE-tricuspid valve replacement system is feasible even in patients with two right ventricular ICD leads and limited echocardiographic visibility.
May Measurement Month 2022: an analysis of blood pressure screening results from Malawi
Authors: Ndhlovu Henry , Chirwa Maureen , Mbulaje Lucia , Chiwanda Johnathan , Kumwanje Samuel , Beaney Thomas , Kerr Gabriele , Poulter Neil R
Published: February 2025

The May Measurement Month (MMM) campaign was carried out in Malawi in 2022 with the aim of raising awareness of raised blood pressure (BP). Here, we report on the findings of the campaign. Adults aged ≥ 18 years were recruited opportunistically in rural and urban areas of Blantyre, Lilongwe Mangochi and Machinga districts in various settings including hospitals/clinics, community places, churches and workplaces. Three seated BP readings were taken for each participant, along with completion of a questionnaire on demographics, lifestyle factors, and comorbidities. Hypertension was defined as a systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg or being on antihypertensive medication. Controlled BP was defined as being on antihypertensive medication with a BP <140/90 mmHg. Multiple imputation was used to estimate any missing BP readings. In total, 20 461 were screened, with a mean age of 42.2 years and 58.2% of whom were female. Of all participants, 5581 (27.3%) had hypertension, of whom 1527 (27.4%) were aware, and 1384 (24.8%) were on antihypertensive medication. Of those on antihypertensive medication, 1020 (73.7%) had controlled BP, and of all participants with hypertension, 18.3% had controlled BP. In conclusion, the MMM campaign in Malawi identified significant numbers of participants with either untreated or inadequately treated hypertension. However, screening was only conducted in only four districts and hence there is a significant opportunity to expand BP screening across Malawi for early detection of hypertension to maximize impact.
Understanding factors influencing personal care workers intentions to leave: A systematic integrative review
Authors: O’Keefe Britt , Yuen Eva , Dow Briony , Perlen Susan , Hutchinson  Alison M
Published: February 2025

Background and Objectives

The global need for older persons’ care, driven by demographic shifts such as an aging population and increased life expectancy, is outpacing the available care workforce. Nursing home operators face complex workforce challenges, including high turnover and low retention, particularly among personal care workers (PCW). The objective of this review was to understand the factors influencing PCWs’ intention to leave.

Research Design and Methods

Following Whittemore and Knafl's methodology and adhering to Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, an integrative review of peer-reviewed literature published between 1997 and 2024 was undertaken. A comprehensive search was conducted across several databases, including Business Source Complete, CINAHL Complete, Medline Complete, APA PsycINFO, and EMBASE. All studies underwent independent screening and quality assessment using the Mixed Methods Appraisal Tool.

Results

Included were 21 articles reporting 20 studies using quantitative (n=17), qualitative (n=3), and mixed methods (n=1), which identified various factors influencing PCWs’ intention to leave. These factors were categorized as individual, job and organizational, and socio-political-environmental. Demographic characteristics, employee satisfaction, health, career development, workplace conditions, leadership, empowerment, resident connections, and societal perceptions influenced personal care workers’ intentions to leave.

Discussion and Implications

The findings of this review reveal opportunities for nursing home operators and policy-makers to implement strategies to mitigate the high rates of turnover through PCW role and organizational reforms. Further, the findings underscore the need for qualitative research exploring the perceptions and experiences shaping the employment intentions of current and former PCWs.
Family Structure and Unmet Care Needs among Older Adults with and without Dementia in the U.S
Authors: Patterson Sarah E , Freedman Vicki A
Published: February 2025

Background and Objectives

Family members provide the bulk of assistance to older adults with care needs, but implications of family structure for unmet care needs—and differences when dementia is present—are less clear.

Research Design and Methods

We use samples of older adults with care needs from the 2015 National Health and Aging Trends Study (NHATS) and the 2017 Panel Study of Income Dynamics (PSID). We examine two measures that indicate whether needs are being met for self-care and mobility activities: having unassisted difficulty with at least one activity (NHATS, PSID) and experiencing any adverse consequences related to a lack of help (NHATS). In NHATS we also combine these to identify individuals with met (no unassisted difficulty; no consequences), self-met (unassisted difficulty only), under-met (any consequence only), and unmet needs (unassisted difficulty, any consequence).

Results

Adverse consequences were reported more often among those with dementia (43%) relative to those without (24%); in contrast, unassisted difficulty was reported by fewer older adults with dementia (68%, 70%) than without dementia (85%, 87%). Having more family members was positively associated (OR=1.039) and having a spouse or partner was inversely associated (OR=0.700) with experiencing adverse consequences. Having stepchildren was associated with lower odds of having unassisted difficulty (OR=0.228, 0.531), but greater odds of unmet (relative to met) needs (RRR=1.610). Most family associations were not moderated by dementia.

Discussion and Implications

Adverse consequences, unassisted difficulty, and unmet need are distinct concepts, and produce different estimates and distinctive relationships with dementia and family structure.
FarmGTEx TWAS-server: An Interactive Web Server for Customized TWAS Analysis
Authors: Zhang Zhenyang , Chen Zitao , Teng Jinyan , Liu Shuli , Lin Qing , Wu Jun , Gao Yahui , Bai Zhonghao ,   The FarmGTEx Consortium, Li Bingjie , Liu George , Zhang Zhe , Pan Yuchun , Zhang Zhe , Fang Lingzhao , Wang Qishan
Published: February 2025

Transcriptome-wide association study (TWAS) is a powerful approach for investigating the molecular mechanisms linking genetic loci to complex phenotypes. However, the complexity of the TWAS analytical pipeline including the construction of gene expression reference panels, gene expression prediction, and association analysis using data from genome-wide association studies (GWAS) poses challenges for genetic studies in many species. In this study, we provide the Farm Animal Genotype-Tissue Expression (FarmGTEx) TWAS-server, an interactive and user-friendly multispecies platform designed to streamline the translation of genetic findings across tissues and species. The server incorporates gene expression data from 49 human tissues (838 individuals), 34 pig tissues (5457 individuals), and 23 cattle tissues (4889 individuals), providing prediction models for 38,180 human genes, 21,037 pig genes, and 17,942 cattle genes. It supports genotype-based gene expression prediction, GWAS summary statistics imputation, customizable TWAS analysis, functional annotations, and result visualization. Additionally, we provide 479,203, 1208, and 657 tissue–gene–trait associations for 1129 humans traits, 41cattle traits, and 11 pigs traits, respectively. Utilizing the TWAS-server, we validated the association of the ABCD4 gene with pig teat numbers. Furthermore, we identified that pig backfat thickness may share genetic similarities with human diastolic blood pressure, sarcoidosis (Lofgren syndrome), and body mass index (BMI). The FarmGTEx TWAS-server offers a comprehensive and accessible platform for researchers to perform TWAS analyses across tissues and species. It is freely available at https://twas.farmgtex.org, with regular updates planned as the FarmGTEx project expands to include more species.
Living on the Rocks: Genomic Analysis of Limestone Langurs Provides Novel Insights into the Adaptive Evolution in Extreme Karst Environments
Authors: Zhijin Liu , Zhang Xiongfei , Wang Peipei , Hong Minheng , Yan Xiaochan , Qi Xiaoqiu , Zhao Qian , Chen Zhenghao , Nie Huajian , Li Hui , Li Ziwen , Zhang Liye , Qi Jiwei , He Chaolei , Van Truong Nguyen , Le Minh D , Nadler Tilo , Imai Hiroo , Roos Christian , Li Ming
Published: February 2025

Understanding how organisms adapt to their environments is a central question in evolutionary biology. Limestone langurs are unique among primates, as they are exclusively found in karst limestone habitats and have evolved mechanisms to tolerate high levels of mineral ions, which are typically associated with metal toxicity affecting organs, cells, and genetic material. We generated a high-quality reference genome (Tfra_5.0) for the limestone langur (Trachypithecus francoisi), along with genome re-sequencing data for 48 langurs representing 15 Trachypithecus species. Genes coding for ion channels (e.g., Na+, K+, and Ca2+) exhibited significantly accelerated evolution in limestone langurs. Limestone langur-specific mutations in Na+ and Ca2+ channels were experimentally confirmed to modify inward ion currents in vitro. Unexpectedly, scans for positive selection also identified genes involved in DNA damage response/repair pathways, a previously unknown adaption. This finding highlights an evolutionary adaptation in limestone langurs that mitigate the increased risk of DNA damage posed by elevated metal ion concentrations. Notably, a limestone langur-specific mutation (E94D) of the melanocortin 1 receptor was associated with increased basal cyclic adenosine monophosphate (cAMP) production, contributing to the species’ darker coat color, which likely serves as camouflage on limestone rocks. Our findings reveal novel adaptive evolutionary mechanisms of limestone langurs and offer broader insights into organismal adaptation to extreme environments, with potential implications for understanding human health, biological evolution, and biodiversity conservation.
Sex Differences in Anti–Epstein-Barr Virus Antibody Responses
Authors: Jackson Sarah S , Francis Julia , Pfeiffer Ruth M , Proietti Carla , Coghill Anna E , Yu Kelly J , Sarathkumara Yomani D , Hsu Wan-Lun , Argirion Ilona , Wang Cheng-Ping , Chen Chien-Jen , Rothman Nathaniel , Lan Qing , Hildesheim Allan , Doolan Denise L , Liu Zhiwei
Published: February 2025

We investigated anti–Epstein-Barr virus (EBV) immunoglobulin A (IgA) and immunoglobulin G (IgG) responses by sex among 387 cancer-free individuals in Asia. Antibody responses were measured using an EBV proteome array to assess age-adjusted, sex-specific associations with 404 EBV antigens in 86 protein sequences via meta-analysis and pathway analysis by EBV stage. Males were more likely to have elevated IgA responses (P = .001) and females had higher IgG responses (P = .003). Significant sex associations were observed across stages of lytic replication. The largest sex differences were seen in latent IgA, but no differences were observed in latent IgG antibodies. Higher IgA responses suggest higher rates of EBV reactivation in males.
Agricultural byproduct-derived biochar for mitigating trace metal risks from soil to rice to public health: implications for sustainable management
Authors: Dong Hao Phu , Nguyen Binh Thanh , Le Thia Hong , Nguyen My Hoang , Le Anh Hoang
Published: February 2025

Heavy metal contamination in soil and its accumulation in rice poses a health risk to over 50% of the global population. Simultaneously, the poor management and underutilization of agricultural biomass waste presents an additional environmental challenge. Converting this biomass into biochar offers a potential solution to these challenges. This study evaluated biochar’s impacts on soil trace element content, rice plant uptake, translocation, accumulation, and associated human health risks while identifying rice response mechanisms to biochar application. A two-season field experiment was conducted using five treatments: T1 (no biochar), T2 and T3 (10 and 20 tons of rice-husk biochar), and T4 and T5 (10 and 20 tons of longan biochar). Eight trace elements, categorized as micronutrients (Fe, Mn, Cu, Zn) and toxic elements (Cd, Pb, Co, Ni), were measured in rice roots, stems, grains, and soil. Biochar application reduced the heavy metal pollution index (HPI) by 5.9% to 11.4% for micronutrients and 2.8% to 4.4% for toxic elements compared to T1. Translocation, bioaccumulation, and phytoextraction indexes tend to increase with biochar, while the hazard index decreased by 5.1-9.5% for micronutrients and 1.3-8.5% for toxic elements, indicating reduced health risks. These results highlight biochar's dual role in enhancing trace element phytoextraction and reducing health risks, with a more pronounced effect on micronutrients. Rice plants responded to reduced micronutrient availability by boosting uptake while lowering toxic element absorption when HPI was high. Briefly, transforming agricultural waste into biochar for rice cultivation offers multiple benefits, promoting agricultural sustainability, environmental health, and consumer safety.
A novel surgical technique for repairing duodenal and bile duct perforations following endoscopic retrograde cholangiopancreatography
Authors: Abdirahman Hana , Barakat Omar , Nichols Alexis , Soares Oluwatobi , Mortus Jared , Chen Vivi
Published: February 2025

Duodenal perforation (DP), though rare, is a severe complication of Endoscopic retrograde cholangiopancreatography (ERCP) with high mortality rates. This report introduces a novel surgical approach for repairing a complex combined bile duct and duodenal perforation. A 37-year-old male with recurrent pyloric stenosis and choledocholithiasis, previously treated with multiple procedures, presented with gastric outlet and bile duct obstruction. Following a complex ERCP, he developed a large combined duodenal and bile duct perforation requiring urgent surgical intervention. A 40% circumferential duodenal perforation combined with bile duct perforation was repaired using a novel approach: a vascularized isolated distal gastric pouch was created and anastomosed to the duodenal and bile duct defects. A Roux-en-Y gastrojejunostomy was performed, and the patient recovered in stable condition. When traditional reconstruction is not feasible for DP, an isolated, vascularized distal gastric pouch offers a less invasive alternative and reduces the risk of morbidity.
Zetetic rights and wrong(ing)s
Authors: Friedman Daniel C
Published: February 2025

What do we owe those with whom we inquire? Presumably, quite a bit. Anything beyond what is necessary to secure knowledge? Yes. In this paper, I argue for a class of ‘zetetic rights.’ These are rights distinctive to participants in group inquiry. Zetetic rights help protect important central interests of inquirers. These include a right to aid, a right against interference, and a right to exert influence over the course of inquiry. Building on arguments by Fricker, I defend these rights, and explore cases of their violation: zetetic wrongings. I argue that zetetic wrongings constitute a distinctive, ubiquitous, and significant form of injustice in our epistemic and zetetic lives. To improve our inquiries and avoid epistemic injustice, we need to contend with zetetic wronging. Making this case helps show that a complete picture of epistemic life must account for the deep influence of our cooperative ties to one another.
Optimizing β-TCP with E-rhBMP-2-infused fibrin for vertical bone regeneration in a mouse calvarium model
Authors: Zhao Kun , Ono Mitsuaki , Mu Xindi , Wang Ziyi , Xie Shichao , Yonezawa Tomoko , Okada Masahiro , Matsumoto Takuya , Kuboki Takuo , Oohashi Toshitaka
Published: February 2025

Effective reconstruction of large bone defects, particularly in thickness, remains one of the major challenges in orthopedic and dental fields. We previously produced an Escherichia coli-based industrial-scale GMP-grade recombinant human bone morphogenetic protein-2 (E-rhBMP-2) and showed that the combination of E-rhBMP-2 with beta-tricalcium phosphate (β-TCP/E-rhBMP-2) can effectively promote bone reconstruction. However, the limited mechanical strength and poor morphology retention of β-TCP granules are key points that need optimization to obtain more effective grafts and further expand its clinical applications. Therefore, we combined β-TCP/E-rhBMP-2 with fibrin gel to enhance its mechanical properties and usability for vertical bone regeneration. We investigated the mechanical properties and vertical bone regeneration effects of the materials applied, with or without fibrin containing E-rhBMP-2, in a calvarial defect model in mice. Compression tests were conducted to assess the initial stability of the materials. Scanning electron microscopy and Fourier transform infrared spectroscopy were conducted to characterize the presence of fibrin on the scaffold. After 4 and 12 weeks of implantation, micro-computed tomography and histological and immunofluorescent analyses were performed to assess the morphology and volume of the newly formed bone. The fibrin-containing groups had significantly higher initial mechanical strength and higher ability to maintain their morphology in vivo compared to the counterparts without fibrin. However, fibrin gel alone suppressed the bone formation ability of β-TCP/E-rhBMP-2 whereas the presence of high doses of E-rhBMP-2 in fibrin gel resulted in material resorption and enhanced new bone formation. In conclusion, fibrin gel significantly improved the mechanical strength and surgical manageability of the β-TCP/E-rhBMP-2 scaffold, and the addition of E-rhBMP-2 to the fibrin gel further enhanced the vertical bone regeneration and initial structural integrity of the scaffold.
Comparisons of PK-Sim and R program for physiologically based pharmacokinetic model development for broiler chickens and laying hens: meloxicam as a case study
Authors: Zhang Zhicheng , Tell Lisa A , Lin Zhoumeng
Published: February 2025

Physiologically based pharmacokinetic (PBPK) models play a critical role in evaluating drug residue concentrations and estimating withdrawal intervals (WDIs) for food-producing animals. These models are facilitated by various programming software (e.g. R program) and predefined PBPK platforms, such as Open Systems Pharmacology (OSP) suite integrated by PK-Sim and Mobi, which offers a user-friendly graphical interface. Both R and OSP are open-source software. However, there is a lack of comparative analyses of both platforms and their potential impact on PBPK models. This study aims to evaluate the influence of different platforms on PBPK workflow, parameters selection, and output results, which is exemplified via a case study for meloxicam in chickens in both platforms. Our findings indicate that while the choice of PBPK platforms affected the workflow and input parameters, the predictive performance of established models remained consistent across both platforms. Both platforms predicted meloxicam pharmacokinetics in plasma and tissues accurately across different exposure scenarios. The PBPK-estimated WDIs under various dosing regimens from both platforms were quite similar. Notable differences between OSP suite and R were primarily observed during sensitivity analysis and parameter identification processes, especially the time consumption. This study offers insight into software variances and their implications for translating PBPK modeling knowledge between users of 2 platforms. Also, it provides a PBPK model structure template implemented in both software platforms for food safety and risk assessment in poultry and a detailed tutorial on expanding the model structure in PK-Sim and Mobi.
A Level-Adjusted Cochlear Frequency-to-Place Map for Estimating Tonotopic Frequency Mismatch With a Cochlear Implant
Authors: Sagi Elad , Svirsky Mario A.
Published: February 2025

Objectives:

To provide a level-adjusted correction to the current standard relating anatomical cochlear place to characteristic frequency (CF) in humans, and to re-evaluate anatomical frequency mismatch in cochlear implant (CI recipients considering this correction. It is proposed that a level-adjusted place-frequency function may represent a more relevant tonotopic benchmark for CIs in comparison to the current standard.

Design:

The present analytical study compiled data from 15 previous animal studies that reported isointensity responses from cochlear structures at different stimulation levels. Extracted outcome measures were CFs and centroid-based best frequencies at 70 dB SPL input from 47 specimens spanning a broad range of cochlear locations. A simple relationship was used to transform these measures to human estimates of characteristic and best frequencies, and nonlinear regression was applied to these estimates to determine how the standard human place-frequency function should be adjusted to reflect best frequency rather than CF. The proposed level-adjusted correction was then compared with average place-frequency positions of commonly used CI devices when programmed with clinical settings.

Results:

The present study showed that the best frequency at 70 dB SPL (BF70) tends to shift away from CF. The amount of shift was statistically significant (signed-rank test z = 5.143, p < 0.001), but the amount and direction of shift depended on cochlear location. At cochlear locations up to 600° from the base, BF70 shifted downward in frequency relative to CF by about 4 semitones on average. Beyond 600° from the base, BF70 shifted upward in frequency relative to CF by about 6 semitones on average. In terms of spread (90% prediction interval), the amount of shift between CF and BF70 varied from relatively no shift to nearly an octave of shift. With the new level-adjusted place-frequency function, the amount of anatomical frequency mismatch for devices programmed with standard-of-care settings is less extreme than originally thought and may be nonexistent for all but the most apical electrodes.

Conclusions:

The present study validates the current standard for relating cochlear place to CF, and introduces a level-adjusted correction for how best frequency shifts away from CF at moderately loud stimulation levels. This correction may represent a more relevant tonotopic reference for CIs. To the extent that it does, its implementation may potentially enhance perceptual accommodation and speech understanding in CI users, thereby improving CI outcomes and contributing to advancements in the programming and clinical management of CIs.
Mid-term Radiologic and Clinical Results of Pediatric-adolescent Lisfranc Injuries
Authors: Sensoz Ersin , Yilmaz Husnu , Engin Eceviz , Onay Tolga
Published: February 2025

Introduction:

The incidence of Lisfranc injury in pediatric-adolescent children is lower compared with adults. There is limited research on adolescent patients in this age group, with only a few case reports of pediatric patients. Furthermore, studies with adequate follow-up are lacking in the literature. This study aims to provide insights into the causes and types of fractures and evaluate mid-term clinical and radiologic outcomes.

Methods:

A retrospective analysis was conducted on pediatric-adolescent patients diagnosed with a Lisfranc injury who underwent surgical treatment between June 2015 and January 2022. Patients underwent open reduction and internal fixation using Kirschner wires and/or screws, had satisfactory imaging, and were followed up for at least 2 years. Radiologic measurements included intermetatarsal distance, meary angle, and calcaneal height angle, done while the patient was standing. Assessments were made using the AOFAS midfoot score, the Oxford Ankle Foot Questionnaire for Children (OxAFQ-C), Visual Analog Scale (VAS) scores, and physical activities.

Results:

The study included 14 surgically treated patients with a minimum 2-year follow-up. The average patient age was 12.6 years, with a mean follow-up of 52.4 months. In pediatric cases, crush injury was the predominant trauma type (P = 0.009). There were no significant differences in calcaneal pitch angle or meary angle between healthy and injured feet (P = 0.2 and 0.1), but a greater intermetatarsal distance was observed on the injured side (P = 0.02). The mean Visual Analog Scale (VAS) score was 1.5, the AOFAS midfoot score averaged 91.5, and the OxAFQ-C score averaged 86.3%.

Conclusions:

The mid-term outcomes for this age group were promising compared with adults. The use of Kirschner wires for fixation is more common in younger patients. Crush injuries and complications like compartment syndrome are more prevalent in the pediatric age group.
Enhancing hemophilia A gene therapy by strategic F8 deletions in AAV vectors
Authors: Zhao Juan-Juan , Tian Sai-Ning , Li Xiang , Peng Zu-Yi , Li Guo-Hua , Zhang Feng , Zhao Mei , Zhang Jian-Ping , Zhang Xiao-Bing
Published: February 2025

Hemophilia A, caused by a deficiency in factor VIII (F8), is a promising target for gene therapy. This study aims to enhance the efficacy of adeno-associated virus serotype 8 (AAV8) vectors, specifically those encoding B-domain-deleted F8 (BDDF8), to treat the condition. We focused on improving therapeutic outcomes by strategically deleting amino acids at the furin cleavage site (RHQR), a modification that is crucial for increasing F8 expression and reducing capsid stress during vector packaging. Using computational modeling with AlphaFold2, combined with western blotting and in vivo clotting assays, we developed and tested several AAV8-BDDF8 variants in a hemophilia A mouse model. The AAV8-BDDF8-ΔRHQR10 variant, which includes a 10-amino acid deletion at the RHQR site, demonstrated a 2- to 3-fold increase in F8 activity, with sustained expression and no hepatotoxicity. This variant also showed reduced capsid stress and enhanced protein expression. However, the observed decline in long-term efficacy highlights the ongoing challenges in AAV-F8 gene therapy, emphasizing the need for continuous improvements. Our findings offer valuable insights for refining AAV-mediated gene therapy in hemophilia A, showing that targeted molecular modifications can significantly enhance therapeutic performance while ensuring safety.
Invasive Arterial Pressure Monitoring: Are We Confident Making Decisions Based on Reliable Values?
Authors: Schortgen Frédérique , Le Bec Caroline
Published: February 2025

A prerequisite for accurate invasive arterial pressure measurement is familiarity with measurement principles and pitfalls. Using an electronic survey, we assessed knowledge about invasive arterial pressure monitoring and current invasive arterial pressure monitoring practices in the ICU. The questionnaire was sent to nurses and physicians who are members of the French Intensive Care Society and the Réseau Européen de Recherche en Ventilation Artificielle network. Three hundred nine nurses and 76 physicians responded. We identified considerable gaps in knowledge and differences in practices that can significantly impact the reliability of invasive arterial pressure measurement, mainly the confusion between zeroing and leveling the transducer and the heterogeneity in external landmarks choice for the phlebostatic axis. In modern critical care, where mean arterial pressure targets are recommended and where patients are awake and/or frequently mobilized, standardized invasive arterial pressure monitoring is required.
Establishing a Protocol to Increase Racial/Ethnic Under-Represented Minority Enrollment on an Active Radiation Oncology Multicenter Randomized Clinical Trial
Authors: Gardner Ulysses G. , Brawley Otis W. , Obi Elizabeth E. , Redmond Kristin J. , McClelland Shearwood
Published: February 2025

Objectives:

In the United States, under-represented racial/ethnic groups lack ample enrollment in clinical trials, yielding ungeneralizable trial results. Barriers to increasing minority enrollment include decreased awareness of clinical trials, lack of access, financial burden and toxicity, medical system mistrust, and discordant physician-patient demographics.

The ongoing Spine Patient Optimal Radiosurgery Treatment for Symptomatic MEtastatic Neoplasms (SPORTSMEN) clinical trial (NCT05617716 on clinicaltrials.gov) has a study design to actively accrue minority patients. We present our protocol addressing key targets to increase minority enrollment on this randomized, phase II clinical trial.

Methods:

Adults with evidence of symptomatic spine metastases are eligible. Baseline demographics (including race/ethnicity) are reported for statistical analysis. Our protocol seeks to minimize barriers to minority enrollment and targets 5 key areas including clinical trial design, access to care, financial toxicity, community engagement, and patient-centered care.

Results and Conclusions:

Increasing clinical trial diversity is a challenge that must be addressed with meaningful intent to present robust level I data that broadens the understanding of treatment response in all demographics. Our protocol takes a patient-centered approach to achieve the objective of concordant racial/ethnic representation in a randomized clinical trial.
Role of Indobufen in coronary artery disease: the story of a neglected drug. A systematic review.
Authors: Pepe Martino , Tritto Rocco , Napoli Gianluigi , Giordano Salvatore , Romito Roberta , Biondi-Zoccai Giuseppe , Corcione Nicola , Cirillo Plinio , Ciccone Marco Matteo
Published: February 2025

The management of antiplatelet therapy in coronary artery disease (CAD) is one of the most debated topics in cardiology. In some clinical scenarios, such as acute coronary syndromes (ACS) and/or percutaneous coronary interventions (PCI), a dual antiplatelet therapy (DAPT) based on the association of a thromboxane A2 (TXA2) pathway inhibitor and a P2Y12 inhibitor is required. Nevertheless, the recent research has been largely focused on the P2Y12 inhibitors, while few data are available on the TXA2 pathway inhibitors, besides aspirin. This gap in the evidence can have relevant clinical implications when aspirin is contraindicated. After years of empirical use, recent clinical studies have shed some light on the efficacy/safety profile of indobufen when compared to aspirin in low-risk CAD patients. However, also encouraged by promising pharmacodynamic data on platelet inhibition, further clinical investigations are strongly advocated.
Decastatin, a novel Non-Collagenous 1 domain from collagen type X, harbors a specific fragment with antiangiogenic properties
Authors: Jansen Stine Marie , Pitek Rastislav , Karsdal Morten Asser , Henriksen Kim
Published: February 2025

The NC1 domains of collagens have been shown to possess antiangiogenic potential and, therefore, are of therapeutic interest for cancer. However, endostatin and other NC1 domains have not been successful in clinical tests. Therefore, we used evolutionary conservation to perform molecular deconstruction of the domains to further understand their structure–activity relationship, thereby deciphering their antiangiogenic potential. Homology exploration revealed that collagen type X contains a highly interesting NC1 domain (decastatin), with several sequences showing significant homology with vastatin, which is a known collagen type VIII-derived NC1 domain. For comparison, endostatin and vastatin were split into fragments, some of which contained highly conserved regions. The testing of these peptides revealed that the peptides containing conserved regions induced signaling, and fragment four of decastatin showed the highest potency of all fragments, with a calculated IC50 value of 2.7 μM in the human umbilical vein endothelial cell (HUVEC)-based tube formation assay, which is like that of an intact NC1 domain. Notably, the corresponding fragment from vastatin (V4) also inhibited tube formation, suggesting that this region is of therapeutic interest. In summary, we used evolutionary conservation to identify a novel NC1 domain of collagen type X, a collagen playing a role in angiogenesis of the growth plate. Furthermore, we provided data indicating that the antiangiogenic activity of NC1 domain–derived peptides reside within their conserved domains. As a result, we identified a fragment called Decastatin fragment 4 (D4) derived from the NC1 domain of collagen type X, and which has potent antiangiogenic activity.
Urodynamic evaluation of prasterone vaginal treatment of mild to moderate urge incontinence in women with vulvovaginal atrophy: multicenter prospective study
Authors: Collà Ruvolo Claudia , Ursino Manuela , Formisano Carmen , Pozzuoli Alberto , Venturella Roberta , Longo Nicola , Di Carlo Costantino
Published: February 2025

Objective

This study aimed to evaluate the effects of intravaginal prasterone treatment on urge urinary symptoms in women affected by genitourinary syndrome of menopause.

Methods

The study was conducted on postmenopausal women with vulvovaginal atrophy and symptoms of increased urinary frequency and urgency with an Overactive Bladder Screener score of >8. Participants underwent urodynamic examination and completed the International Consultation on Incontinence Questionnaire—Short Form (ICIQ-SF) questionnaire before and after 3 months of treatment. Wilcoxon signed rank test for the paired sample was used to compare continuous non parametric variables.

Results

Twenty women were prospectively enrolled (January 2022 to January 2024). The median age and menopausal age were 59 years (interquartile range, 56.0-66.5 y) and 50 years (interquartile range, 49.0-52.5 y), respectively. According to the ICIQ-SF, the mean scores before and after treatment were 9.6 (SD, 5.1) and 2.63 (SD, 2.24), respectively (P > 0.001). According to the urodynamic examination, the median volume infused increased from 70 to 123 mL (P = 0.001) for the first stimulus, from 115 to 202 mL (P = 0.001) for the normal stimulus, from 199 to 290 mL (P = 0.001) for the urge stimulus, and from 251 to 343 mL (P = 0.001) for the maximal bladder filling capacity. At the end of the study, the 42.1% of women reported very much and much better improvement according to the Patient Global Impression of Improvement score.

Conclusions

After 3 months of prasterone treatment, women reported a statistically significant objective increase in bladder compliance through a later voiding stimulus and a subjective reduction in urge incontinence episodes through the validated ICIQ-SF questionnaire.
How to reduce free radicals during phacoemulsification – EPR measurements comparing the production of free radicals in different use cases
Authors: Giger-Lange Christina , Barz Jakob , Heim Heiko
Published: February 2025

PURPOSE:

To detect free radicals during phacoemulsification in different use cases and with emulsification of lens tissue.

SETTING:

Institute for Interfacial Engineering and Biotechnology, Fraunhofer Institute, Stuttgart, Germany.

DESIGN:

Experimental study.

METHODS:

Three experimental setups were used: 1. Setup without running fluidics to produce air bubbles inside the system. 2. Circulation fluidic setup to compare measurements with and without cataractous lens material. 3. A surgery-comparable system that closely mimics a realistic setup.

Porcine lenses were incubated for 1.25h in formalin to simulate middle hard cataracts and emulsified in a test chamber. Free radicals were captured by the spin-trapping agent 5,5’-dimethyl-1-pyrroline N-oxide and measured using electron-paramagnetic resonance spectroscopy.

RESULTS:

Hydroxyl-radicals were the predominant free radicals detected. The maximum amount of radicals was produced when air bubbles were allowed to build up inside the system. Less radicals were produced during lens-emulsified compared to application without lens. This effect was enhanced when the phacotip was in close contact with the lens during the whole procedure. In the surgery-comparable setup, the least amount of free radicals was detected.

CONCLUSION:

For the first time we were able to analyze free radicals during phacoemulsification of lens-tissue. We show that emulsification of lens tissue reduces the production of free radicals, an effect that is enhanced during close contact of the tissue with the phacotip. Also, we show that air-bubbles should be avoided during cataract surgery, as they may enhance free radical production. Furthermore, running fluidics remove most of the radicals making oxidative stress less likely.
Hepatic encephalopathy in patients with cirrhosis: Key clinical considerations for the nurse practitioner and physician assistant
Authors: Hanson Christina , Goacher Elizabeth K.
Published: February 2025

Background:

Hepatic encephalopathy (HE) is a common neurocognitive cirrhosis-related complication with a broad range of symptoms. Timely recognition and treatment of HE, including identifying precipitating factors, when possible, is critical for improving outcomes in patients with cirrhosis. Lactulose and rifaximin therapies, as appropriate, are recommended for patients with cirrhosis and a history of HE episode(s) to reduce risk of HE recurrence.

Objectives:

To provide clinical considerations for nurse practitioners and physician assistants (PAs) on the diagnosis and management of patients with cirrhosis.

Data Sources:

A PubMed search of English-language articles published between January 1, 2008, and March 13, 2024, was performed to identify publications on the diagnosis and treatment of HE.

Results:

Important topics to address when discussing care with patients with cirrhosis and their caregivers include concomitant medication use, recent infection history, comorbid conditions (e.g., diabetes), fall and frailty risks, and sleep quality. In addition, ensuring treatment adherence is important for reducing the risk of future HE episodes and HE-related hospitalizations. Engaging and empowering caregivers helps reinforce the need for patient adherence to treatment and facilitates earlier identification of HE symptoms.

Conclusions:

Early recognition of HE, treatment, and reduction in risk of recurrence are imperative to minimize patient morbidity and mortality.

Implications for Practice:

Nurse practitioners and PAs play an important role in supporting patients with cirrhosis who are at risk for developing HE, as well as their caregivers. Understanding and recognizing precipitating factors and clinical symptoms of HE and treating and preventing HE recurrence can improve patient outcomes.