bluuebunny/crossref_metadata_2025 huggingface dataset:
Inadequacies in the implementation of the law on tax administration for enterprise’s related-party transactions
Authors:   Express Delivery Services Corporation, Vietnam, Truong Chu Giang
Published: October 2023

Related-party transactions are transactions arising between parties having related-party relationship during their production and business processes. Although related-party transactions are legal themselves, they may create conflicts of interest or lead to other illegal situations, so regulatory agencies often scrutinize them carefully. Tax administration for enterprise’s related-party transactions should be stricter than those of enterprises that only have independent transactions, as the implementation of related transactions has the ability to transfer revenues and profits for the purpose of reducing corporation income tax obligation. Within this article, the author focuses on discussing the provisions of law and the inadequacies in practising law enforcement on tax administration for enterprises having related-party transactions based on the analysis of point d, clause 2, Article 5 of Decree No. 132/2020/NĐ-CP (hereinafter referred to as “Decree 132”). Accordingly, the main inadequacies are examined in the identification of the related-party in the loan transaction between the borrowing enterprise and the credit institution, and in the Identification of the related-party when the borrowing enterprise does not”have medium and long-term debts. Corresponding to each inadequacy are the main solutions, including excluding the related-party relationship when the lending enterprise is an independent credit institution from the borrowing enterprise, adjusting the ratio of loan capital to equity ownership and other related solutions.
The impact of FDI and trade openness on income inequality in the ASEAN region
Authors: Pham Duyen My , Nguyen Thai Hoa Kim ,   University of Economics and Law, Phan Thành Thanh
Published: October 2023

The study examines the impact of FDI and trade openness on income inequality in the ASEAN region through instrumental variables and two-stage least squares for panel-data models. The study is based on panel data from Word Bank, SWIID and UNCTAD of 9 ASEAN countries from 1990 to 2020. The model includes six macro control variables: financial development, GDP per capita, education, control of corruption, inflation and unemployment. The result shows FDI has a positive relationship with income inequality. Meanwhile, the group of variables of trade openness has various impacts on income inequality, such as the variable international trade in goods and imports from middle- and low-income countries have the opposite effect. In contrast, the variable exports to low- and middle-income countries and imports from high-income countries have a positive effect on the dependent variable, especially the variable exports to high-income countries are not statistically significant. The variables education, financial development, GDP per capita and inflation have negative effects on inequality, and unemployment and corruption control variables are not significant due to the individual characteristics of the sample. From there, policy implications that reduce income inequality through FDI, trade openness and other factors in the region are suggested.
The influence of perceived destination social responsibility on residents’ pro-tourism behaviors: A study in Da Lat
Authors:   Da Lat University & School of Tourism, Hue University, Mai Lan Thi Kieu , Hoang Hung Trong ,   University of Economics, Hue University, Ho Nga Thi Thuy ,   University of Economics, Hue University
Published: October 2023

Based on the SOR (Stimulus – Organism – Response) framework, this study proposes a model on the influence of perceived destination social responsibility on residents’ pro-tourism behaviors in Dalat City. The study was conducted based on survey data from 357 residents in Dalat, and structural equation modeling (SEM) was utilized to test the proposed relationships among variables in the model. The findings indicate that perceived destination social responsibility positively impacts residents’ pro-tourism behaviors through two mediators: destination preference and destination attachment. In which perceived destination social responsibility has a positive and direct impact on destination attachment and destination preference. Both destination attachment and destination preference have positive and direct influences on residents’ pro-tourism behaviors. In addition, the analysis results show that destination social responsibility does not have a direct influence on residents’ pro-tourism behaviors but only has an indirect influence through two mediators (i.e., destination attachment and destination preference). This study contributes to both theory and practice with regard to destination social responsibility.
The traditional theory application in recognition of ownership to virtual assets
Authors:   Thu Dau Mot University, Vietnam, Le Thi Minh
Published: October 2023

The significant advances of the Internet have made cyberspace develop similarly to physical space. Although the architecture of cyberspace has an automated function, there still exists a need for state management in some cases, especially with the advent and increasing popularity of virtual asset classes. Virtual assets have the characteristics of a regular asset class, such as competition, persistence, and interconnectedness. Treating virtual items the same way as real-world assets would be logical, which This means that virtual assets can also be considered for ownership. However, traditional theories face many difficulties when applied to the virtual world in solving the problem of recording ownership of virtual assets. The article analyzes the content of popular approaches used as the basis for claiming ownership of virtual assets, including John Locke's labor value theory, Hegel's personality theory, and Bentham's pragmatism. At the same time, the article also points out the limitations and unconvincing results of applying these traditional theories to recording ownership of virtual assets. The virtual world is not the natural world for the mere application of John Locke's labor philosophy. Applying Hegel's personality theory leads to other complex operations, including identifying virtual assets. Recognizing ownership of virtual assets does not necessarily create optimal value for Bentham's pragmatist society. Therefore, recognizing ownership rights for virtual assets needs further research on the rationale.
Library Space as a Teaching and Learning Resource: The Experience of One Class
Authors:   Andrews University, Adeogun Margaret
Published: October 2023

Academic libraries today are asked to justify the value they bring to the advancement of learning. The challenge for accountability has pressured many libraries to re-examine anew how students learn, and the best approaches to 21st century learning environment. Libraries are re-examining their assets – information materials, services, abilities and skills, and particularly, the library space. They are deliberating on how they can better support a learning environment that is geared toward knowledge-building and reflects a need for flexible space, time, people, and technology. Library space has turned out to be the library’s most cherished resource. Despite the fact that information items and databases are readily accessible to patrons outside the library building – a situation that could minimize their visits to the library – most academic libraries that have repurposed their spaces for social and academic explorations are experiencing an upsurge in traffic of students. In order to meet the needs of the knowledge society, teaching faculty are beginning to cherish the importance of experiential learning to prepare their students for a knowledge capitalist society where knowledge is the acme of the economy. They now realize that experiential learning cannot take place within the confines of a classroom, but in an open environment with varied resources and technology that stimulate students to think, explore, and create. This is why library spaces are becoming attractive to the teaching faculty as spaces of value, if so designed for exploration, hands-on learning, and collaboration for knowledge building. This paper reviews the teaching and learning experiences of faculty and students’ use of the James White Library Innovation Lab as a teaching and learning space for INEN 221-001 Introduction to Innovation & Entrepreneurship: Foundations of Play.
Towards a Biblical Foundation for a Philosophy of Library Sociality
Authors:   Andrews University, Robertson Terry
Published: October 2023

In this essay, I focus on the sociality of librarianship in the academic setting. How should we as library workers think about the communities we serve? What mindset should guide our interactions with the people who seek our services? How should library workers think about how we collaborate to serve our public? As a profession, librarianship has a solid public service orientation, evidenced by its best community outreach, advocacy, and hospitality practices. Can Biblical teachings emphasized within the Seventh-day Adventist faith community be foundational for this ethos? Does faith integration matter? Correlating insights from Tuomela on group agency, Lankes on the mission of librarians, and the Biblical teachings on Discipleship, Second Coming, and Sabbath, I suggest the integration of work and faith is evidenced by a dispositional orientation that finds expression in a we-mode library sociality.
The Relationship Between Hip and Knee Flexibility and Post-coronary Angiography Pain
Authors:   Department of Physiotherapy, Faculty of Rehabilitation Sciences, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran., Khalifeh Fatimah , Karimi Noureddin ,   Department of Physiotherapy, Faculty of Rehabilitation Sciences, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran., Baraghoosh Parastoo ,   Department of Physiotherapy, Faculty of Rehabilitation Sciences, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran., Naghikhani Mehrdad ,   Department of Physiotherapy, Faculty of Rehabilitation Sciences, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
Published: October 2023

Purpose: Coronary angiography can cause post-procedural pain, and limited flexibility in the hips and knees may contribute to this discomfort. This study was designed to assess the flexibility of the hip and knee and its relationship with pain after femoral angiography. Methods: This cross-sectional study was conducted on 42 participants (27 men and 15 women, aged 30-85 years) after non-emergency angiography at Dr. Shariati Hospital. Demographic data, employment status, and angiography history were collected through an individual data questionnaire. Muscle flexibility was assessed using a goniometer and tape measure, and visual analog scale (VAS) was applied to evaluate the score of pain. A Spearman correlation coefficient and Kruskal-Wallis tests were used to examine the relationship between variables and pain. Results: The analysis revealed no significant difference in mean pain scores between men and women (P=0.662), employment status (P=0.265), or history of angiography (P=0.262). We observed positive correlations between pain and the modified Thomas test for hip extension, active knee extension test, and forward bending test (rho=0.745, rho=0.594, and rho=0.433; P=0.00, P=0.00, and P=0.04, respectively). Conversely, the modified Thomas test for knee flexion showed a negative correlation with pain (rho=-0.591, P=0.00). No significant differences were found between the sit-and-reach test and pain (rho=0.337, P=0.29). Age demonstrated a positive correlation with pain (rho=0.312, P=0.04). However, weight did not show a significant correlation with pain (rho=-0.074, P=0.64). Conclusion: A relationship was observed between some flexibility tests and pain. Reduced hip and knee flexibility correlated with higher pain levels after femoral angiography. While age showed a positive relationship with pain, weight did not show any relationship with pain. These results emphasize the importance of considering flexibility in managing pain after femoral angiography.
Squilibri da COVID-19: revisione integrativa della letteratura
Authors: Lopes Luiz Thiago Oliveira , Oliveira Marcelus de Andrade , Gonçalves Willian Guilherme Lobato , Daher Donizete Vago , Brito Irma da Silva , Dendasck Carla Viana , Dias Cláudio Alberto Gellis de Mattos , Fecury Amanda Alves , Araújo Maria Helena Mendonça de
Published: October 2023

L’alta affinità tra la proteina Spike del virus SARS-CoV-2 e il recettore dell’enzima di conversione dell’angiotensina 2 è postulata come una delle principali ragioni per l’alta taxa di trasmissione virale, che ha portato l’OMS a dichiarare la COVID-19 come Emergenza Sanitaria Pubblica di Interesse Internazionale, nonché ad adottare misure di contenimento della diffusione virale. Inoltre, grazie al meccanismo fisiopatologico del virus, si osservano sintomi non specifici, evoluzione atipica, soprattutto negli anziani e nei pazienti immunodepressi, nonché una progressione più rapida e letale. Allo stesso modo, con l’avanzare della conoscenza sulla storia naturale dell’infezione virale, sono state riscontrate sintomi persistenti e/o conseguenze che causano disfunzioni organiche e impattano negativamente sulla qualità della vita dei pazienti. Di fronte a ciò, lo scopo dell’articolo è stato presentare una revisione integrativa sulle principali conseguenze della COVID-19 negli anni 2021 e 2022. A tal fine, sono stati cercati articoli completi nelle basi di dati di ricerca Scientific Electronic Library Online, Biblioteca Virtual em Saúde e PubMed, nelle lingue portoghese e inglese, ed è stata impiegata la metodologia PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), selezionando 14 articoli. Tra i risultati si evidenziano: la fisiopatogenesi della COVID-19 persistente si basa sulla teoria di fenomeni immuni secondari all’infezione, risposta immunitaria anormale e presenza del virus in siti immunologicamente privilegiati; la fatica, la dispnea, il compromesso cognitivo soggettivo, le conseguenze neurologiche, le malattie infiammatorie del sistema nervoso centrale e la disfunzione olfattiva post-virale sono complicazioni prevalenti; sono state presentate prove di una relazione causale tra la COVID-19 e la tireoidite subacuta; è stato dimostrato un maggior numero di complicazioni e ricoveri nei pazienti con carenza di vitamina D; così come la presenza di sintomi neuropsichiatrici nella popolazione di professionisti della salute. In conclusione, è stata riscontrata la scarsità di lavori direttamente correlati alle conseguenze della COVID-19, rendendo necessario l’approfondimento di tali ricerche al fine di sviluppare protocolli più specifici per le diagnosi.
Transport channels in advanced material handling systems
Authors: Telek Péter
Published: October 2023

To fulfil the increasing requirements of the social and economic environments, the equipment used in material handling processes have to be developed. The machines fitted exactly to certain manufacturing procedures some decades ago, cannot be found in the advanced version, they role are acted by other, earlier rarely used computer-controlled devices. This paper gives an overview about a special group of material handling machines –transport channels -, presented their operation characteristics and application possibilities to cover their usability in advanced handling systems. Statements presented in this paper are the first results of the research to uncover the special parameters and application advantages of these machines, which can show the development directions of them.
Automatic anatomical foot and ankle coordinate toolbox
Authors: Peterson Andrew C. , Kruger Karen M. , Lenz Amy L.
Published: October 2023

Accurate analysis of bone position and orientation in foot and ankle studies relies on anatomical coordinate systems (ACS). Reliable ACSs are necessary for many biomechanical and clinical studies, especially those including weightbearing computed tomography and biplane fluoroscopy. Existing ACS approaches suffer from limitations such as manual input, oversimplifications, or non-physiological methods. To address these shortcomings, we introduce the Automatic Anatomical Foot and Ankle Coordinate Toolbox (AAFACT), a MATLAB-based toolbox that automates the calculation of ACSs for the major fourteen foot and ankle bones. In this manuscript, we present the development and evaluation of AAFACT, aiming to provide a standardized coordinate system toolbox for foot and ankle studies. The AAFACT was evaluated using a dataset of fifty-six models from seven pathological groups: asymptomatic, osteoarthritis, pilon fracture, progressive collapsing foot deformity, clubfoot, Charcot Marie Tooth, and cavovarus. Three analyses were conducted to assess the reliability of AAFACT. Firstly, ACSs were compared between automatically and manually segmented bone models to assess consistency. Secondly, ACSs were compared between individual bones and group mean bones to assess within-population precision. Lastly, ACSs were compared between the overall mean bone and group mean bones to assess the overall accuracy of anatomical representation. Statistical analyses, including statistical shape modeling, were performed to evaluate the reliability, accuracy, and precision of AAFACT. The comparison between automatically and manually segmented bone models showed consistency between the calculated ACSs. Additionally, the comparison between individual bones and group mean bones, as well as the comparison between the overall mean bone and group mean bones, revealed accurate and precise ACSs calculations. The AAFACT offers a practical and reliable solution for foot and ankle studies in clinical and engineering settings. It accommodates various foot and ankle pathologies while accounting for bone morphology and orientation. The automated calculation of ACSs eliminates the limitations associated with manual input and non-physiological methods. The evaluation results demonstrate the robustness and consistency of AAFACT, making it a valuable tool for researchers and clinicians. The standardized coordinate system provided by AAFACT enhances comparability between studies and facilitates advancements in foot and ankle research.
The excitable nature of polymerizing actin and the Belousov-Zhabotinsky reaction
Authors: Riedl Michael , Sixt Michael
Published: October 2023

The intricate regulatory processes behind actin polymerization play a crucial role in cellular biology, including essential mechanisms such as cell migration or cell division. However, the self-organizing principles governing actin polymerization are still poorly understood. In this perspective article, we compare the Belousov-Zhabotinsky (BZ) reaction, a classic and well understood chemical oscillator known for its self-organizing spatiotemporal dynamics, with the excitable dynamics of polymerizing actin. While the BZ reaction originates from the domain of inorganic chemistry, it shares remarkable similarities with actin polymerization, including the characteristic propagating waves, which are influenced by geometry and external fields, and the emergent collective behavior. Starting with a general description of emerging patterns, we elaborate on single droplets or cell-level dynamics, the influence of geometric confinements and conclude with collective interactions. Comparing these two systems sheds light on the universal nature of self-organization principles in both living and inanimate systems.
A rise in the frequency of lasR mutant Pseudomonas aeruginosa among keratitis isolates between 1993 and 2021
Authors: Shanks Robert M. Q. , Atta Sarah , Stella Nicholas A. , Sundar-Raj Chollapadi V. , Romanowski John E. , Grewal Arman S. , Shanks Hazel Q. , Mumper Sonya M. , Dhaliwal Deepinder K. , Mammen Alex , Callaghan Jake D. , Calvario Rachel C. , Romanowski Eric G. , Kowalski Regis P. , Zegans Michael E. , Jhanji Vishal
Published: October 2023

Introduction

Pseudomonas aeruginosa causes vision threatening keratitis. The LasR transcription factor regulates virulence factors in response to the quorum sensing molecule N-3-oxo-dodecanoyl-L-homoserine lactone. P. aeruginosa isolates with lasR mutations are characterized by an iridescent high sheen phenotype caused by a build-up of 2-heptyl-4-quinolone. A previous study demonstrated 22% (n=101) of P. aeruginosa keratitis isolates from India between 2010 and 2016 were sheen positive lasR mutants, and the sheen phenotype correlated with worse clinical outcomes for patients. In this study, a longitudinal collection of P. aeruginosa keratitis isolates from Eastern North America were screened for lasR mutations by the sheen phenotype and sequencing of the lasR gene.

Methods

Keratitis isolates (n=399) were classified by sheen phenotype. The lasR gene was cloned from a subset of isolates, sequenced, and tested for loss of function or dominant-negative status based on an azocasein protease assay. A retrospective chart review compared outcomes of keratitis patients infected by sheen positive and negative isolates.

Results

A significant increase in sheen positive isolates was observed between 1993 and 2021. Extracellular protease activity was reduced among the sheen positive isolates and a defined lasR mutant. Cloned lasR alleles from the sheen positive isolates were loss of function or dominant negative and differed in sequence from previously reported ocular lasR mutant alleles. Retrospective analysis of patient information suggested significantly better visual outcomes for patients infected by sheen positive isolates.

Discussion

These results indicate an increase in lasR mutations among keratitis isolates in the United States and suggest that endemic lasR mutants can cause keratitis.
Identification of risk factors for hypertension in overweight and obese people and analysis of risk factor interactions: an R-based analysis
Authors: Li LuWei , Cheng SiShuai , Xu GuoQuan
Published: October 2023

Objective

This study identified the independent risk factors for hypertension in overweight and obese people and also analyzed the interaction between the risk factors.

Methods

A total of 5,098 overweight and obese people were enrolled in this study. First, the clinical metabolic characteristics of hypertension and control groups were compared. The logistic regression (LR) and classification and regression trees (CRT)-based decision tree (DT) models were used to screen the independent risk factors for hypertension in overweight and obese people. The multiplicative and additive scale analyses were used to analyze the two risk factors with interaction from the perspective of statistics and biological interaction. Finally, the receiver operating characteristic (ROC) and calibration curves were used to analyze the accuracy and identification ability of the LR and DT models.

Results

Age, UA, FPG, SBP, Cr, AST, TG, and FPG were higher in the hypertension group than in the control group (P < 0.05). The results of LR revealed that NAFLD, FPG, age, TG, LDL-c, UA, and Cr were positively correlated with hypertension in overweight and obese people, and GFR was negatively correlated with hypertension in overweight and obese people (P < 0.05). The DT model suggested that the risk factors of age, FPG, and UA interacted with each other. The multiplicative single and multiple factor analysis for FPG + UA, age + UA, age + FPG revealed a positive multiplicative interaction (P < 0.05, B ≠ 0, OR > 1). The additive single and multiple factor analysis for age + UA indicated a positive additive interaction. The ROC and calibration curve analysis indicated that the CRT decision tree, FPG + UA, age + UA, and age + FPG have certain accuracy and discrimination ability.

Conclusion

The independent risk factors for hypertension in overweight and obese people included NAFLD, FPG, age, TG, LDL-c, UA, and Cr. Among these, age + UA exhibited synergistic interaction, thereby providing a reference for the prevention and control of hypertension in overweight and obese people.
Serum YKL-40 in coronary heart disease: linkage with inflammatory cytokines, artery stenosis, and optimal cut-off value for estimating major adverse cardiovascular events
Authors: Song Mowei , Zhang Guofu , Shi Hang , Zhu Erjun , Deng Li , Shen Hongtao
Published: October 2023

Objective

YKL-40, previously known as chitinase-3-like protein 1 (CHI3L1), is an inflammation-related glycoprotein that promotes atherosclerosis, but its application and optimal cut-off value as a prognostic biomarker in coronary heart disease (CHD) require more clinical evidence. Thus, this prospective study aimed to evaluate the linkage of serum YKL-40 with disease features, inflammatory cytokines, and major adverse cardiovascular events (MACEs) in CHD patients.

Methods

A total of 410 CHD patients were enrolled for serum YKL-40 determination via enzyme-linked immunosorbent assay. Meanwhile, serum YKL-40 levels in 100 healthy controls (HCs) were also quantified.

Results

YKL-40 level was higher in CHD patients compared with that in HCs (P < 0.001). YKL-40 was positively linked with hyperlipidemia (P = 0.014), diabetes mellitus (P = 0.001), fasting blood glucose (P = 0.045), C-reactive protein (P < 0.001), the Gensini score (P < 0.001), and stenosis degree (graded by the Gensini score) (P < 0.001) in CHD patients. In addition, an elevated YKL-40 level was associated with increased levels of tumor necrosis factor alpha (P = 0.001), interleukin (IL)-1β (P = 0.001), IL-6 (P < 0.001), and IL-17A (P = 0.002) in CHD patients. The 1-/2-/3-year cumulative MACE rates of CHD patients were 5.5%, 14.4%, and 25.0%, respectively. Regarding the prognostic capability, YKL-40 ≥100 ng/ml (the median cut-off value) (P = 0.003) and YKL-40 ≥150 ng/ml (the third interquartile cut-off value) (P = 0.021) reflected an elevated accumulating MACE rate, whereas accumulating MACE was not different between CHD patients with YKL-40 ≥80 and <80 ng/ml (the first interquartile cut-off value) (P = 0.083).

Conclusion

Serum YKL-40 is positively linked with inflammatory cytokines and the Gensini score, whose high expression cut-off by 100 and 150 ng/ml estimates a higher MACE risk in CHD patients.
Safety and efficacy of immune checkpoint inhibitor cancer therapy in patients with preexisting type 1 diabetes mellitus
Authors: Hilder Robin , Tsai Karen , Quandt Zoe , Isaacs Dayna , Drakaki Alexandra , Xing Yan , In Gino K. , Angell Trevor E. , Lechner Melissa G.
Published: October 2023

Introduction

Immune checkpoint inhibitors (ICI) produce dramatic tumor shrinkage and durable responses in many advanced malignancies, but their use is limited by the development of immune-related adverse events (IRAEs) that occur in up to 60% of patients and often affect endocrine organs. Concern for more severe IRAEs in patients with preexisting autoimmune diseases, including type 1 diabetes mellitus (T1DM), has led to the exclusion of such individuals from clinical trials of ICI therapy. As a result, little is known about the safety and efficacy of ICI in this population. Here, we report safety and treatments outcomes in ICI-treated patients with preexisting T1DM.

Methods

This retrospective case-controlled study evaluated adult patients with T1DM who received ICI therapy for solid malignancies from 2015 to 2021 at four academic medical centers. Patients with prior ICI therapy, bone marrow transplantation, or pregnancy were excluded. We collected data on demographics, cancer diagnosis and treatment, IRAE incidence and severity, and diabetes management. Controls were matched 2:1 by age, sex, cancer diagnosis, and ICI therapy class.

Results

Of 12,142 cancer patients treated with ICI therapy, we identified 11 with a preexisting confirmed diagnosis of T1DM prior to starting ICI therapy. Mean age was 50.6 years, 63.6% were women, and most received anti-PD1/PDL1 monotherapy (10/11) compared with combination therapy (1/11). Grade 3/4 IRAEs were seen in 3/11 subjects with preexisting T1DM and were hepatitis, myositis, and myasthenia gravis. All three cases had interruption of ICI therapy and administration of adjunct therapies, including steroids, IVIG, or mycophenolate mofetil with resolution of the IRAE. The odds of all-grade IRAEs and of severe IRAEs were comparable between cases and controls matched for age, sex, cancer type, and ICI therapy [OR 0.83 (95% CI 0.2–3.56), p = 0.81, and OR 1.69 (0.31–9.36), p = 0.55, respectively]. Overall survival was not different between patients with T1DM and controls (p = 0.54). No patients had hospitalizations for diabetes-related complications during therapy.

Discussion

These data suggest that ICI monotherapy can successfully be used in patients with preexisting T1DM, with IRAE rates comparable with individuals without preexisting T1DM. Larger, prospective studies of these potentially life-saving ICI therapies that include patients with preexisting autoimmunity are warranted.
Original delayed-start ovarian stimulation protocol with a gonadotropin-releasing hormone antagonist, medroxyprogesterone acetate, and high-dose gonadotropin for poor responders and patients with poor-quality embryos
Authors: Takeuchi Kazuhiro , Orita Yuji , Iwakawa Tokiko , Kuwatsuru Yukari , Kuroki Yuko , Fukumoto Yumiko , Mizobe Yamato , Tokudome Mari , Moewaki Harue
Published: October 2023

Introduction

The delayed-start gonadotropin-releasing hormone antagonist protocol seems effective for patients who are poor ovarian responders, but there are insufficient data on whether it is also effective for patients with poor-quality embryos and low rates of good blastocyst formation. Specifically, the effectiveness of delayed-start gonadotropin-releasing hormone antagonists with progesterone has not been adequately investigated. Therefore, we compared the efficacy of the original delayed-start gonadotropin-releasing hormone antagonist protocol using medroxyprogesterone acetate (MPA) and high-dose gonadotropin in patients with poor ovarian response.

Methods

Overall, 156 patients with recurrent assisted reproductive technology failure who underwent the original protocol were included. They received cetrorelix acetate (3 mg) and MPA (10 mg) on cycle day 3, and high-dose gonadotropin was initiated on day 11. When the leading follicle reached 14 mm, ganirelix acetate (0.25 mg) was administered until the trigger day. The number of oocytes retrieved, metaphase II (MII) oocytes, two pronuclear (2PN) zygotes, and good blastocysts and live birth rates were compared between the previous (Cycle A) and original (Cycle B) cycles in three groups (Group A, all patients; Group B, poor responders; and Group C, patients with poor-quality embryos).

Results

In Group A (n=156), the number of MII oocytes (3.6 ± 3.3 versus 4.5 ± 3.6), 2PN zygotes (2.8 ± 2.9 versus 3.8 ± 3.1), good blastocysts (0.5 ± 0.9 versus 1.2 ± 1.6), and live birth rates (0.6 versus 24.4) significantly increased in Cycle B. Similar results were obtained in Group B (n=83; 2PN zygotes [1.7 ± 1.7 versus 2.3 ± 1.8], good blastocysts [0.4 ± 0.7 versus 0.9 ± 1.3], live birth rates [0 versus 18.1]) and Group C (n=73; MII oocytes [5.1 ± 3.8 versus 6.6 ± 4.0], 2PN zygotes [4.0 ± 3.4 versus 5.4 ± 3.4], good blastocysts [0.7 ± 1.1 versus 1.6 ± 1.9], and live birth rates [1.4 versus 31.5]).

Conclusion

This original protocol increased the number of MII oocytes retrieved, 2PN zygotes, good blastocysts, and live birth rates in both poor responders and in patients with poor-quality embryos.
Provision and utilization of maternal health services during the COVID-19 pandemic in 16 hospitals in sub-Saharan Africa
Authors: Semaan Aline , Annerstedt Kristi Sidney , Beňová Lenka , Dossou Jean-Paul , Boyi Hounsou Christelle , Agballa Gottfried , Namazzi Gertrude , Kandeya Bianca , Meja Samuel , Ally Mkoka Dickson , Asefa Anteneh , El-halabi Soha , Hanson Claudia
Published: October 2023

Objective

Maintaining provision and utilization of maternal healthcare services is susceptible to external influences. This study describes how maternity care was provided during the COVID-19 pandemic and assesses patterns of service utilization and perinatal health outcomes in 16 referral hospitals (four each) in Benin, Malawi, Tanzania and Uganda.

Methods

We used an embedded case-study design and two data sources. Responses to open-ended questions in a health-facility assessment survey were analyzed with content analysis. We described categories of adaptations and care provision modalities during the pandemic at the hospital and maternity ward levels. Aggregate monthly service statistics on antenatal care, delivery, caesarean section, maternal deaths, and stillbirths covering 24 months (2019 and 2020; pre-COVID-19 and COVID-19) were examined.

Results

Declines in the number of antenatal care consultations were documented in Tanzania, Malawi, and Uganda in 2020 compared to 2019. Deliveries declined in 2020 compared to 2019 in Tanzania and Uganda. Caesarean section rates decreased in Benin and increased in Tanzania in 2020 compared to 2019. Increases in maternal mortality ratio and stillbirth rate were noted in some months of 2020 in Benin and Uganda, with variability noted between hospitals. At the hospital level, teams were assigned to respond to the COVID-19 pandemic, routine meetings were cancelled, and maternal death reviews and quality improvement initiatives were interrupted. In maternity wards, staff shortages were reported during lockdowns in Uganda. Clinical guidelines and protocols were not updated formally; the number of allowed companions and visitors was reduced.

Conclusion

Varying approaches within and between countries demonstrate the importance of a contextualized response to the COVID-19 pandemic. Maternal care utilization and the ability to provide quality care fluctuated with lockdowns and travel bans. Women's and maternal health workers' needs should be prioritized to avoid interruptions in the continuum of care and prevent the deterioration of perinatal health outcomes.
Characterization and root cause analysis of immunogenicity to pasotuxizumab (AMG 212), a prostate-specific membrane antigen-targeting bispecific T-cell engager therapy
Authors: Penny Hweixian Leong , Hainline Kelly , Theoharis Nathaniel , Wu Bin , Brandl Christian , Webhofer Christian , McComb Mason , Wittemer-Rump Sabine , Koca Gökben , Stienen Sabine , Bargou Ralf C. , Hummel Horst-Dieter , Loidl Wolfgang , Grüllich Carsten , Eggert Tobias , Tran Ben , Mytych Daniel T.
Published: October 2023

Introduction

In oncology, anti-drug antibody (ADA) development that significantly curtails response durability has not historically risen to a level of concern. The relevance and attention ascribed to ADAs in oncology clinical studies have therefore been limited, and the extant literature on this subject scarce. In recent years, T cell engagers have gained preeminence within the prolific field of cancer immunotherapy. These drugs whose mode of action is expected to potently stimulate anti-tumor immunity, may potentially induce ADAs as an unintended corollary due to an overall augmentation of the immune response. ADA formation is therefore emerging as an important determinant in the successful clinical development of such biologics.

Methods

Here we describe the immunogenicity and its impact observed to pasotuxizumab (AMG 212), a prostate-specific membrane antigen (PSMA)-targeting bispecific T cell engager (BiTE®) molecule in NCT01723475, a first-in-human (FIH), multicenter, dose-escalation study in patients with metastatic castration-resistant prostate cancer (mCRPC). To explain the disparity in ADA incidence observed between the SC and CIV arms of the study, we interrogated other patient and product-specific factors that may have explained the difference beyond the route of administration.

Results

Treatment-emergent ADAs (TE-ADA) developed in all subjects treated with at least 1 cycle of AMG 212 in the subcutaneous (SC) arm. These ADAs were neutralizing and resulted in profound exposure loss that was associated with contemporaneous reversal of initial Prostate Surface Antigen (PSA) responses, curtailing durability of PSA response in patients. Pivoting from SC to a continuous intravenous (CIV) administration route remarkably yielded no subjects developing ADA to AMG 212. Through a series of stepwise functional assays, our investigation revealed that alongside a more historically immunogenic route of administration, non-tolerant T cell epitopes within the AMG 212 amino acid sequence were likely driving the high-titer, sustained ADA response observed in the SC arm.

Discussion

These mechanistic insights into the AMG 212 ADA response underscore the importance of performing preclinical immunogenicity risk evaluation as well as advocate for continuous iteration to better our biologics.
Too much of a good thing: a review of primary immune regulatory disorders
Authors: Tsilifis Christo , Slatter Mary A. , Gennery Andrew R.
Published: October 2023

Primary immune regulatory disorders (PIRDs) are inborn errors of immunity caused by a loss in the regulatory mechanism of the inflammatory or immune response, leading to impaired immunological tolerance or an exuberant inflammatory response to various stimuli due to loss or gain of function mutations. Whilst PIRDs may feature susceptibility to recurrent, severe, or opportunistic infection in their phenotype, this group of syndromes has broadened the spectrum of disease caused by defects in immunity-related genes to include autoimmunity, autoinflammation, lymphoproliferation, malignancy, and allergy; increasing focus on PIRDs has thus redefined the classical ‘primary immunodeficiency’ as one aspect of an overarching group of inborn errors of immunity. The growing number of genetic defects associated with PIRDs has expanded our understanding of immune tolerance mechanisms and prompted identification of molecular targets for therapy. However, PIRDs remain difficult to recognize due to incomplete penetrance of their diverse phenotype, which may cross organ systems and present to multiple clinical specialists prior to review by an immunologist. Control of immune dysregulation with immunosuppressive therapies must be balanced against the enhanced infective risk posed by the underlying defect and accumulated end-organ damage, posing a challenge to clinicians. Whilst allogeneic hematopoietic stem cell transplantation may correct the underlying immune defect, identification of appropriate patients and timing of transplant is difficult. The relatively recent description of many PIRDs and rarity of individual genetic entities that comprise this group means data on natural history, clinical progression, and treatment are limited, and so international collaboration will be needed to better delineate phenotypes and the impact of existing and potential therapies. This review explores pathophysiology, clinical features, current therapeutic strategies for PIRDs including cellular platforms, and future directions for research.
Estimating the efficacy of pharmacogenomics over a lifetime
Authors: Ye Zhan , Mayer John , Leary Emili J. , Kitchner Terrie , Dart Richard A. , Brilliant Murray H. , Hebbring Scott J.
Published: October 2023

It is well known that common variants in specific genes influence drug metabolism and response, but it is currently unknown what fraction of patients are given prescriptions over a lifetime that could be contraindicated by their pharmacogenomic profiles. To determine the clinical utility of pharmacogenomics over a lifetime in a general patient population, we sequenced the genomes of 300 deceased Marshfield Clinic patients linked to lifelong medical records. Genetic variants in 33 pharmacogenes were evaluated for their lifetime impact on drug prescribing using extensive electronic health records. Results show that 93% of the 300 deceased patients carried clinically relevant variants. Nearly 80% were prescribed approximately three medications on average that may have been impacted by these variants. Longitudinal data suggested that the optimal age for pharmacogenomic testing was prior to age 50, but the optimal age is greatly influenced by the stability of the population in the healthcare system. This study emphasizes the broad clinical impact of pharmacogenomic testing over a lifetime and demonstrates the potential application of genomic medicine in a general patient population for the advancement of precision medicine.
Case report: A rare case of desmoid-type fibromatosis originating in the small intestine
Authors: Xie Junfeng , Lai Shichang , Wang Yangbiao , Ye Baolong , Huang Zhishun , Xi Kexing
Published: October 2023

Background

Desmoid-type fibromatosis (DF) is characterized by a rare monoclonal fibroblast proliferation that exhibits variable and unpredictable clinical presentation. DF can be classified into sporadic and hereditary types. Despite extensive research efforts, the exact etiology of DF remains elusive.

Case description

A 31-year-old male patient presented to the hospital with a progressively growing mass in the right lower abdomen, accompanied by abdominal discomfort. Symptoms are discovered 1 week before admission. Enteroscopy revealed no evidence of colonic abnormalities, and blood tests did not indicate any abnormalities. Due to the indeterminate nature of the mass during surgery, a partial resection of the ileum and cecum was performed, followed by ileocolonic end-to-end anastomosis, with no postoperative complications. The final pathological diagnosis confirmed primary desmoid-type fibromatosis of the distal ileum (invasive fibromatosis). To effectively manage DF, we recommend a follow-up schedule for patients. This includes appointments every 3 months in the first year following surgery, followed by appointments every 6 months up to the fifth year, and then once a year thereafter. The follow-up examinations should include collection of the patient’s medical history, physical examination, blood tests, ultrasounds, CT scans, and other relevant assessments. During the first year of the follow-up period, no further treatment was administered, and the patient remained disease-free.

Conclusion

Desmoid-type fibromatosis (DF) originating from the small intestine is an extremely rare condition that exhibits local invasiveness and can be life-threatening. Despite its benign histology, DF has a high local recurrence rate and lacks metastatic potential. Diagnosis of DF remains challenging, especially in cases where surgical intervention is not feasible due to asymptomatic patients or partial organ impairment. In such cases, a “watchful waiting” approach is recommended as the initial treatment strategy. However, when preoperative diagnosis is difficult, surgery is typically considered the best option. Given the potential for local recurrence and the uncertain long-term prognosis, regular follow-up is necessary.
Temperature control in sepsis
Authors: Doman Marc , Thy Michael , Dessajan Julien , Dlela Mariem , Do Rego Hermann , Cariou Erwann , Ejzenberg Michael , Bouadma Lila , de Montmollin Etienne , Timsit Jean-François
Published: October 2023

Fever can be viewed as an adaptive response to infection. Temperature control in sepsis is aimed at preventing potential harms associated with high temperature (tachycardia, vasodilation, electrolyte and water loss) and therapeutic hypothermia may be aimed at slowing metabolic activities and protecting organs from inflammation. Although high fever (>39.5°C) control is usually performed in critically ill patients, available cohorts and randomized controlled trials do not support its use to improve sepsis prognosis. Finally, both spontaneous and therapeutic hypothermia are associated with poor outcomes in sepsis.
Complete genome sequence and comparative analysis of a Vibrio vulnificus strain isolated from a clinical patient
Authors: Wu Fei , Zhang Tingting , Wu Qimin , Li Xue , Zhang Miaomiao , Luo Xi , Zhang Yiquan , Lu Renfei
Published: October 2023

Vibrio vulnificus is an opportunistic, global pathogen that naturally inhabits sea water and is responsible for most vibriosis-related deaths. We investigated the genetic characteristics of V. vulnificus isolated from the clinical blood culture specimen of a patient with hepatitis B virus cirrhosis in 2018 (named as V. vulnificus VV2018) by whole genome sequencing (WGS). VV2018 belonged to a novel sequencing type 620 (ST620) and comprised two circular chromosomes, containing 4,389 potential coding sequences (CDSs) and 152 RNA genes. The phylogenetic tree of single nucleotide polymorphisms (SNPs) using 26 representative genomes revealed that VV2108 grouped with two other V. vulnificus strains isolated from humans. The pan-genome of V. vulnificus was constructed using 26 representative genomes to elucidate their genetic diversity, evolutionary characteristics, and virulence and antibiotic resistance profiles. The pan-genome analysis revealed that VV2018 shared a total of 3,016 core genes (≥99% presence), including 115 core virulence factors (VFs) and 5 core antibiotic resistance-related genes, and 309 soft core genes (≥95 and <99% presence) with 25 other V. vulnificus strains. The varG gene might account for the cefazolin resistance, and comparative analysis of the genetic context of varG revealed that two genes upstream and downstream of varG were conserved. The glycosylation (pgl) like genes were found in VV2018 compared with Pgl-related proteins in Neisseria that might affect the adherence of the strain in hosts. The comparative analysis of VV2018 would contribute to a better understanding of the virulence and antibiotic resistance profiles of V. vulnificus. Meanwhile much work remains to be done to better understand the function of pgl-like genes in V. vulnificus.
Genome and transcriptome analysis of Enterococcus faecium from intestinal colonization and Enterococcus faecium from urinary tract infection
Authors: Huang Ge , Zhou Yizheng , Cheng Hai , Lv Tao , Zheng Lisi , Li Chengbin , Chen Yunbo
Published: October 2023

Introduction

Enterococcus faecium is a common pathogen responsible for urinary tract infections (UTIs) and often establishes extensive colonization within the intestinal tract. Our aim was to assess the genomic and transcriptomic differences between colonized E. faecium without UTI (only-colonization) and colonized E. faecium causing UTI (endogenous infections).

Method

We investigated the correlation between fecal isolates from the same patient and UTI-causing isolates using PFGE and WGS, and classified fecal isolates into two groups: those that solely colonized and those associated with endogenous urinary tract infections. We characterized the genomes of colonization-only and endogenously infected isolates by Scoary GWAS, and the transcriptomes of the isolates at 3 h urine exposure to assess pathogen-related changes.

Result

Based on PFGE and WGS, eight isolates of endogenously infected E. faecium and nine isolates of only-colonized E. faecium were characterized and carbon and nitrogen regulated metabolisms such as genes encoding the phosphotransferase (PTS) system were enriched in endogenously infected E. faecium. Transcriptome analysis revealed significant differences in gene expression in the PTS system, lysine synthesis, galactose metabolism and citrate import between endogenously infected and only-colonized E. faecium isolates, highlighting the important role of certain carbon regulatory genes in the colonization and survival of endogenously infected E. faecium.

Conclusion

In only-colonized and endogenously infected isolates, we observed differential expression patterns of genes related to carbon metabolism and amino acids, suggesting that metabolic diversity is a strategy for isolates leading to endogenous infection.