bluuebunny/crossref_metadata_2025 huggingface dataset:
The figure of the influencer under scrutiny: highly exposed, poorly regulated
Authors: González-Díaz Cristina , Quiles-Soler Carmen , Quintas-Froufe Natalia
Published: July 2024

The figure of the influencer has generated an increase in their presence on social networks. Their ability to create content, their credibility and their identification with the consumer represent an added value in commercial communication. However, their disclosures are controversial due to the lack of transparency and differentiation between their commercial and opinion content. The absence of a clear definition of an influencer, the need to regulate their actions and the difficulty of identifying the commercial content of their publications are evidence of the concern to regulate their activity. The aim of this paper is to analyze, in the European context, the specific regulations on commercial disclosures by influencers, as well as to ascertain the point of view of the agents involved. To this end, a content analysis of the guidelines, regulations and/or laws of 24 European Union countries is carried out, complemented by an ad hoc questionnaire that brings together different aspects that can be defined and delimited. The results show a lack of unanimity in the rules and regulations governing influencers, as well as a manifest concern on the part of professionals in the sector to determine their communications. Only two countries, France and Spain, have specific legislation on the subject, limiting commercial disclosure to the existence of consideration and/or number of followers. It is clear that the existing guidelines are, in most cases, more comprehensive in terms of transparency guidelines for identifying advertising than the regulatory texts. The findings question whether the path of legislation is the right one, or whether efforts should instead focus on media and advertising literacy for both influencers and consumers.
Genetic predisposition to type 2 diabetes mellitus and aortic dissection: a Mendelian randomisation study
Authors: Sun Yaodong , Du Dongdong , Zhang Jiantao , Zhao Linlin , Zhang Bufan , Zhang Yi , Song Tianxu , Wu Naishi
Published: July 2024

Background

This Mendelian randomization (MR) study aimed to explore the causal relationship between the genetic predisposition to type 2 diabetes mellitus (T2DM) and aortic dissection (AD), and to assess associations with genetically predicted glycemic traits. The study sought to verify the inverse relationship between T2DM and AD using a more robust and unbiased method, building on the observational studies previously established.

Materials and methods

The study employed a two-sample and multivariable MR approach to analyze genetic data from the DIAbetes Meta-ANalysis of Trans-Ethnic association studies (DIAMANTE) with 74,124 cases and 824,006 controls, and the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) involving up to 196,991 individuals. For AD data, FinnGen Release 10 was used, including 967 cases and 381,977 controls. The research focused on three foundational MR assumptions and controlled for confounders like hypertension. Genetic instruments were selected for their genome-wide significance, and multiple MR methods and sensitivity analyses were conducted.

Results

The study revealed no significant effect of genetic predisposition to T2DM on the risk of AD. Even after adjusting for potential confounders, the results were consistent, indicating no causal relationship. Additionally, glycemic traits such as fasting glucose, fasting insulin, and HbA1c levels did not show a significant impact on AD susceptibility. The findings remained stable across various MR models and sensitivity analyses. In contrast, genetic liability to T2DM and glycemic traits showed a significant association with coronary artery disease (CAD), aligning with the established understanding.

Conclusion

Contrary to previous observational studies, this study concludes that genetic predisposition to T2DM does not confer protection against AD. These findings underscore the imperative for further research, particularly in exploring the preventative potential of T2DM treatments against AD and to facilitate the development of novel therapeutic interventions.
ATAK complex (adrenaline, takotsubo, anaphylaxis, and kounis hypersensitivity-associated coronary syndrome) related to latamoxef administration—a case report
Authors: Li Sheng , Ding Peng , Wang Chunxia , Long Kunlan , Gao Peiyang
Published: July 2024

Background

Adrenaline, stress cardiomyopathy, allergic reactions, and Kounis syndrome (Adrenaline, Takotsubo, Anaphylaxis, Kounis Complex, ATAK) constitute a complex clinical syndrome often associated with endogenous or exogenous adrenaline. Due to its rapid onset, severity, and treatment challenges, it warrants significant attention from clinicians. This article reports a case of Type II Kounis syndrome combined with stress cardiomyopathy (ATAK) triggered by a latamoxef-induced allergy.

Case report

A 67-year-old male patient with an acute exacerbation of chronic obstructive pulmonary disease was admitted to the respiratory department for treatment. The day before discharge, after receiving a latamoxef infusion for 27 min, the patient developed wheezing, dyspnea, chills, profuse sweating, and an elevated body temperature, necessitating transfer to the ICU for monitoring and treatment. The ECG suggested a suspected myocardial infarction, while bedside echocardiography showed a left ventricular ejection fraction of 40%, segmental dysfunction of the left ventricle, and apical rounding. Emergency coronary angiography revealed 50% segmental eccentric stenosis in the mid-segment of the left anterior descending branch and right coronary artery. The final diagnosis was Type II Kounis Syndrome combined with stress cardiomyopathy due to a latamoxef-induced allergy, i.e., ATAK. Despite aggressive treatment, the patient succumbed to severe cardiogenic shock on the third day in the ICU.

Conclusion

ATAK is a critical condition that progresses rapidly. For patients experiencing severe allergic reactions, monitoring biomarkers such as Troponin and ECG changes is crucial for timely recognition. If a patient is diagnosed with Kounis syndrome, caution should be exercised in using adrenaline to prevent ATAK.
An implementation manual for an interprofessional enhanced recovery after surgery protocol in cardiac surgery following international established frameworks
Authors: Schmid M. E. , Dolata L. , König H. , Stock S. , Klotz S. G. R. , Girdauskas E.
Published: July 2024

Introduction

Enhanced Recovery After Surgery (ERAS) protocols represent a paradigm shift in perioperative care, aim to optimize patient outcomes and accelerate recovery. This manual presents findings from implementing the INCREASE study, a bicentric prospective randomized controlled trial focusing on ERAS in minimally invasive heart valve surgery.

Methods

Utilizing the Consolidated Framework for Implementation Research (CFIR) and the Template for Intervention Description and Replication (TIDieR), the study examined contextual factors, intervention components, and implementation strategies.

Results

Key findings from the CFIR analysis revealed critical domains influencing implementation success. These included innovation characteristics, external and internal settings, and individual dynamics. The study showcased ERAS's adaptability to diverse healthcare systems, emphasizing its potential for successful integration across varying contexts. Furthermore, the importance of interprofessional collaboration emerged as a foundation of practical implementation, fostering teamwork, communication, and patient-centered care. Utilizing the TIDieR framework, this manual comprehensively describes ERAS intervention components, detailing preoperative counseling, intraoperative management, and postoperative care strategies. The manual underscored the importance of tailored, patient-centered approaches, highlighting the role of an academic ERAS nurse, early mobilization, and psychosomatic interventions in promoting optimal recovery outcomes.

Discussion

In conclusion, the INCREASE study provided valuable insights for creating an implementation manual for ERAS in cardiac surgery, emphasizing adaptability, collaboration, and ongoing evaluation as key drivers of successful implementation. These findings have broad implications for improving patient care outcomes and advancing perioperative practices in cardiac surgery settings.
Real-world experience of angiotensin receptor-neprilysin inhibitors in patients with heart failure and dialysis
Authors: Yang I-Ning , Huang Chi-Ya , Yang Chun-Ting , Toh Han-Siong , Chang Wei-Ting , Su Li-Wei , Lin Yu-Min , Wang Ming-Cheng , Wang Hsien-Yi , Liao Chia-Te
Published: July 2024

Introduction

Although angiotensin receptor-neprilysin inhibitor (ARNI) has shown promise in patients with heart failure and reduced ejection fraction (HFrEF), the treatment effect in HFrEF patients with end-stage renal disease (ESRD) undergoing dialysis is uncertain. This study aimed to examine the real-world effects of ARNI vs. angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) in this subpopulation.

Methods

This multi-institutional, retrospective study identified 349 HFrEF patients with ESRD on dialysis, who initiated either ARNI or ACEI/ARB therapy. Efficacy outcomes included rates of hospitalization for heart failure (HHF) and mortality, as well as changes in echocardiographic parameters. Safety outcomes encompassed hypotension and hyperkalemia. Treatment effects were assessed using Cox proportional hazards models, with additional sensitivity analyses for robustness.

Results

Out of 349 patients screened, 89 were included in the final analysis (42 in the ARNI group and 47 in the ACEI/ARB group). After 1 year of treatment, echocardiographic measures between the two groups were comparable. The primary composite rate of HHF or mortality was 20.6 events per 100 patient-years in the ARNI group and 26.1 in the ACEI/ARB group; the adjusted hazard ratio was 0.98 (95% CI: 0.28–3.43, P = 0.97). Their safety outcomes did not differ significantly. Sensitivity analyses, including repetitive sampling, propensity score matching, and extended follow-up, corroborated these findings.

Conclusion

ARNI has proven effective in treating HFrEF patients; however, significant benefits were not observed in these patients with ESRD undergoing dialysis compared with ACEI/ARB in this real-world cohort. Future research employing a more extended follow-up period, larger sample size, or randomized design is warranted to investigate the treatment effects in this subpopulation.
Assessment of 4D flow MRI for quantification of left-to-right shunt in pediatric patients with ventricular septal defect: comparison with right heart catheterization
Authors: Zamani-Aliabadi Seyed Mohammad , Qanadli Salah D. , Fatehi-Feyzabad Seyed Hasan , Ghasemnezhad Mohsen , Ghaemi Hamidreza , Azarine Arshid , Mohammadzadeh Ali , Bitarafan-Rajabi Ahmad , Mortezaeian Hojjat , Rezaei-Kalantari Kiara
Published: July 2024

Objectives

The percentage of shunt fraction significantly impacts the management of patients with congenital shunts, influencing strategic choices such as surgical or interventional procedures. This study compared the estimated shunt fraction (the ratio of pulmonary-to-systemic flow, Qp/Qs) for quantifying the left-to-right shunt in children with ventricular septal defect (VSD) using heart catheterization, four-dimensional (4D) flow, and two-dimensional (2D) flow magnetic resonance imaging (MRI). The goal was to establish a non-invasive and reliable measurement ratio between pulmonary and systemic blood flow in these patients.

Methods

Between July 2022 and June 2023, patients scheduled to undergo invasive right heart catheterization were included in this study. MRI was performed one hour before the catheterization procedure. The correlation of shunt fraction was assessed between all methods after calculating the Qp/Qs ratio from 2D and 4D flow MRI and catheterization.

Results

A total of 24 patients (aged 3–15 years, eight females) were ultimately included in the study. The Qp/Qs ratios obtained from 4D flow had a robust correlation (correlation coefficient r = 0.962) compared to those obtained during catheterization. Cardiac catheterization recorded the mean shunt fraction at 1.499 ± 0.396, while 4D flow measured it at 1.403 ± 0.344, with no significant difference between the two techniques. Moreover, there was a reasonable correlation (r = 0.894) between 2D flow measurements of Qp/Qs and the results obtained from catheterization, with a mean shunt fraction of 1.326 ± 0.283.

Conclusion

4D flow MRI has the potential to be a non-invasive method for accurately measuring the left-to-right shunt in children with VSD.
Successful pharmaco-invasive approach using a lower alteplase dose and VA-ECMO support in high-risk pulmonary embolism: case report
Authors: Gutierrez-Gallegos Paola , Jimenez-Franco Vicente , Jerjes-Sanchez Carlos , Quevedo-Salazar Renata , Rodriguez-Rivera Jahir , Paredes-Gutierrez Enrique , Lira-Lozano Daniel , Quintanilla-Gutierrez Juan , Gomez-Gutierrez Rene , de la Peña-Almaguer Erasmo , Torre-Amione Guillermo
Published: July 2024

Despite the elevated mortality rates associated with high-risk pulmonary embolism (PE), this condition remains understudied. Data regarding the effectiveness and safety of invasive therapies such as venoarterial extracorporeal membrane oxygenation (VA-ECMO) in this patient population remains controversial. Here, we present the case of a 61-year-old male with high-risk PE associated with refractory cardiac arrest and cardiogenic shock who underwent a combination of extracorporeal cardiopulmonary resuscitation with VA-ECMO and pharmaco-invasive therapy (mechanical thrombi fragmentation plus lower alteplase dose), resulting in successful pulmonary reperfusion. After a prolonged in-hospital stay, the patient was discharged in stable condition.
An anesthetized rat assay for evaluating the effects of organophosphate-based compounds and countermeasures on intracranial EEG and respiratory rate
Authors: Thinschmidt J. S. , Harden S. W. , Talton J. D. , Frazier C. J.
Published: July 2024

The development of medical countermeasures (MCMs) against organophosphate (OP) induced poisoning is of substantial importance. Use of conventional therapeutics is complicated by off-target effects and restricted penetration of the blood-brain barrier (BBB). Therefore, a concerted effort is underway to discover improved acetylcholinesterase (AChE) reactivators, muscarinic acetylcholine receptor (mAChR) antagonists, and other countermeasures with broader spectrum activity and enhanced CNS efficacy. We recently developed a rat brain slice assay to assess the efficacy of AChE reactivators and mAChR antagonists against the acute effects of the organophosphorus AChE inhibitor 4-nitrophenyl isopropyl methylphosphonate (NIMP) in the basolateral amygdala (BLA). Here we introduce a complimentary anesthetized animal model to evaluate the same compounds in vivo with concurrent monitoring of EEG and respiratory rate. We find that intravenous delivery of 0.5 mg/kg NIMP reliably produces seizure like activity in the BLA, with concurrent respiratory depression and eventual respiratory failure. The central effects of AChE reactivators and mAChR antagonists delivered intravenously are consistent with their expected ability to cross the BBB. Combining our previously described in vitro assay with the methods described here provides a relatively comprehensive set of preclinical tools for evaluating the efficacy of novel MCMs. Notably, using these methods is expected to reduce the need to subject conscious animals to cholinergic crises, which aligns with the AAALAC’s 3Rs principle of refinement.
Unveiling the toxic leadership culture in south African universities: authoritarian behaviour, cronyism and self-serving practices
Authors: Olabiyi Olaniyi J. , Du Plessis Marieta , Van Vuuren Carel Jansen
Published: July 2024

Introduction

Toxicity among staff members of higher education institutions (HEIs) is often under-reported or not reported at all. Experiences of toxic leadership are deemed unmentionable within the consultative and collaborative ideals of HEIs. The underreporting of toxicity among HEI staff may stem from fear of retaliation, inadequate reporting structures, and concerns about alienation or not being taken seriously.

Method

The study explored experiences of leadership behaviours in a South African HEI to identify specific dimensions of toxic leadership behaviours. Using an interpretivist qualitative research design, the study involved analysing 39 interviews of secondary data from two datasets gathered by the research team, comprising 25 and 14 participant responses, respectively.

Results

The study identified four distinct themes of toxic leadership behaviour – authoritarian leadership behaviour, in-group favoritism/groupthink, destructive criticism and self-centredness – with authoritarianism being the most common behaviour displayed.

Conclusion

Presence of toxic leadership within the South African University community, emphasising the necessity for a comprehensive approach and strategy to address this behaviour.
Relationship between triglyceride-glucose index and cognitive function among community-dwelling older adults: a population-based cohort study
Authors: Bai Weimin , An Shuang , Jia Hui , Xu Juan , Qin Lijie
Published: July 2024

Background

The global increase in the aging population presents considerable challenges, particularly regarding cognitive impairment, a major concern for public health. This study investigates the association between the triglyceride-glucose (TyG) index, a measure of insulin resistance, and the risk of cognitive impairment in the elderly.

Methods

This prospective cohort study enrolled 2,959 participants aged 65 and above from the 2015 and 2020 waves of the China Health and Retirement Longitudinal Study (CHARLS). The analysis employed a logistic regression model to assess the correlation between the TyG index and cognitive impairment.

Results

The study included 2,959 participants, with a mean age of 71.2 ± 5.4 years, 49.8% of whom were female. The follow-up in 2020 showed a decrease in average cognitive function scores from 8.63 ± 4.61 in 2015 to 6.86 ± 5.45. After adjusting for confounding factors, a significant association was observed between TyG index quartiles and cognitive impairment. Participants in the highest quartile (Q4) of baseline TyG had a higher risk of cognitive impairment compared to those in the lowest quartile (Q1) (odds ratio [OR]: 1.97, 95% confidence intervals [CI]: 1.28–2.62, P<0.001).

Conclusion

The study highlights a significant connection between elevated TyG index levels and cognitive impairment among older adults in China. These findings suggest that targeted interventions to reduce the TyG index could mitigate cognitive impairment and potentially lower the incidence of dementia.
Advancement in transformer fault diagnosis technology
Authors: Cao Haiou , Zhou Chenbin , Meng Yihua , Shen Jiaoxiao , Xie Xiayin
Published: July 2024

The transformer plays a critical role in maintaining the stability and smooth operation of the entire power system, particularly in power transmission and distribution. The paper begins by providing an overview of traditional fault diagnosis methods for transformers, including dissolved gas analysis and vibration analysis techniques, elucidating their developmental trajectory. Building upon these traditional methods, numerous researchers have aimed to enhance and optimize them through intelligent technologies such as neural networks, machine learning, and support vector machines. These researchers have addressed common issues in traditional fault diagnosis methods, such as the low correlation between characteristic parameters and faults, ambiguous fault descriptions, and the complexity of feature analysis. However, due to the complexity of transformer structures and the uncertainties in operating environments, the collection and analysis of characteristic parameters becomes highly intricate. Researchers have further refined algorithms and feature values based on intelligent diagnostic algorithms for transformers. The goal is to improve diagnostic speed, mitigate the impact of measurement noise, and further advance the adaptability of artificial intelligence technology in the field of transformers. On the other hand, the excellent multi-parameter analysis capability of artificial intelligence technology is more suitable for transformer diagnostic techniques that involve the fusion of multiple information sources. Through the powerful data acquisition, processing, and decision-making capabilities provided by intelligent algorithms, it can comprehensively analyze non-electrical parameters such as oil and gas characteristics, vibration signals, temperature, along with electrical parameters like short-circuit reactance and load ratio. Moreover, it can automatically analyze the inherent relationship between faults and characteristic quantities and provide decision-making suggestions. This technique plays a pivotal role in ensuring transformer safety and power network security, emerging as a prominent direction in transformer fault diagnosis research.
Green finance and the mitigation of corporate debt financing in China: evidence and implications for sustainable finance
Authors: Fu Quan’An
Published: July 2024

To address the pressing challenges posed by environmental issues, numerous countries have been actively exploring green finance practices. Using a sample of listed companies in China from 2008 to 2020, this study aims to enrich the understanding of the economic consequences of green finance. Specifically, it is the first to investigate the causal relationship between green finance and corporate debt financing levels. Our findings reveal that green finance effectively mitigates corporate debt financing levels, and this conclusion remains robust after undergoing a series of rigorous tests. Further analysis reveals that green finance achieves this by alleviating financing constraints and enhancing executive compensation. Heterogeneity analysis demonstrates that the impact of green finance is particularly pronounced in state-owned enterprises, regions with lower marketization levels, superior industrial structures, and lower carbon emissions. Additionally, our research shows that with the strengthening of external environmental regulations, green finance significantly promotes the reduction of long-term debt financing levels but has no significant impact on short-term debt financing levels. The conclusions of this study provide valuable insights for policymakers and enterprises seeking to reduce corporate debt financing levels. Moreover, it offers a new perspective on the economic consequences of green finance, particularly in the context of debt financing.
Multi-level factors influencing climate migration willingness among small-scale farmers
Authors: Kalantari Razieh , Pakravan-Charvadeh Mohammad Reza , Rahimian Mehdi
Published: July 2024

Introduction: Climate change is a pressing global challenge impacting agriculture and rural communities. This study investigates the willingness to migrate against climate change among small-scale farmers and explores the associated socioeconomic and sociodemographic factors.

Method: A sample of 296 small-scale farmers was randomly selected, and data were collected through face-to-face interviews. A logistic regression model was used to assess the association of multi-level factors with willingness to climate migration.

Results: The results showed that different dimensions of adaptation strategies are inversely associated with willingness to migrate in response to climate change. In contrast, human capital was directly associated with the desire to migrate. Also, improving financial capital was indirectly associated with farmers’ willingness to migrate to the rural area. The study also found that education level plays a key role in increasing the probability of being willing to relocate in response to climate change. Specifically, a 1-year increase in education level was associated with a 4.2% increase in the likelihood of being willing to migrate.

Discussion: Therefore, providing financial support for sustainable farming practices to alleviate the economic challenges faced by small-scale farmers, and implementing targeted capacity-building programs to enhance farmers’ adaptive capacity and promote sustainable agricultural development can be suggested. Furthermore, improving farmers’ specialized knowledge regarding the various consequences of climate migration, in conjunction with their general education, can help control and manage their migration.
eDNA metabarcoding: an effective tool for vertebrate diversity studies in the Colombian Amazon and Orinoco basins
Authors: Martinelli Marín Daniela , Lasso Carlos A. , Caballero Gaitan Susana J.
Published: July 2024

The development of fast, cost-effective, non-invasive, and efficient sampling alternatives, such as environmental DNA (eDNA), is crucial for understanding the changes in species biodiversity and distributions worldwide, particularly for low abundance, cryptic, and threatened species. This study utilized environmental eDNA to analyze the variety of aquatic, semi-aquatic, and terrestrial vertebrates in the Colombian Amazon and Orinoco basins. The study focused on four main subregions: Bojonawi Natural Reserve and adjacent areas (Vichada Department), Sierra de la Macarena National Park and Tillavá (Meta Department), Puerto Nariño and adjacent areas (Amazonas Department), and the Municipality of Solano (Caquetá Department). A total of 709 operational taxonomic units (OTUs) were identified across all sampling locations. The Orinoco River had the highest number of fish genera (68), while the Guayabero River had the highest number of tetrapod genera (13). New taxonomic records were found for all locations, with the highest number of previously undetected fish diversity being found in the Bita, Orinoco, and Tillavá rivers, compared to traditional surveys. Likewise, the study identified two fish species, four mammal species, and one reptile species as vulnerable. Additionally, four mammal species were identified as endangered, including the giant otter (Pteronura brasiliensis), two subspecies of the Amazon River dolphin (Inia geoffrensis geoffrensis and Inia geoffrensis humboldtiana), and the tucuxi (Sotalia fluviatilis). Standardizing the methodology and improving current DNA sequence databases for the Neotropics is essential to develop future eDNA studies and enhance our understanding of the region’s diversity.
White spruce presence increases leaf miner effects on aspen growth in interior Alaska
Authors: Cahoon Sean M. P. , Maher Colin , Crawford Daniel , Sullivan Patrick F.
Published: July 2024

Alaska’s boreal forests are experiencing rapid changes in climate that may favor deciduous-dominated systems, with important implications for global biogeochemical and energy cycles. However, aspen (Populus tremuloides Michx.) has experienced substantial defoliation from the aspen leaf miner (Phyllocnistis populiella Cham., hereafter ALM) in Alaska, resulting in significant growth reductions. We conducted a tree-ring and Δ13C study to test the hypothesis that moisture limitation may have predisposed aspen to leaf miner damage. Contrary to our hypothesis, differences in climate-growth correlations between relatively severely and lightly affected trees were negligible during the pre-outbreak decades. Stands with greater summer precipitation had more limited ALM impact, however differences among models were small and multiple climate variables were suitable predictors of ALM impact. The strong negative relationship we detected between tree-ring Δ13C and basal area increment (BAI) suggested that interannual variation in Δ13C was driven primarily by variation in photosynthesis, limiting the utility of Δ13C as a tool to detect stomatal responses to moisture-limitation. Instead, we found that larger, faster-growing individuals on gentler slopes showed a stronger absolute reduction in BAI (pre-ALM BAI−post-ALM BAI), but were similar in relative BAI reduction (pre-ALM BAI/post-ALM BAI), with smaller, slower growing trees. Older trees and stands with greater relative abundance of white spruce [Picea glauca (Moench) Voss] had greater relative ALM impact whereas slower growing trees on steeper slopes were less affected. The significant effect of white spruce abundance on ALM impact was likely due to favorable leaf miner overwintering habitat provided beneath white spruce trees, which can lead to increased leaf miner survival and thus greater reductions in aspen growth. Our results illustrate the subtle but complex biotic interaction between microclimate and pest physiology in determining ALM-induced aspen growth reductions, adding important nuance to a hypothesized increase in deciduous tree cover in Alaska’s boreal forest.
Clinical and molecular characteristics of Kabuki syndrome patients with missense variants—novel features and literature review
Authors: Boniel Snir , Krajewska Maria , Pyrżak Beata , Paluchowska Monika , Majcher Anna , Zarlenga Magdalena , Krenke Katarzyna , Śmigiel Robert , Jeziorek Anetta , Szymańska Krystyna , Szczałuba Krzysztof
Published: July 2024

Kabuki Syndrome (KS) encompasses a spectrum of clinical manifestations, primarily attributed to pathogenic variants in the KMT2D gene. This study aims to elucidate novel features in KS patients with missense variants, contrasting their presentation with both literature-reported cases of patients with missense pathogenic variants as well as other KS patients with truncating pathogenic variants. Employing a survey questionnaire and clinical evaluations, we examined ten KS patients with missense variants, focusing on their dysmorphism characteristics, behavior and psychomotor development. We identified unique features in missense variant patients, including foot hyperesthesia, musicality, and sensory integration disorders. Notably, despite similarities in developmental trajectories, distinct phenotypic traits emerged in missense variant cases, suggesting a potential genotype-phenotype correlation. These findings contribute to a deeper understanding of KS heterogeneity and underscore the importance of genotype-specific characterization for prognostic and therapeutic considerations. Further exploration of genotype-phenotype relationships promises to refine clinical management strategies and enhance patient outcomes in this complex syndrome.
Spesolimab for generalized pustular psoriasis: a review of two key clinical trials supporting initial US regulatory approval
Authors: Gwillim Eran C. , Nichols Anna J.
Published: July 2024

Generalized pustular psoriasis (GPP) is a chronic, rare, and potentially life-threatening inflammatory disease, characterized by the rapid and widespread eruption of small, sterile pustules with surrounding skin erythema. Abnormal signaling of the interleukin-36 (IL-36) pathway appears to have a central role in GPP immunopathology, and provides a rational therapeutic target. Spesolimab is a first-in-class humanized monoclonal antibody that binds specifically to the IL-36 receptor, and antagonizes IL-36 signaling. Spesolimab obtained regulatory approval in the United States (US) in September 2022 for use in the treatment of GPP flares in adults, and was subsequently approved for GPP flare treatment in many other countries across the world. Recently, regulatory approval was granted for subcutaneous dosing of spesolimab for treatment of GPP when not experiencing a flare. Here, we review data from two key clinical trials that supported the initial US regulatory approval; namely, the phase 1 proof-of-concept trial (ClinicalTrials.gov ID, NCT02978690), and Effisayil™ 1 (NCT03782792), which remains the largest and only randomized clinical trial in patients experiencing GPP flares published to date. In the phase 1 proof-of-concept trial, a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 or 1 (clear or almost clear skin) was attained in 5/7 (71%) patients by week 1 and in all 7 patients by week 4; and the mean percent improvement in the Generalized Pustular Psoriasis Area and Severity Index (GPPASI) score from baseline was 59.0% at week 1, 73.2% at week 2, and 79.8% at week 4. In Effisayil™ 1, a GPPGA pustulation subscore of 0 (no visible pustules) was achieved in 19/35 (54%) patients receiving spesolimab at the end of week 1, versus 1/18 (6%) receiving placebo (difference, 49 percentage points; 95% confidence interval [CI], 21 to 67; P<0.001); and a GPPGA total score of 0 or 1 was achieved by 15/35 (43%) patients in the spesolimab group, versus 2/18 (11%) patients in the placebo group (difference, 32 percentage points; 95% CI, 2 to 53; P = 0.02). Infections at week 1 were reported in 6/35 (17%) patients receiving spesolimab and in 1/18 (6%) patients receiving placebo. These data demonstrate the efficacy and safety of spesolimab in providing rapid and sustained clinical improvement for patients with GPP flares, which translates into improved quality of life, by offering a targeted therapy for GPP.
Potential association between obstructive lung diseases and cognitive decline
Authors: Figat Magdalena , Wiśniewska Aleksandra , Plichta Jacek , Miłkowska-Dymanowska Joanna , Majewski Sebastian , Karbownik Michał S. , Kuna Piotr , Panek Michał G.
Published: July 2024

Introduction

Chronic obstructive lung diseases, such as asthma and COPD, appear to have a more extensive impact on overall functioning than previously believed. The latest data from clinical trials suggests a potential link between cognitive deterioration and chronic obstructive inflammatory lung disease. This raises the question of whether these diseases affect cognitive functions and whether any relevant biomarker may be identified.

Methods

This prospective observational study included 78 patients divided equally into asthma, COPD, and control groups (n=26, 27 and 25 respectively). The participants underwent identical examinations at the beginning of the study and after at least 12 months. The test battery comprised 16 questionnaires (11 self-rated, 5 observer-rated, assessing cognition and mental state), spirometry, and blood samples taken for PKA and CREB mRNA evaluation.

Results

A 2.3-fold increase in CREB mRNA was observed between examinations (p=0.014) for all participants; no distinctions were observed between the asthma, COPD, and control groups. Pooled, adjusted data revealed a borderline interaction between diagnosis and CREB expression in predicting MMSE (p=0.055) in COPD, CREB expression is also associated with MMSE (β=0.273, p=0.034) like with the other conducted tests (β=0.327, p=0.024) from COPD patients. No correlations were generally found for PKA, although one significant negative correlation was found between the first and second time points in the COPD group (β=-0.4157, p=0.049),.

Discussion

Chronic obstructive lung diseases, such as asthma and COPD, may have some linkage to impairment of cognitive functions. However, the noted rise in CREB mRNA expression might suggest a potential avenue for assessing possible changes in cognition, especially in COPD; such findings may reveal additional transcription factors linked to cognitive decline.
Understanding tissue-resident macrophages unlocks the potential for novel combinatorial strategies in breast cancer
Authors: Biswas Manjusha
Published: July 2024

Tissue-resident macrophages (TRMs) are an integral part of the innate immune system, but their biology is not well understood in the context of cancer. Distinctive resident macrophage populations are identified in different organs in mice using fate mapping studies. They develop from the yolk sac and self-maintain themselves lifelong in specific tissular niches. Similarly, breast-resident macrophages are part of the mammary gland microenvironment. They reside in the breast adipose tissue stroma and close to the ductal epithelium and help in morphogenesis. In breast cancer, TRMs may promote disease progression and metastasis; however, precise mechanisms have not been elucidated. TRMs interact intimately with recruited macrophages, cytotoxic T cells, and other immune cells along with cancer cells, deciding further immunosuppressive or cytotoxic pathways. Moreover, triple-negative breast cancer (TNBC), which is generally associated with poor outcomes, can harbor specific TRM phenotypes. The influence of TRMs on adipose tissue stroma of the mammary gland also contributes to tumor progression. The complex crosstalk between TRMs with T cells, stroma, and breast cancer cells can establish a cascade of downstream events, understanding which can offer new insight for drug discovery and upcoming treatment choices. This review aims to acknowledge the previous research done in this regard while exploring existing research gaps and the future therapeutic potential of TRMs as a combination or single agent in breast cancer.
Autoimmune encephalitis followed by hemophagocytic lymph histiocytosis: a case report
Authors: Huang Li , Tan Jie , Lin Peihao , Chen Zixuan , Huang Qihua , Yao Haiyan , Jiang Lihong , Long Baoyi , Long Youming
Published: July 2024

Objective

This study aims to report three cases of autoimmune encephalitis followed by hemophagocytic lymphohistiocytosis.

Methods

Data of relevant patients treated between 2019 and 2022 were retrospectively collected from the Department of Neurology at the Second Affiliated Hospital of Guangzhou Medical University.

Results

The age at onset of the three patients was 37, 63, and 36 years, respectively. All three patients were female and presented with cognitive dysfunction and seizures. Behavioral and psychological symptoms were also observed in two cases. All patients were positive for autoantibodies in both the cerebrospinal fluid and serum, while two showed multiple abnormal brain signals on magnetic resonance imaging. All patients exhibited hypocytosis and elevated soluble CD25 and serum ferritin levels. The final diagnoses in two cases were lymphomas, while the remaining case without tumors suffered from a severe infection. All patients received immunotherapy, and the two with lymphoma received anti-tumor treatment. The patient with infection died, and two patients with tumors improved after chemotherapy.

Conclusion

Autoimmune encephalitis followed by hemophagocytic lymphohistiocytosis is a rare and severe condition. Prompt attention should be paid to the decline in blood cell counts, particularly in patients who show a slight improvement after immunotherapy or have a risk of lymphoma. Screening for potential tumors and infections and early treatment may help these patients.
Consequence of alcohol intoxication-mediated efferocytosis impairment
Authors: Brahadeeswaran Subhashini , Tamizhselvi Ramasamy
Published: July 2024

Alcohol ingestion is a widespread habituation that evolved along with a growing population, altering physiological conditions through immunomodulatory function. There is much research that has reported that consumption of alcohol at low and heavy levels causes different biological impacts, including cellular injury, leading to systemic dysfunction and increased inflammatory markers. In the fate of professional phagocytic cells, efferocytosis is an inevitable mechanism activated by the apoptotic cells, thus eliminating them and preventing the accumulation of cell corpses/debris in the microenvironment. Subsequently, it promotes the tissue repair mechanism and maintains cellular homeostasis. Unfortunately, defective efferocytosis is widely found in several inflammatory and age-related diseases such as atherosclerosis, autoimmune diseases, lung injury, fatty liver disease, and neurodegenerative diseases. Alcohol abuse is one of the factors that provoke an immune response that increases the rate of morbidity and mortality in parallel in systemic disease patients. Information regarding the emergence of immunomodulation during alcoholic pathogenesis and its association with efferocytosis impairment remain elusive. Hence, here in this review, we discussed the mechanism of efferocytosis, the role of defective efferocytosis in inflammatory diseases, and the role of alcohol on efferocytosis impairment.
CTLA-4 expression on CD4+ lymphocytes in patients with sepsis-associated immunosuppression and its relationship to mTOR mediated autophagic–lysosomal disorder
Authors: Cheng Wei , Zhang Jiahui , Li Dongkai , Lei Xianli , Wang Hao , Cui Na
Published: July 2024

Background

The aim of this study was to clarify the relationship between expression level of CTLA-4 on CD4+ T cells and sepsis-associated immunosuppression (SAI), and to elucidate the possible mechanism of mTOR pathway mediated autophagic-lysosomal disorder in regulating CTLA-4 expression.

Methods

We enrolled 63 sepsis patients admitted to our ICU between January 1 and June 30, 2023. Peripheral blood mononuclear cells were isolated from the patients within 24 hours of recruitment. Expression levels of mTOR, P62, LC3II, and CTLA-4 on circulating CD4+ T lymphocytes were quantitated using flow cytometry. The association of these markers and relationship between CTLA-4 expression and the incidence of SAI and 28-day mortality were comprehensively analyzed.

Results

Compared with non-immunosuppressed patients with sepsis, patients with SAI had a higher 28-day mortality rate (37.5% vs 13.0%, P=0.039) and higher CTLA-4 mean fluorescence intensity (MFI) on CD4+ T cells (328.7 versus 78.7, P<0.0001). CTLA-4 MFI on CD4+ cells was independently associated with the occurrence of SAI (95% confidence interval: 1.00–1.14, P=0.044). In patients with sepsis and SAI, non-survivors had higher CTLA-4 expression than survivors (sepsis: 427.5 versus 130.6, P=0.002; and SAI: 506.7 versus 225.2, P<0.0001). The sensitivity and specificity of CTLA-4 MFI at predicting 28-day mortality in patients with SAI was 100% and 80% respectively with the cutoff value of 328.7 and the area under the curve of 0.949. The MFI of mTOR, P62, and LC3II on CD4+ T cells were statistically higher in patients with SAI than in non-immunosuppressed patients (267.2 versus 115.9, P<0.0001; 314.8 versus 173.7, P<0.0001; and 184.7 versus 1123.5, P=0.012, respectively); P62 and LC3II were markedly higher in non-survivors than in survivors of sepsis (302.9 versus 208.9, P=0.039; and 244.3 versus 122.8, P<0.0001 respectively). The expression of CTLA-4 statistically correlated with that of LC3II in patients with sepsis, patients with SAI, and patients with SAI who did not survive (correlation coefficient: 0.69, 0.68, and 0.73, respectively, P<0.0001).

Conclusions

CTLA-4 overexpression on CD4+ T cells was markedly associated with the incidence of SAI and had great relevance to 28-day mortality. mTOR pathway mediated autophagic-lysosomal disorder showed significant association with CTLA-4 expression.
Humoral immune responses primed by the alteration of gut microbiota were associated with galactose-deficient IgA1 production in IgA nephropathy
Authors: Gao Li , Li Huixian , Liu Xiaoling , Li Haiyun , Li Peiqi , Lu Wanhong , Xie Xinfang , Lv Jicheng , Jin Jing
Published: July 2024

Introduction

Galactose-deficient IgA1 (GdIgA1) is critical in the formation of immunodeposits in IgA nephropathy (IgAN), whereas the origin of GdIgA1 is unknown. We focused on the immune response to fecal microbiota in patients with IgAN.

Methods

By running 16S ribosomal RNA gene sequencing, we compared IgAN samples to the control samples from household-matched or non-related individuals. Levels of plasma GdIgA1 and poly-IgA complexes were measured, and candidate microbes that can either incite IgA-directed antibody response or degrade IgA through specific IgA protease activities were identified.

Results

The IgAN group showed a distinct composition of fecal microbiota as compared to healthy controls. Particularly, high abundance of Escherichia-Shigella was associated with the disease group based on analyses using receiver operating characteristic (area under curve, 0.837; 95% CI, 0.738–0.914), principle coordinates, and the linear discriminant analysis effect size algorithm (linear discriminant analysis score, 4.56; p < 0.001). Accordingly, the bacterial levels directly correlated with high titers of plasma GdIgA1(r = 0.36, p < 0.001), and patients had higher IgA1 against stx2(2.88 ± 0.46 IU/mL vs. 1.34 ± 0.35 IU/mL, p = 0.03), the main antigen of Escherichia-Shigella. Conversely, the healthy controls showed relatively higher abundance of the commensal bacteria that produce IgA-degrading proteases. Particularly, the abundance of some intestinal bacteria expressing IgA proteases showed an inverse correlation with the levels of plasma GdIgA1 in IgAN.

Conclusion

Our data suggest that mucosal IgA production, including those of GdIgA1, is potentially linked to the humoral response to gut Escherichia-Shigella as one of the sources of plasma GdIgA1. Conversely, the IgA protease-producing microbiota in the gut are suppressed in patients with IgAN.
Corneal application of SOCS1/3 peptides for the treatment of eye diseases mediated by inflammation and oxidative stress
Authors: Ahmed Chulbul M. , Johnson Howard M. , Lewin Alfred S.
Published: July 2024

Several blinding diseases affecting the retina and optic nerve are exacerbated by or caused by dysregulated inflammation and oxidative stress. These diseases include uveitis, age related macular degeneration, diabetic retinopathy and glaucoma. Consequently, despite their divergent symptoms, treatments that reduce oxidative stress and suppress inflammation may be therapeutic. The production of inflammatory cytokines and their activities are regulated by a class of proteins termed Suppressors of Cytokine Signaling (SOCS). SOCS1 and SOCS3 are known to dampen signaling via pathways employing Janus kinases and signal transducer and activator of transcription proteins (JAK/STAT), Toll-like Receptors (TLR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), mitogen activated kinase (MAPK) and NLR family pyrin domain containing 3 (NLRP3). We have developed cell-penetrating peptides from the kinase inhibitory region of the SOCS1 and SOCS3 (denoted as R9-SOCS1-KIR and R9-SOCS3-KIR) and tested them in retinal pigment epithelium (RPE) cells and in macrophage cell lines. SOCS-KIR peptides exhibited anti-inflammatory, anti-oxidant and anti-angiogenic properties. In cell culture, both Th1 and Th17 cells were suppressed together with the inhibition of other inflammatory markers. We also observed a decrease in oxidants and a simultaneous rise in neuroprotective and anti-oxidant effectors. In addition, treatment prevented the loss of gap junction proteins and the ensuing drop in transepithelial electrical resistance in RPE cells. When tested in mouse models by eye drop instillation, they showed protection against autoimmune uveitis, as a prophylactic as well as a therapeutic. Mice with endotoxin-induced uveitis were protected by eye drop administration as well. R9-SOCS3-KIR was particularly effective against the pathways acting through STAT3, e.g. IL-6 and VEGF-A mediated responses that lead to macular degeneration. Eye drop administration of R9-SOCS3-KIR stimulated production of antioxidant effectors and reduced clinical symptoms in mouse model of oxidative stress that replicates the RPE injury occurring in AMD. Because these peptides suppress multiple pathogenic stimuli and because they can be delivered topically to the cornea, they are attractive candidates for therapeutics for uveitis, macular degeneration, diabetic retinopathy and glaucoma.