bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro and in vivo study of butyrylfentanyl and 4‐fluorobutyrylfentanyl in female and male mice: Role of the CRF1 receptor in cardiorespiratory impairment
Authors: Bilel Sabrine , Azevedo Neto Joaquim , Tirri Micaela , Corli Giorgia , Bassi Marta , Fantinati Anna , Serpelloni Giovanni , Malfacini Davide , Trapella Claudio , Calo' Girolamo , Marti Matteo
Published: October 2024

Background and Purpose

Fentanyl analogues have been implicated in many cases of intoxication and death with overdose worldwide. The aim of this study is to investigate the pharmaco‐toxicology of two fentanyl analogues: butyrylfentanyl (BUF) and 4‐fluorobutyrylfentanyl (4F‐BUF).

Experimental Approach

In vitro, we measured agonist opioid receptor efficacy, potency, and selectivity and ability to promote interaction of the μ receptor with G protein and β‐arrestin 2. In vivo, we evaluated thermal antinociception, stimulated motor activity and cardiorespiratory changes in female and male CD‐1 mice injected with BUF or 4F‐BUF (0.1–6 mg·kg−1). Opioid receptor specificity was investigated using naloxone (6 mg·kg−1). We investigated the possible role of stress in increasing cardiorespiratory toxicity using the corticotropin‐releasing factor 1 (CRF1) antagonist antalarmin (10 mg·kg−1).

Key Results

Agonists displayed the following rank of potency at μ receptors: fentanyl > 4F‐BUF > BUF. Fentanyl and BUF behaved as partial agonists for the β‐arrestin 2 pathway, whereas 4F‐BUF did not promote β‐arrestin 2 recruitment. In vivo, we revealed sex differences in motor and cardiorespiratory impairments but not antinociception induced by BUF and 4F‐BUF. Antalarmin alone was effective in blocking respiratory impairment induced by BUF in both sexes but not 4F‐BUF. The combination of naloxone and antalarmin significantly enhanced naloxone reversal of the cardiorespiratory impairments induced by BUF and 4F‐BUF in mice.

Conclusion and Implications

In this study, we have uncovered a novel mechanism by which synthetic opioids induce respiratory depression, shedding new light on the role of CRF1 receptors in cardiorespiratory impairments by μ agonists.
Anti‐inflammatory and remyelinating effects of fexagratinib in experimental multiple sclerosis
Authors: Gurski Fynn , Shirvanchi Kian , Rajendran Vinothkumar , Rajendran Ranjithkumar , Megalofonou Fevronia‐Foivi , Böttiger Gregor , Stadelmann Christine , Bhushan Sudhanshu , Ergün Süleyman , Karnati Srikanth , Berghoff Martin
Published: October 2024

Background and Purpose

FGF, VEGFR‐2 and CSF1R signalling pathways play a key role in the pathogenesis of multiple sclerosis (MS). Selective inhibition of FGFR by infigratinib in MOG35‐55‐induced experimental autoimmune encephalomyelitis (EAE) prevented severe first clinical episodes by 40%; inflammation and neurodegeneration were reduced, and remyelination was enhanced. Multi‐kinase inhibition of FGFR1‐3, CSFR and VEGFR‐2 by fexagratinib (formerly known as AZD4547) may be more efficient in reducing inflammation, neurodegeneration and regeneration in the disease model.

Experimental Approach

Female C57BL/6J mice were treated with fexagratinib (6.25 or 12.5 mg·kg−1) orally or placebo over 10 days either from time of EAE induction (prevention experiment) or onset of symptoms (suppression experiment). Effects on inflammation, neurodegeneration and remyelination were assessed at the peak of the disease (Day 18/20 post immunization) and the chronic phase of EAE (Day 41/42).

Key Results

In the prevention experiment, treatment with 6.25 or 12.5 mg·kg−1 fexagratinib prevented severe first clinical episodes by 66.7% or 84.6% respectively. Mice treated with 12.5 mg·kg−1 fexagratinib hardly showed any symptoms in the chronic phase of EAE. In the suppression experiment, fexagratinib resulted in a long‐lasting reduction of severe symptoms by 91 or 100%. Inflammation and demyelination were reduced, and axonal density, numbers of oligodendrocytes and their precursor cells, and remyelinated axons were increased by both experimental approaches.

Conclusion and Implications

Multi‐kinase inhibition by fexagratinib in a well‐tolerated dose of 1 mg·kg−1 in humans may be a promising approach to reduce inflammation and neurodegeneration, to slow down disease progression and support remyelination in patients.
The first in‐human study to evaluate the antiplatelet properties of the clopidogrel conjugate DT‐678 in acute coronary syndrome patients and healthy volunteers
Authors: Liu Zhihao , Liu Shengcong , Gong Yanjun , Chi Xiying , Wang Ting , Fan Fangfang , Qu Chenxue , Lou Yaxin , Zhang Long , Zhang Bin , Yang Fan , Mohetaboer Momin , Wang Jie , Qiu Lin , Miao Linzi , Lu Yao , You Ran , He Pengkang , Li Yuxi , Yi Tieci , Weng Haoyu , Xia Yulong , Wang Chunyan , Shi Qiuping , Wang Zhi , Jiang Yimeng , Li Yinjuan , Han Chunyu , Wang Yu , Wang Xinghe , Yang Caixia , Chen Y. Eugene , Eitzman Daniel T. , Zhang Haoming , Li Jianping
Published: October 2024

Background and Purpose

DT‐678 is a novel antiplatelet prodrug, capable of releasing the antiplatelet active metabolite of clopidogrel (AM) upon exposure to glutathione. In this study, we investigated factors responsible for clopidogrel high on‐treatment platelet reactivity (HTPR) in acute coronary syndrome (ACS) patients and evaluated the capacity of DT‐678 to overcome HTPR.

Experimental Approach

A total of 300 consecutive ACS patients naive to P2Y12 receptor inhibitors were recruited and genotyped for CYP2C19 alleles. Blood samples were drawn before and after administration of 600‐mg clopidogrel. Platelet reactivity index (PRI) and plasma AM concentrations were determined and grouped according to their CYP2C19 genotypes. DT‐678 was applied ex vivo to whole blood samples to examine its inhibitory effects. To further examine the antiplatelet effectiveness of DT‐678 in vivo, 20 healthy human subjects were recruited in a Phase I clinical trial, and each received a single dose of either 3‐mg DT‐678 or 75‐mg clopidogrel. The pharmacokinetics and pharmacodynamics in different CYP2C19 genotype groups were compared.

Key Results

Statistical analyses revealed that CYP2C19 genotype, body mass index, hyperuricaemia, and baseline PRI were significantly associated with a higher risk of clopidogrel HTPR in ACS patients. The addition of DT‐678 ex vivo decreased baseline PRI regardless of CYP2C19 genotypes, overcoming clopidogrel HTPR. This observation was further confirmed in healthy volunteers receiving 3 mg of DT‐678.

Conclusion and Implications

These results suggest that DT‐678 effectively overcomes clopidogrel HTPR resulting from genetic and/or clinical factors in Chinese ACS patients, demonstrating its potential to improve antiplatelet therapy.
Cultivating emotional resilience in adolescent girls: Effects of a growth emotion mindset lesson
Authors: Rudolph Karen D. , Troop‐Gordon Wendy , Skymba Haley V. , Modi Haina H. , Ye Zihua , Clapham Rebekah B. , Dodson Jillian , Finnegan Megan , Heller Wendy
Published: October 2024

To address the widespread mental health crisis facing adolescent girls, this study examined whether a growth emotion mindset lesson can enhance emotional competence. During 2018–2022, adolescent girls (Mage = 15.68 years; 66.3% White) were randomized to a growth mindset (E‐MIND; N = 81) or brain education (control; N = 82) lesson, completed the Trier Social Stressor Test, and reported on various aspects of emotional competence. Compared with the control group, the E‐MIND group reported more adaptive emotion mindsets, higher emotion regulation self‐efficacy, and more proactive in vivo and daily efforts to regulate emotions (effect sizes = small‐to‐medium to medium), with several differences remaining 4‐month later. Findings provide novel insight into one promising approach for cultivating emotional resilience among adolescent girls.
Comparison of patch testing Brazilian (Green) propolis and Chinese (poplar‐type) propolis: Clinical epidemiological study using data from the Information Network of Departments of Dermatology (IVDK)
Authors: Piontek K. , Radonjic‐Hoesli S. , Grabbe J. , Drewitz K. P. , Apfelbacher C. , Wöhrl S. , Simon D. , Lang C. , Schubert S.
Published: October 2024

Background

Propolis types differ regarding their chemical composition.

Objectives

To compare patch test results based on Brazilian (Green) propolis with data based on Chinese (poplar‐type) propolis, and to evaluate the specifications of raw materials used for the PT preparations.

Methods

In the Information Network of Departments of Dermatology (IVDK), 1290 consecutive patients were patch tested with Brazilian (Green) propolis (NH400, SmartPractice Europe). Patch test reactivity was compared with results obtained with Chinese (poplar‐type) propolis (NA71, SmartPractice Europe) by calculating frequencies and corresponding 95% confidence intervals. Data on the specifications of raw materials used for NH400 and NA71 were obtained from the manufacturer.

Results

Positive reactions to NH400 were found in 303 (23.5%) patients with unclear clinical relevance in most cases. Patients reacting to NH400 were less often sensitised to fragrances and colophony, but more often to nickel sulphate and cobalt chloride than patients reacting to NA71. The NH400 batch used contained high levels of aerobic bacteria, and was not purified by ethanolic extraction.

Conclusions

Pattern of concomitant reactivity along with raw material properties suggests that the high frequency of positive reactions to NH400 may primarily result from bacterial contamination or impurities in the PT preparation rather than from propolis constituents.
Physico‐chemical characterisation and light stability of dyes and pigments found in cultural heritage objects: Insights from microfading testing for assessing light fastness
Authors: del Hoyo‐Meléndez Julio M.
Published: October 2024

Understanding the chemistry of dyes and pigments found in cultural heritage objects and their permanence is central for their preservation. Heritage science research has generally focused on either identification of materials present on actual objects or accelerated and natural ageing of mock‐up samples prepared using historically accurate methods to simulate the materiality of cultural heritage objects. A more recent strategy is the integration of these two research areas, which provides a holistic approach to assess both the chemical composition and stability of materials. Over the last 30 years, microfading testing (MFT) has notably contributed to understanding materials' responsiveness to light, minimising damage to objects from museum lighting and revealing insights into molecular structures of dyes and pigments, when employed in conjunction with other techniques. By combining MFT with diverse analytical methods, including imaging, spectroscopy, microscopy and chromatography, a more comprehensive approach is achieved. This joined‐up strategy contributes to improved decision‐making processes in the conservation and preservation of cultural heritage objects.
Epidemiological Characteristics of Upper Respiratory Tract Pathogens in Children in Guangdong, China
Authors: Zhao Qianwen , Ke Peifeng , Hu Liangshan , Jiang Changhong , Su Rong , Lv Weifeng , Li Qixin , Jiang Lingxiao , Cao Donglin
Published: October 2024

Objective

Researches on the epidemiology of various respiratory pathogens at multiple testing points in the pediatric population are limited, and these are crucial for the prevention of respiratory tract infections in children.

Methods

We obtained 1788 upper respiratory tract swabs from children exhibiting symptoms of respiratory infection (notably fever with a body temperature exceeding 38.5°C) across five hospitals in Guangdong between November 2020 and June 2022. We used the multiplex probe amplification (MPA) PCR testing to identify 11 respiratory viruses and subsequently analyzed the prevalence characteristics of these pathogens among febrile children in hospitals.

Results

The overall detection rate of the pathogens was 58.1% (1039/1788). Human rhinovirus (HRV) exhibited the highest detection rate at 19.0% (339/1788), succeeded by human parainfluenza virus (HPIV), human adenovirus (HAdV), and respiratory syncytial virus (RSV). The positivity and coinfection rates were higher in children aged 5 years and below compared to those above 5 years. Moreover, a distinct pathogen spectrum was observed across different age groups. Hospitalized patients demonstrated a significantly higher positivity and coinfection rate compared to outpatients. During COVID‐2019, RSV appeared a counter‐seasonal trend.

Conclusion

Respiratory viral infections in children display distinct characteristics concerning age, hospitalization status, and seasonality. Children under the age of 5 and minor patients admitted to hospitals at least be tested for RSV, HRV, HPIV, and HAdV. The epidemiological patterns of RSV in the post‐epidemic period require ongoing surveillance.
Reexamining Transplant Outcomes in Acute Kidney Injury Kidneys Through Machine Learning
Authors: Jadlowiec Caroline C. , Thongprayoon Charat , Suppadungsuk Supawadee , Tangpanithandee Supawit , Leeaphorn Napat , Heilman Raymond , Cooper Matthew , Cheungpasitporn Wisit
Published: October 2024

Background

Despite many people awaiting kidney transplant, kidney allografts from acute kidney injury (AKI) donors continue to be underutilized. We aimed to cluster kidney transplant recipients of AKI kidney allografts using an unsupervised machine learning (ML) approach.

Methods

Using Organ Procurement and Transplantation Network–United Network for Organ Sharing (OPTN/UNOS) data, a consensus clustering cohort analysis was performed in 12 356 deceased donor kidney transplant recipients between 2015 and 2019 in whom donors had a terminal serum creatinine ≥1.5 mg/dL. Significant cluster characteristics were determined, and outcomes were compared.

Results

The median donor terminal creatinine was 2.2 (interquartile range [IQR] 1.7–3.3) mg/dL. Cluster analysis was performed on 12 356 AKI kidney recipients, and three clinically distinct clusters were identified. Young, sensitized kidney re‐transplant patients characterized Cluster 1. Cluster 2 was characterized by first‐time kidney transplant patients with hypertensive and diabetic kidney diseases. Older diabetic recipients characterized Cluster 3. Clusters 1 and 2 donors were young and met standard kidney donor profile index (KDPI) criteria; Cluster 3 donors were older, more likely to have hypertension or diabetes, and meet high KDPI criteria. Cluster 1 had a higher risk of acute rejection, 3‐year patient death, and graft failure. Cluster 3 had a higher risk of death‐censored graft failure, patient death, and graft failure at 1 and 3 years. Cluster 2 had the best patient‐, graft‐, and death‐censored graft survival at 1 and 3 years. Compared to non‐AKI kidney recipients, the AKI clusters showed a higher incidence of delayed graft function (DGF, AKI: 43.2%, 41.7%, 45.3% vs. non‐AKI: 25.5%); however, there were comparable long‐term outcomes specific to death‐censored graft survival (AKI: 93.6%, 93.4%, 90.4% vs. non‐AKI: 92.3%), patient survival (AKI: 89.1%, 93.2%, 84.2% vs. non‐AKI: 91.2%), and overall graft survival (AKI: 84.7%, 88.2%, 79.0% vs. non‐AKI: 86.0%).

Conclusions

In this unsupervised ML approach study, AKI recipient clusters demonstrated differing, but good clinical outcomes, suggesting opportunities for transplant centers to incrementally increase kidney utilization from AKI donors.
Transient Elastography for Noninvasive Evaluation of Posttransplant Liver Graft Fibrosis in Turkish Children, Ege University Children Hospital Experience
Authors: Dogan Barut , Kunay Bora , Umman Veysel , Kıran Taşçı Ezgi , Kumcuoğlu Ziya , Gulbahar Fatih , Nart Deniz , Karakoyun Miray , Cetin Funda , Aydogdu Sema
Published: October 2024

Objectives

The influence of advancing fibrosis on graft survival in the context of pediatric liver transplantation accentuates the critical role of protocol‐driven liver biopsies, a practice adopted by numerous medical centers. Consequently, the exigency for noninvasive methodologies to assess graft fibrosis assumes heightened importance when conventional clinical and laboratory parameters fail to reveal signs of liver damage.

Methods

This study aimed to assess the reliability of transient elastography (TE) in pediatric liver transplant recipients to detect graft fibrosis and compare the results of TE in patients who underwent biopsy.

Results

This prospective cohort study included liver transplanted children who underwent biopsy at Ege University Children's Hospital between October 1, 2021, and October 31, 2022, and a healthy control group. According to TE, fibrosis was detected in 40 patients, and no fibrosis was detected in 50. The median time to develop fibrosis was 100 months (95% CI [83.1–116.8]). A statistically significant positive correlation existed between LSM and METAVIR fibrosis score (r = 0.562, p = 0.001). There was a statistically significant difference in LSM between patients with F2 fibrosis (7.8–8.8 kPa ± 3.2) compared to patients with F0 fibrosis (5.2 kPa ± 0.7) (p = 0.005) and F1 fibrosis (6.1 kPa ± 1.5) (p = 0.041), on ANOVA.

Conclusion

Liver allograft fibrosis is common in long‐term follow‐up in children who have undergone liver transplantation. Abnormal TE may guide physicians to consider liver biopsy to detect late allograft fibrosis in these children.
Detecting Cholangiocarcinoma in the Setting of Primary Sclerosing Cholangitis: Is Biliary Tract Fluorescence In Situ Hybridization Helpful?
Authors: Miller Lauren J. , Holmes Isabella M. , Chen‐Yost Heather I. , Smola Brian , Lew Madelyn , Pang Judy
Published: October 2024

Introduction/Objective

Biliary brushing cytology (BB) to detect cholangiocarcinoma (CCA) is integral in the surveillance of patients with primary sclerosing cholangitis (PSC). Since reactive changes can mimic carcinoma, indeterminant results are frequent. Fluorescence in situ hybridization (FISH) using the UroVysion probe set has been advocated to enhance the detection of CCA. This study evaluates the performance of FISH for detecting CCA in patients with and without PSC.

Materials and Methods

A query of our pathology database for atypical and suspicious BB with concurrent FISH results was performed from 2014 to 2021. FISH (using UroVysion probe set containing centromere enumeration probes to chromosomes 3, 7, and 17) was positive if at least 5 cells demonstrated polysomy. Electronic medical records were reviewed to identify patients with PSC and CCA. CCA was confirmed by pathology or clinical impression.

Results

Of the 65 patients (103 BB) in the PSC cohort, 59 patients (94 BB) without CCA and 6 patients (9 BB) with CCA were identified. 33 non‐PSC patients (41 BB) with CCA were included for comparison. Positive FISH was highest in non‐PSC patients with CCA (10/41 BB, 24%). Positive FISH was seen in both PSC with (1/9 BB, 11%) and without (2/94 BB, 2%) CCA.

Conclusions

FISH positivity was lower than expected and was positive in PSC patients without CCA. These results question the clinical utility of FISH for CCA surveillance in PSC patients.
Artificial Intelligence Echocardiography in Resource‐Limited Regions: Applications and Challenges
Authors: Hamza Izhan , Pellikka Patricia A. , Abdulla Amer , Ahmad Masood
Published: October 2024

Artificial intelligence (AI) is revolutionizing cardiac imaging, including echocardiography. However, AI has scarce penetration in resource‐limited regions. The implementation of AI‐aided echocardiography (AIE) poses unique challenges and opportunities in resource‐limited areas. Some obvious advantages of AIE include aiding image acquisition, interpretation, and triaging patients based on severity. The challenges AIE faces in resource‐limited regions include a lack of data accessibility for model development, physician apprehension, and an outdated regulatory framework. Based on our early experience with AI, we believe AIE in resource‐limited regions will enhance health equity, improve access to the technology, and lead to cost savings. However, significant efforts are needed to realize these objectives.
Noninvasive Left Ventricular Pressure‐Strain Loop for Quantitative Assessment of Early Left Ventricular Systolic Dysfunction in Patients With Chronic Kidney Disease
Authors: Wang Qin , Wang Jin‐Ping , Li Yan , Zhang Jie , Wang Rui , Xu Hai‐Yun
Published: October 2024

Background

Patients with chronic kidney disease (CKD) possess a pronounced risk for cardiovascular events. A noninvasive left ventricular pressure‐strain loop (LV‐PSL) has recently been introduced to detect subtler changes in cardiac function. This study aims to investigate the value of LV‐PSL for quantitative assessment of myocardial work (MW) in patients with CKD.

Methods

Seventy‐five patients with CKD were enrolled retrospectively (37 patients with CKD Stages 2–3, and 38 patients with CKD Stages 4–5), and 35 healthy volunteers were included as controls. All subjects underwent transthoracic echocardiography. LV‐PSL analysis was performed to estimate LV MW and efficiency. Global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE) were obtained by echocardiography, and the differences among the groups were compared.

Results

There was a significant increase in GWW and reduction in GWE in patients with CKD compared to normal controls (p < 0.05). No significant difference in GWI and GCW was observed among the three groups. Multiple linear regression revealed that increased GWW was significantly associated with age, serum creatinine, and systolic pressure, and decreased GWE was associated with age, serum creatinine, and GLS.

Conclusion

LV‐PSL can be used for noninvasive quantitative assessment of MW in patients with CKD, providing a new sensitive approach for the clinical assessment of myocardial function.
Cardiovascular Magnetic Resonance Imaging of Takotsubo Syndrome: Evolving Diagnostic and Prognostic Perspectives
Authors: Cau Riccardo , Masala Salvatore , Manelli Lorenzo , Porcu Michele , Scaglione Mariano , D'Angelo Tommaso , Salgado Rodrigo , Saba Luca
Published: October 2024

Takotsubo syndrome (TS) is a temporary form of left ventricular (LV) dysfunction characterized by a distinct pattern of LV impairment, often triggered by a physical or emotional stressful event. Historically, TS was considered a benign condition due to its prompt restoration of myocardial function and generally excellent outcomes. However, recent studies have shown that complications similar to those seen after myocardial infarction can occur, necessitating careful monitoring of these patients. Among noninvasive imaging techniques, cardiovascular magnetic resonance (CMR) is becoming increasingly important in evaluating patients with TS. CMR offers a unique ability to noninvasively assess myocardial tissue characteristics, allowing for detecting the typical features of TS, such as specific wall motion abnormalities and myocardial edema. Beyond its well‐established diagnostic utility in the clinical management of TS, CMR has also proven valuable in prognosis and risk stratification for these patients. Advances in CMR, including myocardial strain and parametric mapping have expanded its role in the diagnosis, prognosis, and follow‐up of these patients. This review aims to provide a comprehensive overview of the potential applications of CMR in the diagnostic and prognostic evaluation of TS patients. It explores the emerging use of novel CMR imaging biomarkers that may enhance diagnosis, improve prognostic accuracy, and contribute to the overall management of these patients.
Cerebral venous thrombosis in elderly patients
Authors: Garcia Victor , Bicart‐Sée Louise , Crassard Isabelle , Legris Nicolas , Zuber Mathieu , Pico Fernando , Guidoux Céline , Obadia Michael , Boulenoir Naouel , Smadja Didier , Mazighi Mikael , Lavenu‐Bombled Cecile , Baudry Elodie , Lapergue Bertrand , Turc Guillaume , Tuppin Philippe , Denier Christian
Published: October 2024

Background and purpose

We aimed to report the characteristics of cerebral venous thrombosis (CVT) in elderly people (aged ≥65 years).

Methods

This multicenter retrospective cohort included elderly patients hospitalized for a first CVT in nine Paris–Ile‐de‐France hospitals between 2011 and 2021. The estimated incidence was compared to CVT recorded by the French health insurance data system. Lariboisière Hospital's CVT registry allowed comparisons of our elderly cohort with individuals younger than 65 years.

Results

One hundred fourteen patients were included in this study (mean age = 74.2 years, range = 65–93, 61% female). The CVT annual incidence in Ile‐de‐France was 5.9–7.1 per million elderly individuals versus 8.5 per million nationwide. Headaches and focal deficits were the most common initial clinical features (50% and 51%, respectively), followed by seizures and confusion (40% and 27%). Treatment included anticoagulation (93%) and, rarely, endovascular procedure (2%) or craniectomy (1%). Compared with adult patients aged <65 years (younger adults), elderly patients presented fewer headaches (50% vs. 96%, p < 0.01) and intracranial hypertension (7% vs. 22%, p < 0.01) but more seizures and focal deficits (40% vs. 27% and 51% vs. 38%, respectively, p < 0.01). Underlying cancer, hemopathy, and locoregional infections were more frequent in elderly patients than among younger adults (p < 0.01). The prognosis of patients from our elderly cohort was poorer than that of younger adults; 8% died in the acute phase, and 73% had a favorable outcome at 1 year (vs. 1.7% and 87%, respectively, p < 0.01).

Conclusions

CVT in elderly patients has a specific clinical presentation, epidemiology, and risk factors such as cancer or hemopathy, justifying specialized management.
Inhibition of Ubiquitin C‐Terminal Hydrolase L1 Facilitates Cutaneous Wound Healing via Activating TGF‐β/Smad Signalling Pathway in Fibroblasts
Authors: Pan Huihui , Song Jinru , An Qing , Chen Junyi , Zheng Wenyue , Zhang Litian , Gu Jingjing , Deng Chengcheng , Yang Bin
Published: October 2024

Ubiquitin C‐terminal hydrolase L1 (UCHL1) plays vital roles in cell proliferation, angiogenesis, inflammation and oxidative stress. Nevertheless, it is unclear whether UCHL1 could regulate the biologic behaviour of cells and ultimately influences wound healing. We aim to illustrate the roles and the underlying mechanism of UCHL1 in cutaneous wound healing. Murine full‐thickness excisional wound model was utilised to study the effects of UCHL1 on wound healing through topical administration of the UCHL1 inhibitor LDN57444, followed by assessment of wound areas and histological alterations. Subsequently, ethynyldeoxyuridine, scratch and transwell assays were performed to examine fibroblast migration and proliferation. The extracellular matrix (ECM)‐related genes expression and transforming growth factor‐β (TGF‐β)/Smad signalling pathways activation were investigated by immuno‐fluorescent staining, Western blots and quantitative reverse transcription polymerase chain reaction. We identified elevated UCHL1 expression in non‐healing wound tissues. The UCHL1 expression displayed a dynamic change and reached a peak on Day‐7 post‐wounding during the healing process in mice. Cutaneous administration of LDN57444 promoted wound healing by facilitating collagen deposition, myofibroblast activation and angiogenesis. In vitro experiments demonstrated that UCHL1 concentration dependently inhibited migration, ECM synthesis and activation of human dermal fibroblasts, which was mechanistically related to downregulation of TGF‐β/Smad signalling. Furthermore, these effects could be reversed by TGF‐β inhibitor SB431542. Our findings reveal that UCHL1 is a negative regulator of cutaneous wound healing and considered as a novel prospective therapeutic target for effective wound healing.
Sliding window based adaptative fuzzy measure for edge detection
Authors: Marco‐Detchart Cedric , Lucca Giancarlo , Santos Silva Miquéias Amorim , Rincon Jaime A. , Julian Vicente , Dimuro Graçaliz
Published: October 2024

In this work, we explore the impact of adaptive fuzzy measures on edge detection, aiming to enhance how computers interpret images by identifying edges more accurately. Traditional methods rely on analysing changes in image brightness to locate edges, but they often use fixed rules that do not account for the unique characteristics of each image. Our approach differs by adjusting fuzzy measures based on the information within specific areas of an image under a sliding window approach, utilizing a variety of fusion functions and generalizations of the Choquet integral to analyse and combine pixel data. The proposed method is flexible, allowing for the adaptation of measures in response to the image's local features. We put our method to the test against the well‐established Canny edge detector to evaluate its effectiveness. Our experimental results suggest that by adapting fuzzy measures for each image section, we can improve edge detection results.
An agent‐based model to simulate the public acceptability of social innovations
Authors: Rodríguez‐Arias Alejandro , Sánchez‐Maroño Noelia , Guijarro‐Berdiñas Bertha , Alonso‐Betanzos Amparo , Lema‐Blanco Isabel , Dumitru Adina
Published: October 2024

The successful adoption of social innovations, such as renewable energy systems or pollution reduction plans in cities, depends, to a large extent, on the willingness and participation of the population in their development and implementation. We present an agent‐based model (ABM) to analyze the process of citizen acceptability of a social innovation that uses a variety of agents to represent individual citizens and relevant groups of citizens. Citizen agents make use of the HUMAT cognitive decision‐making model, based on psychosocial theories, to decide on their support for the social innovation considering how their needs will be satisfied if they decide to support (or not) the innovation project, and the influence exerted by the agents in their environment. The ABM was initially developed to represent the urban and transport planning superblock project in the city of Vitoria‐Gasteiz (Spain). The ABM simulations make it possible to study the evolution of public acceptance of social innovation, with the results providing insights to the social dynamics and individual factors that affect the acceptance of the project, enabling an evaluation of how to devise new policies that increase public acceptance. Sufficiently generic to be easily adaptable to different types of social innovations, the ABM is a powerful tool to explore different scenarios and design strategies that foster the acceptance and sustainable adoption of social innovations.
Unbundling marriage law
Authors: Lifshitz Shahar
Published: October 2024

This article illuminates the legal regulation of the economic rights of non‐marital partners at separation or death. Current approaches have typically fallen into two categories: one advocating for the separation of legal regimes based on formal status, treating cohabitant partners as strangers, and the other taking a functional approach, treating cohabitation and marriage as substantively identical. However, both approaches fail to offer a coherent alternative for regulating cohabitation. This article proposes a novel third option – the institutional, autonomy‐based, pluralist model. The pluralist model acknowledges the legal commitment between cohabitants while carefully distinguishing the legal regulation of cohabitation from that of marriage. Unlike prevailing models that offer a “package deal,” the pluralist model selectively applies only suitable components of marriage law to non‐marital relationships, considering thoughtful criteria for their applicability and ensuring a nuanced approach. The pluralist model offers a middle ground between treating cohabitants as strangers and treating them as married for purposes of regulating marital property, spousal support, and inheritance. Ultimately, it provides a framework that considers the complexities of non‐married relationships while maintaining a desirable level of legal clarity.
Lies my child welfare system has told me: The critical importance of centering families' voices in family policing legal advocacy
Authors: Katz Sarah , Lee April
Published: October 2024

The web of law, regulation and policy which forms the modern day “child welfare” system is organized around one central unifying principle: the notion that these laws, regulations and policies are necessary to protect and save children. Yet an ever‐growing and overwhelming chorus of “lived experts” – individuals who have been impacted as a parent and/or child by what is more aptly called the family policing system – as well as by advocates and scholars, are drawing attention to the degree of harm the system causes to the families it purports to help. Even though the harms the family policing system causes are well known, the family policing system continues to justify these harms as warranted in the name of protecting children. More concerning, even well‐meaning advocates and scholars who acknowledge the harms, implicitly and explicitly continue to perpetuate the big lie that the family policing system's intention is benevolent and caring. The impetus for any law is a story; law identifies a problem and seeks to resolve it. But what happens when the story is false? The stories we tell about the need for family policing perpetuate harm and replicate systemic racism. Most importantly, the impact of these false narratives can be felt through generations of families leaving devastated communities. The stories, perspectives and opinions of those most impacted by the system historically have been, and continue to be, intentionally left out of the making of law and policy, and even in the teaching of the law. Unless the actual perspectives of families are present to challenge the stories that are woven into the law, these narratives will continue to create significant obstacles to critical thought about the law, prevent meaningful legal change, and ultimately cause continued harm to families and communities. In this essay, in the tradition of participatory law scholarship (Note: Rachel Lopez, Participatory Law Scholarship, 123 Colum. L. Rev. 1795 (2023) [“Participatory Law Scholarship or (PLS)… is an emerging genre of legal scholarship written in collaboration with authors… who have no formal training in the law but rather expertise in its function and dysfunction through lived experience.”]), the authors, a parent and professional advocate, and a clinical law professor and attorney, seek to unpack the myths which are built into the laws of family policing. In reckoning with these myths, the paper seeks to propose a critical framework to both acknowledge the intentional trauma and harm caused by the family policing system, and to disrupt and dismantle the fictions that are the underpinnings of the laws and regulations that continue to perpetuate these harms. Ultimately, this paper argues that by centering the lived expertise of families' voices and perspectives in legal advocacy, we can form a cogent vision for true safety for families and communities.
A critical re‐analysis of biochar properties prediction from production parameters and elemental analysis
Authors: Lebrun Thauront Johanne , Soja Gerhard , Schmidt Hans‐Peter , Abiven Samuel
Published: October 2024

Biochar is the product of intentional pyrolysis of organic feedstocks. It is made under controlled conditions in order to achieve desired physico‐chemical characteristics. These characteristics ultimately affect biochar properties as a soil amendment. When biochar is used for carbon storage, an important property is its persistence in soil, often described by the proportion of biochar carbon remaining in soil after a 100 years (). We analyzed published data on 1230 biochars to re‐evaluate the effect of pyrolysis parameters on biochar characteristics and the possibility to predict from the maximum temperature reached during pyrolysis (HTT). We showed that biochar ash and nitrogen (N) contents were mostly affected by feedstock type. The oxygen to carbon (O:C) and hydrogen to carbon (H:C) ratios were mostly affected by the extent of pyrolysis (a combination of HTT and pyrolysis duration), except for non (ligno)cellulosic feedstocks (plastic waste, sewage sludge). The volatile matter (VM) content was affected by both feedstock type and the extent of pyrolysis. We demonstrated that HTT is the main driver of H:C ‐‐ an indicator of persistence ‐‐ but that it is not measured accurately enough to precisely predict H:C, let alone persistence. We examined the equations to estimate available in the literature and showed that calculated from HTT presented little agreement with calculated from H:C. The sign and magnitude of the bias depended on the equation used to calculate and the dispersion was usually large. This could lead to improper compensation of carbon emissions and wrong reporting of carbon sinks in national carbon accounting schemes. We recommend not to use HTT as a predictor for persistence and stress the importance to rapidly develop more accurate proxies of biochar C persistence in soil.
Sense of Place in Latin America: Mobilities, Territorialities, and Fear
Authors: Ortega‐Iturriaga Adrián , Bocco Gerardo , Urquijo Pedro S. , Serrano Javier O.
Published: October 2024

Sense of place has become relevant in Latin America in recent decades. Although many scholars have looked at people‐place relationships there, language barriers have limited the international exposure of these studies. By assembling a collection of works mainly published in Spanish and Portuguese, we trace the fields of research where the concept has taken root and reflect upon the regional characteristics of sense of place. Overall, this review provides empirical insights into the human experience of place in a culturally diverse region marked by historical injustices, inequalities, and instability. These structures have created specific, often ambivalent senses of place, organized around resistance and adaptation. A more nuanced understanding of sense of place, which emphasizes the richness and complexities of people‐place connections, will help avoid oversimplification and idealization in future theories. To frame our analysis, we investigate sense of place from the perspective of humanistic geography. Overlapping with other non‐representational inquiries, the humanistic lens focuses on human‐environment relationships—encompassing experiences, behaviors, ideas, and feelings—to deepen our understanding of the intricate and multifaceted human condition and the essential role of place in human life. Our review shows that sense of place has proven helpful in shedding light on critical Latin American socio‐spatial phenomena such as mobilities, territorialities, and fear. Regionally, researchers center on marginalized and oppressed senses of place framed by longstanding structural inequalities stemming from a colonial legacy, capitalism, and neoliberalism. We highlight “geographies of terror,” “diabolic places,” and “necroplaces” as powerful categories that address the grim reality in the region.
Development of the World Federation of Hemophilia Shared Decision‐Making Tool
Authors: Coffin Donna , Skinner Mark W. , Thornburg Courtney D. , Hayes Brendan K. , Sannié Thomas , Kaeser Gwendolyn E. , Chadwick Julia , Naccache Mayss , Pierce Glenn F.
Published: October 2024

Introduction

The use of shared decision‐making (SDM) in clinical settings is becoming more prevalent. The evolving and increasingly complex treatment landscape of haemophilia management has augmented the need and desire for SDM between patients and their healthcare team. SDM tools have been used in other chronic conditions and can be an effective form of education for patients and clinicians.

Aim

The World Federation of Hemophilia (WFH) partnered with people with haemophilia (PWH), patient advocacy groups, and healthcare practitioners to form an expert working group to develop an educational tool for PWH and their caregivers. The primary objectives included educating PWH on the available prophylactic treatments and facilitating discussion between PWH and their healthcare team.

Methods

The tool was proposed and developed by the expert working group, workshopped at conference round tables, and evaluated in two focus groups.

Results

The interactive WFH SDM Tool guides users through the SDM treatment journey and provides an opportunity for reflection on current disease impact and treatment preferences, educational fact sheets and videos, and a comparison between treatment classes. Two forms of the SDM Tool are available: an online platform with a summary page that may be printed and shared and a printable workbook. All evidence in the tool is based on the prescribing information or phase III clinical trial publications. The Tool will be updated twice each year.

Conclusion

The WFH SDM Tool is the first available resource that translates published guidance on SDM in haemophilia into a practical, user‐friendly tool aimed at facilitating patient‐centred treatment decisions.
Evaluating the benefits of emicizumab prophylaxis for haemophilia A with inhibitors: A cost‐effectiveness and budget impact analysis in Thailand's upper‐middle income setting
Authors: Kengkla Kirati , Wilairat Preyanate , Natesirinilkul Rungrote , Sosothikul Darintr , Phisalprapa Pochamana , Saokaew Surasak
Published: October 2024

Background

In Thailand, an upper‐middle‐income country, managing haemophilia A (HA) with inhibitors poses significant challenges, often necessitating bypassing agents (BPAs) for bleeding control. This study evaluates the cost‐effectiveness and budget impact of emicizumab, a novel prophylactic agent, as an alternative to both episodic and prophylactic BPA treatments from a societal perspective.

Methods

A Markov model was employed to estimate the lifetime societal costs and outcomes of emicizumab prophylaxis for HA patients with inhibitors. Treatment efficacy, cost, and epidemiological data were obtained through a comprehensive literature review and incorporated into the model. A 5‐year budget impact analysis complemented the cost‐utility analysis, with a 3% annual discount rate applied to future costs and outcomes.

Results

In the base‐case scenario, emicizumab prophylaxis in HA patients aged 2 years and above demonstrated superior cost‐effectiveness, yielding 18.1 quality‐adjusted life years (QALYs) per patient over a lifetime and resulting in cost savings of 138 million Thai Baht (THB) compared to BPA prophylaxis. Compared to episodic BPA treatment, emicizumab yielded 30.5 QALYs and saved 25 million THB per patient. The 5‐year budget impact was projected at 1775 million THB.

Conclusions

Emicizumab offers a cost‐saving approach for HA treatment with inhibitors in Thailand, promising significant health benefits and budgetary savings. This supports its potential inclusion in Thailand's National List of Essential Medicines to enhance haemophilia care access.

Highlights

Managing haemophilia A (HA) with inhibitors in Thailand, an upper‐middle‐income country, faces challenges due to limited access to effective treatments or newer drugs for bleeding management.

Emicizumab prophylaxis found to as a cost‐effective and viable alternative to traditional treatments, effectively preventing bleeding in Thai HA patients over 2 years old with inhibitors.

Demonstrating improved clinical outcomes and reduced costs, emicizumab prophylaxis outperforms episodic BPA treatments, positioning it as a superior treatment option for HA patients with inhibitors in Thailand.
Examining trends in the incidence of HIV infection among people with a history of drug use to inform an outbreak investigation and response: A retrospective cohort study
Authors: Trayner Kirsten M. A. , Palmateer Norah E. , McAuley Andrew , Yeung Alan , Cullen Beth L. , Wallace Lesley A. , Roy Kirsty , Metcalfe Rebecca , Peters Erica , Craik Julie , Carter Daniel , Campbell John , Ritchie Trina , Shepherd Samantha J. , Gunson Rory N. , Hutchinson Sharon J.
Published: October 2024

Background

In the context of an outbreak of HIV among people who inject drugs in Glasgow, Scotland, identified in 2015, our objectives were to: (1) develop epidemiological methods to estimate HIV incidence using data linkage, and (2) examine temporal changes in HIV incidence to inform public health responses.

Methods

This was a retrospective cohort study involving data linkage of laboratory HIV testing data to identify individuals with a history of drug use. Person‐years (PY) and Poisson regression were used to estimate incidence by time period (pre‐outbreak: 2000–2010 and 2011–2013; early outbreak: 2014–2016; ongoing outbreak: 2017–2019).

Results

Among 13 484 individuals tested for HIV, 144 incident HIV infections were observed from 2000 to 2019. Incidence rates increased from pre‐outbreak periods (1.00/1000 PY (95% confidence interval, CI: 0.60–1.65) in 2000–2010 and 1.70/1000 PY (95% CI: 1.14–2.54) in 2011–2013) to 3.02/1000 PY (95% CI: 2.36–3.86) early outbreak (2014–2016) and 2.35 (95% CI 1.74–3.18) during the ongoing outbreak period (2017–2019). Compared with the pre‐outbreak period (2000–2010), the incidence rates were significantly elevated during both the early outbreak (2014–16) (adjusted incidence rate ratio (aIRR) = 2.87, 95% CI: 1.62–5.09, p < 0.001) and the ongoing outbreak periods (2017–19) (aIRR = 2.12, 95% CI: 1.16–3.90, p = 0.015).

Conclusions

Public health responses helped to curb the rising incidence of HIV infection among people with a history of drug use in Glasgow, but further efforts are needed to reduce it to levels observed prior to the outbreak. Data linkage of routine diagnostic test data to assess and monitor incidence of HIV infection provided enhanced surveillance, which is important to inform outbreak investigations and guide national strategies on elimination of HIV transmission.
Infection risk with JAK inhibitors in dermatoses: a meta‐analysis
Authors: Ireland Patrick A. , Verheyden Matthew , Jansson Nicholas , Sebaratnam Deshan , Sullivan John
Published: October 2024

Evolving evidence suggests that Janus Kinase Inhibitors (JAKi) may predispose to certain infections, including tuberculosis and human herpes viruses. This review aimed to compare the infection risk in patients on a systemic JAKi for a dermatologic indication to a placebo. A systematic review was carried out from inception to June 2023, using the EMBASE, Medline, SCOPUS, and Cochrane Library of Registered Trials databases. Eligible studies included placebo‐controlled randomized trials that investigated the incidence of infection in patients with a dermatologic indication. Primary outcomes included the most commonly reported infections pertaining to serious and opportunistic infections, upper respiratory tract infections, nasopharyngitis, herpes simplex, varicella zoster, tuberculosis, neutropenia, and lymphopenia. A meta‐analysis of incidence ratios was conducted to determine odds ratios (OR), with a 95% confidence interval (CI) analysis. The meta‐analysis found no increased risk of serious (OR: 0.92, 95% CI: 0.61–1.43, P = 0.74) or opportunistic infections (OR: 0.65, 95% CI: 0.32–1.31, P = 0.23). The incidence of varicella‐zoster infections was significantly higher in the JAKi cohort (OR: 1.72, 95% CI: 1.08–2.72, P = 0.022). From 25 studies, there was no overall increased risk of herpes simplex infections (OR: 1.43, 95% CI: 0.93–2.23, P = 0.102) to placebo; however, a significantly higher risk in those with atopic dermatitis to alopecia areata was demonstrated (OR: 1.73, 95% CI: 1.13–2.69, P = 0.013). The results of this analysis do not suggest an increased risk of serious and opportunistic infections in those on JAKi compared to placebo. However, they support an increased risk of varicella‐zoster infections and a higher risk of herpes simplex infections in those with atopic dermatitis to alopecia areata. The results of this report support these agents' short‐term safety but signal that vigilance should be practiced in patients at risk for serious or recurrent herpes virus infections.