bluuebunny/crossref_metadata_2025 huggingface dataset:
Unilateral Oophorectomy and Age at Natural Menopause: A Longitudinal Community‐Based Cohort Study
Authors: Brennand Erin A. , Scime Natalie V. , Manion Rebecca , Huang Beili
Published: October 2024

Objective

To determine the association between unilateral oophorectomy (UO) and age at natural menopause.

Design

Secondary analysis of survey data from Alberta's Tomorrow Project (2000–2022).

Setting

Prospective cohort study in Alberta, Canada.

Population

23 630 women; 548 experienced UO and 23 082 did not experience UO.

Methods

Flexible parametric survival analysis was used to analyse age at natural menopause, and logistic regression was used to analyse early menopause and premature ovarian insufficiency by UO status, controlling for birth year, parity, age at menarche, past infertility, hormonal contraceptive use and smoking.

Main Outcome Measures

Age at natural menopause occurred by a final menstrual period without medical cause and sub‐classified as early menopause (< 45 years) and premature ovarian insufficiency (< 40 years).

Results

Compared to no UO, any UO was associated with elevated risk of earlier age at natural menopause, which was strongest in early midlife (adjusted HR at age 40 1.71, 95% CI 1.31–2.19) and diminished over time. Compared to age 55 years at UO, risks of earlier age at natural menopause were largest and uniform in magnitude when UO occurred between approximately ages 20–40 years (adjusted HR for UO at age 30 2.32, 1.46–3.54) and then diminished as age at UO approached the average age at natural menopause. Any UO was associated with higher odds of early menopause (adjusted OR 1.90, 1.30–2.79) and premature ovarian insufficiency (adjusted OR 3.75, 1.72–8.16).

Conclusions

Unilateral oophorectomy is associated with earlier age at natural menopause, particularly when performed before 40 years of age.
A cluster of multi‐drug intoxications involving xylazine, benzimidazole opioids (nitazenes) and novel benzodiazepines in South Australia
Authors: Partridge Emma , Stockham Peter , Kenneally Michaela , Luong Andrew , Kostakis Chris , Alfred Sam
Published: October 2024

Objective

To highlight the detection of xylazine and nitrazolam in conjunction with benzimidazole opioids (nitazenes) and other novel benzodiazepines in a cluster of patients after putative heroin use.

Methods

Deidentified clinical and analytical data were gathered from patients enrolled in the Emerging Drugs Network of Australia system.

Results

In December 2023, three adults presented to the ED with sedation following putative use of heroin. Toxicological analysis of blood samples identified xylazine, protonitazene, metonitazene, bromazolam and nitrazolam. Local health authorities subsequently issued an alert.

Conclusion

This is the first signal of xylazine and nitrazolam use in Australia. These results demonstrate toxico‐surveillance programmes with analytical confirmation of drugs are invaluable in monitoring illicit drug use.
Metabolic differences in Zingiber officinale Roscoe by geographical origin determined via multiplatform metabolomics and method for simultaneous analysis of six phenolic compounds
Authors: Yoon Dahye , Choi Bo‐Ram , Kim Hyoung‐Geun , Lee Dae Young
Published: October 2024

Ginger, which is the rhizome of Zingiber officinale Roscoe, is widely distributed and consumed. The taste and aroma of ginger differ depending on its geographical origin. To distinguish the origin of ginger, ginger extracts from Korea, Peru, and China were analyzed using ultra‐performance liquid chromatography (UPLC) coupled to quadrupole time‐of‐flight mass spectrometry and nuclear magnetic resonance spectroscopy for metabolomics. Korean ginger contained more 10‐gingerol, and Peruvian ginger contained more 6‐gingerol and 8‐gingerol. Several amino acids negatively correlated with gingerols, suggesting that amino acids are related to the biosynthesis of gingerols. Sugars, which are the main energy source, positively correlated with gingerols. Organic acids and gingerols were also positively correlated, indicating that both organic acids and gingerols are used for adaptation to the environment surrounding the root. We confirmed the features of the primary and secondary metabolites by verifying the correlation between metabolites and differences in metabolites according to ginger origin. We additionally optimized a simultaneous UPLC analytical method of marker compounds for the simple and rapid quality control of ginger. This method exhibits excellent linearity, sensitivity, and reproducibility. Using metabolomics, differences in origin were observed, and a low‐end equipment analysis method for quality control can be used in the ginger industry.
Beyond the Airports Act: Investigating the Privatisation of Airports by Local Governments in Regional Australia
Authors: Wasiela Linda , Charles Michael B. , Noble David
Published: October 2024

Costs associated with running local airports are spurring some local governments to pursue alternative governance arrangements. Some regional councils are considering privatisation, with four having already gone down this path. Although some of these arrangements broadly follow those specified by the Airports Act 1996, other arrangements have led to fragmented processes and reduced public engagement in local communities. The study reveals that, while long‐term leasing aims to alleviate the council's financial burden, it can negatively impact the broader public interest. The findings suggest the need for more transparent and adaptable governance models to ensure that regional airports serve both commercial interests and public needs.
Contextualizing aging clocks and properly describing biological age
Authors: Johnson Adiv A. , Shokhirev Maxim N.
Published: October 2024

Usage of the phrase “biological age” has picked up considerably since the advent of aging clocks and it has become commonplace to describe an aging clock's output as biological age. In contrast to this labeling, biological age is also often depicted as a more abstract concept that helps explain how individuals are aging internally, externally, and functionally. Given that the bulk of molecular aging is tissue‐specific and aging itself is a remarkably complex, multifarious process, it is unsurprising that most surveyed scientists agree that aging cannot be quantified via a single metric. We share this sentiment and argue that, just like it would not be reasonable to assume that an individual with an ideal grip strength, VO2 max, or any other aging biomarker is biologically young, we should be careful not to conflate an aging clock with whole‐body biological aging. To address this, we recommend that researchers describe the output of an aging clock based on the type of input data used or the name of the clock itself. Epigenetic aging clocks produce epigenetic age, transcriptomic aging clocks produce transcriptomic age, and so forth. If a clock has a unique name, such as our recently developed epigenetic aging clock CheekAge, the name of the clock can double as the output. As a compromise solution, aging biomarkers can be described as indicators of biological age. We feel that these recommendations will help scientists and the public differentiate between aging biomarkers and the much more elusive concept of biological age.
Examining the financial and commercial literacy of Australian Indigenous small business owners
Authors: Brimble Mark , Weaven Scott , Wildman Karen L. , Blue Levon , Bodle Kerry , Frazer Lorelle
Published: October 2024

Financial and commercial literacy are essential skills for small business owners to navigate an increasingly complex financial landscape. This study examines the financial and commercial literacy of 592 Indigenous and non‐Indigenous small business owners. We found that small business owners had low levels of financial and commercial literacy with significant differences for Indigenous small business owners located in remote areas and for non‐Indigenous small business owners who are female, young, and who have lower levels of education. We demonstrate the need for more support to improve financial literacy among small business owners to enhance the long‐term sustainability of their enterprises.
Unexplained Recurrent Pregnancy Loss: Clinical Application of Immunophenotyping
Authors: Monticciolo Irene , Guarano Alice , Inversetti Annalisa , Barbaro Greta , Di Simone Nicoletta
Published: October 2024

Problem

Recurrent pregnancy loss (RPL) is defined as the failure of two or more pregnancies and affects approximately 5% of couples, often without a clear cause. The etiologies of RPL include factors such as maternal age, endocrine dysfunction, uterine abnormalities, chromosomal abnormalities, thrombophilias, infections, and autoimmune disorders. However, these conditions account for only 50%–60% of RPL cases. Research has explored whether an altered immune system, compared to the physiological state, may be linked to RPL. This review aims to determine whether specific immunophenotypes are associated with unexplained Recurrent Pregnancy Loss (uRPL) and whether targeted therapies addressing specific immunophenotypic alterations can improve pregnancy outcomes.

Methods

A literature review was conducted using Pubmed/Medline, Scopus, and Embase databases, analyzing data from 95 articles published between 2001 and 2023. The roles of various cells of the immune system (B lymphocytes, T lymphocytes, natural killer cells, macrophages) in different tissues (peripheral blood, menstrual blood) were specifically investigated in women with uRPL.

Discussion and Conclusion

Specific immunophenotypes have been demonstrated to be associated with this condition. However, there is a need to standardize immunophenotyping assays and conduct more trials to stratify RPL risk and improve potential therapeutic strategies.
Enhancing health assessments with large language models: A methodological approach
Authors: Wang Xi , Zhou Yujia , Zhou Guangyu
Published: October 2024

Health assessments have long been a significant research topic within the field of health psychology. By analyzing the results of subject scales, these assessments effectively evaluate physical and mental health status. Traditional methods, based on statistical analysis, are limited in accuracy due to their reliance on linear scoring methods. Meanwhile, machine learning approaches, despite their potential, have not been widely adopted due to their poor interpretability and dependence on large amounts of training data. Recently, large language models (LLMs) have gained widespread attention for their powerful natural language understanding capabilities, offering a viable solution to these issues. This study investigates the application of LLMs in enhancing physical and mental health assessments, introducing ScaleLLM. ScaleLLM employs language and knowledge alignment to turn LLMs into expert evaluators for health psychology scales. Experimental results indicate that ScaleLLM can improve the accuracy and interpretability of health assessments.
Robust Predictive Performance of the SALT‐M Score for Clinical Outcomes in Asian Patients With Acute‐on‐Chronic Liver Failure
Authors: Kim Kunhee , Yim Seung Hyuk , Lee Jae Geun , Joo Dong Jin , Kim Myoung Soo , Park Jun Yong , Ahn Sang Hoon , Kim Deok‐Gie , Lee Hye Won
Published: October 2024

Background

Acute‐on‐chronic liver failure (ACLF) is a syndrome of patients with chronic liver disease presenting with multiple organ failures. Recently, Sundaram‐ACLF‐LT Mortality (SALT‐M) score has been developed to predict 1‐year post‐liver transplantation mortality. We validated the SALT‐M score in a large‐volume, Asian single‐centre cohort.

Aims

We validated the SALT‐M score in a large‐volume, Asian single‐centre cohort.

Methods

We analysed 224 patients of ACLF grade 2–3. Area under the receiver operating characteristic curve (AUROC) and concordance index (c‐index) were used to assess and compare the predictability of posttransplant mortality of SALT‐M and other scores. Moreover, we compared the survivals of patients with high and low SALT‐M, in conjunction with MELD score and ACLF grade.

Results

The AUROC for prediction of 1‐year post‐LT survival was higher in SALT‐M (0.691) than in MELD, MELD‐Na, MELD 3.0 and delta‐MELD. Similarly, the c‐index of the SALT‐M (0.650) was higher than aforementioned MELD systems. When categorised by the cut‐off of SALT‐M ≥ 20 and MELD ≥ 30, patients with high SALT‐M exhibited lower post‐LT survival than those with low SALT‐M scores regardless of high or low MELD (40.0% for high SALT‐M/high MELD vs. 42.9% for high SALT‐M/low MELD vs. 73.8% for low SALT‐M/high MELD vs. 63.7% for low SALT‐M/low MELD, p < 0.001). In patients with ACLF grade 3, SALT‐M effectively stratified the posttransplant mortality (39.4% for high SALT‐M vs. 63.1% for low SALT‐M, p = 0.018).

Conclusions

SALT‐M outperformed previous MELD systems for predicting posttransplant mortality in Asian LT cohort with severe ACLF. Transplantability for patients with severe ACLF could be determined based on SALT‐M.
Impact of HADS Anxiety and Depression Scores on the Efficacy of Dietary Interventions for Irritable Bowel Syndrome
Authors: O'Connor Anthony , Gill Sarah , Neary Elaine , White Sarah , Ford Alexander C.
Published: October 2024

Background

Anxiety and depression are associated strongly with irritable bowel syndrome (IBS). Dietary therapies are used increasingly in the management of IBS, but the impact of common mental disorders on response to these has not been well studied.

Aims

To examine whether symptoms compatible with common mental disorders influence response to dietary interventions.

Methods

Prospective cohort study of adults, with either diarrhoea‐predominant or mixed bowel habits, IBS Severity Scoring System [IBS‐SSS] score ≥ 75 points. Participants completed the Hospital Anxiety and Depression score (HADS) and attended initially for British Dietary Association advice for IBS. IBS‐SSS was re‐checked 3 months later to assess response. If primary endpoint (≥ 50 point decrease in IBS‐SSS) was not achieved, patients were offered low fermentable oligo‐, di‐ and monosaccharides and polyol diet and repeated IBS‐SSS after another 3 months. Secondary endpoints included of change in IBS‐SSS and effect of symptom severity on response.

Results

In total, 448 patients took part, average age of 42 years and 79.0% were female. 69.9% of participants had HADS‐A scores ≥ 8 and 39.3% with HADS‐D scores ≥ 8. Average IBS‐SSS score at baseline was 290 (SD 86). No significant difference was noted in achievement of the primary endpoint according to HADS‐A scores (53.4% vs. 62.2% by ITT in those with HADS‐A ≥ 8 vs. HADS‐A < 8, p = 0.09). Patients with HADS‐D ≥ 8 were significantly less likely to achieve the primary endpoint compared with those with HADS‐D < 8 (43.8% vs. 64.0% by ITT, p < 0.01).

Conclusion

Understanding psychological profile of patients can help predicting their response to IBS dietary interventions.
Germany's evolving role in global affairs: Positioning as a middle power in the Indo‐Pacific region
Authors: Wunderlich Jens‐Uwe , Luo Chih‐Mei
Published: October 2024

In 2020 Germany released its Indo‐Pacific guidelines in response to global shifts and escalating Sino‐US rivalries in the region. This article scrutinises Germany's ambitions and stance in the Indo‐Pacific, utilising the middle power concept as an analytical tool. It argues that Germany's Indo‐Pacific strategy is broadly in line with its wider foreign policy approach rather than marking a radical shift. Divided into three sections, the article explores middle power theories, Germany's foreign policy approach and Germany's Indo‐Pacific tilt. Assessing Germany's progress in the Indo‐Pacific, the paper employs a middle power framework based on capabilities, identity and engagement. We argue that Germany seems intent on positioning itself as a civilian middle power, evident in its deeply engrained norms determining identity and guiding engagement. The article uses a qualitative approach, drawing from primary material such as official statements of German policymakers and policy documents, supplemented by secondary sources covering the literature on middle power dynamics, the Indo‐Pacific region and Germany's foreign policy. Employing thematic documentary analysis, the paper identifies recurring patterns and trends in Germany's evolving role in the Indo‐Pacific.
A case of laparoscopic spleen‐preserving distal pancreatectomy for small solid pseudopapillary neoplasm in an adult male with anomalous splenic vein confluence
Authors: Uemura Sunao , Daike Rikiya , Yorita Kenji , Yamai Hiromichi , Yoshida Mitsuteru , Hokimoto Norihiro , Matsuoka Hisashi , Iwabu Jun , Izaki Fuyumi , Okazaki Michiyo , Tanida Nobuyuki
Published: October 2024

Although anomalies of the celiac and/or superior mesenteric arteries are occasionally encountered during abdominal surgery, anomalous venous confluence is seldom reported during pancreatic surgery. Herein, we present a rare case of laparoscopic spleen‐preserving distal pancreatectomy (LSPDP) for the treatment of a solid pseudopapillary neoplasm in an asymptomatic 37‐year‐old male with an anomalous splenic vein (SpV) confluence. Computed tomography angiography (CTA) revealed an anomaly of the SpV, which coursed transversely through the superior border of the pancreas, over the celiac artery and into the portal vein, along the superior line of the common hepatic artery. We successfully performed an LSPDP without peripancreatic vessel injury by exposing the SpV and splenic artery through an approach from the superior position of the pancreas. Preoperative imaging, especially CTA, is crucial to ensuring a safe, successful laparoscopic pancreatectomy.
When is the use of intravenous immunoglobulin appropriate in immune thrombocytopenia?
Authors: Dubois Sydney , Layese Richard , Limal Nicolas , Languille Laetitia , Kini‐Matondo Willy , Mahevas Matthieu , Michel Marc , Audureau Etienne , Godeau Bertrand
Published: October 2024

Intravenous immunoglobulin (IVIg) is the gold standard treatment for severe cases of immune thrombocytopenia (ITP). However, its cost, limited duration of efficacy and market supply tension have led French guidelines to reserve IVIg for ITP patients with formal contra‐indications to corticosteroids, with French bleeding score (‘Khellaf score’) > 8, and corticosteroid‐resistant patients either with Khellaf score ≤ 8 or in preparation for an invasive procedure or during pregnancy. We studied the prescribing practices of IVIg for ITP in real‐life conditions and assessed their compliance with French guidelines. A monocentric retrospective study was conducted between 2016 and 2020 among 114 patients hospitalized in our unit, for a total of 208 IVIg treatments. In 37% of cases, the Khellaf score was >8, validating IVIg prescription according to French guidelines. In the remaining cases, reasons noted for use of IVIg included corticosteroid resistance (33.7%), preparation for an invasive procedure (8.5%), context of pregnancy (6.6%) and contra‐indication to corticosteroids (3.3%). After analysis, IVIg prescription was considered valid according to current French guidelines in 84.4% of cases. Non‐compliant IVIg prescription was more frequent in younger patients (p = 0.027). Concomitant anti‐coagulation was also noted as an argument for IVIg prescription outside of the current French guidelines.
Phase II trial of imatinib mesylate in patients with PDGFRA/B‐negative hypereosinophilic syndrome
Authors: Kim Dong Hyun , Kim Seokhyeon , Park Seonyang , Byun Ja Min , Hong Junshik , Shin Dong‐Yeop , Kim Inho , Bang Soo Mee , Lee Jeong‐Ok , Lee Ji Yun , Kim Sang‐A , Kim Ki Hwan , Chung Yeun‐Jun , Jung Seung‐Hyun , Koh Youngil , Yoon Sung‐Soo
Published: October 2024

The role of imatinib in PDGFRA/B‐negative hypereosinophilic syndromes (HES) is controversial because of the heterogeneity of HES and the scarcity of prospective studies. We conducted a phase II clinical trial to evaluate the efficacy of imatinib in PDGFRA/B‐negative HES. Thirty‐two patients were treated with imatinib (100–400 mg daily), and the molecular basis of their response was identified using whole‐exome sequencing (WES) and whole‐transcriptome sequencing (WTS). The haematological response rate was 46.9%, with a complete haematological response (CHR) rate of 18.8%. The median time to response was 1.5 months. Among the six patients who achieved CHR, five maintained it until the 24th cycle of imatinib and one lost response after 20 months. The median progression‐free survival was 4.3 months. WES and WTS were conducted for 11 patients. The number of non‐silent mutations did not differ between responders and non‐responders. Nine differentially expressed genes, including SNORD15A, were downregulated in responders. STAT5B::RARA, PAK2::PIGX, and FIP1L1::CHIC2 fusions were identified in patients with sustained responses, and RNF130::BRAF and WNK1::KDM5A fusions were identified in non‐responders. Imatinib, along with an appropriate biomarker, could be a promising option for PDGFRA/B‐negative HES.
Early transtympanic administration of rhBDNF exerts a multifaceted neuroprotective effect against cisplatin‐induced hearing loss
Authors: Pisani Anna , Rolesi Rolando , Mohamed‐Hizam Veronica , Montuoro Raffaele , Paludetti Gaetano , Giorgio Cristina , Cocchiaro Pasquale , Brandolini Laura , Detta Nicola , Sirico Anna , Amendola Pier Giorgio , Novelli Rubina , Aramini Andrea , Allegretti Marcello , Paciello Fabiola , Grassi Claudio , Fetoni Anna Rita
Published: October 2024

Background and Purpose

Cisplatin‐induced sensorineural hearing loss is a significant clinical challenge. Although the potential effects of brain‐derived neurotrophic factor (BDNF) have previously been investigated in some ototoxicity models, its efficacy in cisplatin‐induced hearing loss remains uncertain. This study aimed to investigate the therapeutic potential of recombinant human BDNF (rhBDNF) in protecting cells against cisplatin‐induced ototoxicity.

Experimental Approach

Using an in vivo model of cisplatin‐induced hearing loss, we investigated the beneficial effects of transtympanic administration of rhBDNF in a thermogel solution on hearing function and cochlear injury, using electrophysiological, morphological, immunofluorescence and molecular analyses.

Key Results

Our data showed that local rhBDNF treatment counteracted hearing loss in rats receiving cisplatin by preserving synaptic connections in the cochlear epithelium and protecting hair cells (HCs) and spiral ganglion neurons (SGNs) against cisplatin‐induced cell death. Specifically, rhBDNF maintains the balance of its receptor levels (pTrkB and p75), boosting TrkB‐CREB pro‐survival signalling and reducing caspase 3‐dependent apoptosis in the cochlea. Additionally, it activates antioxidant mechanisms while inhibiting inflammation and promoting vascular repair.

Conclusion and Implications

Collectively, we demonstrated that early transtympanic treatment with rhBDNF plays a multifaceted protective role against cisplatin‐induced ototoxicity, thus holding promise as a novel potential approach to preserve hearing in adult and paediatric patients undergoing cisplatin‐based chemotherapy.
Poverty Dynamics and Caries Status in Young Adolescents
Authors: Carbajal Rodriguez Gisselle , van Meijeren‐van Lunteren Agatha W. , Wolvius Eppo B. , Kragt Lea
Published: October 2024

Objectives

To investigate whether timing, accumulation and trajectories of poverty are associated with dental caries in young adolescents.

Methods

The study was conducted within the Generation R Study, which is an ongoing population‐based prospective cohort study conducted in Rotterdam, the Netherlands. This study included 2653 children. Information about household income and number of children and adults living in a household at six time points from pregnancy to 13 years old was retrieved from parental questionnaires to construct the poverty variable. Dental caries was assessed with the decayed, missing and filled teeth index through intraoral photographs at the age of 13 years. Sociodemographic and oral health‐related characteristics were included as possible confounders. The association between poverty and dental caries was analysed on the basis of the three lifecourse theories, that is, critical period, cumulative risk and social mobility model. For the latter, we used latent class growth analysis (LCGA) to identify poverty trajectories over time. Next, the associations were studied with Hurdle Negative Binomial Models.

Results

Poverty at birth and intermittent poverty up to the age of 13 were significantly associated with dental caries at 13 years of age (OR 1.41, 95% CI 1.01–1.99; OR 1.36, 95% CI 1.01–1.83 respectively) and with an increased mean number of decayed teeth by 34% (95% CI 1.02–1.76; 95% CI 1.05–1.71, respectively). LCGA showed four trajectories for the probabilities of poverty. All trajectories were significantly associated with dental caries at 13 years of age, with the ‘downward mobility’ trajectory showing the strongest association with dental caries (OR 1.55, 95% CI 1.05–2.29) and an increasing mean number of decayed teeth by 58% (95% CI 1.18–2.12) than the ‘stable absent’ trajectory.

Conclusion

Poverty at birth, intermittent poverty and downward poverty trajectory were associated with higher odds and higher mean number of decayed teeth at 13 years of age. The three lifecourse models influenced dental caries status during adolescence, hence strategies and policies targeted to improve socioeconomic conditions on deprived children should be implemented.
SOXC Enhances NGN2‐Mediated Reprogramming of Glioblastoma Cells Into Neuron‐Like Cells by Modulating RhoA and RAC1/CDC42 Pathway Activity
Authors: Yang Jianjing , Zhu Xiaohong , Wang Fan , Chen Zhen , Zhang Ying , Chen Jiawei , Ni Haoqi , Zhang Chun‐Li , Zhuge Qichuan
Published: October 2024

Background

Glioblastoma represents the most frequently diagnosed malignant neoplasm within the central nervous system. Human glioblastoma cells can be phenotypically reprogrammed into neuron‐like cells through the forced expression of NEUROG2 and SOXC factors. NEUROG2 serves as a pioneer factor, establishing an initial framework for this transformation. However, the specific role of SOXC factors has not been fully elucidated.

Methods

In this study, we used ChIP‐seq to determine the potential target gene of NGN2. RNA‐seq has been used to evaluate the transcriptional change during NGN2‐SOX11‐mediated neuron reprogramming. Immunofluorescence was used to determine the neuron reprogramming efficacy and cell proliferation ability. ChIP‐qPCR, Co‐IP, and Western Blot were performed to investigate the mechanism.

Results

Our findings reveal that SOXC factors, in contrast to their previously identified function as transcriptional activators, act as transcriptional repressors. They achieve this by recruiting TRIM28 to suppress the expression of ECT2, a RhoGEF. This suppression results in the differential regulation of RhoA, RAC1, and CDC42 activities throughout the reprogramming process. We further establish that small molecules targeting RhoA and its effectors can substitute for SOXC factors in facilitating the neuronal reprogramming of glioblastoma cells.

Conclusion

These results underscore the pivotal role of SOXC factors' transcriptional repression and illuminate one of their specific downstream targets.
Long‐term natural history in type II and III spinal muscular atrophy: a 4‐year international study on the Hammersmith Functional Motor Scale Expanded
Authors: Coratti Giorgia , Bovis Francesca , Pera Maria Carmela , Civitello Matthew , Rohwer Annemarie , Salmin Francesca , Glanzman Allan M. , Montes Jacqueline , Pasternak Amy , De Sanctis Roberto , Dunaway Young Sally , Duong Tina , Mizzoni Irene , Milev Evelin , Sframeli Maria , Morando Simone , Albamonte Emilio , D'Amico Adele , Catteruccia Michela , Brolatti Noemi , Pane Marika , Scoto Mariacristina , Messina Sonia , Escudero Jesica Exposito , De Waele Liesbeth , Hirano Michio , Zolkipli‐Cunningham Zarazuela , Darras Basil T. , Bertini Enrico , Nascimiento Osorio Andres , Bruno Claudio , Goemans Natalie , Sansone Valeria A. , Day John , Baranello Giovanni , Muntoni Francesco , Finkel Richard , Mercuri Eugenio ,   the ISMAC/international SMA consortium
Published: October 2024

Background and purpose

Spinal muscular atrophy (SMA) is a genetic disorder caused by SMN1 gene mutations. Although studies on available disease‐modifying treatments have reported their efficacy and safety, long‐term natural history data are lacking for comparison. The aim of this prospective study was to report 4‐year changes on the Hammersmith Functional Motor Scale Expanded (HFMSE) in type II and III SMA in relation to several variables such as age, functional status and SMN2 copy number.

Methods

The study involves retrospective analysis of prospectively collected data from international datasets (Belgium, Italy, Spain, USA, UK). HFMSE longitudinal changes were analyzed using linear mixed effect models, examining annualized HFMSE change and its association with variables such as age at baseline, sex, motor function, SMN2 copy number.

Results

In SMA type II (n = 226), the 4‐year mean change was −2.20 points. The largest mean changes were observed in sitters aged 5–14 years and the lowest in those who lost the ability to sit unsupported. In SMA type III (n = 162), the 4‐year mean change was −2.75 points. The largest mean changes were in those aged 7–15 years, whilst the lowest were in those below 7 and in the SMA type IIIa subgroup over 15. Age and score at baseline were predictive of 4‐year changes.

Conclusions

Our findings provide natural history reference data for comparison with long‐term follow‐up of clinical trials or real‐world data, highlighting the need to define patterns of changes in smaller SMA subgroups instead of reporting mean changes across an entire SMA cohort.
Transforming Lung Disease Diagnosis With Transfer Learning Using Chest X‐Ray Images on Cloud Computing
Authors: Choudhry Imran Arshad , Iqbal Saeed , Alhussein Musaed , Qureshi Adnan N. , Aurangzeb Khursheed , Naqvi Rizwan Ali
Published: October 2024

In the context of Cloud and Fog computing settings, recent developments in deep learning techniques show great potential for changing several fields, including healthcare. In this study, we make a contribution to this changing field by proposing an enhanced deep learning‐based strategy for classifying chest X‐ray images, using pre‐trained models such as RetinaNet, EfficientNet and Faster‐R‐CNN, which we use through transfer learning. Our strategy outperforms single models and traditional techniques by leveraging critical data gleaned from multiple models, demonstrating the ability of deep learning to improve diagnostic precision. Our approach presents a novel dual‐check system in the context of worries about security, privacy and trust in Cloud and Fog‐based Smart Systems. In this case, a decision support system uses chest X‐ray images to make an initial diagnosis that is then confirmed by a medical practitioner. This cooperative strategy not only reduces diagnostic errors that come from machine and human sources but also emphasises how crucial it is to incorporate AI‐driven solutions into safe and reliable healthcare ecosystems. Our approach raises the bar for the quality of patient care and healthcare outcomes by overcoming the drawbacks of traditional diagnostic methods that depend on the subjective opinions of physicians. Our work brings out how deep learning might transform clinical diagnostics by distinguishing inflammatory regions in chest X‐ray images. Research is needed to fully grasp the transformative potential of deep learning in medical image processing, especially as the healthcare industry continues to embrace AI‐driven solutions. Further research endeavours have to dig into tactics like broadening the scope of datasets, executing data augmentation methodologies and incorporating bespoken features to augment the elasticity and effectiveness of AI‐driven diagnostic systems.
Real‐world trends in acute viral hepatitis in Japan: A nationwide questionnaire‐based survey
Authors: Okushin Kazuya , Kanto Tatsuya , Korenaga Masaaki , Ikeuchi Kazuhiko , Kishida Toshiyuki , Kado Akira , Fujishiro Mitsuhiro , Tsutsumi Takeya , Takura Tomoyuki , Yotsuyanagi Hiroshi ,   Kind Nationwide Institution Group for Hepatitis Treatment in Japan (Knight‐Japan)
Published: October 2024

Aim

The actual incidence of acute viral hepatitis in Japan remains unclear. We aimed to investigate trends in the incidence of acute hepatitis B and C infections in Japan.

Methods

A nationwide, multicenter, retrospective questionnaire‐based survey was conducted. Participating hospitals received questionnaires through nationwide geographically distributed regional core centers certified as specialists in hepatitis treatment. The questionnaire included hospital size and the number of patients diagnosed with acute hepatitis B or C during each fiscal year (FY) from 2015 to 2022. The sex distribution in each FY was also documented. Comparisons were made before and during the COVID‐19 era (2015–2019 vs. 2020–2022), and between populous and non‐populous prefectures.

Results

Responses to the questionnaires were obtained from 127 institutions in 29 prefectures covering eight regions in Japan. A median of 127.0 patients with acute hepatitis B (interquartile range [IQR] 106.5–131.8 patients) were reported during each FY, and the incidence significantly decreased during the fiscal years 2020–2022 compared with the fiscal years 2015–2020 (median 96.0 [IQR 91.0–103.0] patients vs. 131.0 [IQR 128.0–134.0] patients; p = 0.03). A median of 10.0 (IQR, 7.8–13.5) patients were reported with acute hepatitis C during each FY. The proportions of men in acute hepatitis B and C were significantly higher in populous prefectures.

Conclusions

Populous prefectures had a higher proportion of men among viral hepatitis patients than non‐populous prefectures. Estimating the high‐risk populations in each area could provide insights to advance the elimination of viral hepatitis.
Incorporating online writing resources into self‐regulated learning strategy‐based instruction: An intervention study
Authors: Yabukoshi Tomoko , Mizumoto Atsushi
Published: October 2024

Background

While self‐regulated learning (SRL) strategy‐based writing instruction has been proposed in English as a foreign language (EFL) classrooms, there is insufficient evidence with Japanese EFL learners and little discussion on incorporating online resources into SRL strategy‐based writing instruction, despite the availability of various online platforms.

Objectives

This study proposed an SRL strategy‐based instruction for technology‐assisted writing and explored its immediate and sustained impacts on Japanese tertiary EFL learners' writing performance, reported use of SRL strategies, self‐efficacy beliefs and perceived acceptance of technology.

Methods

The research design used was a pre‐experimental pre‐test, post‐test and delayed post‐test design with a quantitative approach using convenience sampling. Participants were 44 students enrolled in an academic writing course at a Japanese university. Over an 8‐week period, these students received SRL strategy‐based writing instruction supported by online writing resources. The research instruments included writing tests and questionnaires assessing SRL strategies, self‐efficacy and technology acceptance at the beginning of the intervention (Time 1), immediately after the intervention (Time 2) and 1 month after the intervention (Time 3). The data analysis techniques involved ANOVA, post‐hoc tests, and examination of the effect sizes.

Results and Conclusion

The results showed statistically significant improvements in students' writing performance, SRL strategy use, self‐efficacy and technology acceptance from Time 1 to Time 2 and persistent impacts at Time 3, suggesting the intervention's potential to improve EFL writing. This study contributes to EFL writing pedagogy by exploring the immediate and sustained impacts of teaching SRL strategies in a technology‐enhanced writing environment.
Reactive oxygen species and aldehyde dehydrogenase 1A as prognosis and theragnostic biomarker in acute myeloid leukaemia patients
Authors: Venton G. , Colle J. , Tichadou A. , Quessada J. , Baier C. , Labiad Y. , Perez M. , De Lassus L. , Loosveld M. , Arnoux I. , Abbou N. , Ceylan I. , Martin G. , Costello R.
Published: October 2024

Acute myeloid leukaemia (AML) remains a major unmet medical, despite recent progress in targeted molecular therapies. One aspect of leukaemic cell resistance to chemotherapy is the development of clones with increased capacity to respond to cellular stress and the production of reactive oxygen species (ROS), thanks in particular to a high aldehyde dehydrogenases (ALDH) 1A1/2 activity. At diagnosis, ROS level and ALDH1A1/2 activity in AML patients BM are correlated with the different ELN 2022 prognostic groups and overall survival (OS). A significant lower ALDH1A1/2 activity in BM was observed in the favourable ELN2022 subgroup compared to the intermediate and adverse group (p < 0.01). In the same way, the ROS levels were significantly lower in the favourable ELN 2022 subgroup compared to the intermediate group (p < 0.0001) and adverse group (p < 0.0002). ROShigh AML patients had a significantly lower median overall survival (OS) (8.2 months) than ROSlow patients (24.6 months) (p = 0.0368). After first‐line therapy, a significant increase of ROS level (p = 0.015) and ALDH1A1/2 activity (0 = 0.0273) in leukaemic blasts was observed, especially in the refractory ones. ABD‐3001, a competitive and irreversible inhibitor of ALDHs 1 and 3, can in vitro inhibit the proliferation of patient‐derived leukaemic cells in accordance with redox balance. In multivariate analysis, ROS level was the most significant (p < 0.05) and the strongest predictive factor for the sensitivity of cells to ABD‐3001. The safety profile of ABD‐3001 is currently being assessed through the first inhuman multicenter phase 1 clinical trial “ODYSSEY” (NCT05601726) for patients with relapsed AML.
Phenotypically plastic drug‐resistant chronic myeloid leukaemia cell line displays enhanced cellular dynamics in a zebrafish xenograft model
Authors: Baykal Seda , Yuce Zeynep , Ozhan Gunes
Published: October 2024

Understanding the mechanisms by which cancer cells switch between different adaptive states and evade therapeutic interventions is essential for clinical management. In this study, the in vivo cellular dynamics of a new chronic myeloid leukaemia cell line displaying altered phenotype and resistance to tyrosine kinase inhibitors were investigated in correlation with their parental cells for invasiveness/metastasis, angiogenic potential and population kinetics. We showed that the cells exhibiting drug resistance and plastic phenotype possess an increased capacity for invasion compared to their parental cells, that exposure to imatinib mesylate has the potential to enhance cellular motility and that in a leukaemic cell population, even a minority of plastic cells exhibit improved migratory ability. Furthermore, we show that these plastic cells have angiogenic and extravasation potential. The present study provides significant insights into the cellular dynamics displayed by a TKI‐resistant, phenotypically plastic CML cell line, using a zebrafish (Danio rerio) xenograft model.
Unveiling the therapeutic potential of miR‐146a: Targeting innate inflammation in atherosclerosis
Authors: Ardinal Azizah Puspitasari , Wiyono Alice Valeria , Estiko Reza Ishak
Published: October 2024

Atherosclerosis is the foremost vascular disease, precipitating debilitating complications. Although therapeutic strategies have historically focused on reducing cholesterol deposition, recent insights emphasize the pivotal role of inflammation. Innate inflammation significantly contributes to plaque instability and rupture, underscoring the need for intervention across all disease stages. Numerous studies have highlighted the therapeutic potential of targeting innate immune pathways in atherosclerosis, revealing significant advancements in understanding the molecular mechanisms underlying inflammatory processes within arterial lesions. Notably, research has demonstrated that the modulation of microRNA‐146a (miR‐146a) expression impacts innate inflammation, effectively halts atherosclerosis progression, and enhances plaque stability by targeting interleukin‐1 receptor‐associated kinase (IRAK) and activating TNF receptor‐associated factor 6 (TRAF6), a signalling pathway involving toll‐like receptors (TLRs). Understanding the intricate mechanisms involved is crucial. This study provides a comprehensive analysis of the evidence and underlying mechanisms through which miR‐146a exerts its effects. Integrating these findings into clinical practice may herald a transformative era in managing atherosclerotic cardiovascular disease.
Single‐cell sequencing analysis reveals the dynamic tumour ecosystems of primary and metastatic lymph nodes in nasopharyngeal carcinoma
Authors: Xu Dahua , Zhang Nihui , Shen Yutong , Zheng Dehua , Xu Zhizhou , Li Peihu , Cai Jiale , Tian Guanghui , Wei Qingchen , Wang Hong , Jiang Hongyan , Cao Meng , Wang Bo , Li Kongning
Published: October 2024

Lymph node metastasis contributed to the leading cause and treatment failure in nasopharyngeal carcinoma (NPC). The microenvironment and the cellular communications of lymph node metastasized tumours determine the tumour progression and therapeutic effect, but the ecosystems about the lymph node metastasis (LNM) for NPC patients remain poorly characterized. Here, we integrated the transcriptomes of 47,618 single cells from eight samples related to NPC LNM. The dynamic immune ecosystems and immunosuppressive microenvironment including T cells, myeloid cells and B cells were observed in the lymph node metastatic samples compared with primary tumours. Additionally, the heterogeneity of epithelial cells was also revealed, and several clusters with expression programs that were associated with the progression‐free survival of NPC patients were identified. Additionally, our data revealed the complex intercellular communications from primary to lymph node metastasis. The rewiring of CCL signalling which plays an important role in tumour metastasis was further identified. Altogether, we systematically characterized the ecosystem of NPC primary and lymph node metastasized tumours, which may shed light on the development of a therapeutic strategy to improve clinical outcomes of NPC patients with lymph node metastasis.
Defining and Operationalising Defiant Non‐Compliance in the EU: The Rule of Law Case
Authors: Closa Carlos , Hernández Gisela
Published: October 2024

Existing literature often attributes non‐compliance to either a lack of resources or implementation costs. However, the rule of law crises in Hungary and Poland present a different picture: a deliberate strategy aimed at not complying with EU enforcement actions. This article differentiates this model from previous ones and terms it ‘defiant non‐compliance’, which is characterised by four types of domestic actions (ignoring the Commission's recommendations and warnings; not complying with Court of Justice of the EU (CJEU) rulings; questioning the role of the CJEU as the sole final interpreter of EU law; and impeding national courts' right to raise preliminary questions). A defiant rhetoric questioning the authority and legitimacy of the enforcing authorities accompanies these actions. The article distils defiant non‐compliance by systematising empirical evidence on these governments' reactions to EU enforcement. This model of non‐compliance severely threatens the foundations of the EU, as it erodes the notion of a community of law‐abiding member states' governments.
Prediction of Rheological Properties of Flour From Physicochemical Properties Using Multiple Regression Techniques and Artificial Neuronal Networks
Authors: Cingöz Ali , Nacar Sinan
Published: October 2024

This study has two main objectives: (i) to determine the physicochemical and rheological properties of different flours and (ii) to estimate the alveograph parameters obtained as a result of experimental studies. In this context, physicochemical (protein, ash, falling number, wet gluten, gluten index, Zeleny, and delayed sedimentation) and alveograph parameters (P, L, G, W, P/L, and IE) of 150 different bread and pastry flours were determined. Multiple regression analysis (MRA) and artificial neural network (ANN) methods were then used to predict alveograph results from this experimentally obtained data set. Root mean square error (RMSE), mean absolute error (MAE), Nash‐Sutcliffe (NSEC), and relative error (RE) performance statistics were used to evaluate the CS prediction capabilities of the methods. It was found that the flours were in the range of 11.01%–13.82% protein, 325–403 s falling number, and 30–61 mL Zeleny and delayed sedimentation values. The ANN method showed better predictive performance than the regression‐based method. W was the best estimated parameter in the ANN model. This was followed by G, L, Ie, P/L, and P values. Considering the RMSE value of the W parameter, it was observed that the ANN method provided an improvement of 5.16, 1.76, and 2.15 times compared to the regression method for the training, validation, and test sets, respectively.
Patient‐reported disease burden in the Accelerate Clinical Trials in Charcot–Marie–Tooth Disease Study
Authors: Rehbein T. , Purks J. , Dilek N. , Behrens‐Spraggins S. , Sowden J. E. , Eichinger K. J. ,   the ACT‐CMT Study Group, Burns J. , Pareyson D. , Scherer S. S. , Reilly M. M. , Shy M. E. , McDermott M. P. , Heatwole C. R. , Herrmann D. N.
Published: October 2024

Background and Aims

The Charcot–Marie–Tooth Disease Health Index (CMT‐HI) is a disease‐specific, patient‐reported disease burden measure. As part of an international clinical trial readiness study, individuals with CMT1A (ages 18–75 years) underwent clinical outcome assessments (COAs), including the CMT‐HI, to capture their longitudinal perspective on the disease burden.

Methods

Two hundred and fifteen participants underwent serial COAs including the CMT‐HI, CMT Functional Outcome Measure (CMT‐FOM), CMT Neuropathy Score (CMTNSv2R), and CMT Exam Score (CMTES/CMTES‐R). Correlations between the total and subscale scores for the CMT‐HI and other COAs were determined. Changes in the CMT‐HI scores over 12 months were assessed using paired t‐tests. The minimum clinically important difference (MCID) for the CMT‐HI and its subscales were calculated by anchoring to a participant global impression of change scale.

Results

At baseline, CMT1A participants were 44.5 ± 15 years old (range: 18–75) and 58% were women. The mean CMT‐HI was 25.7 ± 18.8 (range: 0–91.9; 100 reflecting maximal disease burden). The CMT‐HI correlated with the CMT‐FOM (r = .54, p < .0001), CMTNSv2R (r = .48, p < .0001), and CMTES/CMTES‐R (r = .52/r = .54, p < .0001). Disease burden was greater in women than in men (CMT‐HI 29.1 ± 19.1 vs. 21.2 ± 17.3, p = .001). Over 12 months, there was a nonsignificant mean increase in CMT‐HI of 0.40 ± 10.0 (n = 189, p = .89). The MCID for the CMT‐HI total score was 3.8 points (95% CI: 1.7–5.9).

Discussion

Patient‐reported disease burden in CMT1A as measured by the CMT‐HI is associated with measures of neurologic impairment and physical functioning. Women reported a higher disease burden than men. These data will inform the design of clinical trials in CMT1A.