bluuebunny/crossref_metadata_2025_split huggingface dataset:
A practical evidence-based approach to management of type 2 diabetes in children and young people (CYP): UK consensus
Authors: White Billy , Ng S. M. , Agwu J. C. , Barrett T. G. , Birchmore N. , Kershaw M. , Drew J. , Kavvoura F. , Law J. , Moudiotis C. , Procter E. , Paul P. , Regan F. , Reilly P. , Sachdev P. , Sakremath R. , Semple C. , Sharples K. , Skae M. , Timmis A. , Williams E. , Wright N. , Soni A. 
Published: April 2024

Abstract
Background
Type 2 diabetes in young people is an aggressive disease with a greater risk of complications leading to increased morbidity and mortality during the most productive years of life. Prevalence in the UK and globally is rising yet experience in managing this condition is limited. There are no consensus guidelines in the UK for the assessment and management of paediatric type 2 diabetes.

Methods
Multidisciplinary professionals from The Association of Children’s Diabetes Clinicians (ACDC) and the National Type 2 Diabetes Working Group reviewed the evidence base and made recommendations using the Grading Of Recommendations, Assessment, Development and Evaluation (GRADE) methodology.

Results and discussion
Young people with type 2 diabetes should be managed within a paediatric diabetes team with close working with adult diabetes specialists, primary care and other paediatric specialties. Diagnosis of diabetes type can be challenging with many overlapping features. Diabetes antibodies may be needed to aid diagnosis. Co-morbidities and complications are frequently present at diagnosis and should be managed holistically. Lifestyle change and metformin are the mainstay of early treatment, with some needing additional basal insulin. GLP1 agonists should be used as second-line agents once early ketosis and symptoms are controlled. Glycaemic control improves microvascular but not cardiovascular risk. Reduction in excess adiposity, smoking prevention, increased physical activity and reduction of hypertension and dyslipidaemia are essential to reduce major adverse cardiovascular events.

Conclusions
This evidence-based guideline aims to provide a practical approach in managing this condition in the UK.
Blood leukocytes as a non-invasive diagnostic tool for thyroid nodules: a prospective cohort study
Authors: Wang Feihang , Zhao Danyang , Xu Wang-yang , Liu Yiying , Sun Huiyi , Lu Shanshan , Ji Yuan , Jiang Jingjing , Chen Yi , He Qiye , Gong Chengxiang , Liu Rui , Su Zhixi , Dong Yi , Yan Zhiping , Liu Lingxiao 
Published: April 2024

Abstract
Background
Thyroid nodule (TN) patients in China are subject to overdiagnosis and overtreatment. The implementation of existing technologies such as thyroid ultrasonography has indeed contributed to the improved diagnostic accuracy of TNs. However, a significant issue persists, where many patients undergo unnecessary biopsies, and patients with malignant thyroid nodules (MTNs) are advised to undergo surgery therapy.

Methods
This study included a total of 293 patients diagnosed with TNs. Differential methylation haplotype blocks (MHBs) in blood leukocytes between MTNs and benign thyroid nodules (BTNs) were detected using reduced representation bisulfite sequencing (RRBS). Subsequently, an artificial intelligence blood leukocyte DNA methylation (BLDM) model was designed to optimize the management and treatment of patients with TNs for more effective outcomes.

Results
The DNA methylation profiles of peripheral blood leukocytes exhibited distinctions between MTNs and BTNs. The BLDM model we developed for diagnosing TNs achieved an area under the curve (AUC) of 0.858 in the validation cohort and 0.863 in the independent test cohort. Its specificity reached 90.91% and 88.68% in the validation and independent test cohorts, respectively, outperforming the specificity of ultrasonography (43.64% in the validation cohort and 47.17% in the independent test cohort), albeit with a slightly lower sensitivity (83.33% in the validation cohort and 82.86% in the independent test cohort) compared to ultrasonography (97.62% in the validation cohort and 100.00% in the independent test cohort). The BLDM model could correctly identify 89.83% patients whose nodules were suspected malignant by ultrasonography but finally histological benign. In micronodules, the model displayed higher specificity (93.33% in the validation cohort and 92.00% in the independent test cohort) and accuracy (88.24% in the validation cohort and 87.50% in the independent test cohort) for diagnosing TNs. This performance surpassed the specificity and accuracy observed with ultrasonography. A TN diagnostic and treatment framework that prioritizes patients is provided, with fine-needle aspiration (FNA) biopsy performed only on patients with indications of MTNs in both BLDM and ultrasonography results, thus avoiding unnecessary biopsies.

Conclusions
This is the first study to demonstrate the potential of non-invasive blood leukocytes in diagnosing TNs, thereby making TN diagnosis and treatment more efficient in China.
Goat flock abortion: a retrospective study at Abergelle Agricultural Research Center, Tigray, Ethiopia
Authors: Assefa Guash Abay , Teklue Teshale , Hagazi Mebrahtom , Mezgebe Gebretnsae , Aregawi Weldegebrial G. , Tesfaye Adehanom Baraki 
Published: April 2024

Abstract
Background
Small ruminants are the principal component of livestock production in Tigray region, Ethiopia. But their productivity is affected by various factors. According to farmers and expert observation, goat abortion is among the leading causes of production losses in Tanqua-Abergelle district. However, study findings that examine the extent of distribution and economic impact of abortion cases in goats in the district are scarce. This retrospective study investigated the occurrence of abortion and its associated risk factors in three goat breed types at Abergelle Agricultural Research Center goat breeding site over a seven year period. The study included a total of does above one year old, and data were collected from a casebook that was specifically prepared for abortion cases. A thorough follow up was conducted to identify abortion cases. Additionally, a community survey was conducted in selected villages where the research center is located.

Results
The overall abortion proportion was 29.8% in the goat farm. Begait goat breeds had the highest abortion proportion (50.9%, CI 0.36–0.64) in 2015/16. Multivariate logistic regression analysis identified year, season, age and breed as major risk factors of abortion occurrence at flock level. Accordingly, the likelihood of goats experiencing abortion during the dry season (proportion = 34) was 1.87 times higher compared to those in the wet season (proportion = 22.8). Begait breeds had a higher incidence of abortion (proportion 37.5%, OR 4.87, CI 2.49–10.35) compared to other breeds. Age was negatively associated with abortion, suggesting that older goats (OR = 0.67) had a higher relative risk than younger goats (OR = 0.57). Moreover, the study noted a high incidence of abortion during the years 2014/15 to 2016/17 (proportion = 35.7–39.7). Within-breed analysis revealed that age and season were significant risk factors for Abergelle and Begait breeds, respectively by using a multivariate logistic regression analysis. A community survey indicated that 89.7% households responded their goats experienced abortion.

Conclusions
This study highlighted the high prevalence of goat abortion at Abergelle and identifies important risk factors associated with its occurrence. The findings can inform targeted interventions to reduce abortion rates and improve goat productivity in the district.
A WNT mimetic with broad spectrum FZD-specificity decreases fibrosis and improves function in a pulmonary damage model
Authors: Patel Mehaben , Post Yorick , Hill Natalie , Sura Asmiti , Ye Jay , Fisher Trevor , Suen Nicholas , Zhang Mengrui , Cheng Leona , Pribluda Ariel , Chen Hui , Yeh Wen-Chen , Li Yang , Baribault Hélène , Fletcher Russell B. 
Published: April 2024

Abstract
Background
Wnt/β-catenin signaling is critical for lung development and AT2 stem cell maintenance in adults, but excessive pathway activation has been associated with pulmonary fibrosis, both in animal models and human diseases such as idiopathic pulmonary fibrosis (IPF). IPF is a detrimental interstitial lung disease, and although two approved drugs limit functional decline, transplantation is the only treatment that extends survival, highlighting the need for regenerative therapies.

Methods
Using our antibody-based platform of Wnt/β-catenin modulators, we investigated the ability of a pathway antagonist and pathway activators to reduce pulmonary fibrosis in the acute bleomycin model, and we tested the ability of a WNT mimetic to affect alveolar organoid cultures.

Results
A WNT mimetic agonist with broad FZD-binding specificity (FZD1,2,5,7,8) potently expanded alveolar organoids. Upon therapeutic dosing, a broad FZD-binding specific Wnt mimetic decreased pulmonary inflammation and fibrosis and increased lung function in the bleomycin model, and it impacted multiple lung cell types in vivo.

Conclusions
Our results highlight the unexpected capacity of a WNT mimetic to effect tissue repair after lung damage and support the continued development of Wnt/β-catenin pathway modulation for the treatment of pulmonary fibrosis.
Harnessing alkaline-pH regulatable promoters for efficient methanol-free expression of enzymes of industrial interest in Komagataella Phaffii
Authors: Albacar Marcel , Casamayor Antonio , Ariño Joaquín 
Published: April 2024

Abstract
Background
The yeast Komagataella phaffii has become a very popular host for heterologous protein expression, very often based on the use of the AOX1 promoter, which becomes activated when cells are grown with methanol as a carbon source. However, the use of methanol in industrial settings is not devoid of problems, and therefore, the search for alternative expression methods has become a priority in the last few years.

Results
We recently reported that moderate alkalinization of the medium triggers a fast and wide transcriptional response in K. phaffii. Here, we present the utilization of three alkaline pH-responsive promoters (pTSA1, pHSP12 and pPHO89) to drive the expression of a secreted phytase enzyme by simply shifting the pH of the medium to 8.0. These promoters offer a wide range of strengths, and the production of phytase could be modulated by adjusting the pH to specific values. The TSA1 and PHO89 promoters offered exquisite regulation, with virtually no enzyme production at acidic pH, while limitation of Pi in the medium further potentiated alkaline pH-driven phytase expression from the PHO89 promoter. An evolved strain based on this promoter was able to produce twice as much phytase as the reference pAOX1-based strain. Functional mapping of the TSA1 and HSP12 promoters suggests that both contain at least two alkaline pH-sensitive regulatory regions.

Conclusions
Our work shows that the use of alkaline pH-regulatable promoters could be a useful alternative to methanol-based expression systems, offering advantages in terms of simplicity, safety and economy.
Triglyceride to high-density lipoprotein cholesterol ratio associated with long-term adverse clinical outcomes in patients deferred revascularization following fractional flow reserve
Authors: Li Fanqi , Li Xiaofang , Zhou Jiabao , Lin Qiuzhen , Zhou Yong , Zhu Jiayi , Wu Keke , Zhao Donghui , Li Qiuyu , Wang Haixiong , Liu Qiming 
Published: April 2024

Abstract
Background
Guidelines on coronary intermediate lesions strongly recommend deferred revascularization after detecting a normal fractional flow reserve (FFR). Researches about triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) on cardiovascular diseases has also been well conducted. However, the association of TG/HDL-C and long-term adverse clinical outcomes remains unknown for patients deferred revascularization following FFR.

Methods
This study retrospectively included 374 coronary artery disease (CAD) patients with non-significant coronary lesions diagnosed by coronary angiography (CAG) and FFR. The main outcome measure was the combination of major adverse cardiovascular and cerebrovascular events (MACCEs). All patients were categorized into three subgroups in terms of TG/HDL-C tertiles (T1 < 0.96, 0.96 ≤ T2 < 1.58, T3 ≥ 1.58). Three different Cox regression models were utilized to reveal the association between TG/HDL-C and prevalence of MACCEs.

Results
47 MACCEs were recorded throughout a median monitoring period of 6.6 years. The Kaplan-Meier survival curves showed a higher MACCEs rate occurred in the higher TG/HDL-C group (5.6% vs. 12.9% vs. 19.4%, log-rank P < 0.01). After adjustment, patients in T3 suffered a 2.6-fold risk compared to the T1 group (T3 vs. T1: HR 2.55, 95% CI 1.05–6.21, P = 0.038; T2 vs. T1: HR 1.71, 95% CI 0.65–4.49, P = 0.075; P for trend = 0.001). The restricted cubic spline (RCS) analysis demonstrated that the HR for MACCEs rose as TG/HDL-C increased. Both the receiver operating characteristic (ROC) and time-dependent ROC proved the excellent predictive ability of TG/HDL-C.

Conclusion
The study illustrates that TG/HDL-C correlates with the risk of MACCEs in CAD patients deferred revascularization following FFR. TG/HDL-C could serve as a dependable predictor of cardiovascular events over the long term in this population.
The interaction of inflammasomes and gut microbiota: novel therapeutic insights
Authors: Manshouri Shirin , Seif Farhad , Kamali Monireh , Bahar Mohammad Ali , Mashayekh Arshideh , Molatefi Rasol 
Published: April 2024

AbstractInflammasomes are complex platforms for the cleavage and release of inactivated IL-1β and IL-18 cytokines that trigger inflammatory responses against damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). Gut microbiota plays a pivotal role in maintaining gut homeostasis. Inflammasome activation needs to be tightly regulated to limit aberrant activation and bystander damage to the host cells. Several types of inflammasomes, including Node-like receptor protein family (e.g., NLRP1, NLRP3, NLRP6, NLRP12, NLRC4), PYHIN family, and pyrin inflammasomes, interact with gut microbiota to maintain gut homeostasis. This review discusses the current understanding of how inflammasomes and microbiota interact, and how this interaction impacts human health. Additionally, we introduce novel biologics and antagonists, such as inhibitors of IL-1β and inflammasomes, as therapeutic strategies for treating gastrointestinal disorders when inflammasomes are dysregulated or the composition of gut microbiota changes.
Advances in lymphatic metastasis of non-small cell lung cancer
Authors: Zhang Xiaofei , Ma Li , Xue Man , Sun Yanning , Wang Zhaoxia 
Published: April 2024

AbstractLung cancer is a deeply malignant tumor with high incidence and mortality. Despite the rapid development of diagnosis and treatment technology, abundant patients with lung cancer are still inevitably faced with recurrence and metastasis, contributing to death. Lymphatic metastasis is the first step of distant metastasis and an important prognostic indicator of non-small cell lung cancer. Tumor-induced lymphangiogenesis is involved in the construction of the tumor microenvironment, except promoting malignant proliferation and metastasis of tumor cells, it also plays a crucial role in individual response to treatment, especially immunotherapy. Thus, this article reviews the current research status of lymphatic metastasis in non-small cell lung cancer, in order to provide some insights for the basic research and clinical and translational application in this field.
Role of STING in the treatment of non-small cell lung cancer
Authors: Tang Wenhua , Zhou Wenjie , Ji Mei , Yang Xin 
Published: April 2024

AbstractNon-small cell lung cancer (NSCLC) is a prevalent form of lung cancer. Patients with advanced NSCLC are currently being treated with various therapies, including traditional radiotherapy, chemotherapy, molecular targeted therapies and immunotherapy. However, a considerable proportion of advance patients who cannot benefit from them. Consequently, it is essential to identify a novel research target that offers an encouraging perspective. The stimulator of interferon genes (STING) has emerged as such a target. At present, it is confirmed that activating STING in NSCLC tumor cells can impede the proliferation and metastasis of dormant tumor cells. This review focuses on the role of STING in NSCLC treatment and the factors influencing its activation. Additionally, it explores the correlation between STING activation and diverse therapy modalities for NSCLC, such as radiotherapy, chemotherapy, molecular targeted therapies and immunotherapy. Furthermore, it proposes the prospect of innovative therapy methods involving nanoparticles, with the aim of using the features of STING to develop more strategies for NSCLC therapy.
Complement networks in gene-edited pig xenotransplantation: enhancing transplant success and addressing organ shortage
Authors: Yuan Yinglin , Cui Yuanyuan , Zhao Dayue , Yuan Yuan , Zhao Yanshuang , Li Danni , Jiang Xiaomei , Zhao Gaoping 
Published: April 2024

AbstractThe shortage of organs for transplantation emphasizes the urgent need for alternative solutions. Xenotransplantation has emerged as a promising option due to the greater availability of donor organs. However, significant hurdles such as hyperacute rejection and organ ischemia–reperfusion injury pose major challenges, largely orchestrated by the complement system, and activated immune responses. The complement system, a pivotal component of innate immunity, acts as a natural barrier for xenotransplantation. To address the challenges of immune rejection, gene-edited pigs have become a focal point, aiming to shield donor organs from human immune responses and enhance the overall success of xenotransplantation. This comprehensive review aims to illuminate strategies for regulating complement networks to optimize the efficacy of gene-edited pig xenotransplantation. We begin by exploring the impact of the complement system on the effectiveness of xenotransplantation. Subsequently, we delve into the evaluation of key complement regulators specific to gene-edited pigs. To further understand the status of xenotransplantation, we discuss preclinical studies that utilize gene-edited pigs as a viable source of organs. These investigations provide valuable insights into the feasibility and potential success of xenotransplantation, offering a bridge between scientific advancements and clinical application.
Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson’s disease through Mfn2-cGAS signaling
Authors: Wang Min , Tian Tian , Zhou Hong , Jiang Si-Yuan , Jiao Ying-Ying , Zhu Zhu , Xia Jiang , Ma Jian-Hua , Du Ren-Hong 
Published: April 2024

Abstract
Background
Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson’s disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined.

Methods
Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD.

Results
We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration.

Conclusions
This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.
Minimal detectable change of gait and balance measures in older neurological patients: estimating the standard error of the measurement from before-after rehabilitation data thanks to the linear mixed-effects models
Authors: Caronni Antonio , Picardi Michela , Scarano Stefano , Rota Viviana , Guidali Giacomo , Bolognini Nadia , Corbo Massimo 
Published: April 2024

Abstract
Background
Tracking gait and balance impairment in time is paramount in the care of older neurological patients. The Minimal Detectable Change (MDC), built upon the Standard Error of the Measurement (SEM), is the smallest modification of a measure exceeding the measurement error. Here, a novel method based on linear mixed-effects models (LMMs) is applied to estimate the standard error of the measurement from data collected before and after rehabilitation and calculate the MDC of gait and balance measures.

Methods
One hundred nine older adults with a gait impairment due to neurological disease (66 stroke patients) completed two assessment sessions before and after inpatient rehabilitation. In each session, two trials of the 10-meter walking test and the Timed Up and Go (TUG) test, instrumented with inertial sensors, have been collected. The 95% MDC was calculated for the gait speed, TUG test duration (TTD) and other measures from the TUG test, including the angular velocity peak (ωpeak) in the TUG test’s turning phase. Random intercepts and slopes LMMs with sessions as fixed effects were used to estimate SEM. LMMs assumptions (residuals normality and homoscedasticity) were checked, and the predictor variable ln-transformed if needed.

Results
The MDC of gait speed was 0.13 m/s. The TTD MDC, ln-transformed and then expressed as a percentage of the baseline value to meet LMMs’ assumptions, was 15%, i.e. TTD should be < 85% of the baseline value to conclude the patient’s improvement. ωpeak MDC, also ln-transformed and expressed as the baseline percentage change, was 25%.

Conclusions
LMMs allowed calculating the MDC of gait and balance measures even if the test-retest steady-state assumption did not hold. The MDC of gait speed, TTD and ωpeak from the TUG test with an inertial sensor have been provided. These indices allow monitoring of the gait and balance impairment, which is central for patients with an increased falling risk, such as neurological old persons.

Trial registration
NA.