bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Real-World Data of Emicizumab in Previously Untreated and Minimally Treated Patients with Hemophilia a Infants from China
Authors: Yin Qixaun , Mao Qianqian , Li Zhengping , Li Gang , Chen Zhenping , Wu Runhui 
Published: December 2024

Introduction
Emicizumab (EMI) is safe and efficient in pediatric patients with hemophilia A (HA). However, real-world data regarding immune response, pharmacokinetics (PK) and pharmacodynamics (PD) during EMI for previously untreated (PUP) and minimally treated (MTP) patients with HA infants(&lt;3y) are limited in China. This study investigated the immune response and PK/PD of EMI in PUP and MTP with HA infants in China.
Methods
We performed a retrospective analysis of pediatric HA patients to collect data on PUPs and MTPs at our Comprehensive Hemophilia Care Center. Data included patients' baseline characteristics, therapy details, bleeding episode of pre- and post-EMI, and adverse events. Immune response included anti-emicizumab antibodies (ADAs) and factor VIII (FVIII) inhibitors. Laboratory analyses included FVIII-like activity and EMI concentration measurements.
Results
Sixteen PUPs and MTPs with HA had received EMI prophylaxis for a median (range) duration of 21.8 (4.9-47.0) months by July 2024. The median age at the beginning of EMI was 11.8 (5.8-33.3) months. At the initiation of EMI, all patients were inhibitor-negative.
While on EMI, EMI showed effectively prevented bleeding even: the median annualized bleeding rate (ABR) of 0.6 (0.0-1.9), annualized joint bleeding rate (AJBR) of 0.0 (0.0-0.3), and annualized spontaneous bleeding rate (ASBR) of 0.0 (0.0-1.59). Seven(43.8%) patients reached zero-bleeding rate (ZBR).
No drug-related serious adverse events were observed.
In the loading phase, patients with median age of 10.8 (5.8-32.9) months and body mass index (BMI) of 17.8 (15.6-21.6) received a median EMI loading dose of 3.0 (2.4-3.5) mg/kg. Their median EMI concentration was 65.9 (36.2-79.9) μg/mL and FVIII-like activity was 27.0 (13.5-35.4) IU/dL. Even though the mdian EMI 4-weekly maintenance dosage [4.8 (4.0-5.6)mg/kg] was below the internationally recommended dosage (6mg/kg), patients reached EMI concentration of 50.2 (36.0-76.8) μg/mL, and FVIII-like activity of 14.9 (10.4-30.4) IU/dL. EMI concentration was correlated with FVIII-like activity (rs=0.858，p＜0.001).
Four (25%) patients received a total of 9 administrations of factor-based therapy. During the long-term follow-up period, the median number of exposure days (EDs) was only 0 (0-3) days. No patients tested positive for ADAs or FVIII inhibitors.
Conclusion
EMI has demonstrated favorable tolerability and efficacy in PUPs and MTPs with HA in infants. Using EMI at substandard doses can still achieve relatively high maintenance concentrations. Furthermore, the concentration of EMI correlates well with their FVIII-like activity. No patients developed ADAs or FVIII inhibitors.
Evans Syndrome: A Systematic Review
Authors: Gouli Sugam , KC Ojbindra , Mostafa Mariam , Shrestha Asis , Niraula Sujan , Dulal Aliza 
Published: December 2024

Introduction:
Evans syndrome is a rare autoimmune disease that consists of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia(ITP) with or without neutropenia. Evans syndrome can be classified as primary(idiopathic) vs secondary (presence of underlying causes). The presence of AIHA and ITP might not occur concomitantly and might precede one another. Treatment options in evans syndrome are variable but mostly involves corticosteroid, rituximab and splenectomy in refractory cases.
Methods:
Two independent investigators searched databases PUBMED, MEDLINE, EMBASE with key word “evans syndrome” and included articles containing 5 or more cases of Evans syndrome in adults, excluding articles on pregnant , infants and children. Further data about patient characteristics, clinical features and treatment were extracted for analysis.
Results:
10 studies (9 retrospective and 1 prospective studies) fulfilled our inclusion criteria.The number of female patients was 52.2% (275/527) vs 47.8% (252/527) male patients. Among them 68.4%(335/490) had primary Evans syndrome compared to 31.6%(155/490) had secondary evans syndrome due to underlying causes. ITP and AIHA occurred simultaneously in 52.4%(276/527) cases, ITP before AIHA in 34.2%(180/527) cases, AIHA before ITP in 23.1%(122/527) cases. Among the patients with positive Direct Antiglobulin Test(DAT), 46.6%(116/249) had positive IgG , 33.3%(83/249) had positive IgG +C3d and 6.4%(16/249) had positive C3d . Only 6 studies had data on neutropenia that was present in 8.2% (18/219) cases. All patients were treated with corticosteroids, 18.4% (47/256) were received rituximab and 16.3%(76/466) refractory cases received splenectomy. We had mortality data from six studies which showed that 40.87% (188/460) cases had died.
Conclusion:
Our review showed that the clinical presentation of Evans syndrome can be variable and quite challenging. Most cases are primary Evans syndrome however looking for underlying causes in secondary Evans syndrome and other differentials is also important. Evans syndrome though rare has high mortality.
Impact of Intravenous Immunoglobulin (IVIG) on Venous Thromboembolism/Pulmonary Embolism in Immune Thrombocytopenic Purpura- an NIS 2020 Database Analysis
Authors: Sanjeevi Aditya , Bhandari Samikchhya Keshary , Kharel Himal , Jose Domench Daniel Idoate , Vijay Rao Aniket 
Published: December 2024

Background: The current study probed into the interplay between intravenous immunoglobulin administration and immune thrombocytopenic purpura on risk for venous thromboembolism (VTE) and pulmonary embolism (PE). Both ITP and IVIG have been independently reported to be associated with an increased risk for thrombosis. We aimed to investigate how IVIG administration influences the incidence of VTE/PE in the setting of ITP and to clarify if IVIG modulates the thrombotic risk inherent to ITP.
Methods: We conducted a retrospective analysis of the NIS database 2020 with an International Classification of Diseases (ICD)-10 diagnosis code for ITP, comorbidities, risk factors for VTE/PE along with the proportion of patients receiving IVIG and a diagnosis of VTE/PE. All statistical analyses were done by using STATA version SE18.0. The multivariate regression analysis was done after adjusting for demographic variables and comorbidities to estimate the adjusted odds ratio (aOR) of developing VTE/PE in those suffering from ITP that received IVIG
Results: There were 56,530 hospitalizations with a diagnosis of ITP. The median patient age was 58.9 (95% CI 58.3-59.5), and 56.55% of the patients were females. 26.9% of the patients have a Charlson Comorbidity Index (CCI) score of 0, while 16.5% scored 1 and 13.55% scored 2; 43.05% scored 3. The proportion of the patients who had IVIG out of the 56,530 hospitalizations for ITP is 4265.605 of the 56,530 who suffered VTE/PE. In this regard, a subgroup analysis among patients with ITP receiving IVIG was performed after adjusting for age, gender, race, CCI, and the risk factors of VTE/PE such as smoking, oral contraceptive intake, obesity, history of thrombosis, thrombophilia, cancer, myeloproliferative neoplasms, fracture, COPD, and varicose veins using multivariate regression analysis. This revealed that ITP patients who received IVIG had significantly decreased odds of developing VTE/PE with an aOR of 0.23 (95% CI of 0.05-0.91, p=0.037). This lowering of the thrombotic events in IVIG recipients may indicate a protective effect of IVIG in ITP.
Conclusion: Despite the intrinsic prothrombotic state associated with ITP, our results showed that intravenous immunoglobulin therapy in ITP was associated with a significantly reduced odds of VTE/PE. This would indicate that IVIG could reduce some of the thrombotic risks associated with ITP. These results are encouraging and need replication on larger prospective studies to clearly elucidate the mechanisms behind such an observed protective effect.
Continuous Positive Airway Pressure and Mandibular Advancement Splints: The CHOICE Multi-center Open-Label Randomized Clinical Trial
Authors: Hamoda Mona M , Huynh Nelly , Ayas Najib T. , Rompre Pierre , Bansback Nick , Masse Jean-François , Arcache Patrick , Lavigne Gilles , Series Frederic , Fleetham John A , Almeida Fernanda R. 
Published: December 2024

RATIONALEAdherence to Continuous Positive Airway Pressure (CPAP) for Obstructive Sleep Apnoea (OSA) continues to be low with high termination rates. Alternative therapies to CPAP are needed.OBJECTIVESTo compare objective adherence to CPAP and Mandibular Advancement Splints (MAS) and to evaluate their effectiveness. Additionally, to identify treatment usage patterns and the clinical effectiveness of having both therapies.METHODSThis multi-center, double-randomized, three-phase trial (titration/cross-over/observation) was conducted at three Canadian universities. Eligible participants were treatment-naïve with mild to severe OSA.MEASUREMENTS AND MAIN RESULTSPrimary outcome was objectively measured adherence (hours/night) during cross-over phase. Secondary outcomes included efficacy during cross-over phase; adherence during observational phase; patient-centered outcomes, blood pressure and side-effects during cross-over and observational phases. Duration of cross-over and observational phases were 2.5 and 6 months respectively.Eighty-one participants were enrolled in the first randomization. Seventy-nine entered the adaptation/titration phase [mean age (sd); 52·3 (10·8) years, 58 males], 73 entered the cross-over phase (included in the intention-to-treat analysis) and 64 completed the observation phase. Mean objective adherence over 1-month, MAS showed higher adherence than CPAP, 6·0versus5·3 h/night (difference= 0·7 h/night, 95% CI: 0·3–1·2 h, p<0·001). Mean CPAP-MAS difference (95% CI) in efficacy of 10·4 (7·8–13) events/hour, p<0·001. During the observation phase 55% (35/64) of participants chose to alternate therapies. All treatments led to substantial improvement in patient-centered outcomes.CONCLUSIONSDespite the higher efficacy of CPAP and higher adherence to MAS, both demonstrate comparable clinical effectiveness on patient-centered outcomes. Having both CPAP and MAS can improve long-term management of OSA.
The miR-6240 target gene Igf2bp3 promotes myoblast fusion by enhancing myomaker mRNA stability
Authors: Huang Yuxin , Wang Wei , Fan Xinhao , Liu Xiaoqin , Liu Weiwei , Wang Zishuai , Li Yixing , Yang Yalan , Tang Zhonglin 
Published: December 2024

Abstract
Background
Myoblast fusion plays a crucial role in myogenesis. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) functions as an RNA N6-methyladenosine reader and exerts important roles in various biological processes. While our prior study suggested Igf2bp3 contributes to myogenesis, its molecular regulatory mechanism is largely unclear.

Methods
Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot were used for gene expression analysis. siRNA and CRISPRi technologies were conducted to knockdown the expression of Igf2bp3. CRISPR/Cas9 technology was performed to knockout Igf2bp3. The Igf2bp3 overexpression vector was designed using the pcDNA3.1(+) vector. Immunofluorescence detection was employed for subcellular localization and cell differentiation analysis. Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2′-deoxyuridine (EdU) assays were conducted for cell proliferation and fusion detection. The dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were utilized for regulatory mechanism analysis of Igf2bp3.

Results
The overexpression of Igf2bp3 enhances myoblast fusion while knockdown of Igf2bp3 blocks the formation of myotubes. miR-6240 promotes myoblast proliferation while preventing myoblast differentiation and fusion by targeting the 3′ untranslated rgion (UTR) of Igf2bp3. Notably, the impacts of miR-6240 mimics on myoblast proliferation, differentiation, and fusion can be effectively counteracted by the overexpression of Igf2bp3. Moreover, our findings elucidate a direct interaction between Igf2bp3 and the myoblast fusion factor myomaker (Mymk). Igf2bp3 binds to Mymk to enhance its mRNA stability. This interaction results in increased expression of Mymk and heightened myoblast fusion.

Conclusions
Our study unveils Igf2bp3 as a novel post-transcriptional regulator of myoblast fusion through the miR-6240/Mymk axis, significantly contributing to our understanding of skeletal muscle development.

Graphical Abstract
Human liver organoids are susceptible to Plasmodium vivax infection
Authors: Nitaramorn Norapat , Kobpornchai Porntida , Tongkrajang Nongnat , Chaisri Urai , Imwong Mallika , Kulkeaw Kasem 
Published: December 2024

Abstract
Background
The eradication of Plasmodium vivax malaria is complicated due to the presence of hypnozoites, the hidden dormant form of the parasite that is present in the liver. Currently available drug regimens are effective at killing hypnozoites but cause side effects and are difficult to administer. Studies testing drugs for liver-stage malaria remain rare and mainly rely on the use of cancerous or immortalized hepatic cells and primary hepatocytes.

Methods
Organoids were used as platform to model liver-stage vivax malaria. Hepatic endoderm cells, endothelial progenitor cells and mesenchymal cells were generated from human induced pluripotent stem cells and self-assembled into liver organoids on top of Matrigel layer. Liver characteristic and maturity were examined through genes and proteins expression of liver markers, and liver functional tests before infected with Plasmodium vivax sporozoites. The infection was then verified by the detection of parasitophorous vacuole membrane proteins, Upregulated in Infectious Sporozoite 4 (UIS4), and blood-stage infection following co-culture with human reticulocytes.

Results
Generated liver organoids showed upregulation of liver specific transcripts including hepatic nuclear factor 4A (HNF4A), alpha-fetoprotein (AFP), and albumin (ALB) which also confirmed by the protein expression. Furthermore, those organoids resembled mature hepatocytes in terms of albumin secretion, fat and glycogen storage and cytochrome activity. Following invasion of P. vivax sporozoites, PvUIS4 was detected and the hepatic merozoites could develop into ring-stage and early trophozoites in human reticulocytes. Moreover, differential expression patterns of genes involved in lipid and cholesterol synthesis were also detected.

Conclusions
Stem cell-derived liver organoids resemble mature liver cells in terms of liver functions and are susceptible to infection with P. vivax sporozoites, paving the way for studies on the mechanism of hypnozoite formation and testing of possible hypnozoitocidal drugs.
Choroid plexus aging: structural and vascular insights from the HCP-aging dataset
Authors: Sun Zhe , Li Chenyang , Zhang Jiangyang , Wisniewski Thomas , Ge Yulin 
Published: December 2024

Abstract
Background
The choroid plexus (ChP), a highly vascularized structure within the ventricles, is essential for cerebrospinal fluid (CSF) production and metabolic waste clearance, crucial for neurofluid homeostasis and cognitive function. ChP enlargement is seen in normal aging and neurodegenerative diseases like Alzheimer’s disease (AD). Despite its key role of in the blood-CSF barrier (BCSFB), detailed studies on age-related changes in its perfusion and microstructure remain limited.

Methods
We analyzed data from 641 healthy individuals aged between 36 and 90, using the Human Connectome Project Aging (HCP-A) dataset. Volumetric, perfusion, and diffusion metrics of the ChP were derived from structural MRI, arterial spin labeling (ASL), and diffusion-weighted imaging (DWI), respectively. Partial correlations were used to explore age-related ChP changes, and independent t-tests to examine sex differences across age decades. One-way ANOVA was employed to compare perfusion characteristics among ChP, gray matter (GM), and white matter (WM). Relationships between volume, perfusion, and diffusion were investigated, adjusting for age and sex. Additionally, the distribution of cyst-like structures within the ChP and their diffusion/perfusion MRI characteristics were analyzed across different age groups.

Results
The ChP undergoes notable changes with age, including an increase in volume (r2 = 0.2, P < 0.001), a decrease in blood flow (r2 = 0.17, P < 0.001), and elevated mean diffusivity (MD) values (r2 = 0.16, P < 0.001). Perfusion characteristics showed significant differences between the ChP, GM, and WM (P < 0.001). Both the ChP and GM exhibited age-related declines in CBF, with a more pronounced decline in the ChP. A negative correlation was observed between the age-related increase in ChP volume and the decrease in CBF, suggesting compensatory dystrophic hyperplasia in response to perfusion decline. Cyst-like structures in ChP, characterized by lower MD and reduced CBF, were found to be more prevalent in older individuals.

Conclusions
Our findings provide a detailed quantitative assessment of age-related changes in ChP perfusion and diffusion, which may affect CSF production and circulation, potentially leading to waste solute accumulation and cognitive impairment.

Grant support
This work was supported in part by the NIH U01AG052564, P30AG066512, P01AG060882, RF1 NS110041, R01 NS108491, U24 NS135568.
Development and validation of a model based on preoperative dual-layer detector spectral computed tomography 3D VOI-based quantitative parameters to predict high Ki-67 proliferation index in pancreatic ductal adenocarcinoma
Authors: Zeng Dan , Zhang Jiayan , Song Zuhua , Li Qian , Zhang Dan , Li Xiaojiao , Wen Youjia , Ren Xiaofang , Wang Xinwei , Zhang Xiaodi , Tang Zhuoyue 
Published: December 2024

Abstract
Objective
To develop and validate a model integrating dual-layer detector spectral computed tomography (DLCT) three-dimensional (3D) volume of interest (VOI)-based quantitative parameters and clinical features for predicting Ki-67 proliferation index (PI) in pancreatic ductal adenocarcinoma (PDAC).

Materials and methods
A total of 162 patients with histopathologically confirmed PDAC who underwent DLCT examination were included and allocated to the training (114) and validation (48) sets. 3D VOI-iodine concentration (IC), 3D VOI-slope of the spectral attenuation curves, and 3D VOI-effective atomic number were obtained from the portal venous phase. The significant clinical features and DLCT quantitative parameters were identified through univariate analysis and multivariate logistic regression. The discrimination capability and clinical applicability of the clinical, DLCT, and DLCT-clinical models were quantified by the Receiver Operating Characteristic curve (ROC) and Decision Curve Analysis (DCA), respectively. The optimal model was then used to develop a nomogram, with the goodness-of-fit evaluated through the calibration curve.

Results
The DLCT-clinical model demonstrated superior predictive capability and a satisfactory net benefit for Ki-67 PI in PDAC compared to the clinical and DLCT models. The DLCT-clinical model integrating 3D VOI-IC and CA125 showed area under the ROC curves of 0.939 (95% CI, 0.895–0.982) and 0.915 (95% CI, 0.834–0.996) in the training and validation sets, respectively. The nomogram derived from the DLCT-clinical model exhibited favorable calibration, as depicted by the calibration curve.

Conclusions
The proposed model based on DLCT 3D VOI-IC and CA125 is a non-invasive and effective preoperative prediction tool demonstrating favorable predictive performance for Ki-67 PI in PDAC.

Critical relevance statement
The dual-layer detector spectral computed tomography-clinical model could help predict high Ki-67 PI in pancreatic ductal adenocarcinoma patients, which may help clinicians provide appropriate and individualized treatments.

Key Points

Dual-layer detector spectral CT (DLCT) could predict Ki-67 in pancreatic ductal adenocarcinoma (PDAC).

The DLCT-clinical model improved the differential diagnosis of Ki-67.

The nomogram showed satisfactory calibration and net benefit for discriminating Ki-67.

Graphical Abstract
MRI analysis of relative tumor enhancement in liver metastases and correlation with immunohistochemical features
Authors: Barajas Ordonez Felix , Gottschling Sebastian , Eger Kai Ina , Borggrefe Jan , Jechorek Dörthe , Surov Alexey 
Published: December 2024

Abstract
Objective
Investigate the association between the relative tumor enhancement (RTE) of gadoxetic acid across various MRI phases and immunohistochemical (IHC) features in patients with liver metastases (LM) from colorectal cancer (CRC), breast cancer (BC), and pancreatic cancer (PC).

Methods
A retrospective analysis was conducted on 68 patients with LM who underwent 1.5-T MRI scans. Non-contrast and contrast-enhanced T1-weighted (T1-w) gradient echo (GRE) sequences were acquired before LM biopsy. RTE values among LM groups were compared by cancer type using analysis of variance. The relationships between RTE and IHC features tumor stroma ratio, cell count, Ki67 proliferation index, and CD45 expression were evaluated using Spearman’s rank correlation coefficients.

Results
Significant differences in RTE were observed across different MRI phases among patients with BCLM, CRCLM, and PCLM: arterial phase (0.75 ± 0.42, 0.37 ± 0.36, and 0.44 ± 0.19), portal venous phase (1.09 ± 0.41, 0.59 ± 0.44, and 0.53 ± 0.24), and venous phase (1.11 ± 0.45, 0.65 ± 0.61, and 0.50 ± 0.20). In CRCLM, RTE inversely correlated with mean Ki67 (r = −0.50, p = 0.01) in the hepatobiliary phase. Negative correlations between RTE and CD45 expression were found in PCLM and CRCLM in the portal venous phase (r = −0.69, p = 0.01 and r = −0.41, p = 0.04) and the venous phase (r = −0.65, p = 0.01 and r = −0.44, p = 0.02).

Conclusion
Significant variations in RTE were identified among different types of LM, with correlations between RTE values and IHC markers such as CD45 and Ki67 suggesting that RTE may serve as a non-invasive biomarker for predicting IHC features in LM.

Critical relevance statement
RTE values serve as a predictive biomarker for IHC features in liver metastasis, potentially enhancing non-invasive patient assessment, disease monitoring, and treatment planning.

Key Points

Few studies link gadoxetic acid-enhanced MRI with immunohistochemistry in LM.

RTE varies by liver metastasis type and correlates with CD45 and Ki67.

RTE reflects IHC features in LM, aiding non-invasive assessment.

Graphical Abstract