bluuebunny/crossref_metadata_2025_split huggingface dataset:
Application of a localized morphometrics approach to imaging-derived brain phenotypes for genotype-phenotype associations in pediatric mental health and neurodevelopmental disorders
Authors: Dagasso Gabrielle , Wilms Matthias , MacEachern Sarah J. , Forkert Nils D. 
Published: December 2024

IntroductionQuantitative global or regional brain imaging measurements, known as imaging-specific or -derived phenotypes (IDPs), are commonly used in genotype-phenotype association studies to explore the genomic architecture of the brain and how it may be affected by neurological diseases (e.g., Alzheimer's disease), mental health (e.g., depression), and neurodevelopmental disorders (e.g., attention-deficit hyperactivity disorder [ADHD]). For this purpose, medical images have been used as IDPs using a voxel-wise or global approach via principal component analysis. However, these methods have limitations related to multiple testing or the inability to isolate high variation regions, respectively.MethodsTo address these limitations, this study investigates a localized, principal component analysis-like approach for dimensionality reduction of cross-sectional T1-weighted MRI datasets utilizing diffeomorphic morphometry. This approach can reduce the dimensionality of images while preserving spatial information and enables the inclusion of spatial locality in the analysis. In doing so, this method can be used to explore morphometric brain changes across specific components and spatial scales of interest and to identify associations with genome regions in a multivariate genome-wide association study. For a first clinical feasibility study, this method was applied to data from the Adolescent Brain Cognitive Development (ABCD) study, including adolescents with ADHD (n = 1,359), obsessive-compulsive disorder (n = 1,752), and depression (n = 1,766).ResultsMeaningful associations of specific morphometric features with genome regions were identified with the data and corresponded to previous found brain regions in the respective mental health and neurodevelopmental disorder cohorts.DiscussionIn summary, the localized, principal component analysis-like approach can reduce the dimensionality of medical images while still being able to identify meaningful local brain region alterations that are associated with genomic markers across multiple scales. The proposed method can be applied to various image types and can be easily integrated in many genotype-phenotype association study setups.
The embryo stage at fresh ET does not affect the cumulative live birth rate in women with a thin endometrium: a retrospective matched-controlled cohort study
Authors: Han Qiao-Song , Chen Yan-Hua , Zhang Bin , Song Jing-Yan , Xu Ying , Li Heng-Bing , Guo Zi-Zhen , Sun Zhen-Gao 
Published: December 2024

BackgroundThe blastocyst-stage embryo has been considered more advantageous for increasing the cumulative live birth rate (CLBR) at fresh embryo transfer (ET) compared to the cleavage-stage embryo. However, it remains uncertain whether this advantage extends to specialized subpopulations, such as women with thin endometrium (TE), who are characteristic of impaired endometrial receptivity. Thus, this study aims to evaluate the difference in the CLBR between cleavage-stage and blastocyst-stage embryos at fresh ET specifically in women with TE.MethodsA retrospective cohort comprising 1089 women from three centers, ranging from September 2017 to January 2022, was established. These women were diagnosed with TE (defined as endometrium thickness &lt;= 8 mm) and underwent their first fresh ET. To create a comparable cohort between the cleavage and blastocyst groups while adjusting for key covariates, the propensity score matching (PSM) method was employed. The primary outcome assessed was the CLBR per woman. Both cohorts underwent Kaplan-Meier analysis, Cox proportional hazard models, cumulative incidence function (CIF) curve analysis, and Fine-Grey competing risk models to ascertain the impact of embryo stage at fresh ET on CLBR. Additionally, a sensitivity analysis was conducted within a subgroup defining thin endometrium as an endometrium thickness (EMT) &lt; 7 mm.ResultsIn the matched cohort after PSM, the CLBR was comparable between groups (p=0.331). However, the cleavage-stage fresh ET was associated with an elevated risk of low birth weight (LBW) (p=0.005) and small for gestational age (SGA) (p=0.037). Kaplan-Meier analysis showed that the median number of embryo transfer cycles was 2 in the cleavage group and 3 in the blastocyst group. The CLBR for the cleavage group reached 78.1%, while the blastocyst group reached 60.0% after 5 cycles of embryo transfers (log-rank test, p=0.09). A multivariable Cox proportional hazard model indicated no significant association between the embryo stage at fresh ET and CLBR (HR=0.80, 95% CI=0.60-1.07). The CIF curve and Fine-Grey competing risk models demonstrated similar results. These analyses were repeated in the original cohort before PSM and in the subgroup with EMT &lt; 7 mm, and the results remained robust.ConclusionFor TE women receiving fresh ET, the choice between the cleavage-stage embryo and the blastocyst-stage embryo yields comparable CLBR. However, selecting the cleavage-stage embryo is associated with increased risks of LBW and SGA births.
Elevated circulating homocysteine concentrations delayed nerve conduction velocity and increase the risk of diabetic kidney disease in patients with type 2 diabetes
Authors: Lv Nannan , Jia Luzhu , Liu Fei , Cheng Lan , Liu Feng , Kuang Jinsong , Chen Xin 
Published: December 2024

IntroductionChina has the largest population of individuals with diabetes, and the prevalence of various complications among patients with type 2 diabetes remains high. Diabetic nephropathy affects approximately 20% to 40% of diabetic patients, becoming a major cause of chronic kidney disease and end-stage renal disease. Furthermore, around 50% of patients develop diabetic peripheral neuropathy (DPN), which is closely associated with physical disability, increased healthcare costs, and reduced work productivity. There is an urgent need for novel strategies in prevention, diagnosis, and treatment to improve patient outcomes.MethodsIn this study, 163 patients with type 2 diabetes were selected as the observation group and further divided into three subgroups based on homocysteine (HCY) levels. The study measured several clinical parameters, including homocysteine, blood glucose, blood lipids, glycated hemoglobin, urinary microalbumin, urinary albumin-to-creatinine ratio (ACR), electromyography, and highly-sensitive C-reactive protein (CRP), among others. The levels of these indicators were analyzed and compared across the subgroups.ResultsThe results revealed significant differences in uric acid, creatinine, urinary microalbumin, urinary ACR, and nerve conduction velocity (right tibial nerve sensory conduction) among different HCY levels in patients with type 2 diabetes (P &lt; 0.05). Linear regression analysis indicated that homocysteine levels were associated with systolic blood pressure, glycated hemoglobin, fasting C-peptide, uric acid, creatinine, urinary microalbumin, and nerve conduction velocity (including motor conduction velocity of the ulnar nerve and sensory conduction velocity of the sural nerve).DiscussionThe clinical assessment of homocysteine in diabetic patients holds significant importance in the prevention of microvascular complications. Lowering HCY levels may offer a promising therapeutic approach for managing microvascular disease in diabetes.
Unveiling risk factors for post-COVID-19 syndrome development in people with type 2 diabetes
Authors: Matviichuk Anton , Yerokhovych Viktoriia , Zemskov Sergii , Ilkiv Yeva , Gurianov Vitalii , Shaienko Zlatoslava , Falalyeyeva Tetyana , Sulaieva Oksana , Kobyliak Nazarii 
Published: December 2024

IntroductionPost-COVID-19 syndrome (PCS) is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-associated chronic condition characterized by long-term violations of physical and mental health. People with type 2 diabetes (T2D) are at high risk for severe COVID-19 and PCS.AimThe current study aimed to define the predictors of PCS development in people with T2D for further planning of preventive measures and improving patient outcomes.Materials and methodsThe data were collected through the national survey targeting persons with T2D concerning the history of COVID-19 course and signs and symptoms that developed during or after COVID-19 and continued for more than 12 weeks and were not explained by an alternative diagnosis. In total, 469 patients from different regions of Ukraine were enrolled in the study. Among them, 227 patients reported PCS development (main group), while 242 patients did not claim PCS symptoms (comparison group). Stepwise multivariate logistic regression and probabilistic neural network (PNN) models were used to select independent risk factors.ResultsBased on the survey data, 8 independent factors associated with the risk of PCS development in T2D patients were selected: newly diagnosed T2D (OR 4.86; 95% CI 2.55–9.28; p&lt;0.001), female sex (OR 1.29; 95% CI 0.86–1.94; p=0.220), COVID-19 severity (OR 1.35 95% CI 1.05–1.70; p=0.018), myocardial infarction (OR 2.42 95% CI 1.26–4.64; p=0.002) and stroke (OR 3.68 95% CI 1.70–7.96; p=0.001) in anamnesis, HbA1c above 9.2% (OR 2.17 95% CI 1.37–3.43; p=0.001), and the use of insulin analogs (OR 2.28 95% CI 1.31–3.94; p=0.003) vs human insulin (OR 0.67 95% CI 0.39–1.15; p=0.146). Although obesity aggravated COVID-19 severity, it did not impact PCS development. In ROC analysis, the 8-factor multilayer perceptron (MLP) model exhibited better performance (AUC 0.808; 95% CІ 0.770–0.843), allowing the prediction of the risk of PCS development with a sensitivity of 71.4%, specificity of 76%, PPV of 73.6% and NPV of 73.9%.ConclusionsPatients who were newly diagnosed with T2D, had HbA1c above 9.2%, had previous cardiovascular or cerebrovascular events, and had severe COVID-19 associated with mechanical lung ventilation were at high risk for PCS.
Association between thyroid hormone sensitivity and carotid plaque risk: a health examination cohort-based study
Authors: Gong Rui , Wang Shi , Ding Hongqiong , Yu Lixia , Xu Ming , Xu Sanping , Ling Yan 
Published: December 2024

IntroductionThe involvement of thyroid hormone in cardiovascular disease remains debated. The aim of our research was to ascertain whether thyroid hormone sensitivity indices are related to carotid plaque (CAP) risk in the general population.MethodsWe recruited 5,360 participants for health examinations to explore the correlation between thyroid hormone sensitivity indices and CAP risk. We then compared baseline characteristics of participants with CAP to those without CAP based on multivariate logistic regression analysis. Additionally, we conducted subgroup analyses stratified by gender and age to further elucidate this relationship.ResultsAmong the 5,360 participants, 1,055 (19.7%) were diagnosed with CAP. After adjusting for various confounding factors, our results showed a positive association between CAP risk and the indices (TFQI, PTFQI, TSHI, and TT4RI). Conversely, the FT3/FT4 ratio showed a negative correlation with CAP risk. Sex-based subgroup analysis revealed a stronger correlation between thyroid hormone sensitivity and CAP in females compared to males. In the age subgroup, the significant association was observed in older individuals (age &gt;60) compared to middle-aged participants (age ≤60).ConclusionOur study suggests a significant correlation between thyroid hormone sensitivity and CAP, particularly in females and participants over the age of 60.
Association between arthropathies and postpartum hemorrhage: a bidirectional Mendelian randomization study
Authors: Wu Zhao , Yuan Chengyu , Peng Xue 
Published: December 2024

BackgroundResearch links arthropathies with adverse pregnancy outcomes. This study aims to explore its connection to postpartum hemorrhage (PPH) through Mendelian randomization (MR) analysis.MethodsThe study used GWAS data from the IEU OpenGWAS database for PPH and arthropathies. After selecting instrumental variables, bidirectional MR analysis was conducted using MR-Egger, Weighted median, Simple mode, Weighted mode, and IVW methods. Sensitivity analysis was then performed to assess MR results reliability. Finally, enrichment analysis of genes corresponding to arthropathies SNPs in forward MR was conducted to explore their biological function and signaling pathways.ResultsThe forward MR results revealed that arthropathies was causally related to PPH, and arthropathies was a risk factor for PPH. Whereas, there was not a causal relationship between PPH and arthropathies by reverse MR analysis. It illustrated the reliability of the MR analysis results by the sensitivity analysis without heterogeneity, horizontal pleiotropy, and SNPs of severe bias by LOO analysis. Furthermore, a total of 33 genes corresponding to SNPs of arthropathies were obtained, which were mainly enriched in regulation of response to biotic stimulus, spliceosomal snRNP complex and ligase activity in GO terms, and natural killer cell-mediated cytotoxicity in KEGG pathways.ConclusionThis study supported that arthropathies was a risk factor for PPH, and the pathways involved the genes corresponding to SNPs were analyzed, which could provide important reference and evidence for further exploring the molecular mechanism between arthropathies and PPH.
Widening the infantile hypotonia with psychomotor retardation and characteristic Facies-1 Syndrome’s clinical and molecular spectrum through NALCN in-silico structural analysis
Authors: Vecchio Davide , Macchiaiolo Marina , Gonfiantini Michaela V. , Panfili Filippo M. , Petrizzelli Francesco , Liorni Niccolò , Cortellessa Fabiana , Sinibaldi Lorenzo , Rana Ippolita , Agolini Emanuele , Cocciadiferro Dario , Colantoni Nicole , Semeraro Michela , Rizzo Cristiano , Deodati Annalisa , Cotugno Nicola , Caggiano Serena , Verrillo Elisabetta , Nucci Carlotta G. , Alkan Serpil , Saraiva Jorge M. , De Sá Joaquim , Almeida Pedro M. , Krishna Jayanth , Buonuomo Paola S. , Martinelli Diego , Dionisi Vici Carlo , Caputo Viviana , Bartuli Andrea , Novelli Antonio , Mazza Tommaso 
Published: December 2024

IntroductionInfantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1, MIM#615419) is a rare, birth onset, autosomal recessive disorder caused by homozygous or compound heterozygous truncating variants in NALCN gene (MIM#611549) resulting in a loss-of-function effect.MethodsWe enrolled a new IHPRF1 patients’ cohort in the framework of an international multicentric collaboration study. Using specialized in silico pathogenicity predictors and ad hoc structural analyses, we assessed the mechanistic consequences of the deleterious variants retrieved on NALCN structure and function.ResultsTo date 38 different NALCN variants have been retrieved from 33 different families, 26 from unrelated and 22 from related patients. We report on five new IHPRF1 patients from four different families, harboring four newly identified and one previously retrieved variant that exhibited a markedly significant functional impact, thereby compromising the functionality of the protein complex.DiscussionBy widening the functional spectrum of biallelic variants affecting the NALCN gene, this article broadens the IHPRF1 syndrome’s genotype-phenotype correlation and gives new insight into its pathogenic mechanism, diagnosis, and clinical management.
Unraveling metabolic signatures in SARS-CoV-2 variant infections using multiomics analysis
Authors: Lee Sunho , Lee Jueun , Lyoo Kwang-Soo , Shin Yourim , Shin Dong-Min , Kim Jun-Won , Yang Jeong-Sun , Kim Kyung-Chang , Lee Joo-Yeon , Hwang Geum-Sook 
Published: December 2024

IntroductionThe emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, notably delta and omicron, has significantly accelerated the global pandemic, worsening conditions worldwide. However, there is a lack of research concerning the molecular mechanisms related to immune responses and metabolism induced by these variants. MethodsHere, metabolomics combined with transcriptomics was performed to elucidate the immunometabolic changes in the lung of hamsters infected with delta and omicron variants.ResultsBoth variants caused acute inflammation and lung pathology in intranasally infected hamsters. Principal component analysis uncovered the delta variant significantly altered lung metabolite levels between the pre- and post-infection states. Additionally, metabolic pathways determined by assessment of metabolites and genes in lung revealed significant alterations in arginine biosynthesis, glutathione metabolism, and tryptophan metabolism upon infection with both variants and closely linked to inflammatory cytokines, indicating immune activation and oxidative stress in response to both variants. These metabolic changes were also evident in the serum, validating the presence of systemic alterations corresponding to those identified in lung. Notably, the delta variant induced a more robust metabolic regulation than the omicron variant. DiscussionThe study suggests that multi-omics is a valuable approach for understanding immunometabolic responses to infectious diseases, and providing insights for effective treatment strategies.
Linsitinib inhibits proliferation and induces apoptosis of both IGF-1R and TSH-R expressing cells
Authors: Luffy Maximilian , Ganz Anna-Lena , Wagner Stefanie , Wolf Jan , Ropertz Julian , Zeidan Ryan , Kent Jeffrey D. , Douglas Raymond S. , Kahaly George J. 
Published: December 2024

BackgroundThe insulin-like growth factor 1 receptor (IGF-1R) and the thyrotropin receptor (TSH-R) are expressed on orbital cells and thyrocytes. These receptors are targeted in autoimmune-induced thyroid eye disease (TED). Effective therapeutic treatment of TED inhibits activation of the IGF-1R/TSH-R complex.MethodsThe inhibitory effect on cell proliferation of a small molecule targeting IGF-1R phosphorylation (Linsitinib) was investigated in an IGF-1R expressing cell line and a Chinese Hamster Ovary (CHO) cell line overexpressing TSH-R. An IGF-1R monoclonal antibody antagonist, Teprotumumab served as control. Both cell lines were plated in a 96-well format and treated with both compounds for 24 hours. After addition of tetrazolium, absorbance was measured. The apoptosis marker caspase-3/7 activity was measured. The half-maximal inhibitory concentration (IC50) of TSH-R-Ab induced stimulation (stimulatory monoclonal antibody, mAb, M22) of the TSH-R cell line was evaluated with a cell-based bioassay for blocking TSH-R-Ab. Cells were treated with ten rising concentrations of either Linsitinib, Linsitinib + Metformin, Teprotumumab, or a blocking TSH-R mAb (K1-70).ResultsLinsitinib strongly inhibited the proliferation of both cell lines at several concentrations: 31,612.5 ng/mL (IGF-1R cell line -78%, P=0.0031, TSH-R cell line -75%, P=0.0059), and at 63,225 ng/mL (IGF-1R cell line -73%, P=0.0073, TSH-R cell line -73%, P=0.0108). Linsitinib induced apoptosis of both cell lines, both morphologically confirmed and with an increased caspase-3/7 activity at concentrations of 31,612.5 ng/mL (IGF-1R cell line P=0.0158, TSH-R cell line P=0.0048) and 63,225 ng/mL (IGF-1R cell line P=0.0005, TSH-R cell line P=0.0020). Linsitinib markedly inhibited proliferation of the IGF-1R cell line at all concentrations compared to Teprotumumab (P=0.0286). Teprotumumab inhibition was significant only at 15,806.25 ng/mL with the TSH-R cell line (-15%, P=0.0396). In addition, in the TSH-R-Ab blocking bioassay, Linsitinib and the tested compounds demonstrated strong inhibition across all ten dilutions (100%).ConclusionsLinsitinib effectively induces apoptosis and inhibits proliferation of both IGF-1R and TSH-R expressing target cells, therefore demonstrating its therapeutic potential to block the reported crosstalk of the two mediators in autoimmune TED.
Development and validation of clinical criteria for critical illness-associated immune dysfunction: based on the MIMIC-IV database
Authors: Zhou Yanyou , Tao Linfeng , Yang Shengsheng , Li Juntu , Liu Jun 
Published: December 2024

BackgroundCritical illness-associated immune dysfunction (CIID) is prevalent in the ICU and frequently resulted in uncontrollably immune responses. Critical immunological dysfunction is understood to be important, although there are currently no clinically accepted diagnostic criteria for it. Given this, we examined the literature and developed an initial diagnostic criterion that we validated using the MIMIC-IV database.MethodsWe searched the related literature in the last 32 years. Patients admitted to the ICU for the first time were selected by screening the MIMIC-IV database. Different criteria were used to categorize patients into groups related to immune dysfunction (ID) and non-immune dysfunction (NID). Within the ID group, patients were subdivided into three subgroups: hyperinflammatory (HI), immunosuppression (IS), and a subgroup combining immunosuppression and hyperinflammation (HI+IS). The APACHE II was used to measure the patients’ severity. The association between immune dysfunction and mortality after 30 or 180 days was evaluated through the KM curves and COX regression analysis.ResultsBy summarizing relevant literature, we proposed the initial diagnostic criteria. The analysis included 43,965 patients, with approximately 77% meeting the diagnostic criteria for CIID. We observed that patients with immune dysfunction possessed higher APACHE II scores and there were differences in peak APACHE II among the three subgroups. When comparing patients’ 30-day mortality in the COX model, it is evident that patients in the IS subgroup had the lowest risk and patients in the HI subgroup the greatest risk after accounting for all covariates. In contrast, patients in the IS subgroup had the highest risk of death, those in the HI subgroup had the lowest risk when comparing long-term mortality. In summary, we propose and validate diagnostic criteria related to CIID. Subgroup analyses were carried out, which also revealed variations between the three groups.ConclusionThe diagnostic criteria were confirmed by the MIMIC-IV database, demonstrating the diagnostic criteria were scientifically valid and reliable.