bluuebunny/crossref_metadata_2025_split huggingface dataset:
CastNet: a systems-level sequence evolution simulator
Authors: Rivera-Rivera Carlos J. , Grbic Djordje 
Published: June 2023

Abstract
Background
Simulating DNA evolution has been done through coevolution-agnostic probabilistic frameworks for the past 3 decades. The most common implementation is by using the converse of the probabilistic approach used to infer phylogenies which, in the simplest form, simulates a single sequence at a time. However, biological systems are multi-genic, and gene products can affect each other’s evolutionary paths through coevolution. These crucial evolutionary dynamics still remain to be simulated, and we believe that modelling them can lead to profound insights for comparative genomics.

Results
Here we present CastNet, a genome evolution simulator that assumes each genome is a collection of genes with constantly evolving regulatory interactions in between them. The regulatory interactions produce a phenotype in the form of gene expression profiles, upon which fitness is calculated. A genetic algorithm is then used to evolve a population of such entities through a user-defined phylogeny. Importantly, the regulatory mutations are a response to sequence mutations, thus making a 1–1 relationship between the rate of evolution of sequences and of regulatory parameters. This is, to our knowledge, the first time the evolution of sequences and regulation have been explicitly linked in a simulation, despite there being a multitude of sequence evolution simulators, and a handful of models to simulate Gene Regulatory Network (GRN) evolution. In our test runs, we see a coevolutionary signal among genes that are active in the GRN, and neutral evolution in genes that are not included in the network, showing that selective pressures imposed on the regulatory output of the genes are reflected in their sequences.

Conclusion
We believe that CastNet represents a substantial step for developing new tools to study genome evolution, and more broadly, coevolutionary webs and complex evolving systems. This simulator also provides a new framework to study molecular evolution where sequence coevolution has a leading role.
Generation of sheep with defined FecBB and TBXT mutations and porcine blastocysts with KCNJ5G151R/+ mutation using prime editing
Authors: Zhou Shiwei , Lenk Laura Johanna , Gao Yawei , Wang Yuhui , Zhao Xiaoe , Pan Menghao , Huang Shuhong , Sun Kexin , Kalds Peter , Luo Qi , Lillico Simon , Sonstegard Tad , Scholl Ute I. , Ma Baohua , Petersen Bjoern , Chen Yulin , Wang Xiaolong 
Published: June 2023

Abstract
Background
Rewriting the genomes of living organisms has been a long-standing aim in the biological sciences. The revelation of the CRISPR/Cas9 technology has revolutionized the entire biological field. Since its emergence, this technology has been widely applied to induce gene knockouts, insertions, deletions, and base substitutions. However, the classical version of this system was imperfect for inducing or correcting desired mutations. A subsequent development generated more advanced classes, including cytosine and adenine base editors, which can be used to achieve single nucleotide substitutions. Nevertheless, these advanced systems still suffer from several limitations, such as the inability to edit loci without a suitable PAM sequence and to induce base transversions. On the other hand, the recently emerged prime editors (PEs) can achieve all possible single nucleotide substitutions as well as targeted insertions and deletions, which show promising potential to alter and correct the genomes of various organisms. Of note, the application of PE to edit livestock genomes has not been reported yet.

Results
In this study, using PE, we successfully generated sheep with two agriculturally significant mutations, including the fecundity-related FecBB p.Q249R and the tail length-related TBXT p.G112W. Additionally, we applied PE to generate porcine blastocysts with a biomedically relevant point mutation (KCNJ5 p.G151R) as a porcine model of human primary aldosteronism.

Conclusions
Our study demonstrates the potential of the PE system to edit the genomes of large animals for the induction of economically desired mutations and for modeling human diseases. Although prime-edited sheep and porcine blastocysts could be generated, the editing frequencies are still unsatisfactory, highlighting the need for optimizations in the PE system for efficient generation of large animals with customized traits.
Factors associated with pediatric febrile illnesses in 27 countries of Sub-Saharan Africa
Authors: Ssentongo Paddy , Chinchilli Vernon M. , Shah Khush , Harbaugh Thaddeus , Ba Djibril M. 
Published: June 2023

Abstract
Background
Evidence on the relative importance of various factors associated with febrile illness in children and their heterogeneity across countries can inform the prevention, identification, and management of communicable diseases in resource-limited countries. The objective of the study is to assess the relative significance of factors associated with childhood febrile illness in 27 sub-Saharan African countries.

Methods
This cross-sectional study of 298,327 children aged 0 to 59 months assessed the strengths of associations of 18 factors with childhood fevers, using Demographic and Health Surveys (2010-2018) from 27 sub-Saharan African countries. A total of 7 child level factors (i.e., respiratory illness, diarrhea, breastfeeding initiation; vitamin A supplements; child's age; full vaccination; sex), 5 maternal factors (maternal education; maternal unemployment; antenatal care; maternal age, and maternal marriage status) and 6 household factors (household wealth; water source; indoor pollution, stool disposal; family planning needs and rural residence) were assessed. Febrile illness was defined as the presence of fever in 2 weeks preceding the survey.

Results
Among the 298,327 children aged 0 to 59 months included in the analysis, the weighted prevalence of fever was 22.65% (95% CI, 22.31%-22.91%). In the pooled sample, respiratory illness was the strongest factor associated with fever in children (adjusted odds ratio [aOR], 5.46; 95% CI, 5.26-5.67; P < .0001), followed by diarrhea (aOR, 2.96; 95% CI, 2.85-3.08; P < .0001), poorest households (aOR, 1.33; 95% CI,1.23-1.44; P < .0001), lack of maternal education (aOR, 1.25; 95% CI, 1.10-1.41; P < .0001), and delayed breastfeeding (aOR, 1.18; 95% CI, 1.14-1.22; P < .0001. Febrile illnesses were more prevalent in children older than >6 months compared to those 6 months and younger. Unsafe water, unsafe stool disposal, and indoor pollution were not associated with child fever in the pooled analysis but had a large country-level heterogeneity.

Conclusions
Major causes of fevers in sub-Saharan Africa could be attributed to respiratory infections and possibly viral infections, which should not be treated by antimalarial drugs or antibiotics. Point-of-care diagnostics are needed to identify the pathogenic causes of respiratory infections to guide the clinical management of fevers in limited-resource countries.
Predicting hyperkalemia in patients with advanced chronic kidney disease using the XGBoost model
Authors: Chang Hsin-Hsiung , Chiang Jung-Hsien , Tsai Chun-Chieh , Chiu Ping-Fang 
Published: June 2023

Abstract
Background
Hyperkalemia is a common complication of chronic kidney disease (CKD). Hyperkalemia is associated with mortality, CKD progression, hospitalization, and high healthcare costs in patients with CKD. We developed a machine learning model to predict hyperkalemia in patients with advanced CKD at an outpatient clinic.

Methods
This retrospective study included 1,965 advanced CKD patients between January 1, 2010, and December 31, 2020 in Taiwan. We randomly divided all patients into the training (75%) and testing (25%) datasets. The primary outcome was to predict hyperkalemia (K+ > 5.5 mEq/L) in the next clinic vist. Two nephrologists were enrolled in a human-machine competition. The area under the receiver operating characteristic curves (AUCs), sensitivity, specificity, and accuracy were used to evaluate the performance of XGBoost and conventional logistic regression models with that of these physicians.

Results
In a human-machine competition of hyperkalemia prediction, the AUC, PPV, and accuracy of the XGBoost model were 0.867 (95% confidence interval: 0.840–0.894), 0.700, and 0.933, which was significantly better than that of our clinicians. There were four variables that were chosen as high-ranking variables in XGBoost and logistic regression models, including hemoglobin, the serum potassium level in the previous visit, angiotensin receptor blocker use, and calcium polystyrene sulfonate use.

Conclusions
The XGBoost model provided better predictive performance for hyperkalemia than physicians at the outpatient clinic.
Neuroinflammation and Brain Disease
Authors: Bersano A. , Engele J. , Schäfer M.K.E. 
Published: June 2023

AbstractStarting from the perspective of an immune-privileged site, our knowledge of the inflammatory processes within the central nervous system has increased rapidly over the last 30 years, leading to a rather puzzling picture today. Of particular interest is the emergence of disease- and injury-specific inflammatory responses within the brain, which may form the basis for future therapeutic approaches. To advance this important topic, we invite authors to contribute research and clinical papers to the Collection “Neuroinflammation and Brain Disease”.
Exploration of the role of emotional expression of treatment-resistant schizophrenia patients having followed virtual reality therapy: a content analysis
Authors: Hudon Alexandre , Lammatteo Veronica , Rodrigues-Coutlée Sophie , Dellazizzo Laura , Giguère Sabrina , Phraxayavong Kingsada , Potvin Stéphane , Dumais Alexandre 
Published: June 2023

Abstract
Background
Emotional responses are an important component of psychotherapeutic processes. Avatar therapy (AT) is a virtual reality-based therapy currently being developed and studied for patients suffering from treatment resistant schizophrenia. Considering the importance of identifying emotions in therapeutical processes and their impact on the therapeutic outcome, an exploration of such emotions is needed.

Methods
The aim of this study is to identify the underlying emotions at the core of the patient-Avatar interaction during AT by content analysis of immersive sessions transcripts and audio recordings. A content analysis of AT transcripts and audio recordings using iterative categorization was conducted for 16 patients suffering from TRS who underwent AT between 2017 and 2022 (128 transcripts and 128 audio recordings). An iterative categorization technique was conducted to identify the different emotions expressed by the patient and the Avatar during the immersive sessions.

Results
The following emotions were identified in this study: Anger, Contempt/ Disgust, Fear, Sadness, Shame/ Embarrassment, Interest, Surprise, Joy and Neutral. Patients expressed mostly neutral, joy and anger emotions whereas the Avatar expressed predominantly interest, disgust/contempt, and neutral emotions.

Conclusions
This study portrays a first qualitative insight on the emotions that are expressed in AT and serves as a steppingstone for further investigation in the role of emotions in the therapeutic outcomes of AT.
Knowledge support for environmental information on pharmaceuticals: experiences among Swedish Drug and Therapeutics Committees
Authors: Linder Elkanah , Wettermark Björn , Ovesjö Marie-Louise , Sporrong Sofia Kälvemark , Ramström Helena 
Published: June 2023

Abstract
Background
Two publicly available Swedish knowledge support systems, “Pharmaceuticals and Environment” on Janusinfo.se and Fass.se, provide environmental information on pharmaceuticals. Janusinfo is provided by the public healthcare system in Stockholm and Fass is provided by the pharmaceutical industry. The objectives of this study were to investigate the experiences among Swedish Drug and Therapeutics Committees (DTCs) with using the databases, retrieve development proposals for these, and investigate the DTCs’ challenges with working with pharmaceuticals in the environment.

Methods
A cross-sectional survey with 21 questions, both closed and open-ended, was distributed electronically in March 2022 to Sweden’s 21 DTCs. Descriptive statistics and inductive categorization were used for the analysis.

Results
A total of 132 respondents from 18 regions filled out the survey. The average regional response rate was 42%. The DTCs used the knowledge supports to consider environmental aspects of pharmaceuticals in their formularies and in education. Respondents were more familiar with Janusinfo compared to Fass but appreciated the availability of both. The DTCs especially valued the concrete proposals for certain active pharmaceutical ingredients on Janusinfo. Respondents requested that all medicinal products have environmental information on Fass. Challenges included lack of data, lack of transparency from the pharmaceutical industry and difficulties considering the environmental aspect of pharmaceuticals in their healthcare practice. Respondents wanted more knowledge, clear messages, and legislation to support their work to reduce the negative environmental impact of pharmaceuticals.

Conclusions
This study demonstrates that knowledge supports for environmental information on pharmaceuticals are valuable for the DTCs in Sweden, but the respondents experienced challenges in their work in this field. The study can provide insights to those in other countries interested in considering environmental aspects in their formulary decision-making.
Gene S-phase kinase associated protein 2 is a novel prognostic marker in human neoplasms
Authors: Li Guo-Sheng , Huang Tao , Zhou Hua-Fu 
Published: June 2023

Abstract
Background
Neoplasms are a series of diseases affecting human health. Prognostic and tumor status–related markers for various tumors should be identified.

Methods
Based on 19,515 samples from multiple sources, for the first time, this study provided an overview of gene S-phase kinase associated protein 2 (SKP2) in pan-cancer. Differential SKP2 expression in multiple comparison groups was identified by the Kruskal–Wallis test and Wilcoxon rank-sum test. The prognosis significance of SKP2 in individuals with neoplasm was evaluated through univariate Cox regression analysis and Kaplan-Meier curves. The area under the curve was utilized to detect the accuracy of SKP2 in predicting cancer status. Spearman’s rank correlation coefficients were calculated in all correlation analyses. Gene set enrichment analysis was used to identify essential signaling pathways of SKP2 in human neoplasms.

Results
The study disclosed the upregulated SKP2 expression in 15 neoplasms and decreased SKP2 expression in three cancers (p < 0.05). The transcription factor Forkhead Box M1 may contribute to the increased expression levels of SKP2 in certain tumors. Over-expressed SKP2 represented a risk factor for the prognosis of most cancer patients (hazard ratio > 1, p < 0.05). SKP2 expression made it feasible to distinguish neoplasm and control tissues of 21 neoplasms (sensitivity = 0.79, specificity = 0.87, area under the curve = 0.90), implying its potential in screening a series of neoplasms. Further, the research revealed the close association of SKP2 expression with DNA methyltransferases, mismatch repair genes, microsatellite instability, tumor mutational burden, neoantigen count, and immunity.

Conclusions
SKP2 plays an essential role in multiple neoplasms and may serve as a marker for treating and identifying these neoplasms.
Duration-dependent impact of cardiometabolic diseases and multimorbidity on all-cause and cause-specific mortality: a prospective cohort study of 0.5 million participants
Authors: Han Yuting , Hu Yizhen , Yu Canqing , Sun Dianjianyi , Pang Yuanjie , Pei Pei , Yang Ling , Chen Yiping , Du Huaidong , Liu Jingchao , Schmidt Dan , Avery Daniel , Chen Junshi , Chen Zhengming , Li Liming , Lv Jun 
Published: June 2023

Abstract
Background
The association of incident cardiometabolic multimorbidity (CMM) with mortality risk is rarely studied, and neither are the durations of cardiometabolic diseases (CMDs). Whether the association patterns of CMD durations with mortality change as individuals progress from one CMD to CMM is unclear.

Methods
Data from China Kadoorie Biobank of 512,720 participants aged 30–79 was used. CMM was defined as the simultaneous presence of two or more CMDs of interest, including diabetes, ischemic heart disease, and stroke. Cox regression was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the duration-dependent associations of CMDs and CMM with all-cause and cause-specific mortality. All information on exposures of interest was updated during follow-up.

Results
During a median follow-up of 12.1 years, 99,770 participants experienced at least one incident CMD, and 56,549 deaths were documented. Among 463,178 participants free of three CMDs at baseline, compared with no CMD during follow-up, the adjusted HRs (95% CIs) between CMM and all-cause mortality, mortality from circulatory system diseases, respiratory system diseases, cancer, and other causes were 2.93 (2.80–3.07), 5.05 (4.74–5.37), 2.72 (2.35–3.14), 1.30 (1.16–1.45), and 2.30 (2.02–2.61), respectively. All CMDs exhibited a high mortality risk in the first year of diagnosis. Subsequently, with prolonged disease duration, mortality risk increased for diabetes, decreased for IHD, and sustained at a high level for stroke. With the presence of CMM, the above association estimates inflated, but the pattern of which remained.

Conclusion
Among Chinese adults, mortality risk increased with the number of the CMDs and changed with prolonged disease duration, the patterns of which varied among the three CMDs.
Real-world hepatitis C treatment outcomes and reinfections among people who inject drugs at a needle and syringe program in Stockholm, Sweden
Authors: Lindqvist K. , Thorin Z. , Kåberg M. 
Published: June 2023

Abstract
Background
People who inject drugs (PWID) represent a population with an increased prevalence of hepatitis C (HCV) infections. HCV treatment among PWID is essential to reach the WHO goal of eliminating HCV as a major public health threat by 2030. Despite better understanding of PWID subgroups and changes in risk behaviors over time, more knowledge about HCV treatment outcomes in different HCV prevalence populations and settings is warranted to enhance the continuum of care.

Methods
All Stockholm Needle and Syringe Program (NSP) participants who initiated HCV treatment between October 2017 and June 2020 were HCV RNA tested at end of treatment and twelve weeks thereafter to confirm cure with a sustained virological response (SVR). All cured participants were prospectively followed from SVR to the last negative HCV RNA test or a subsequent reinfection, until October 31, 2021.

Results
Overall, 409 NSP participants initiated HCV treatment, 162 at the NSP and 247 in another treatment setting. There were a total of 6.4% treatment dropouts (n = 26), 11.7% among participants treated at the NSP and 2.8% among those treated elsewhere (p < 0.001). Stimulant use (p < 0.05) and not being in an opioid agonist treatment program (p < 0.05) was associated with dropout. More participants treated outside the NSP were lost to follow-up between end of treatment and SVR (p < 0.05). During follow-up post-SVR, 43 reinfections occurred, corresponding to a reinfection rate of 9.3/100 PY (95% CI 7.0, 12.3). Factors associated with reinfection were younger age (p < 0.001), treatment while in prison (p < 0.01) and homelessness (p < 0.05).

Discussion
In this high HCV prevalence NSP setting, with a majority of stimulant users, treatment success was high and the level of reinfections manageable. To reach HCV elimination, there is a need to target specific PWID subgroups for HCV treatment, in both harm reduction and adjacent healthcare settings frequented by PWID.
Metabolomic phenotyping of obesity for profiling cardiovascular and ocular diseases
Authors: Zhong Pingting , Tan Shaoying , Zhu Zhuoting , Bulloch Gabriella , Long Erping , Huang Wenyong , He Mingguang , Wang Wei 
Published: June 2023

Abstract
Background
We aimed to evaluate the impacts of metabolomic body mass index (metBMI) phenotypes on the risks of cardiovascular and ocular diseases outcomes.

Methods
This study included cohorts in UK and Guangzhou, China. By leveraging the serum metabolome and BMI data from UK Biobank, this study developed and validated a metBMI prediction model using a ridge regression model among 89,830 participants based on 249 metabolites. Five obesity phenotypes were obtained by metBMI and actual BMI (actBMI): normal weight (NW, metBMI of 18.5–24.9 kg/m2), overweight (OW, metBMI of 25–29.9 kg/m2), obesity (OB, metBMI ≥ 30 kg/m2), overestimated (OE, metBMI-actBMI > 5 kg/m2), and underestimated (UE, metBMI-actBMI < − 5 kg/m2). Additional participants from the Guangzhou Diabetes Eye Study (GDES) were included for validating the hypothesis. Outcomes included all-cause and cardiovascular (CVD)-cause mortality, as well as incident CVD (coronary heart disease, heart failure, myocardial infarction [MI], and stroke) and age-related eye diseases (age-related macular degeneration [AMD], cataracts, glaucoma, and diabetic retinopathy [DR]).

Results
In the UKB, although OE group had lower actBMI than NW group, the OE group had a significantly higher risk of all-cause mortality than those in NW prediction group (HR, 1.68; 95% CI 1.16–2.43). Similarly, the OE group had a 1.7–3.6-fold higher risk than their NW counterparts for cardiovascular mortality, heart failure, myocardial infarction, and coronary heart disease (all P < 0.05). In addition, risk of age-related macular denegation (HR, 1.96; 95% CI 1.02–3.77) was significantly higher in OE group. In the contrast, UE and OB groups showed similar risks of mortality and of cardiovascular and age-related eye diseases (all P > 0.05), though the UE group had significantly higher actBMI than OB group. In the GDES cohort, we further confirmed the potential of metabolic BMI (metBMI) fingerprints for risk stratification of cardiovascular diseases using a different metabolomic approach.

Conclusions
Gaps of metBMI and actBMI identified novel metabolic subtypes, which exhibit distinctive cardiovascular and ocular risk profiles. The groups carrying obesity-related metabolites were at higher risk of mortality and morbidity than those with normal health metabolites. Metabolomics allowed for leveraging the future of diagnosis and management of ‘healthily obese’ and ‘unhealthily lean’ individuals.