bluuebunny/crossref_metadata_2025 huggingface dataset:
Generic model to unravel the deeper insights of viral infections: an empirical application of evolutionary graph coloring in computational network biology
Authors: Kole Arnab , Bag Arup Kumar , Pal Anindya Jyoti , De Debashis
Published: February 2024

Purpose

Graph coloring approach has emerged as a valuable problem-solving tool for both theoretical and practical aspects across various scientific disciplines, including biology. In this study, we demonstrate the graph coloring’s effectiveness in computational network biology, more precisely in analyzing protein–protein interaction (PPI) networks to gain insights about the viral infections and its consequences on human health. Accordingly, we propose a generic model that can highlight important hub proteins of virus-associated disease manifestations, changes in disease-associated biological pathways, potential drug targets and respective drugs. We test our model on SARS-CoV-2 infection, a highly transmissible virus responsible for the COVID-19 pandemic. The pandemic took significant human lives, causing severe respiratory illnesses and exhibiting various symptoms ranging from fever and cough to gastrointestinal, cardiac, renal, neurological, and other manifestations.

Methods

To investigate the underlying mechanisms of SARS-CoV-2 infection-induced dysregulation of human pathobiology, we construct a two-level PPI network and employed a differential evolution-based graph coloring (DEGCP) algorithm to identify critical hub proteins that might serve as potential targets for resolving the associated issues. Initially, we concentrate on the direct human interactors of SARS-CoV-2 proteins to construct the first-level PPI network and subsequently applied the DEGCP algorithm to identify essential hub proteins within this network. We then build a second-level PPI network by incorporating the next-level human interactors of the first-level hub proteins and use the DEGCP algorithm to predict the second level of hub proteins.

Results

We first identify the potential crucial hub proteins associated with SARS-CoV-2 infection at different levels. Through comprehensive analysis, we then investigate the cellular localization, interactions with other viral families, involvement in biological pathways and processes, functional attributes, gene regulation capabilities as transcription factors, and their associations with disease-associated symptoms of these identified hub proteins. Our findings highlight the significance of these hub proteins and their intricate connections with disease pathophysiology. Furthermore, we predict potential drug targets among the hub proteins and identify specific drugs that hold promise in preventing or treating SARS-CoV-2 infection and its consequences.

Conclusion

Our generic model demonstrates the effectiveness of DEGCP algorithm in analyzing biological PPI networks, provides valuable insights into disease biology, and offers a basis for developing novel therapeutic strategies for other viral infections that may cause future pandemic.
In silico prediction of the metabolism of Blastocrithidia nonstop, a trypanosomatid with non-canonical genetic code
Authors: Opperdoes Fred R. , Záhonová Kristína , Škodová-Sveráková Ingrid , Bučková Barbora , Chmelová Ľubomíra , Lukeš Julius , Yurchenko Vyacheslav
Published: February 2024

Background

Almost all extant organisms use the same, so-called canonical, genetic code with departures from it being very rare. Even more exceptional are the instances when a eukaryote with non-canonical code can be easily cultivated and has its whole genome and transcriptome sequenced. This is the case of Blastocrithidia nonstop, a trypanosomatid flagellate that reassigned all three stop codons to encode amino acids.

Results

We in silico predicted the metabolism of B. nonstop and compared it with that of the well-studied human parasites Trypanosoma brucei and Leishmania major. The mapped mitochondrial, glycosomal and cytosolic metabolism contains all typical features of these diverse and important parasites. We also provided experimental validation for some of the predicted observations, concerning, specifically presence of glycosomes, cellular respiration, and assembly of the respiratory complexes.

Conclusions

In an unusual comparison of metabolism between a parasitic protist with a massively altered genetic code and its close relatives that rely on a canonical code we showed that the dramatic differences on the level of nucleic acids do not seem to be reflected in the metabolisms. Moreover, although the genome of B. nonstop is extremely AT-rich, we could not find any alterations of its pyrimidine synthesis pathway when compared to other trypanosomatids. Hence, we conclude that the dramatic alteration of the genetic code of B. nonstop has no significant repercussions on the metabolism of this flagellate.
Genome-wide identification, structural characterization and gene expression analysis of the WRKY transcription factor family in pea (Pisum sativum L.)
Authors: Xiong Ruiqi , Peng Zhonghua , Zhou Hui , Xue Guoxing , He Ailing , Yao Xin , Weng Wenfeng , Wu Weijiao , Ma Chao , Bai Qing , Ruan Jingjun
Published: February 2024

Background

The WRKY gene family is one of the largest families of transcription factors in higher plants, and WRKY transcription factors play important roles in plant growth and development as well as in response to abiotic stresses; however, the WRKY gene family in pea has not been systematically reported.

Results

In this study, 89 pea WRKY genes were identified and named according to the random distribution of PsWRKY genes on seven chromosomes. The gene family was found to have nine pairs of tandem duplicates and 19 pairs of segment duplicates. Phylogenetic analyses of the PsWRKY and 60 Arabidopsis WRKY proteins were performed to determine their homology, and the PsWRKYs were classified into seven subfamilies. Analysis of the physicochemical properties, motif composition, and gene structure of pea WRKYs revealed significant differences in the physicochemical properties within the PsWRKY family; however, their gene structure and protein-conserved motifs were highly conserved among the subfamilies. To further investigate the evolutionary relationships of the PsWRKY family, we constructed comparative syntenic maps of pea with representative monocotyledonous and dicotyledonous plants and found that it was most recently homologous to the dicotyledonous WRKY gene families. Cis-acting element analysis of PsWRKY genes revealed that this gene family can respond to hormones, such as abscisic acid (ABA), indole-3-acetic acid (IAA), gibberellin (GA), methyl jasmonate (MeJA), and salicylic acid (SA). Further analysis of the expression of 14 PsWRKY genes from different subfamilies in different tissues and fruit developmental stages, as well as under five different hormone treatments, revealed differences in their expression patterns in the different tissues and fruit developmental stages, as well as under hormone treatments, suggesting that PsWRKY genes may have different physiological functions and respond to hormones.

Conclusions

In this study, we systematically identified WRKY genes in pea for the first time and further investigated their physicochemical properties, evolution, and expression patterns, providing a theoretical basis for future studies on the functional characterization of pea WRKY genes during plant growth and development.
Frailty efficacy as a predictor of clinical and cognitive complications in patients undergoing coronary artery bypass grafting: a prospective cohort study
Authors: Bakhtiari Mehrnoosh , Shaker Farhad , Shirmard Fatemeh Ojaghi , Jalali Arash , Vakili-Basir Ahmad , Balabandian Mohammad , Khamene Sima Shamshiri , Mohammadkhawajah Izat , Shafiee Akbar , Badrkhahan Seyedeh Zahra , Hosseini Kaveh
Published: February 2024

Background

Frailty is proposed as a predictor of outcomes in patients undergoing major surgeries, although data on the association of frailty and coronary artery bypass grafting (CABG) are lacking. We assessed the association between frailty and cognitive and clinical complications following CABG.

Methods

This prospective study included patients aged over 60 years undergoing elective CABG at Tehran Heart Center from 2020 to 2022. Baseline and three-month follow-up data on frailty using the Frail scale and clinical Frail scale, functional status using the Lawton Instrumental Activities of Daily Living Scale (IADL), cognitive function by Montreal Cognitive Assessment (MoCA), and depression by the Geriatric Depression Scale (GDS) were obtained. The incidence of adverse outcomes was investigated at the three-month follow-up. Outcomes between frail and non-frail groups were compared utilizing T-tests and Mann-Whitney U tests, as appropriate.

Results

We included 170 patients with a median age of 66 ± 4 years (75.3% male). Of these, 58 cases were classified as frail, and 112 individuals were non-frail, preoperatively. Frail patients demonstrated significantly worse baseline MOCA scores (21.08 vs. 22.41, P = 0.045), GDS (2.00 vs. 1.00, P = 0.009), and Lawton IADL (8.00 vs. 6.00, P < 0.001) compared to non-frail. According to 3-month follow-up data, postoperative MOCA and GDS scores were comparable between the two groups, while Lawton IADL (8.00 vs. 6.00, P < 0.001) was significantly lower in frail cases. A significantly higher rate of readmission (1.8% vs. 12.1%), sepsis (7.1% vs. 19.0%), as well as a higher Euroscore (1.5 vs. 1.9), was observed in the frail group. A mildly significantly more extended ICU stay (6.00 vs. 5.00, p = 0.051) was shown in the frail patient.

Conclusion

Frailty showed a significant association with a worse preoperative independence level, cognitive function, and depression status, as well as increased postoperative complications.
The pertinence of gastric cancer and interleukin 10–819 single nucleotide polymorphisms: a meta-analysis and systematic review
Authors: Mao Qianqian , Liu Yanwen , Chen Xi , Liu Cheng Jiang
Published: February 2024

Purpose

Cytokines regulate the interaction between the immune system and malignant tumors. Among them, interleukin-10 (IL-10) is a multifunctional anti-inflammatory cytokine mainly produced by immune cells. The correlation between gastric cancer and T/C single nucleotide polymorphism (SNP) of interleukin-10 (IL-10) promoter−819(rs1800871)was opaque and remained to be determined. We aim to explore the pertinence of gastric cancer and SNP of interleukin 10–819 by meta-analysis via five statistical models.

Methods

Databases including PubMed, Cochrane Library, Embase, the Scopus, and Google Scholars were comprehensively retrieved for the eligible studies on the related topic from inception to March 2022. Odds ratios (ORs) were generated for dichotomous variants by meta-analysis in each model via STATA 17.0 MP. The statistical models comprised recessive model, over-dominant model, allele model, co-dominant model and dominant model. Subgroup analysis was performed to investigate the difference across races as well as the source of heterogeneity if necessary.

Results

Eventually a total of 15 articles reporting 7779 patients were enrolled in our study. There were 2383 patients and 5396 controls, collectively. There was no correlation between gastric cancer and IL-10 819 in recessive model, co-dominant model or dominant model, and subgroup analysis showed that Asian, Latin American and Caucasian had no correlation with the risk of gastric cancer. In the allelic model, there was significant correlation between gastric cancer and IL-10 819 (OR = 3.96%, 95%CI: 3.28 to 3.78). In the over-dominant model, there is no correlation between gastric cancer and IL-10 819, but subgroup analysis uncovered significant vulnerability of Asian people with regard to gastric cancer.

Conclusions

In our study, both Asians, Latin Americans, and Europeans showed an increased risk of gastric cancer in the allelic model, whereas only Asians showed significant susceptibility in the super dominant model. Of course, more large cohort studies are needed to confirm our results.
Safety and feasibility of minimally invasive gastrectomy following preoperative chemotherapy for highly advanced gastric cancer
Authors: Tanaka Tsuyoshi , Suda Koichi , Shibasaki Susumu , Serizawa Akiko , Akimoto Shingo , Nakauchi Masaya , Matsuoka Hiroshi , Inaba Kazuki , Uyama Ichiro
Published: February 2024

Background

This study aimed to determine the safety and feasibility of minimally invasive gastrectomy in patients who underwent preoperative chemotherapy for highly advanced gastric cancer.

Methods

Preoperative chemotherapy was indicated for patients with advanced large tumors (≥ cT3 and ≥ 5 cm) and/or bulky node metastasis (≥ 3 cm × 1 or ≥ 1.5 cm × 2). Between January 2009 and March 2022, 150 patients underwent preoperative chemotherapy followed by gastrectomy with R0 resection, including conversion surgery (robotic, 62; laparoscopic, 88). The outcomes of these patients were retrospectively examined.

Results

Among them, 41 and 47 patients had stage IV disease and underwent splenectomy, respectively. Regarding operative outcomes, operative time was 475 min, blood loss was 72 g, morbidity (grade ≥ 3a) rate was 12%, local complication rate was 10.7%, and postoperative hospital stay was 14 days (Interquartile range: 11–18 days). Fifty patients (33.3%) achieved grade ≥ 2 histological responses. Regarding resection types, total/proximal gastrectomy plus splenectomy (29.8%) was associated with significantly higher morbidity than other types (distal gastrectomy, 3.2%; total/proximal gastrectomy, 4.9%; P < 0.001). Specifically, among splenectomy cases, the rate of postoperative complications associated with the laparoscopic approach was significantly higher than that associated with the robotic approach (40.0% vs. 0%, P = 0.009). In the multivariate analysis, splenectomy was an independent risk factor for postoperative complications [odds ratio, 8.574; 95% confidence interval (CI), 2.584–28.443; P < 0.001].

Conclusions

Minimally invasive gastrectomy following preoperative chemotherapy was feasible and safe for patients with highly advanced gastric cancer. Robotic gastrectomy may improve surgical safety, particularly in the case of total/proximal gastrectomy combined with splenectomy.
Utility and predictive value of the CRAFITY score in advanced hepatocellular carcinoma treated with transarterial chemoembolization plus tyrosine kinase inhibitors and PD-1 inhibitor
Authors: Zhang Lijie , Sun Tao , Sun Bo , Zhang Kailu , Zheng Yuting , Li Na , Chen Lei , Zheng Chuansheng , Liang Bin , Shi Heshui
Published: February 2024

Background

The prognostic significance of the CRAFITY score (CRP and AFP in ImmunoTherapY) has been demonstrated in hepatocellular carcinoma (HCC) patients receiving immunotherapy. The purpose of this study was to investigate the utility and the predictive value of CRAFITY score in HCC after transarterial chemoembolization (TACE) in combination with tyrosine kinase inhibitors (TKIs) and immunotherapy.

Materials and methods

Data from patients with advanced HCC treated with TACE plus TKIs and PD-1 inhibitor from January 2019 to June 2022 were collected and analyzed retrospectively. Patients with AFP ≥ 100 ng/mL and those with CRP ≥ 1 mg/dL were assigned a CRAFITY score of 1 point. Patients were divided into three groups according to their CRAFITY score (CRAFITY-low, 0 points; CRAFITY-intermediate, 1 point; and CRAFITY-high, 2 points). The differences in overall survival (OS), progression-free survival (PFS) and adverse events (AEs) were compared among the three groups. Tumor response was evaluated at 3, 6 and 12 months after the first combination treatment. Risk factors for OS and PFS were assessed.

Results

A total of 70 patients were included. The patients were assigned CRAFITY scores of 0 points (CRAFITY-low, n = 25 [35.71%]), 1 point (CRAFITY-intermediate, n = 29 [41.42%]), and 2 points (CRAFITY-high, n = 16 [22.81%]). Multivariate analysis showed that lower CRAFITY score was an independent factor for the improved OS (P =.045) and PFS (P <.001). TACE session was also associated with the OS (P =.048) in the multivariate analysis. The CRAFITY-low cohort achieved a higher objective response rate (ORR) at the 3-month evaluation of tumor response. However, there was no significant difference in ORR and disease control rate (DCR) observed at the 6-month follow-up. DCR showed a statistically significant difference among three groups during the 12-month follow-up period. The percentage of patients with protein urea was highest in the CRAFITY-high group. No significance differences were observed in grade ≥ 3 AEs in three groups.

Conclusion

The CRAFITY score is simple and could be useful for predicting treatment outcomes, tumor response and AEs of the HCC patients receiving TACE plus TKIs and PD-1 inhibitor therapy.
Rotational stability of monofocal and diffractive multifocal toric intraocular lens with identical design and material: a propensity score based prospective comparative study
Authors: Shi Runhan , Ma Dongmei , Zeng Qiulin , Hua Zhixiang , Shen Wenqian , Cai Lei , Yang Jin
Published: February 2024

Purpose

To compare the rotational stability of a monofocal and a diffractive multifocal toric intraocular lens(IOLs) with identical design and material.

Methods

This prospective study enrolled patients who underwent plate-haptic toric IOL (AT TORBI 709 M and AT LISA 909 M) implantation. Propensity score matching (PSM) was performed to balance baseline factors. Follow-up examinations were conducted at 1 h, 1 day, 3 days, 1 week, 2 weeks, 1 month, and 3 months postoperatively. A linear mixed model of repeated measures was used to investigate the changes in IOL rotation over time. A 2-week timeframe was utilized to assess differences in IOL rotation between the two groups.

Result

After PSM, a total of 126 eyes were selected from each group for further analysis. Postoperatively, the time course of IOL rotation change in the two groups remained consistent, with the greatest rotation occurring between 1 h and 1 day postoperatively. At the 2-week postoperative mark, the monofocal toric IOL exhibited a higher degree of rotation compared to the multifocal toric IOL (5.40 ± 7.77° vs. 3.53 ± 3.54°, P = 0.015). In lens thickness(LT) ≥ 4.5 mm and white-to-white distance(WTW) ≥ 11.6 mm subgroups, the monofocal toric IOL rotated greater than the multifocal toric IOL (P = 0.026 and P = 0.011, respectively).

Conclusion

The diffractive multifocal toric IOL exhibits superior rotational stability compared to the monofocal toric IOL, especially in subgroups LT ≥ 4.5 mm and WTW ≥ 11.6 mm. Moreover, the time course of IOL rotation change is consistent for both, with the maximum rotation occurring between 1 h and 1 day postoperatively.
Abnormalities of retinal function in type 2 diabetes mellitus patients without clinical diabetic retinopathy detected by multifocal electroretinogram
Authors: Li Rong-Rong , Yang Yang , Zhang Meng-Ge , Wang Jie , Chen Hong , Liu Shan , Miao Hui , Wang Yun-Chang
Published: February 2024

Objective

To study the changes of retinal function in type 2 diabetes mellitus(DM) patients without apparently diabetic retinopathy via multifocal electroretinogram. Methods: Thirty-six type 2 DM patients (72 eyes) without visible diabetic retinopathy were selected as the experimental group, and thirty-five healthy subjects (70 eyes) were selected as the control group. All subjects were underwent multifocal electroretinogram (mf- ERG).

Results

Compared with the control group, the implicit time delay of the P1 wave in the first ring, third ring, fourth ring, and fifth ring of the experimental group was significant (t = -3.154, p = 0.004, t = -8.21, p = 0.000, t = -3.067, p = 0.004, t = -4.443, p = 0.000, respectively). The implicit time of the N1 wave in the fourth- and fifth-ring were also significantly delayed compared with the control group (t = -3.549, p = 0.001, t = 2.961, p = 0.005, respectively). Compared with the control group, the implicit time of the P1 wave and N1 wave in the temporal region of the experimental group were delayed (t = -2.148, p = 0.037, t = -2.834, p = 0.007, respectively). There were no significant difference between the experimental group and the control group of the temporal area in the amplitude density of P1 wave, N1 wave. There was no difference in the implicit time and amplitude density of the N1 and P1 waves in the nasal region between the experimental group and the control group. The multifocal electroretinogram complex parameters showed better specificity and sensitivity in the diagnosis of diabetic retinopathy.

Conclusion

The multifocal electroretinogram can detect abnormal changes in the retina of type 2 DM patients without visible diabetic retinopathy. The multifocal electroretinogram complex parameter is a potential indicator for the early diagnosis of diabetic retinopathy.
Dental caries and mean values of DMFT among children with cerebral palsy: a systematic review and meta-analysis
Authors: Zemene Melkamu Aderajew , Dessie Anteneh Mengist , Anley Denekew Tenaw , Ahunie Mengesha Assefa , Gebeyehu Natnael Atnafu , Adella Getachew Asmare , Kassie Gizachew Ambaw , Mengstie Misganaw Asmamaw , Seid Mohammed Abdu , Abebe Endeshaw Chekol , Gesese Molalegn Mesele , Tesfa Natnael Amare , Kebede Yenealem Solomon , Moges Natnael , Bantie Berihun , Feleke Sefineh Fenta , Dejenie Tadesse Asmamaw , Bayih Wubet Alebachew , Chanie Ermias Sisay
Published: February 2024

Introduction

One of the most prevalent causes of physical disability in children is cerebral palsy (CP), which is a series of complicated neurological disorders. Children with cerebral palsy suffer from multiple problems and potential disabilities, including dental caries. Hence, this study aimed to determine the pooled prevalence of dental caries and mean DMFT (Decayed, Missed, and Filled Permanent Teeth) among children with cerebral palsy in Africa and Asia.

Methods

A comprehensive search of the literature was made to locate relevant studies in PubMed/Medline, HINARI, Web of Science, Science Direct, the Cochrane Library, the Worldwide Science Database, and Google Scholar. The data were extracted in Microsoft Excel and transferred to Stata version 17 software for further analysis. A random-effect model was employed to estimate the pooled prevalence of dental caries and the pooled mean value of DMFT among children with cerebral palsy in Africa and Asia. Heterogeneity between studies was checked using the Cochrane Q test and I2 test statistics. Sub-group analysis by continent was done, and sensitivity analysis was checked. A small study effect was checked using Egger’s statistical test at the 5% level of significance.

Results

In this study, 25 original studies conducted in 17 countries in Africa and Asia that fulfilled the eligibility criteria were included in the review. The overall pooled prevalence of dental caries in Africa and Asia among children with cerebral palsy was 55.6% (95% CI: 42.4, 68.8). The pooled prevalence of dental caries among children with cerebral palsy in Africa was 42.43% (95% CI: 30.39, 54.58), and it was slightly higher in Asia with 64% (95% CI: 48.32, 79.72). In the random effect model analysis, the pooled mean DMFT of dental caries in children with cerebral palsy was 2.25 (95% CI: 1.86, 2.64). The pooled mean DMFT in Africa was 1.47 (95% CI: 0.86, 2.09), and in Asia it was 3.01 (95% CI: 2.43, 3.60).

Conclusion

In this study, we found that children with cerebral palsy experienced an alarming rate of dental caries. In these settings, dental caries affected roughly more than half of the children with cerebral palsy. Hence, oral health promotion initiatives should target children with CP, and this group of children must receive early preventive dental care.
Evaluation of major salivary glands with ultrasonography in multiple sclerosis patients
Authors: Kıranatlı Mustafa , Yurttaş Melike , Güngör Müjgan , Canbaz Kabay Sibel
Published: February 2024

Background

This study aimed to investigate the homogeneity of the major salivary glands in multiple sclerosis (MS) patients using ultrasonography (USG), assess DMFT indices, measure resting salivary flow rates, and compare these values with healthy individuals.

Methods

In this study, 20 individuals diagnosed with Relapsing-Remitting Multiple Sclerosis (RRMS) (mean age 36.15 ± 8.51) and 20 systemically healthy individuals (mean age 35.7 ± 9.22) were included. Oral and radiologic examinations were performed in all individuals. The parotid and submandibular salivary glands were examined using USG, and their homogeneity was assessed based on the scoring system recommended by the Outcome Measures in Rheumatology Clinical Trials (OMERACT) study group. Resting salivary flow rates and DMFT indices were measured, and the obtained data were subjected to statistical analysis.

Results

The parotid glands exhibited more heterogeneity on USG within the MS patient group than the control group, with a statistically significant difference between the two groups (p = 0.015). A statistically significant correlation was observed in total homogeneity values between the patient and control groups (p = 0.021). Furthermore, the MS patient group exhibited higher DMFT indices and lower salivary flow rates than the control group. The difference between the DMFT indices and salivary flow rate between the patient groups was statistically significant (p = 0.004 and p = 0.002 respectively).

Conclusions

The parenchyma of the major salivary glands in MS patients exhibited decreased homogeneity than the healthy controls. Additionally, the MS group showed a decrease in salivary flow rate and an increase in the DMFT index. Autonomic dysfunction and medications used for MS are thought to cause salivary gland hypofunction and dry mouth. It can be interpreted that hyposalivation and motor skill losses in MS patients lead to an increase in DMFT index.
Assessing the relationship between gut microbiota and endometriosis: a bidirectional two-sample mendelian randomization analysis
Authors: Dang Chunxiao , Chen Zhenting , Chai Yuyan , Liu Pengfei , Yu Xiao , Liu Yan , Liu Jinxing
Published: February 2024

Background

An increasing body of observational studies have indicated an association between gut microbiota and endometriosis. However, the causal relationship between them is not yet clear. In this study, we employed Mendelian randomization method to investigate the causal relationship between 211 gut microbiota taxa and endometriosis.

Methods

Independent genetic loci significantly associated with the relative abundance of 211 gut microbiota taxa, based on predefined thresholds, were extracted as instrumental variables. The primary analytical approach employed was the IVW method. Effect estimates were assessed primarily using the odds ratio and 95% confidence intervals. Supplementary analyses were conducted using MR-Egger regression, the weighted median method, the simple mode and the weighted mode method to complement the IVW results. In addition, we conducted tests for heterogeneity, horizontal pleiotropy, sensitivity analysis, and MR Steiger to assess the robustness of the results and the strength of the causal relationships.

Results

Based on the IVW method, we found that the family Prevotellaceae, genus Anaerotruncus, genus Olsenella, genus Oscillospira, and order Bacillales were identified as risk factors for endometriosis, while class Melainabacteria and genus Eubacterium ruminantium group were protective factors. Additionally, no causal relationship was observed between endometriosis and gut microbiota. Heterogeneity tests, pleiotropy tests, and leave-one-out sensitivity analyses did not detect any significant heterogeneity or pleiotropic effects.

Conclusions

Our MR study has provided evidence supporting a potential causal relationship between gut microbiota and endometriosis, and it suggests the absence of bidirectional causal effects. These findings could potentially offer new insights for the development of novel strategies for the prevention and treatment of endometriosis.
Maternal health care utilization following the implementation of the free maternal health care policy in Ghana: analysis of Ghana demographic and health surveys 2008–2014
Authors: Azaare John , Aninanya Gifty Apiung , Abdulai Kasim , Adane Francis , Bio Robert Bagngmen , Hushie Martin
Published: February 2024

Background

In July 2008, Ghana introduced a ‘free’ maternal health care policy (FMHCP) through the national health insurance scheme (NHIS) to provide comprehensive antenatal, delivery and post-natal care services to pregnant women. In this study, we evaluated the ‘free’ policy impact on antenatal care uptake and facility-level delivery utilization since the policy inception.

Methods

The study used two rounds of repeated cross-sectional data from the Ghana Demographic and Health Survey (GDHS, 2008–2014) and constructed exposure variable of the FMHCP using mothers’ national health insurance status as a proxy variable and another group of mothers who did not subscribe to the policy. We then generated the propensity scores of the two groups, ex-post, and matched them to determine the impact of the ‘free’ maternal health care policy as an intervention on antenatal care uptake and facility-level delivery utilization, using probit and logit models.

Results

Antenatal care uptake and facility-level delivery utilization increased by 8 and 13 percentage points difference, observed coefficients; 0.08; CI: 95% [0.06–0.10]; p < 0.001 and 0.13; CI: 95% [0.11–0.15], p < 0.001, respectively. Pregnant women were 1.97 times more likely to make four plus [a WHO recommended number of visits at the time] antenatal care visits and 1.87 times more likely to give birth in a health care facility of any level in Ghana between 2008 and 2104; aOR = 1.97; CI: 95% [1.61–2.4]; p < 0.001 and aOR = 1.87; CI: 95% [1.57–2.23]; p < 0.001, respectively.

Conclusions

Antenatal care uptake and facility-level delivery utilization improved significantly in Ghana indicating a positive impact of the FMHCP on maternal health care utilization in Ghana since its implementation.
Developing a practical neurodevelopmental prediction model for targeting high-risk very preterm infants during visit after NICU: a retrospective national longitudinal cohort study
Authors: Chung Hao Wei , Chen Ju-Chieh , Chen Hsiu-Lin , Ko Fang-Yu , Ho Shinn-Ying ,   on behalf of the Taiwan Premature Infant Follow-up Network, Chang Jui-Hsing , Tsou Kuo-Inn , Tsao Po-Nien , Mu Shu-Chi , Hsu Chyong-Hsin , Lien Reyin , Lin Hung-Chih , Hsiao Chien-Chou , Huang Chao-Ching , Chen Chih-Cheng
Published: February 2024

Background

Follow-up visits for very preterm infants (VPI) after hospital discharge is crucial for their neurodevelopmental trajectories, but ensuring their attendance before 12 months corrected age (CA) remains a challenge. Current prediction models focus on future outcomes at discharge, but post-discharge data may enhance predictions of neurodevelopmental trajectories due to brain plasticity. Few studies in this field have utilized machine learning models to achieve this potential benefit with transparency, explainability, and transportability.

Methods

We developed four prediction models for cognitive or motor function at 24 months CA separately at each follow-up visits, two for the 6-month and two for the 12-month CA visits, using hospitalized and follow-up data of VPI from the Taiwan Premature Infant Follow-up Network from 2010 to 2017. Regression models were employed at 6 months CA, defined as a decline in The Bayley Scales of Infant Development 3rd edition (BSIDIII) composite score > 1 SD between 6- and 24-month CA. The delay models were developed at 12 months CA, defined as a BSIDIII composite score < 85 at 24 months CA. We used an evolutionary-derived machine learning method (EL-NDI) to develop models and compared them to those built by lasso regression, random forest, and support vector machine.

Results

One thousand two hundred forty-four VPI were in the developmental set and the two validation cohorts had 763 and 1347 VPI, respectively. EL-NDI used only 4–10 variables, while the others required 29 or more variables to achieve similar performance. For models at 6 months CA, the area under the receiver operating curve (AUC) of EL-NDI were 0.76–0.81(95% CI, 0.73–0.83) for cognitive regress with 4 variables and 0.79–0.83 (95% CI, 0.76–0.86) for motor regress with 4 variables. For models at 12 months CA, the AUC of EL-NDI were 0.75–0.78 (95% CI, 0.72–0.82) for cognitive delay with 10 variables and 0.73–0.82 (95% CI, 0.72–0.85) for motor delay with 4 variables.

Conclusions

Our EL-NDI demonstrated good performance using simpler, transparent, explainable models for clinical purpose. Implementing these models for VPI during follow-up visits may facilitate more informed discussions between parents and physicians and identify high-risk infants more effectively for early intervention.
Bio-upcycling of even and uneven medium-chain-length diols and dicarboxylates to polyhydroxyalkanoates using engineered Pseudomonas putida
Authors: Ackermann Yannic S. , de Witt Jan , Mezzina Mariela P. , Schroth Christoph , Polen Tino , Nikel Pablo I. , Wynands Benedikt , Wierckx Nick
Published: February 2024

Bio-upcycling of plastics is an emerging alternative process that focuses on extracting value from a wide range of plastic waste streams. Such streams are typically too contaminated to be effectively processed using traditional recycling technologies. Medium-chain-length (mcl) diols and dicarboxylates (DCA) are major products of chemically or enzymatically depolymerized plastics, such as polyesters or polyethers. In this study, we enabled the efficient metabolism of mcl-diols and -DCA in engineered Pseudomonas putida as a prerequisite for subsequent bio-upcycling. We identified the transcriptional regulator GcdR as target for enabling metabolism of uneven mcl-DCA such as pimelate, and uncovered amino acid substitutions that lead to an increased coupling between the heterologous β-oxidation of mcl-DCA and the native degradation of short-chain-length DCA. Adaptive laboratory evolution and subsequent reverse engineering unravelled two distinct pathways for mcl-diol metabolism in P. putida, namely via the hydroxy acid and subsequent native β-oxidation or via full oxidation to the dicarboxylic acid that is further metabolized by heterologous β-oxidation. Furthermore, we demonstrated the production of polyhydroxyalkanoates from mcl-diols and -DCA by a single strain combining all required metabolic features. Overall, this study provides a powerful platform strain for the bio-upcycling of complex plastic hydrolysates to polyhydroxyalkanoates and leads the path for future yield optimizations.

Graphical Abstract
Classification and clinical significance of immunogenic cell death-related genes in Plasmodium falciparum infection determined by integrated bioinformatics analysis and machine learning
Authors: Zhang Yan-hui , Xie Li-hua , Li Jian , Qi Yan-wei , Shi Jia-jian
Published: February 2024

Background

Immunogenic cell death (ICD) is a type of regulated cell death that plays a crucial role in activating the immune system in response to various stressors, including cancer cells and pathogens. However, the involvement of ICD in the human immune response against malaria remains to be defined.

Methods

In this study, data from Plasmodium falciparum infection cohorts, derived from cross-sectional studies, were analysed to identify ICD subtypes and their correlation with parasitaemia and immune responses. Using consensus clustering, ICD subtypes were identified, and their association with the immune landscape was assessed by employing ssGSEA. Differentially expressed genes (DEGs) analysis, functional enrichment, protein-protein interaction networks, and machine learning (least absolute shrinkage and selection operator (LASSO) regression and random forest) were used to identify ICD-associated hub genes linked with high parasitaemia. A nomogram visualizing these genes' correlation with parasitaemia levels was developed, and its performance was evaluated using receiver operating characteristic (ROC) curves.

Results

In the P. falciparum infection cohort, two ICD-associated subtypes were identified, with subtype 1 showing better adaptive immune responses and lower parasitaemia compared to subtype 2. DEGs analysis revealed upregulation of proliferative signalling pathways, T-cell receptor signalling pathways and T-cell activation and differentiation in subtype 1, while subtype 2 exhibited elevated cytokine signalling and inflammatory responses. PPI network construction and machine learning identified CD3E and FCGR1A as candidate hub genes. A constructed nomogram integrating these genes demonstrated significant classification performance of high parasitaemia, which was evidenced by AUC values ranging from 0.695 to 0.737 in the training set and 0.911 to 0.933 and 0.759 to 0.849 in two validation sets, respectively. Additionally, significant correlations between the expressions of these genes and the clinical manifestation of P. falciparum infection were observed.

Conclusion

This study reveals the existence of two ICD subtypes in the human immune response against P. falciparum infection. Two ICD-associated candidate hub genes were identified, and a nomogram was constructed for the classification of high parasitaemia. This study can deepen the understanding of the human immune response to P. falciparum infection and provide new targets for the prevention and control of malaria.
Establishment and validation of a nomogram predicting the risk of deep vein thrombosis before total knee arthroplasty
Authors: Wang Zehua , Mao Xingjia , Guo Zijian , Che Guoyu , Xiang Changxin , Xiang Chuan
Published: February 2024

Purpose

This study aimed to analyze the independent risk factors contributing to preoperative DVT in TKA and constructed a predictive nomogram to accurately evaluate its occurrence based on these factors.

Methods

The study encompassed 496 patients who underwent total knee arthroplasty at our hospital between June 2022 and June 2023. The dataset was randomly divided into a training set (n = 348) and a validation set (n = 148) in a 7:3 ratio. The least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression analysis were used to screen the predictors of preoperative DVT occurrence in TKA and construct a nomogram. The performance of the predictive models was evaluated using the concordance index (C-index), calibration curves, and the receiver operating characteristic (ROC) curves. Decision curve analysis was used to analyze the clinical applicability of nomogram.

Results

A total of 496 patients who underwent TKA were included in this study, of which 28 patients were examined for lower extremity DVT preoperatively. Platelet crit, Platelet distribution width, Procalcitonin, prothrombin time, and D-dimer were predictors of preoperative occurrence of lower extremity DVT in the nomograms of the TKA patients. In addition, the areas under the curve of the ROC of the training and validation sets were 0.935 (95%CI: 0.880–0.990) and 0.854 (95%CI: 0.697-1.000), and the C-indices of the two sets were 0.919 (95%CI: 0.860–0.978) and 0.900 (95%CI: 0.791–1.009). The nomogram demonstrated precise risk prediction of preoperative DVT occurrence in TKA as confirmed by the calibration curve and decision curve analysis.

Conclusions

This Nomogram demonstrates great differentiation, calibration and clinical validity. By assessing individual risk, clinicians can promptly detect the onset of DVT, facilitating additional life monitoring and necessary medical interventions to prevent the progression of DVT effectively.
Potential crosstalk between SPP1 + TAMs and CD8 + exhausted T cells promotes an immunosuppressive environment in gastric metastatic cancer
Authors: Du Yan , Lin Yilin , Gan Lin , Wang Shuo , Chen Shuang , Li Chen , Hou Sen , Hu Bozhi , Wang Bo , Ye Yingjiang , Shen Zhanlong
Published: February 2024

Background

Immunotherapy brings new hope to patients with advanced gastric cancer. However, liver metastases can reduce the efficacy of immunotherapy in patients. Tumor-associated macrophages (TAMs) may be the cause of this reduction in efficacy. SPP1 + TAMs are considered to have immunosuppressive properties. We aimed to investigate the involvement of SPP1 + TAMs in the metastasis of gastric cancer.

Methods

The single-cell transcriptome was combined with batched BULK datasets for analysis. Animal models were used to verify the analysis results.

Results

We reveal the interaction of SPP1 + TAMs with CD8 + exhausted T cells in metastatic cancer. Among these interactions, GDF15-TGFBR2 may play a key immunosuppressive role. We constructed an LR score to quantify interactions based on ligands and receptors. The LR score is highly correlated with various immune features and clinical molecular subtypes. The LR score may also guide the prediction of the efficacy of immunotherapy and prognosis.

Conclusions

The crosstalk between SPP1 + TAMs and CD8 + exhausted T cells plays a key immunosuppressive role in the gastric metastatic cancer microenvironment.

Graphical Abstract
Prevention of neointimal hyperplasia after coronary artery bypass graft via local delivery of sirolimus and rosuvastatin: network pharmacology and in vivo validation
Authors: Ryu Ji-yeon , Jang Eui Hwa , Lee JiYong , Kim Jung-Hwan , Youn Young-Nam
Published: February 2024

Background

Coronary artery bypass graft (CABG) is generally used to treat complex coronary artery disease. Treatment success is affected by neointimal hyperplasia (NIH) of graft and anastomotic sites. Although sirolimus and rosuvastatin individually inhibit NIH progression, the efficacy of combination treatment remains unknown.

Methods

We identified cross-targets associated with CABG, sirolimus, and rosuvastatin by using databases including DisGeNET and GeneCards. GO and KEGG pathway enrichment analyses were conducted using R studio, and target proteins were mapped in PPI networks using Metascape and Cytoscape. For in vivo validation, we established a balloon-injured rabbit model by inducing NIH and applied a localized perivascular drug delivery device containing sirolimus and rosuvastatin. The outcomes were evaluated at 1, 2, and 4 weeks post-surgery.

Results

We identified 115 shared targets between sirolimus and CABG among databases, 23 between rosuvastatin and CABG, and 96 among all three. TNF, AKT1, and MMP9 were identified as shared targets. Network pharmacology predicted the stages of NIH progression and the corresponding signaling pathways linked to sirolimus (acute stage, IL6/STAT3 signaling) and rosuvastatin (chronic stage, Akt/MMP9 signaling). In vivo experiments demonstrated that the combination of sirolimus and rosuvastatin significantly suppressed NIH progression. This combination treatment also markedly decreased the expression of inflammation and Akt signaling pathway-related proteins, which was consistent with the predictions from network pharmacology analysis.

Conclusions

Sirolimus and rosuvastatin inhibited pro-inflammatory cytokine production during the acute stage and regulated Akt/mTOR/NF-κB/STAT3 signaling in the chronic stage of NIH progression. These potential synergistic mechanisms may optimize treatment strategies to improve long-term patency after CABG.

Graphical Abstract
A single-domain antibody for the detection of pathological Tau protein in the early stages of oligomerization
Authors: De Leiris Nicolas , Perret Pascale , Lombardi Charlotte , Gözel Bülent , Chierici Sabine , Millet Philippe , Debiossat Marlène , Bacot Sandrine , Tournier Benjamin B. , Chames Patrick , Lenormand Jean-Luc , Ghezzi Catherine , Fagret Daniel , Moulin Marcelle
Published: February 2024

Background

Soluble oligomeric forms of Tau protein have emerged as crucial players in the propagation of Tau pathology in Alzheimer’s disease (AD). Our objective is to introduce a single-domain antibody (sdAb) named 2C5 as a novel radiotracer for the efficient detection and longitudinal monitoring of oligomeric Tau species in the human brain.

Methods

The development and production of 2C5 involved llama immunization with the largest human Tau isoform oligomers of different maturation states. Subsequently, 2C5 underwent comprehensive in vitro characterization for affinity and specificity via Enzyme-Linked Immunosorbent Assay and immunohistochemistry on human brain slices. Technetium-99m was employed to radiolabel 2C5, followed by its administration to healthy mice for biodistribution analysis.

Results

2C5 exhibited robust binding affinity towards Tau oligomers (Kd = 6.280 nM ± 0.557) and to Tau fibers (Kd = 5.024 nM ± 0.453), with relatively weaker binding observed for native Tau protein (Kd = 1791 nM ± 8.714) and amyloid peptide (Kd > 10,000 nM). Remarkably, this SdAb facilitated immuno-histological labeling of pathological forms of Tau in neurons and neuritic plaques, yielding a high-contrast outcome in AD patients, closely mirroring the performance of reference antibodies AT8 and T22. Furthermore, 2C5 SdAb was successfully radiolabeled with 99mTc, preserving stability for up to 6 h post-radiolabeling (radiochemical purity > 93%). However, following intravenous injection into healthy mice, the predominant uptake occurred in kidneys, amounting to 115.32 ± 3.67, 97.70 ± 43.14 and 168.20 ± 34.52% of injected dose per gram (% ID/g) at 5, 10 and 45 min respectively. Conversely, brain uptake remained minimal at all measured time points, registering at 0.17 ± 0.03, 0.12 ± 0.07 and 0.02 ± 0.01% ID/g at 5, 10 and 45 min post-injection respectively.

Conclusion

2C5 demonstrates excellent affinity and specificity for pathological Tau oligomers, particularly in their early stages of oligomerization. However, the current limitation of insufficient blood–brain barrier penetration necessitates further modifications before considering its application in nuclear medicine imaging for humans.
Development, implementation, and evaluation of the effectiveness of an intervention program to improve the sexual competence of young adult women about to get married: a protocol study
Authors: Mousavi Zahra Sadat , Janighorban Mojgan , Noroozi Mahnaz
Published: February 2024

Background

Having competence in initiating sexual interactions is one of the challenges of sexual health in any society. Given that the social, cultural, and religious background of some societies can prevent the acquisition of sexual competence in young women, this study will be done to design, implement, and determine the effectiveness of an intervention program to improve the sexual competence of young women on the eve of marriage.

Methods

The current research is a mixed-method study in a qualitative-quantitative sequence. In the first phase, a qualitative study will be conducted to explore the needs of sexual competence in young adult women about to get married and ways to improve it. Then, after the literature review and combining it with the results of the qualitative study, a draft of the intervention program will be developed. After reviewing the content of the program and validating it in the panel of experts, the final program will be developed. In the second phase, the effect of the program to promote the sexual competence of adult women about to get married will be determined in a quantitative study with a two-group quasi-experimental method.

Discussion

Providing a comprehensive and practical intervention program to promote sexual competence based on cultural, social, and religious background can help to improve the quality of sexual interactions of young women about to get married, reduce harm caused by lack of sexual competence, and ensure women’s sexual health.