Effectiveness of animal-assisted activities and therapies for autism spectrum disorder: a systematic review and meta-analysis.

Background: Given the rising interest in complementary therapeutic strategies for autism spectrum disorder (ASD), this research aims to provide a comprehensive analysis of the impact of animal-assisted activities and therapies (AAAT) on various ASD symptoms. Methods: A meticulous search of databases, including Scopus and PubMed, was conducted to gather relevant research on AAAT for ASD. This process led to the selection of 45 studies encompassing 1,212 participants. The chosen studies were then subjected to a meta-analysis to evaluate the efficacy of AAAT in alleviating core ASD symptoms. Results: The meta-analysis revealed significant improvements in several core ASD symptoms due to AAAT. Notably, there were improvements in social communication (MD = -4.96, 95% CI [-7.49, -2.44]), irritability (MD = -2.38, 95% CI [-4.06, -0.71]), hyperactivity (MD = -4.03, 95% CI [-6.17, -1.89]), and different word usage skills (MD = 20.48, 95% CI [7.41, 33.55]). However, social awareness (MD = -1.63, 95% CI [-4.07, 0.81]), social cognition (MD = -3.60, 95% CI [-9.36, 2.17]), social mannerisms (MD = -0.73, 95% CI [-2.55, 1.09]), social motivation (MD = -1.21, 95% CI [-2.56, 0.13]), lethargy (MD = -1.12, 95% CI [-3.92, 1.68]), and stereotypical behaviors (MD = -0.23, 95% CI [-1.27, 0.80]) did not significantly improve. Conclusion: The study demonstrates the potential of AAAT in improving certain core symptoms of ASD, such as social communication, irritability, hyperactivity, and word usage skills. However, the effectiveness of AAAT in other ASD symptom domains remains uncertain. The research is limited by the absence of long-term follow-up data and a high risk of bias in existing studies. Therefore, while the findings indicate the promise of AAAT in specific areas, caution is advised in generalizing its efficacy across all ASD symptoms.

Health-related quality of life in patients with inborn errors of immunity: a bibliometric analysis.

Background: Inborn Errors of Immunity (IEI) are characterized by a heightened susceptibility to infections, allergies, and various other health complications. Health-Related Quality of Life (HRQOL) in patients with IEI is a critical area of research that demands attention due to the impact of IEI on patients' lives. This study utilized bibliometric methods, aiming to comprehensively explore the research content and hotspots in the field of HRQOL in patients with IEI. Methods: This bibliometric analysis utilized data from the Science Citation Index Expanded (SCIE) and Social Sciences Citation Index (SSCI) within the Web of Science core datasets up to January 1, 2024. The study focused on literature that addressed HRQOL in IEI patients, involving a total of 1,807 authors and 309 articles published across 112 journals. The analysis included publication volume and growth trends, country and institutional contributions, authorship, and journal analysis. Results: The research found that despite the importance of HRQOL in IEI, the volume of publications in this field remains consistently low, with no significant increase in trend. The USA leads in publication and citation volumes, reflecting a geographical imbalance in research contributions. Key journals in this field include the Journal of Clinical Immunology, Frontiers in Immunology, and the Journal of Allergy and Clinical Immunology. The study highlights that while treatments like hematopoietic stem cell transplants and gene therapy have improved patient IEI survival rates, they still often come with significant side effects impacting HRQOL. The analysis underlines the need for comprehensive HRQOL assessments in IEI, considering the physical and psychological impacts of treatments. Conclusions: This study represents a bibliometric analysis focusing on HRQOL in patients with. It underscores the need for more extensive and systematic research in this area, emphasizing the importance of a multidisciplinary approach. Despite advancements in medical treatments for IEI, there is a crucial need to focus on HRQOL to enhance patient satisfaction and overall well-being. The findings advocate for more personalized treatment plans and a better understanding of the psychosocial needs of patients with IEI to improve their quality of life.

In-silico assessment of high-risk non-synonymous SNPs in ADAMTS3 gene associated with Hennekam syndrome and their impact on protein stability and function.

Hennekam Lymphangiectasia-Lymphedema Syndrome 3 (HKLLS3) is a rare genetical disorder caused by mutations in a few genes including ADAMTS3. It is characterized by lymphatic dysplasia, intestinal lymphangiectasia, severe lymphedema and distinctive facial appearance. Up till now, no extensive studies have been conducted to elucidate the mechanism of the disease caused by various mutations. As a preliminary investigation of HKLLS3, we sorted out the most deleterious nonsynonymous single nucleotide polymorphisms (nsSNPs) that might affect the structure and function of ADAMTS3 protein by using a variety of in silico tools. A total of 919 nsSNPs in the ADAMTS3 gene were identified. 50 nsSNPs were predicted to be deleterious by multiple computational tools. 5 nsSNPs (G298R, C567Y, A370T, C567R and G374S) were found to be the most dangerous and can be associated with the disease as predicted by different bioinformatics tools. Modelling of the protein shows it can be divided into segments 1, 2 and 3, which are connected by short loops. Segment 3 mainly consists of loops without substantial secondary structures. With prediction tools and molecular dynamics simulation, some SNPs were found to significantly destabilize the protein structure and disrupt the secondary structures, especially in segment 2. The deleterious effects of mutations in segment 1 are possibly not from destabilization but from other factors such as the change in phosphorylation as suggested by post-translational modification (PTM) studies. This is the first-ever study of ADAMTS3 gene polymorphism, and the predicted nsSNPs in ADAMST3, some of which have not been reported yet in patients, will serve for diagnostic purposes and further therapeutic implications in Hennekam syndrome, contributing to better diagnosis and treatment.

Identifying New Clusterons: Application of TBEV Analyzer 3.0.

Early knowledge about novel emerging viruses and rapid determination of their characteristics are crucial for public health. In this context, development of theoretical approaches to model viral evolution are important. The clusteron approach is a recent bioinformatics tool which analyzes genetic patterns of a specific E protein fragment and provides a hierarchical network structure of the viral population at three levels: subtype, lineage, and clusteron. A clusteron is a group of strains with identical amino acid (E protein fragment) signatures; members are phylogenetically closely related and feature a particular territorial distribution. This paper announces TBEV Analyzer 3.0, an analytical platform for rapidly characterizing tick-borne encephalitis virus (TBEV) strains based on the clusteron approach, workflow optimizations, and simplified parameter settings. Compared with earlier versions of TBEV Analyzer, we provide theoretical and practical enhancements to the platform. Regarding the theoretical aspect, the model of the clusteron structure, which is the core of platform analysis, has been updated by analyzing all suitable TBEV strains available in GenBank, while the practical enhancements aim at improving the platform's functionality. Here, in addition to expanding the strain sets of prior clusterons, we introduce eleven novel clusterons through our experimental results, predominantly of the European subtype. The obtained results suggest effective application of the proposed platform as an analytical and exploratory tool in TBEV surveillance.

In Silico Analysis Revealed Five Novel High-Risk Single-Nucleotide Polymorphisms (rs200384291, rs201163886, rs193141883, rs201139487, and rs201723157) in ELANE Gene Causing Autosomal Dominant Severe Congenital Neutropenia 1 and Cyclic Hematopoiesis.

Single-nucleotide polymorphisms in the ELANE (Elastase, Neutrophil Expressed) gene are associated with severe congenital neutropenia, while the ELANE gene provides instructions for making a protein called neutrophil elastase. We identified disease susceptibility single-nucleotide polymorphisms (SNPs) in the ELANE gene using several computational tools. We used cutting-edge computational techniques to investigate the effects of ELANE mutations on the sequence and structure of the protein. Our study suggested that eight nsSNPs (rs28931611, rs57246956, rs137854448, rs193141883, rs201723157, rs201139487, rs137854451, and rs200384291) are the most deleterious in ELANE gene and disturb protein structure and function. The mutants F218L, R34W, G203S, R193W, and T175M have not yet been identified in patients suffering from SCN and cyclic hematopoiesis, while C71Y, P139R, C151Y, G214R, and G203C reported in our study are already associated with both of the disorders. These mutations are shown to destabilize structure and disrupt ELANE protein activation, splicing, and folding and might diminish trypsin-like serine protease efficiency. Prediction of posttranslation modifications highlighted the significance of deleterious nsSNPs because some of nsSNPs affect potential phosphorylation sites. Gene-gene interactions showed the relation of ELANE with other genes depicting its importance in numerous pathways and coexpressions. We identified the deleterious nsSNPs, constructed mutant protein structures, and evaluated the impact of mutation by employing molecular docking. This research sheds light on how ELANE failure upon mutation results in disease progression, including congenital neutropenia, and validation of these novel predicted nsSNPs is required through the wet lab.

Novel Disease-Associated Missense Single-Nucleotide Polymorphisms Variants Predication by Algorithms Tools and Molecular Dynamics Simulation of Human TCIRG1 Gene Causing Congenital Neutropenia and Osteopetrosis.

T Cell Immune Regulator 1, ATPase H + Transporting V0 Subunit A3 (TCIRG1 gene provides instructions for making one part, the a3 subunit, of a large protein complex known as a vacuolar H + -ATPase (V-ATPase). V-ATPases are a group of similar complexes that act as pumps to move positively charged hydrogen atoms (protons) across membranes. Single amino acid changes in highly conserved areas of the TCIRG1 protein have been linked to autosomal recessive osteopetrosis and severe congenital neutropenia. We used multiple computational approaches to classify disease-prone single nucleotide polymorphisms (SNPs) in TCIRG1. We used molecular dynamics analysis to identify the deleterious nsSNPs, build mutant protein structures, and assess the impact of mutation. Our results show that fifteen nsSNPs (rs199902030, rs200149541, rs372499913, rs267605221, rs374941368, rs375717418, rs80008675, rs149792489, rs116675104, rs121908250, rs121908251, rs121908251, rs149792489 and rs116675104) variants are likely to be highly deleterious mutations as by incorporating them into wild protein they destabilize the wild protein structure and function. They are also located in the V-ATPase I domain, which may destabilize the structure and impair TCIRG1 protein activation, as well as reduce its ATPase effectiveness. These mutants have not yet been identified in patients suffering from CN and osteopetrosis while (G405R, R444L, and D517N) reported in our study are already associated with osteopetrosis. Mutation V52L reported in our study was identified in a patient suspected for CN. Finally, these mutants can help to further understand the broad pool of illness susceptibilities associated with TCIRG1 catalytic kinase domain activation and aid in the development of an effective treatment for associated diseases.

Identification of The Immune Subtype Among Muscle-invasive Bladder Cancer Patients by Multiple Datasets.

BACKGROUND: Immunotherapies including PD-1/PD-L1 antibodies have been approved for the treatment of Muscle-invasive Bladder Cancer (MIBC) patients. However, immunotherapies could only be beneficial for about 20% MIBC patients. Thus, identification of the immune subtype is becoming increasingly important. This study aimed to explore the immune subtype by analyzing the gene expression profiles. METHODS: A total of 6 datasets including (GSE13507, GSE31684, GSE32548, GSE32894, GSE69795, and TCGA-BLCA) were downloaded. The gene expression profiles from different datasets were combined since the batch effects were removed. We performed unsupervised clustering analysis to identify the immune subtype by the combined gene expression profiles. The tumor-infiltration levels of 22 immune cells, immune scores, and tumor purity were calculated, and the survival analysis was performed to investigate the prognosis difference between immune subtypes. The enriched pathways for each immune subtype were obtained. RESULTS: We identified four novel immune subtypes (referred to S1, S2, S3, and S4) among MIBC patients. We found that S1 was enriched in immune scores had the best prognosis. In contrast, S3 was poor in immune scores and had the worst prognosis. Subtype S1, S2, S3, and S4 were enriched in immune-related pathways, extracellular matrix-related pathways, metabolism-related pathways, and cancer-related pathways, respectively. CONCLUSION: The current study suggests that the immune subtypes based on gene expression profiles could contribute to select the appropriate MIBC patient for immunotherapies.

Care of patients with inborn errors of immunity in thirty J Project countries between 2004 and 2021.

Introduction: The J Project (JP) physician education and clinical research collaboration program was started in 2004 and includes by now 32 countries mostly in Eastern and Central Europe (ECE). Until the end of 2021, 344 inborn errors of immunity (IEI)-focused meetings were organized by the JP to raise awareness and facilitate the diagnosis and treatment of patients with IEI. Results: In this study, meeting profiles and major diagnostic and treatment parameters were studied. JP center leaders reported patients' data from 30 countries representing a total population of 506 567 565. Two countries reported patients from JP centers (Konya, Turkey and Cairo University, Egypt). Diagnostic criteria were based on the 2020 update of classification by the IUIS Expert Committee on IEI. The number of JP meetings increased from 6 per year in 2004 and 2005 to 44 and 63 in 2020 and 2021, respectively. The cumulative number of meetings per country varied from 1 to 59 in various countries reflecting partly but not entirely the population of the respective countries. Altogether, 24,879 patients were reported giving an average prevalence of 4.9. Most of the patients had predominantly antibody deficiency (46,32%) followed by patients with combined immunodeficiencies (14.3%). The percentages of patients with bone marrow failure and phenocopies of IEI were less than 1 each. The number of patients was remarkably higher that those reported to the ESID Registry in 13 countries. Immunoglobulin (IgG) substitution was provided to 7,572 patients (5,693 intravenously) and 1,480 patients received hematopoietic stem cell therapy (HSCT). Searching for basic diagnostic parameters revealed the availability of immunochemistry and flow cytometry in 27 and 28 countries, respectively, and targeted gene sequencing and new generation sequencing was available in 21 and 18 countries. The number of IEI centers and experts in the field were 260 and 690, respectively. We found high correlation between the number of IEI centers and patients treated with intravenous IgG (IVIG) (correlation coefficient, cc, 0,916) and with those who were treated with HSCT (cc, 0,905). Similar correlation was found when the number of experts was compared with those treated with HSCT. However, the number of patients treated with subcutaneous Ig (SCIG) only slightly correlated with the number of experts (cc, 0,489) and no correlation was found between the number of centers and patients on SCIG (cc, 0,174). Conclusions: 1) this is the first study describing major diagnostic and treatment parameters of IEI care in countries of the JP; 2) the data suggest that the JP had tremendous impact on the development of IEI care in ECE; 3) our data help to define major future targets of JP activity in various countries; 4) we suggest that the number of IEI centers and IEI experts closely correlate to the most important treatment parameters; 5) we propose that specialist education among medical professionals plays pivotal role in increasing levels of diagnostics and adequate care of this vulnerable and still highly neglected patient population; 6) this study also provides the basis for further analysis of more specific aspects of IEI care including genetic diagnostics, disease specific prevalence, newborn screening and professional collaboration in JP countries.

Predicting the Most Deleterious Missense Nonsynonymous Single-Nucleotide Polymorphisms of Hennekam Syndrome-Causing CCBE1 Gene, In Silico Analysis.

Hennekam lymphangiectasia-lymphedema syndrome has been linked to single-nucleotide polymorphisms in the CCBE1 (collagen and calcium-binding EGF domains 1) gene. Several bioinformatics methods were used to find the most dangerous nsSNPs that could affect CCBE1 structure and function. Using state-of-the-art in silico tools, this study examined the most pathogenic nonsynonymous single-nucleotide polymorphisms (nsSNPs) that disrupt the CCBE1 protein and extracellular matrix remodeling and migration. Our results indicate that seven nsSNPs, rs115982879, rs149792489, rs374941368, rs121908254, rs149531418, rs121908251, and rs372499913, are deleterious in the CCBE1 gene, four (G330E, C102S, C174R, and G107D) of which are the highly deleterious, two of them (G330E and G107D) have never been seen reported in the context of Hennekam syndrome. Twelve missense SNPs, rs199902030, rs267605221, rs37517418, rs80008675, rs116596858, rs116675104, rs121908252, rs147974432, rs147681552, rs192224843, rs139059968, and rs148498685, are found to revert into stop codons. Structural homology-based methods and sequence homology-based tools revealed that 8.8% of the nsSNPs are pathogenic. SIFT, PolyPhen2, M-CAP, CADD, FATHMM-MKL, DANN, PANTHER, Mutation Taster, LRT, and SNAP2 had a significant score for identifying deleterious nsSNPs. The importance of rs374941368 and rs200149541 in the prediction of post-translation changes was highlighted because it impacts a possible phosphorylation site. Gene-gene interactions revealed CCBE1's association with other genes, showing its role in a number of pathways and coexpressions. The top 16 deleterious nsSNPs found in this research should be investigated further in the future while researching diseases caused CCBE1 gene specifically HS. The FT web server predicted amino acid residues involved in the ligand-binding site of the CCBE1 protein, and two of the substitutions (R167W and T153N) were found to be involved. These highly deleterious nsSNPs can be used as marker pathogenic variants in the mutational diagnosis of the HS syndrome, and this research also offers potential insights that will aid in the development of precision medicines. CCBE1 proteins from Hennekam syndrome patients should be tested in animal models for this purpose.

Defining muscle-invasive bladder cancer immunotypes by introducing tumor mutation burden, CD8+ T cells, and molecular subtypes.

Immunotherapy, especially anti-PD-1, is becoming a pillar of modern muscle-invasive bladder cancer (MIBC) treatment. However, the objective response rates (ORR) are relatively low due to the lack of precise biomarkers to select patients. Herein, the molecular subtype, tumor mutation burden (TMB), and CD8+ T cells were calculated by the gene expression and mutation profiles of MIBC patients. MIBC immunotypes were constructed using clustering analysis based on tumor mutation burden, CD8+ T cells, and molecular subtypes. Mutated genes, enriched functional KEGG pathways and GO terms, and co-expressed network-specific hub genes have been identified. We demonstrated that ORR of immunotype A patients identified by molecular subtype, CD8+ T cells, and TMB is about 36% predictable. PIK3CA, RB1, FGFR3, KMT2C, MACF1, RYR2, and EP300 are differentially mutated among three immunotypes. Pathways such as ECM-receptor interaction, PI3K-Akt signaling pathway, and TGF-beta signaling pathway are top-ranked in enrichment analysis. Low expression of ACTA2 was associated with the MIBC survival benefit. The current study constructs a model that could identify suitable MIBC patients for immunotherapy, and it is an important step forward to the personalized treatment of bladder cancers.

Newborn Screening through TREC, TREC/KREC System for Primary Immunodeficiency with limitation of TREC/KREC. Comprehensive Review.

INTRODUCTION: Newborn screening (NBS) by quantifying T cell receptor excision circles (TRECs) and Kappa receptor excision circles in neonatal dried blood spots (DBS) enables early diagnosis of different types of primary immune deficiencies. Global newborn screening for PID, using an assay to detect T-cell receptor excision circles (TREC) in dried blood spots (DBS), is now being performed in all states in the United States. In this review, we discuss the development and outcomes of TREC, TREC/KREC combines screening, and continued challenges to implementation. OBJECTIVE: To review the diagnostic performance of published articles for TREC and TREC/ KREC based NBS for PID and its different types. METHODS: Different research resources were used to get an approach for the published data of TREС and KREC based NBS for PID like PubMed, Scopus, Google Scholar, Research gate EMBASE. We extracted TREC and KREC screening Publisher with years of publication, content and cut-off values, and a number of retests, repeat DBS, and referrals from the different published pilot, pilot cohort, Case series, and cohort studies. RESULTS: We included the results of TREC, combined TREC/KREC system based NBS screening from different research articles, and divided these results between the Pilot studies, case series, and cohort. For each of these studies, different parameter data are excluded from different articles. Thirteen studies were included, re-confirming 89 known SCID cases in case series and reporting 53 new SCID cases in 3.15 million newborns. Individual TREC contents in all SCID patients were <25 TRECs/µl (except in those evaluated with the New York State assay). CONCLUSION: TREC and KREC sensitivity for typical SCID and other types of PID was 100 %. It shows its importance and anticipating the significance of implementation in different undeveloped and developed countries in the NBS program in upcoming years. Data adapting the screening algorithm for pre-term/ill infants reduce the amount of false-positive test results.

A co-expression network for differentially expressed genes in bladder cancer and a risk score model for predicting survival.

BACKGROUND: Urothelial bladder cancer (BLCA) is one of the most common internal malignancies worldwide with poor prognosis. This study aims to explore effective prognostic biomarkers and construct a prognostic risk score model for patients with BLCA. METHODS: Weighted gene co-expression network analysis (WGCNA) was used for identifying the co-expression module related to the pathological stage of BLCA based on the RNA-Seq data retrieved from The Cancer Genome Atlas database. Prognostic biomarkers screened by Cox proportional hazard regression model and random forest were used to construct a risk score model that can predict the prognosis of patients with BLCA. The GSE13507 dataset was used as the independent testing dataset to test the performance of the risk score model in predicting the prognosis of patients with BLCA. RESULTS: WGCNA identified seven co-expression modules, in which the brown module consisted of 77 genes was most significantly correlated with the pathological stage of BLCA. Cox proportional hazard regression model and random forest identified TPST1 and P3H4 as prognostic biomarkers. Elevated TPST1 and P3H4 expressions were associated with the high pathological stage and worse survival. The risk score model based on the expression level of TPST1 and P3H4 outperformed pathological stage indicators and previously proposed prognostic models. CONCLUSION: The gene co-expression network-based study could provide additional insight into the tumorigenesis and progression of BLCA, and our proposed risk score model may aid physicians in the assessment of the prognosis of patients with BLCA.

Identification of miR-200c and miR141-Mediated lncRNA-mRNA Crosstalks in Muscle-Invasive Bladder Cancer Subtypes.

Basal and luminal subtypes of muscle-invasive bladder cancer (MIBC) have distinct molecular profiles and heterogeneous clinical behaviors. The interactions between mRNAs and lncRNAs, which might be regulated by miRNAs, have crucial roles in many cancers. However, the miRNA-dependent crosstalk between lncRNA and mRNA in specific MIBC subtypes still remains unclear. In this study, we first classified MIBC into two conservative subtypes using miRNA, mRNA and lncRNA expression data derived from The Cancer Genome Atlas. Then we investigated subtype-related biological pathways and evaluated the subtype classification performance using Decision Trees, Random Forest and eXtreme Gradient Boosting (XGBoost). At last, we explored potential miRNA-mediated lncRNA-mRNA crosstalks based on co-expression analysis. Our results show that: (1) the luminal subtype is primarily characterized by upregulation of metabolism-related pathways while the basal subtype is predominantly characterized by upregulation of epithelial-mesenchymal transition, metastasis, and immune system process-related pathways; (2) the XGBoost prediction model is consistently robust for classification of the molecular subtypes of MIBC across four datasets (The area under the ROC curve > 0.9); (3) the expression levels of the molecules in the miR-200c and miR141-mediated lncRNA-mRNA crosstalks differ considerably between the two subtypes and have close relationships with the prognosis of MIBC. The miR-200c and miR-141-dependent mRNA-lncRNA crosstalks might be of great significance in tumorigenesis and tumor progression and may serve as the novel prognostic predictors and classification markers of MIBC subtypes.