bluuebunny/crossref_metadata_2025 huggingface dataset:
Does FHL Tendon Transfer Alter the Outcome of Haglund Deformity Treatment by Using Debridement and Ostectomy in Patients Older Than 50 Years? A Single-Blinded Randomized Controlled Trial
Authors: Sabaghzadeh Amir , Ghanbari Naser , Gholamshahi Hediye , Zakeri Amir Mohammad , Shakeri Jousheghan Saman , Aslani Mohammadamin , Khoshkholghsima Maryam , Movahedinia Mohmmad
Published: July 2024

Background:

Chronic Achilles tendinopathy following Haglund disease is a common ankle condition that is difficult to manage. In this study, we will compare the clinical outcomes of debridement and ostectomy with and without FHL tendon transfer in treating Haglund deformity.

Methods:

Forty eligible patients aged >50 years who did not respond to conservative treatment were randomly divided into 2 groups for surgical approach: using flexor hallucis longus (FHL) tendon transfer (FHL group) or “standard procedure” (control group). The main surgical treatment included debridement and ostectomy. AOFAS and VISA-A scores were obtained from all patients pre- and postoperatively.

Results:

Twenty patients were assigned to each of the 2 groups and were observed for at least 1 year. The American Orthopaedic Foot & Ankle Society (AOFAS) ankle hindfoot scores and the Victorian Institute of Sports Assessment self-administered Achilles (VISA-A) questionnaires scores improved more in the FHL group; however, the average difference in the change in scores did not reach the levels previously reported for minimal clinically important differences. Surgical complications and hallux function were not significantly different between the 2 groups.

Conclusion:

We found that FHL tendon transfer may improve the clinical outcome scores of Achilles tendon treatment in patients aged >50 years using debridement and ostectomy. However, tendon transfer increases the time of surgery and creates additional skin incisions, which may cause more short-term wound complications, and the significance of the differences in outcome improvement may not be clinically meaningful.

Level of Evidence:

Level II, grade A recommendation.
Ruxolitinib for pediatric patients with treatment-naïve and steroid-refractory acute graft-versus-host disease: the REACH4 study
Authors: Locatelli Franco , Kang Hyoung Jin , Bruno Bénédicte , Gandemer Virginie , Rialland Fanny , Faraci Maura , Takahashi Yoshiyuki , Koh Katsuyoshi , Bittencourt Henrique , Cleary Grace , Rosko Christine , Li Xuechan , St Pierre Annie , Prahallad Anirudh , Diaz-de-Heredia Cristina
Published: July 2024

In REACH4, a phase 1/2, open-label, single-arm, multicenter study, the pharmacokinetics (PK), efficacy, and safety of ruxolitinib were evaluated in treatment-naïve and steroid-refractory pediatric patients with grade 2 to 4 acute graft-versus-host disease (aGVHD; n = 45). Ruxolitinib dosing was based on age and targeted the exposure in adults receiving 10 mg twice daily; group 1 (aged ≥12 to <18 years) received 10 mg twice daily and preliminary starting doses for groups 2 (aged ≥6 to <12 years) and 3 (aged ≥2 to <6 years) were 5 mg twice daily and 4 mg/m2 twice daily, respectively. The phase 1 primary objective was to assess ruxolitinib PK parameters and define an age-appropriate recommended phase 2 dose (RP2D) for patients aged <12 years. The phase 2 primary objective was to measure the activity of ruxolitinib as assessed by overall response rate (ORR) at day 28; the key secondary objective was to assess the durable ORR at day 56. Ruxolitinib exposure was comparable across age groups; starting doses were confirmed as the RP2D. The median duration of ruxolitinib exposure was 3.8 months (range, 0.3-11.2). ORR in all patients was 84.4% (90% confidence interval [CI], 72.8-92.5) at day 28, with a durable ORR at day 56 of 66.7% (90% CI, 53.4-78.2); high response rates were observed across age groups and in both treatment-naïve and steroid-refractory subgroups. Adverse events were consistent with those expected in patients with aGVHD (anemia, decreased neutrophil and leukocyte count) treated with ruxolitinib. In pediatric patients with aGVHD, ruxolitinib showed clinically meaningful efficacy with no new safety signals. This trial was registered at www.clinicaltrials.gov as #NCT03491215.
Critical role of tripartite fusion and LBD truncation in certain RARA- and all RARG-related atypical APL
Authors: Zhou Xiaosu , Chen Xue , Chen Jiaqi , Wen Lijun , Zhang Zhanglin , Qin Ya-Zhen , Cao Panxiang , Xing Haizhou , Mi Yingchang , Wang Wei , Zhang Guangsen , Li Ji , Wu Huanling , Zhang Zhifen , Zhang Jian , Su Zhan , Wang Fang , Zhang Yang , Ma Xiaoli , Fang Jiancheng , Wu Ping , Wang Tong , Fan Gaowei , Zhao Yang , Jin David , Zhang Xian , Ma Xiujuan , Wu Qisheng , Zhang Zhihua , Wang Linya , Ma Futian , Xiao Xia , Wu Chengye , Sun Kai , Tang Ruijie , Zhang Yun , Wu Sanyun , Gao Ran , Zhang Leping , Zheng Huyong , Zhao Yanli , Zhu Hong-Hu , Lu Daopei , Lu Peihua , Chen Suning , Liu Hongxing
Published: July 2024

Atypical acute promyelocytic leukemia (aAPL) presents a complex landscape of retinoic acid receptor (RAR) fusion genes beyond the well-known PML::RARA fusion. Among these, 31 individually rare RARA and RARG fusion genes have been documented, often reported in the canonical X::RAR bipartite fusion form. Intriguingly, some artificially mimicked bipartite X::RAR fusions respond well to all-trans retinoic acid (ATRA) in vitro, contrasting with the ATRA resistance observed in patients. To unravel the underlying mechanisms, we conducted a comprehensive molecular investigation into the fusion transcripts in 27 RARA fusion gene–positive aAPL (RARA-aAPL) and 21 RARG-aAPL cases. Our analysis revealed an unexpected novel form of X::RAR::X– or X::RAR::Y–type tripartite fusions in certain RARA-aAPL and all RARG-aAPL cases, with shared features and notable differences between these 2 disease subgroups. In RARA-aAPL cases, the occurrence of RARA 3′ splices was associated with their 5′ fusion partner genes, mapping across the coding region of helix 11_12 (H11_12) within the ligand-binding domain (LBD), resulting in LBD-H12 or H11_12 truncation. In RARG-aAPL cases, RARG 3′ splices were consistently localized to the terminus of exon 9, leading to LBD-H11_12 truncation. Significant differences were also observed between RARA and RARG 5′ splice patterns. Our analysis also revealed extensive involvement of transposable elements in constructing RARA and RARG 3′ fusions, suggesting transposition mechanisms for fusion gene ontogeny. Both protein structural analysis and experimental results highlighted the pivotal role of LBD-H11_12/H12 truncation in driving ATRA unresponsiveness and leukemogenesis in tripartite fusion–positive aAPL, through a protein allosteric dysfunction mechanism.
A predictive model for therapy failure in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitor therapy
Authors: Zhang Xiaoshuai , Liu Bingcheng , Huang Jian , Zhang Yanli , Xu Na , Gale Robert Peter , Li Weiming , Liu Xiaoli , Zhu Huanling , Pan Ling , Yang Yunfan , Lin Hai , Du Xin , Liang Rong , Chen Chunyan , Wang Xiaodong , Li Guohui , Liu Zhuogang , Zhang Yanqing , Liu Zhenfang , Hu Jianda , Liu Chunshui , Li Fei , Yang Wei , Meng Li , Han Yanqiu , Lin Li’e , Zhao Zhenyu , Tu Chuanqing , Zheng Caifeng , Bai Yanliang , Zhou Zeping , Chen Suning , Qiu Huiying , Yang Lijie , Sun Xiuli , Sun Hui , Zhou Li , Liu Zelin , Wang Danyu , Guo Jianxin , Pang Liping , Zeng Qingshu , Suo Xiaohui , Zhang Weihua , Zheng Yuanjun , Huang Xiaojun , Jiang Qian
Published: July 2024

Although tyrosine kinase inhibitor (TKI) therapy has markedly improved the survival of people with chronic-phase chronic myeloid leukemia (CML), 20% to 30% of people still experienced therapy failure. Data from 1955 consecutive patients with chronic-phase CML diagnosed by the European LeukemiaNet recommendations from 1 center receiving initial imatinib or a second-generation (2G) TKI therapy were interrogated to develop a clinical prediction model for TKI-therapy failure. This model was subsequently validated in 3454 patients from 76 other centers. Using the predictive clinical covariates associated with TKI-therapy failure, we developed a model that stratified patients into low-, intermediate- and high-risk subgroups with significantly different cumulative incidences of therapy failure (P < .001). There was good discrimination and calibration in the external validation data set, and the performance was consistent with that of the training data set. Our model had the better prediction discrimination than the Sokal and European Treatment and Outcome Study long-term survival scores, with the greater time-dependent area under the receiver-operator characteristic curve values and a better ability to redefine the risk of therapy failure. Our model could help physicians estimate the likelihood of initial imatinib or 2G TKI–therapy failure in people with chronic-phase CML.
JAK2/mTOR inhibition fails to prevent acute GVHD despite reduced Th1/Th17 cells: final phase 2 trial results
Authors: Pidala Joseph , Holtan Shernan G. , Walton Kelly , Kim Jongphil , Cao Biwei , Elmariah Hany , Mishra Asmita , Bejanyan Nelli , Nishihori Taiga , Khimani Farhad , Perez Lia , Faramand Rawan G. , Davila Marco L. , McSain Shannon , Pleskow Jordan , Baron Jeffrey , Anasetti Claudio , Moran Segura Carlos , Weisdorf Daniel J. , Blazar Bruce R. , Miller Jeffrey S. , Bachanova Veronika , El Jurdi Najla , Betts Brian C.
Published: July 2024

Our phase 1 graft-versus-host disease (GVHD) prevention trial of JAK2 inhibitor, pacritinib (PAC; recommended phase 2 dose: 100 mg orally twice a day on day 0 to +70) plus sirolimus and tacrolimus (SIR/TAC) demonstrated the regimen was safe and free of pan-JAK myelosuppression after allogeneic hematopoietic cell transplantation (alloHCT). PAC inhibits interleukin 6 (IL-6) receptor activity and pathogenic T helper cell 1 (Th1)/Th17 differentiation in preclinical models and the phase 1 trial. Herein, we report on our completed phase 2 trial of PAC/SIR/TAC after 8/8 human leukocyte antigen matched alloHCT. This single-arm phase 2 trial (NCT02891603) was powered to determine if PAC/SIR/TAC suppressed percentage phosphorylated STAT3 (pSTAT3)+ CD4+ T cells at day +21 (primary end point: percentage pSTAT3+ CD4+ T cells ≤ 35%) and estimated grade II to IV acute GVHD by day +100. The impact of PAC/SIR/TAC on T-cell subsets, CD28 (pS6 and pH3ser10), and IL-2 receptor (pSTAT5) signal transduction was also evaluated. Eligible patients (n = 28) received alloHCT for hematologic malignancies or myeloproliferative neoplasms. Reduced or myeloablative intensity conditioning was permitted. PAC/SIR/TAC met the primary end point, reducing percentage pSTAT3+ CD4+ T cells to 9.62% at day +21. Th1/Th17 cells were decreased at day +21, increasing the ratio of regulatory T cells to Th1 and Th17 cells with PAC/SIR/TAC at recommended phase 2 dose PAC compared with dose level 1 PAC. The cumulative incidence of grade II to IV acute GVHD by day +100 with PAC/SIR/TAC was similar to historic SIR/TAC values (46% vs 43%). Although PAC/SIR/TAC suppressed pSTAT3 and Th1/Th17 cells, the regimen did not improve acute GVHD prevention.
Diagnostic guidelines for familial hemophagocytic lymphohistiocytosis revisited
Authors: Henter Jan-Inge , Sieni Elena , Eriksson Julia , Bergsten Elisabet , Hed Myrberg Ida , Canna Scott W. , Coniglio Maria Luisa , Cron Randy Q. , Kernan Kate F. , Kumar Ashish R. , Lehmberg Kai , Minoia Francesca , Naqvi Ahmed , Ravelli Angelo , Tang Yong-Min , Bottai Matteo , Bryceson Yenan T. , Horne AnnaCarin , Jordan Michael B.
Published: July 2024

Current hemophagocytic lymphohistiocytosis 2004 (HLH-2004)–based diagnostic criteria for familial hemophagocytic lymphohistiocytosis (FHL) are based on expert opinion. Here, we performed a case-control study to test and possibly improve these criteria. We also developed 2 complementary expert opinion–based diagnostic strategies for FHL in patients with signs/symptoms suggestive of HLH, based on genetic and cellular cytotoxicity assays. The cases (N = 366) were children aged <16 years with verified familial and/or genetic FHL (n = 341) or Griscelli syndrome type 2 (n = 25); 276 from the HLH-94/HLH-2004 databases and 90 from the Italian HLH Registry. All fulfilled the HLH-94/HLH-2004 patient inclusion criteria. Controls were 374 children with systemic-onset juvenile idiopathic arthritis (sJIA) and 329 + 361 children in 2 cohorts with febrile infections that could be confused with HLH and sepsis, respectively. To provide complete data sets, multiple imputations were performed. The optimal model, based on 17 variables studied, revealed almost similar diagnostic thresholds as the existing criteria, with accuracy 99.1% (sensitivity 97.1%; specificity 99.5%); the original HLH-2004 criteria had accuracy 97.4% (sensitivity 99.0%; specificity 97.1%). Because cellular cytotoxicity assays here constitute a separate diagnostic strategy, HLH-2004 criteria without natural killer (NK)–cell function was also studied, which showed accuracy 99.0% (sensitivity, 96.2%; specificity, 99.5%). Thus, we conclude that the HLH-2004 criteria (without NK-cell function) have significant validity in their current form when tested against severe infections or sJIA. It is important to exclude underlying malignancies and atypical infections. In addition, complementary cellular and genetic diagnostic guidelines can facilitate necessary confirmation of clinical diagnosis.
Exacerbations of bronchiectasis
Authors: De Angelis Alessandro , Johnson Emma D. , Sutharsan Sivagurunathan , Aliberti Stefano
Published: July 2024

Bronchiectasis presents a significant challenge due to its rising prevalence, associated economic burden and clinical heterogeneity. This review synthesises contemporary understanding and literature of bronchiectasis exacerbations, addressing the transition from stable state to exacerbations, underlining the importance of early and precise recognition, rigorous severity assessment, prompt treatment, and prevention measures, as well as emphasising the need for strategies to assess and improve early and long-term patient outcomes. The review highlights the interplay between stable state phases and exacerbations in bronchiectasis, introducing the concept of “exogenous and endogenous changes in airways homeostasis” and the “adapted island model” with a particular focus on “frequent exacerbators”, a group of patients associated with specific clinical characteristics and worse outcomes. The pathophysiology of exacerbations is explored through the lens of microbial and nonmicrobial triggers and the presence and the activity of comorbidities, elaborating on the impact of both exogenous insults, such as infections and pollution, and endogenous factors such as inflammatory endotypes. Finally, the review proposes a multidisciplinary approach to care, integrating advancements in precision medicine and biomarker research, paving the way for tailored treatments that challenge the traditional antibiotic paradigm.
A permutable MLP-like architecture for disease prediction from gut metagenomic data
Authors: Jiang Cong , Yang Jian , Peng Xiaogang , Li Xiaozheng
Published: July 2024

Metagenomic data plays a crucial role in analyzing the relationship between microbes and diseases. However, the limited number of samples, high dimensionality, and sparsity of metagenomic data pose significant challenges for the application of deep learning in data classification and prediction. Previous studies have shown that utilizing the phylogenetic tree structure to transform metagenomic abundance data into a 2D matrix input for convolutional neural networks (CNNs) improves classification performance. Inspired by the success of a Permutable MLP-like architecture in visual recognition, we propose Metagenomic Permutator (MetaP), which applied the Permutable MLP-like network structure to capture the phylogenetic information of microbes within the 2D matrix formed by phylogenetic tree. Our experiments demonstrate that our model achieved competitive performance compared to other deep neural networks and traditional machine learning, and has good prospects for multi-classification and large sample sizes. Furthermore, we utilize the SHAP (SHapley Additive exPlanations) method to interpret our model predictions, identifying the microbial features that are associated with diseases.
Preliminary study of BF/C2 on immune mechanism of grass carp against GCRV infection
Authors: Wei Yuling , Xiao Yu , Liu Qiaolin , Du Zongjun , Xiao Tiaoyi
Published: July 2024

BF/C2 is a crucial molecule in the coagulation complement cascade pathway and plays a significant role in the immune response of grass carp through the classical, alternative, and lectin pathways during GCRV infection. In vivo experiments demonstrated that the mRNA expression levels of BF/C2 (A, B) in grass carp positively correlated with GCRV viral replication at various stages of infection. Excessive inflammation leading to death coincided with peak levels of BF/C2 (A, B) mRNA expression and GCRV viral replication. Correspondingly, BF/C2 (A, B) recombinant protein, CIK cells and GCRV co-incubation experiments yielded similar findings. Therefore, 3 h (incubation period) and 9 h (death period) were selected as critical points for this study. Transcriptome sequencing analysis revealed significant differences in the expression of BF/C2A and BF/C2B during different stages of CIK infection with GCRV and compared to the blank control group (PBS). Specifically, the BF/C2A_3 and BF/C2A_9 groups exhibited 2729 and 2228 differentially expressed genes (DEGs), respectively, with 1436 upregulated and 1293 downregulated in the former, and 1324 upregulated and 904 downregulated in the latter. The BF/C2B_3 and BF/C2B_9 groups showed 2303 and 1547 DEGs, respectively, with 1368 upregulated and 935 downregulated in the former, and 818 upregulated and 729 downregulated in the latter. KEGG functional enrichment analysis of these DEGs identified shared pathways between BF/C2A and PBS groups at 3 and 9 h, including the C-type lectin receptor signaling pathway, protein processing in the endoplasmic reticulum, Toll-like receptor signaling pathway, Salmonella infection, apoptosis, tight junction, and adipocytokine signaling pathway. Additionally, the BF/C2B groups at 3 and 9 h shared pathways related to protein processing in the endoplasmic reticulum, glycolysis/gluconeogenesis, and biosynthesis of amino acids. The mRNA levels of these DEGs were validated in cellular models, confirming consistency with the sequencing results. In addition, the mRNA expression levels of these candidate genes (mapk1, il1b, rela, nfkbiab, akt3a, hyou1, hsp90b1, dnajc3a et al.) in the head kidney, kidney, liver and spleen of grass carp immune tissue were significantly different from those of the control group by BF/C2 (A, B) protein injection in vivo. These candidate genes play an important role in the response of BF/C2 (A, B) to GCRV infection and it also further confirmed that BF/C2 (A, B) of grass carp plays an important role in coping with GCRV infection.
Comparative transcriptomic profiles of Paulownia catalpifolia under different degrees of chilling stress during the seedling stage
Authors: Liu Baojun , Su Jiang , Fu Chuanming , Xian Kanghua , He Jinxiang , Huang Ningzhen
Published: July 2024

Background

Paulownia, an ecologically and economically valuable plant species native to China, is notable for its excellent timber quality and strong adaptability. Among them, Paulownia catalpifolia displays the ability to survive in cold climate, a trait associated with northern China. Yet, the molecular information for its cold-tolerance has not been explored. This study was to investigate the changes in physiological indices and transcript levels of P. catalpifolia following cold exposure, which could provide evidence for revealing whether there were differences in the genetic basis of inducing physiological perturbations between moderate low temperature (MLT) and extreme low temperature (ELT).

Results

The detection of physiological indices under diverse degrees of chilling stress showed similar patterns of alteration. Enhanced accumulation of osmoregulatory substances, such as soluble sugar and soluble protein, were more conducive under ELT compared to MLT in P. catalpifolia. Moreover, we observed leaf wilting symptoms distinctly after exposure to ELT for 48 h, while this effect was not obvious after MLT exposure for 48 h. Comparative transcriptomic analysis between MLT and ELT demonstrated 13,688 differentially expressed genes (DEGs), most of them appeared after 12 h and 48 h of treatment. GO and KEGG analyses elucidated prominent enrichment in aromatic-L-amino-acid decarboxylase activity term and carbohydrate metabolism pathways. Therefore, it was speculated that the DEGs involved in the above processes might be related to the difference in the contents of soluble protein and soluble sugar between MLT and ELT. Time series clustering analyses further highlighted several key genes engaged in the ‘Glycosyltransferases’, ‘Galactose metabolism’ and ‘Starch and sucrose metabolism’ pathways as well as the ‘tyrosine decarboxylase activity’ term. For instance, cellulose synthase-like A (CLSA2/9), raffinose synthase (RafS2), β-amylase (BAM1) and tyrosine/DOPA decarboxylase (TYDC1/2/5) genes, diverging in their expression trends between MLT and ELT, might significantly affect the soluble sugar and soluble protein abundance within P. catalpifolia.

Conclusion

Between MLT and ELT treatments, partial overlaps in response pathways of P. catalpifolia were identified, while several genes regulating the accumulation of osmotic adjustment substances had disparate expression patterns. These findings could provide a novel physiological and molecular perspective for P. catalpifolia to adapt to complex low temperature habitats.
Genome sequencing of Elaeocarpus spp. stem blight pathogen Pseudocryphonectria elaeocarpicola reveals potential adaptations to colonize woody bark
Authors: Yang Yuchen , Xiong Dianguang , Zhao Danyang , Huang Huayi , Tian Chengming
Published: July 2024

Background

Elaeocarpus spp. stem blight, caused by Pseudocryphonectria elaeocarpicola, is a destructive disease, which will significantly reduce the productivity and longevity of Elaeocarpus spp. plants, especially in the Guangdong Province of China. However, few information is available for P. elaeocarpicola. To unravel the potential adaptation mechanism of stem adaptation, the whole genome of P. elaeocarpicola was sequenced by using the DNBSEQ and PacBio platforms.

Results

P. elaeocarpicola harbors 44.49 Mb genome with 10,894 predicted coding genes. Genome analysis revealed that the P. elaeocarpicola genome encodes a plethora of pathogenicity-related genes. Analysis of carbohydrate-active enzymes (CAZymes) revealed a rich variety of enzymes participated in plant cell wall degradation, which could effectively degrade cellulose, hemicellulose and xyloglucans in the plant cell wall and promote the invasion of the host plant. There are 213 CAZyme families found in P. elaeocarpicola, among which glycoside hydrolase (GH) family has the largest number, far exceeding other tested fungi by 53%. Besides, P. elaeocarpicola has twice as many genes encoding chitin and cellulose degradation as Cryphonectria parasitica, which belong to the same family. The predicted typical secreted proteins of P. elaeocarpicola are numerous and functional, including many known virulence effector factors, indicating that P. elaeocarpicola has great potential to secrete virulence effectors to promote pathogenicity on host plants. AntiSMASH revealed that the genome encoded 61 secondary metabolic gene clusters including 86 secondary metabolic core genes which was much higher than C. parasitica (49). Among them, two gene cluster of P. elaeocarpicola, cluster12 and cluster52 showed 100% similarity with the mycotoxins synthesis clusters from Aspergillus steynii and Alternaria alternata, respectively. In addition, we annotated cytochrome P450 related enzymes, transporters, and transcription factors in P. elaeocarpicola, which are important virulence determinants of pathogenic fungi.

Conclusions

Taken together, our study represents the first genome assembly for P. elaeocarpicola and reveals the key virulence factors in the pathogenic process of P. elaeocarpicola, which will promote our understanding of its pathogenic mechanism. The acquired knowledge lays a foundation for further exploration of molecular interactions with the host and provide target for management strategies in future research.
Genomic analysis reveals the association of KIT and MITF variants with the white spotting in swamp buffaloes
Authors: Dai Dongmei , Sari Eka Meutia , Si Jingfang , Ashari Hidayat , Dagong Muhammad Ihsan Andi , Pauciullo Alfredo , Lenstra Johannes A. , Han Jianlin , Zhang Yi
Published: July 2024

Background

Swamp-type buffaloes with varying degrees of white spotting are found exclusively in Tana Toraja, South Sulawesi, Indonesia, where spotted buffalo bulls are highly valued in accordance with the Torajan customs. The white spotting depigmentation is caused by the absence of melanocytes. However, the genetic variants that cause this phenotype have not been fully characterized. The objective of this study was to identify the genomic regions and variants responsible for this unique coat-color pattern.

Results

Genome-wide association study (GWAS) and selection signature analysis identified MITF as a key gene based on the whole-genome sequencing data of 28 solid and 39 spotted buffaloes, while KIT was also found to be involved in the development of this phenotype by a candidate gene approach. Alternative candidate mutations included, in addition to the previously reported nonsense mutation c.649 C > T (p.Arg217*) and splice donor mutation c.1179 + 2T > A in MITF, a nonsense mutation c.2028T > A (p.Tyr676*) in KIT. All these three mutations were located in the genomic regions that were highly conserved exclusively in Indonesian swamp buffaloes and they accounted largely (95%) for the manifestation of white spotting. Last but not the least, ADAMTS20 and TWIST2 may also contribute to the diversification of this coat-color pattern.

Conclusions

The alternative mutations identified in this study affect, at least partially and independently, the development of melanocytes. The presence and persistence of such mutations may be explained by significant financial and social value of spotted buffaloes used in historical Rambu Solo ceremony in Tana Toraja, Indonesia. Several de novo spontaneous mutations have therefore been favored by traditional breeding for the spotted buffaloes.
Evaluating genomic inbreeding of two Chinese yak (Bos grunniens) populations
Authors: Chen Shi-Yi , Luo Zhihao , Jia Xianbo , Zhou Junkun , Lai Song-Jia
Published: July 2024

Background

Yaks are a vital livestock in the Qinghai-Tibetan Plateau area for providing food products, maintaining sustainable ecosystems, and promoting cultural heritage. Because of uncontrolled mating, it is impossible to estimate inbreeding level of yak populations using the pedigree-based approaches. With the aims to accurately evaluate inbreeding level of two Chinese yak populations (Maiwa and Jiulong), we obtained genome-wide single nucleotide polymorphisms (SNPs) by DNA sequencing and calculated five SNP-by-SNP estimators ($$\:{F}_{HOM}$$, $$\:{F}_{L\&H}$$, $$\:{F}_{VR1}$$, $$\:{F}_{VR2}$$, and $$\:{F}_{YAN}$$), as well as two segment-based estimators of runs of homozygosity (ROH, $$\:{F}_{ROH}$$) and homozygous-by-descent (HBD, $$\:{F}_{HBD}$$). Functional implications were analyzed for the positional candidate genes located within the related genomic regions.

Results

A total of 151,675 and 190,955 high-quality SNPs were obtained from 71 Maiwa and 30 Jiulong yaks, respectively. Jiulong had greater genetic diversity than Maiwa in terms of allele frequency and nucleotide diversity. The two populations could be genetically distinguished by principal component analysis, with the mean differentiation index (Fst) of 0.0054. The greater genomic inbreeding levels of Maiwa yaks were consistently supported by all five SNP-by-SNP estimators. Based on simple proportion of homozygous SNPs ($$\:{F}_{HOM}$$), a lower inbreeding level was indicated by three successfully sequenced old leather samples that may represent historical Maiwa yaks about five generations ago. There were 3304 ROH detected among all samples, with mean and median length of 1.97 Mb and 1.0 Mb, respectively. A total of 94 HBD segments were found among all samples, whereas 92 of them belonged to the shortest class with the mean length of 10.9 Kb. Based on the estimates of $$\:{F}_{ROH}$$ and $$\:{F}_{HBD}$$, however, there was no difference in inbreeding level between Maiwa and Jiulong yaks. Within the genomic regions with the significant Fst or enriched by ROH, we found several candidate genes and pathways that have been reported to be related to diverse production traits in farm animals.

Conclusions

We successfully evaluated the genomic inbreeding level of two Chinese yak populations. Although different estimators resulted in inconsistent conclusions on their genomic inbreeding levels, our results may be helpful to implement the genetic conservation and utilization programs for the two yak populations.
Mining key genes associated with phosphorus deficiency through genome-wide identification and characterization of cucumber SPX family genes
Authors: Li Jialin , Hu Linyue , Luan Qianqian , Zhang Jingdan , Feng Xueru , Li Hongmei , Wang Zenghui , He Wenxing
Published: July 2024

Background

Proteins harboring the SPX domain are crucial for the regulation of phosphate (Pi) homeostasis in plants. This study aimed to identify and analyze the entire SPX gene family within the cucumber genome.

Results

The cucumber genome encompassed 16 SPX domain-containing genes, which were distributed across six chromosomes and categorized into four distinct subfamilies: SPX, SPX-MFS, SPX-EXS and SPX-RING, based on their structure characteristics. Additionally, gene duplications and synteny analysis were conducted for CsSPXs, revealing that their promoter regions were enriched with a variety of hormone-responsive, biotic/abiotic stress and typical P1BS-related elements. Tissue expression profiling of CsSPX genes revealed that certain members were specifically expressed in particular organs, suggesting essential roles in cucumber growth and development. Under low Pi stress, CsSPX1 and CsSPX2 exhibited a particularly strong response to Pi starvation. It was observed that the cucumber cultivar Xintaimici displayed greater tolerance to low Pi compared to black-spined cucumber under low Pi stress conditions. Protein interaction networks for the 16 CsSPX proteins were predicted, and yeast two-hybrid assay revealed that CsPHR1 interacted with CsSPX2, CsSPX3, CsSPX4 and CsSPX5, implying their involvement in the Pi signaling pathway in conjunction with CsPHR1.

Conclusion

This research lays the foundation for further exploration of the function of the CsSPX genes in response to low Pi stress and for elucidating the underlying mechanism.
Designing a model of emergency medical services preparedness in response to mass casualty incidents: a mixed-method study
Authors: Saadatmand Vahid , Ahmadi Marzaleh Milad , Shokrpour Nasrin , Abbasi Hamid Reza , Peyravi Mahmoud Reza
Published: July 2024

Background

Emergency medical services preparedness in mass casualty incidents is one of the most important concerns in emergency systems. A mass casualty incident is a sudden event with several injured individuals that overwhelms the local health care system. This study aimed to identify and validate the components of emergency medical services readiness in mass casualty incidents which ultimately led to designing a conceptual model.

Methods

This research was an explanatory mixed-method study conducted in five consecutive stages in Iran between November 2021 and September 2023. First, a systematic review was carried out to extract the components of emergency medical services preparedness in mass casualty incidents based on the PRISMA guideline. Second, a qualitative study was designed to explore the preparedness components through in-depth semi-structured interviews and analyzed using the content analysis approach. Third, the integration of the components extracted from the two stages of the systematic review and qualitative study was done by an expert panel. Fourth, the obtained components were validated using the Delphi technique. Two rounds were done in the Delphi phase. Finally, the conceptual model of emergency medical services preparedness in mass casualty incidents was designed by a panel of experts.

Results

10 articles were included in the systematic review stage and sixteen main components were extracted and classified into four categories. In the second stage, thirteen components were extracted from the qualitative study and classified into five categories. Then, the components of the previous two phases were integrated into the panel of experts and 23 components were identified. After validation with the Delphi technique, 22 components were extracted. Lastly, the final components were examined by the panel of experts, and the conceptual schematic of the model was drawn.

Conclusions

It is necessary to have an integrated framework and model of emergency medical service readiness in the planning and management of mass casualty incidents. The components and the final model of this research were obtained after the systematic scientific steps, which can be used as a scheme to improve emergency medical service preparedness in response to mass casualty incidents.
Leveraging community health workers for COVID-19 response in Democratic Republic of Congo, Nigeria, Senegal, and Uganda: roles, barriers, and facilitators
Authors: Namuhani Noel , Babirye Ziyada , Monje Fred , Salawu Mobolaji M. , Bosonkie Marc , Bello Segun , Kabwama Steven N. , Egbende Landry , Bamgboye Eniola A. , Tusubira Andrew , Kashiya Yves , Kizito Susan , Afolabi Rotimi Felix , Adebowale Ayo S. , Dairo Magbagbeola David , Diallo Issakha , Leye Mamadou M. M. , Ndiaye Youssou , Fall Mane , Bassoum Oumar , Seck Ibrahima , Fawole Olufunmilayo I. , Mapatano Mala Ali , Ndejjo Rawlance , Wanyenze Rhoda K. , Kiwanuka Suzanne N.
Published: July 2024

Background

The Corona Virus Disease 2019 (COVID-19) pandemic overwhelmed health systems and disrupted the delivery of health services globally. Community Health Workers (CHWs) play a critical role in linking communities to health systems, supporting the prevention and control of diseases in many low- and middle-income countries. However, their roles, barriers, and facilitators in the response and control of the COVID-19 pandemic have not been well documented. We described the roles of CHWs in the COVID-19 response, including the barriers and facilitators.

Methods

A cross-sectional study design was used to assess the COVID-19 response in the Democratic Republic of Congo (DRC), Nigeria, Senegal, and Uganda. This involved 110 key informant interviews with policymakers, health facility managers, district health managers, and CHWs to understand the role of CHWs in the COVID 19 response, selected purposively. The total sample size was based on information saturation in each of the countries. A document review on the COVID-19 response was also conducted. We searched Google, Google Scholar, and PubMed for published and grey literature. Data from the selected documents were extracted into a Google master matrix in MS Excel and analyzed thematically.

Results

In COVID-19 Control, CHWs supported community-based surveillance, contact tracing, risk communication, community mobilization, and home-based care. To support the continuity of other non-COVID-19 services, the CHWs conducted community mobilization, sensitizations, outreaches, referrals, and patient follow-ups. CHWs were challenged by movement restrictions, especially in the initial stages of the lockdown, inadequate PPE, increased workload, low allowances, and motivation. CHW were facilitated by trainings, the development of guidelines, development partners’ support/funding, and the provision of personal protective equipment (PPE) and tools.

Conclusion

CHWs supported both the COVID-19 control and continuity of non-COVID-19 health care during the COVID-19 pandemic. CHWs are a critical resource that must be adequately supported to build resilient health systems.
Clinical and physiological risk factors contributing to the restricted mobility in older adults: a longitudinal analysis
Authors: Jiang Xin , Tan Huiying , Ren Huixia , Zhou Huiting , Chen Jingmei , Wang Zhen , Guo Yi , Zhou Junhong
Published: July 2024

Background

Mobility limitations (e.g., using wheelchair) have been closely linked to diminished functional independence and quality of life in older adults. The regulation of mobility is pertaining to multiple neurophysiologic and sociodemographic factors. We here aimed to characterize the relationships of these factors to the risk of restricted mobility in older adults.

Methods

In this longitudinal study, 668 older adults with intact mobility at baseline completed the baseline assessments of clinical characteristics, cognitive function, sleep quality, activities of daily living (ADL), walking performance, beat-to-beat blood pressure, and structural MRI of the brain. Then 506 of them (mean age = 70.7 ± 7.5 years) responded to the follow-up interview on the mobility limitation (as defined by if using wheelchair, cane, or walkers, or being disabled and lying on the bed) after 18 ± 3.5 months. Logistic regression analyses were performed to examine the relationships between the baseline characteristics and the follow-up mobility restriction.

Results

At baseline, compared to intact-mobility group (n = 475), restricted-mobility group (n = 31) were older, with lower score of ADL and the Montreal Cognitive Assessment (MoCA), greater score of Pittsburgh Sleep Quality Index (PSQI), poorer cardio- and cerebral vascular function, and slower walking speeds (ps < 0.05). The logistic regression analysis demonstrated that participants who were with history of falls, uncontrolled-hypertension, and/or greater Fazekas scale (odds ratios (ORs):1.3 ~ 13.9, 95% confidence intervals (CIs) = 1.1 ~ 328.2), walked slower, and/or with lower ADL score (ORs: 0.0026 ~ 0.9; 95%CI: 0.0001 ~ 0.99) at baseline, would have significantly greater risk of restricted mobility (p < 0.05; VIFs = 1.2 ~ 1.9).

Conclusions

These findings provide novel profile of potential risk factors, including vascular characteristics, psycho-cognitive and motor performance, for the development of restricted mobility in near future in older adults, ultimately helping the design of appropriate clinical and rehabilitative programs for mobility in this population.
Association between fibrinogen levels and stroke-associated pneumonia in acute ischemic stroke patients
Authors: Li Xiaoqiang , Du Hui , Song Zhibin , Meiqi  , Zhang Guifeng , Yuan Suhua , Yuanfeng  , Wang Hui
Published: July 2024

Purpose

Prior research had indicated a relationship between fibrinogen and stroke-associated pneumonia (SAP), yet the nature of this relationship had not been thoroughly investigated. Therefore, this study was designed to elucidate the prognostic value of fibrinogen levels in forecasting the occurrence of SAP among patients with acute ischemic stroke (AIS).

Patients and methods

In this retrospective cross-sectional analysis, we included 1092 patients who had experienced AIS and were admitted to our facility within 72 h of the onset of their symptoms. Based on the SAP diagnostic criteria, patients were classified into two groups: SAP and non-SAP. The correlation between serum fibrinogen concentration and SAP was examined using univariate analysis. Curve fitting and multivariable logistic regression model were utilized for statistical evaluation.

Results

Out of the ischemic stroke patients included in the study, SAP was identified in 112 (10.26%) patients. A direct correlation was observed between fibrinogen levels and the incidence of SAP. An increase in fibrinogen levels corresponded with a heightened incidence of SAP. Multivariable logistic regression revealed a significant positive association between fibrinogen levels and SAP incidence (OR = 1.53, 95% confidence interval [CI]: 1.18, 1.99)).

Conclusion

A linear relationship between serum fibrinogen levels and the incidence of SAP in ischemic stroke patients was shown. The serum fibrinogen levels were positively and linearly correlated to SAP risk.
Switching from injectable to other Disease Modifying Therapies may improve sexual dysfunction in people with Multiple Sclerosis
Authors: Ala Sara , Amirkafi Ali , Kohandel Kosar , Shahmohammadi Sareh , Sahraian Mohammad Ali
Published: July 2024

Background

Multiple Sclerosis (MS) a central nervous system autoimmune disorder, mainly affecting young adults and more prevalent among women, can lead to sexual dysfunction (SD) among both males and females with MS. Female sexual dysfunction can be defined as dyspareunia, a lack of sexual desire, disorders in the arousal and orgasm phases, and sexual pain disorders. The purpose of this study is to investigate the changes in sexual function among females with MS whose treatment was switched from first-line injectable medications to other agents after a six-month duration. And assess the changes in all three domains of SD.

Methods

In this longitudinal study females diagnosed with MS, aged between 18 and 50 years old, and were candidates for switching their treatment from interferon beta-1a (intra-muscular and subcutaneous), and Glatiramer Acetate (GA), to Fingolimod, Dimethyl Fumarate (DMF), or Natalizumab (NTZ) due to patients’ convenience and tolerability and adverse events were included. “Multiple Sclerosis Intimacy and Sexuality Questionnaire-19” was used to evaluate the SD changes before and six months after the new treatment initiation. Statistical analysis was conducted using SPSS V.24 software. Histograms and the Shapiro-Wilk test were used to assess the normality of the variables; due to the non-normal distribution of quantitative variables (except for age), the Wilcoxon signed-rank test was used to compare the scores, before and six months after the medication change. The level of significance was considered less than 0.05.

Results

Out of 107 female participants (average age: 35.09 ± 5.61), The mean of overall MSISQ-19 scores, before and six months after the medication change were not significant (p-value = 0.091). However, considering the subdomains, the medication changes only affected the tertiary subdomain of MSISQ-19 (p-value = 0.017). Still, the scores of other subdomains did not change significantly (p-value = 0.761 for primary SD and 0.479 for secondary SD). Also, there wasn’t any significant difference between EDSS before and after the medication change (p-value = 0.461).

Conclusions

To our knowledge, this was the first study, assessing the effect of MS medication change on the improvement of SD among patients. According to the results of the presented cross-sectional study, we found that during a six-month period, the tertiary subdomain of MSISQ-19 symptoms improved significantly, while the changes in other SD domains were not significant.
Peripartum outcomes and immune responses after SARS-CoV-2 infection in the third trimester of pregnancy
Authors: Shen Qi , Dong Shuai , Shah Neelam Kumari , Liang Yuan , Wang Jie , Shan Yan-Hong , He Jin
Published: July 2024

Background

SARS-CoV-2 infection in pregnant women during the third trimester resulted in overall adverse pregnancy outcomes compared to non-infected controls and a unique humoral and cellular response at delivery. In this study we aimed to assess the impact of SARS-CoV-2 infection on maternal/neonatal peripartum outcomes andimmunological profiles.

Method

In this study, we recruited 304 SARS-CoV-2 infected pregnant women and 910 SARS-CoV-2 non-infected pregnant women who were admitted for delivery. Peripartum and neonates’ outcomes response to SARS-CoV-2 infection were analyzed. Furthermore, we characterized the antibody and cytokines profile in SARS-CoV-2 infected maternal blood (MB) and cord blood (CB). We also assessed routine laboratory tests and liver function tests in MB before labor. Unpaired T test, Mann-Whitney test and Spearman test were used to analyze the data.

Results

SARS-CoV-2 infected pregnant women were significantly associated with increased risk of adverse pregnancy outcomes, including preterm labor (13.8% vs. 9.5%, p = 0.033) and meconium-stained amniotic fluid (8.9% vs. 5.5%, p = 0.039). The risk of low birth weight (< 2500 g) (10.5% vs. 6.5%, p = 0.021) and Apgar score < 8 at 1-minute (9.2% vs. 5.8%, p = 0.049) significantly increased in newborns from COVID-19 positive mothers than their counterparts. Our results showed that antibodies were increased in adverse-outcome SARS-CoV-2 infected mothers and their neonates, and abnormal proportion of immune cells were detected in SARS-CoV-2 infected mothers. While the immune response showed no difference between adverse-outcome infected pregnant women and normal-outcome infected pregnant women. Thus, SARS-CoV-2 infection during the third trimester of pregnancy induced a unique humoral and cellular response at delivery.

Conclusion

SARS-CoV-2 infection closer to delivery could incline to adverse pregnancy outcomes. Therefore, the utmost care is required for SARS-CoV-2 infected pregnant women and their newborns.

Trial registration

The study protocol was approved by the Institutional Review Board of the First Hospital of Jilin University with the approval code number 23K170-001, and informed consent was obtained from all enrolled patients prior to sample collection.
AT-0174, a novel dual IDO1/TDO2 enzyme inhibitor, synergises with temozolomide to improve survival in an orthotopic mouse model of glioblastoma
Authors: Bickerdike Michael J. , Nafia Imane , Bessede Alban , Chen Cheng-Bang , Wangpaichitr Medhi
Published: July 2024

Background

Glioblastoma is an aggressive brain cancer, usually of unknown etiology, and with a very poor prognosis. Survival from diagnosis averages only 3 months if left untreated and this only increases to 12–15 months upon treatment. Treatment options are currently limited and typically comprise radiotherapy plus a course of the DNA-alkylating chemotherapeutic temozolomide. Unfortunately, the disease invariably relapses after several months of treatment with temozolomide, due to the development of resistance to the drug. Increased local tryptophan metabolism is a feature of many solid malignant tumours through increased expression of tryptophan metabolising enzymes. Glioblastomas are notable for featuring increased expression of the tryptophan catabolizing enzymes indole-2,3-dioxygenase-1 (IDO1), and especially tryptophan-2,3-dioxygenase-2 (TDO2). Increased IDO1 and TDO2 activity is known to suppress the cytotoxic T cell response to tumour cells, and this has led to the proposal that the IDO1 and TDO2 enzymes represent promising immuno-oncology targets. In addition to immune modulation, however, recent studies have also identified the activity of these enzymes is important in the development of resistance to chemotherapeutic agents.

Methods

In the current study, the efficacy of a novel dual inhibitor of IDO1 and TDO2, AT-0174, was assessed in an orthotopic mouse model of glioblastoma. C57BL/6J mice were stereotaxically implanted with GL261(luc2) cells into the striatum and then administered either vehicle control, temozolomide (8 mg/kg IP; five 8-day cycles of treatment every 2 days), AT-0174 (120 mg/kg/day PO) or both temozolomide + AT-0174, all given from day 7 after implantation.

Results

Temozolomide decreased tumour growth and improved median survival but increased the infiltration of CD4+ Tregs. AT-0174 had no significant effect on tumour growth or survival when given alone, but provided clear synergy in combination with temozolomide, further decreasing tumour growth and significantly improving survival, as well as elevating CD8+ T cell expression and decreasing CD4+ Treg infiltration.

Conclusion

AT-0174 exhibited an ideal profile for adjunct treatment of glioblastomas with the first-line chemotherapeutic drug temozolomide to prevent development of CD4+ Treg-mediated chemoresistance.