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Background Acute bacterial meningitis (ABM) is a serious health issue in Yemen where civil war, which continues unabated, has crippled the healthcare system. We conducted a nationwide retrospective observational study in Yemeni sentinel hospitals to identify the prevalence, aetiology, vaccination coverage and spatio-temporal pattern of ABM in children aged <5 years before and during the civil war, 2014–20. Methods Cerebrospinal fluid samples were collected from hospitalized children and were analysed macroscopically for appearance and microscopically by Gram stain and white blood cell count. Culture and latex agglutination tests were performed. Data on the prevalence of and vaccination coverage for ABM were obtained from the Ministry of Health. Joinpoint regression was used to assess the annual percent change (APC) of ABM prevalence and vaccination coverage. Pearson's correlation was used to evaluate the association between ABM prevalence and vaccination coverage. Results In total, 11 339 hospitalized children had suspected cases of ABM (prevalence, 40.07/100 000 of the whole Yemeni population) and 2.6% (293/11 339) of suspected ABM cases were confirmed (prevalence, 1.04/100 000 of the whole Yemeni population). The dominant pathogens were Streptococcus pneumoniae , Neisseria meningitidis and Haemophilus influenzae type b (Hib). The civil war reduced the Hib and pneumococcal vaccination coverage (APC = –1.92), reaching its lowest (79.5%) in 2018. The prevalence of suspected ABM increased (APC = 3.46), reaching its maximum (6.08/100 000 of the whole Yemeni population) in 2019. The conflict inversely correlated with the ABM prevalence and vaccination coverage (Pearson correlation coefficient (r), –0.69 to –0.53). Ta'izz region, which was severely affected by the civil war, had the highest prevalence of suspected ABM (120.90/100 000 of the whole Yemeni population) and lowest vaccination coverage (60%). Conclusions The civil war had a negative impact on vaccination coverage and coincided with increasing prevalence of ABM in Yemen. Streptococcus pneumoniae is the dominant causative pathogen. [ABSTRACT FROM AUTHOR]

Aims This study investigated the epidemiological characteristics of new-onset dementia in patients with atrial fibrillation (AF) and the association of catheter ablation with different subtypes of dementia. Methods and results We conducted a population-based, retrospective cohort study using data from the Taiwan National Health Insurance Research Database. In total, 136 774 patients without a history of dementia were selected after 1:1 propensity score matching based on age (with AF vs. without AF). A competing risk model was used to investigate the three subtypes of dementia: Alzheimer's disease, vascular dementia, and other/mixed dementia. Inverse probability of treatment weighting (IPTW) was performed to minimize the impact on dementia risk due to the imbalanced baseline characteristics. After a median follow-up period of 6.6 years, 8704 events of new-onset dementia occurred. Among all AF patients developing dementia, 73% were classified as having Alzheimer's disease, 16% as having vascular dementia, and 11% as having other/mixed dementia. The cumulative incidence of dementia in AF patients was higher than those without AF (log-rank test: P < 0.001 for both before and after IPTW). In patients with AF undergoing catheter ablation, the total dementia risk decreased significantly [ P = 0.015, hazard ratio (HR): 0.74, 95% confidence interval (CI): 0.58–0.94] after multivariable adjustment, but not for the subtype of vascular dementia (P = 0.59, HR: 0.86, 95% CI: 0.49–1.50). Conclusion Patients with AF have a higher incidence of all types of dementia, including Alzheimer's disease, vascular dementia, and a mixed type of dementia. Alzheimer's disease is less likely to occur in patients with AF undergoing catheter ablation. [ABSTRACT FROM AUTHOR]

Aims Atrial fibrillation (AF) is one of the major causes of ischaemic stroke. In addition to clinical risk evaluated by the CHA2DS2-VASC score, the impact of genetic factors on the risk of AF-related thromboembolic stroke has been largely unknown. We found several copy number variations (CNVs) in novel genes that were associated with thromboembolic stroke risk in our AF patients by genome-wide approach. Among them, the gasdermin D (GSDMD) gene was related to inflammation. We aimed to test whether GSDMD deletion was associated with AF-related stroke. Methods and results A total of 400 patients with documented non-familial AF were selected, of which 100 patients were diagnosed with ischaemic stroke. The baseline characteristics of age, sex, valvular heart disease, coronary artery disease, heart failure, and CHA2DS2-VASc scores were not statistically different between cases and controls. We found that individuals who carried GSDMD homozygous deletion genotype had a higher risk for ischaemic stroke (odds ratio 2.195; 95% confidence interval, 1.24–3.90; P = 0.007), even adjusted by CHA2DS2-VASc scores. We also validated the association of GSDMD with AF stroke in a large Caucasian population (UK Biobank). Conclusion We found a link between the homozygous deletion of the GSDMD gene and an increased risk of stroke in patients with AF. This may implicate the use of therapy targeting GSDMD in the prevention of ischaemic stroke for AF patients. [ABSTRACT FROM AUTHOR]

Background: Palmitic acid (PA) has a lipotoxic effect on blood vessels, leading to endothelial dysfunction and cell death. The underlying mechanisms are not yet fully understood. Aim: We sought to investigate the effects of PA on endothelial cells, with an emphasis on ferroptosis. Methods:Rat corpus cavernosum endothelial cells (RCCECs) and human umbilical vein endothelial cells (HUVECs)were treated with PA to induce a pattern of cell death, as evidenced by the evaluation of cell viability. The differentially expressed genes were measured via RNA sequencing to reveal potential mechanisms. The intracellular levels of glutathione (GSH), malondialdehyde (MDA), ferrous ion (Fe2+), and reactive oxygen species (ROS) were evaluated using commercial kits. Western blot was performed to determine the expressions of relative proteins. Outcomes: At the end of the study period, the evaluated outcomes were cell viability, transcriptome profiles, the expressions of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), as well as levels of GSH, MDA, Fe2+, and ROS. Results: PA-induced cell death of RCCECs and HUVECswas demonstrated in a dose- and time-dependent manner. Based on the findings of RNAsequencing (RNA-seq), enrichment of many biological processes associated with cell cycle and response to stimulus occurred. More importantly, ferroptosiswas highlighted in the bioinformatic analysis of both endothelial cells. The levels of intracellular Fe2+, MDA, and ROSwere significantly increased following PA exposure while GSH was decreased, suggesting excessive iron accumulation, development of lipid peroxidation, and imbalanced redox homeostasis. Mechanistically, PA decreased the protein expression levels of GPX4 and SLC7A11 in endothelial cells, both of which played crucial roles in ferroptotic cell death. Clinical Translation: This study suggests that ferroptosis may be a useful target for novel therapeutic interventions for endothelial dysfunction and cell death in vascular diseases such as erectile dysfunction. Strengths and Limitations: In this study, we found that ferroptosis could participate in PA-induced endothelial dysfunction and cell death. A limitation of the study is that it did not shed light on the overall mechanisms of this process. Therefore, further research on the intricate networks of regulating ferroptosis is needed. Conclusion: Overall, the occurrence of ferroptosis was demonstrated in the PA-treated HUVECs and RCCECs in this study. [ABSTRACT FROM AUTHOR]

Background The role of postmastectomy radiotherapy (PMRT) in patients with node-positive hormone receptor-positive (HoR) and HER2-positive breast cancer (BC) regarding AJCC pathological prognostic staging (PPS) has not been fully determined. This study aimed to validate PPS in patients with node-positive HoR+/HER2+ BC after mastectomy and to investigate the role of PPS on PMRT decision-making in this patient subset. Methods Patients diagnosed with BC from the Surveillance, Epidemiology, and End Results database were included. Patients were classified based on the anatomical staging (AS) and PPS. Breast cancer-specific survival (BCSS) was calculated. Results In total, 6862 patients were included: 4306 (62.8 per cent) patients received PMRT and 2556 (37.2 per cent) patients had not. Compared to AS, PPS downstaged 5260 patients (76.7 per cent) and no patients were upstaged. The C-index was similar between PPS and AS (0.690 versus 0.682; P  = 0.346). Regarding AS, patients who received PMRT had significantly better BCSS than those who had not in stage IIIA (P  = 0.017) and stage IIIC (P  < 0.001) disease, but not in stage IB (P  = 0.675), IIA (P  = 0.677), IIB (P  = 0.100), and IIIB (P  = 0.747) disease. Regarding PPS, patients who received PMRT had significantly better BCSS than those who had not in stage IIIA (P  = 0.038) and stage IIIB (P  = 0.017) disease, but not in stage IA (P  = 0.336), IB (P  = 0.893), IIA (P  = 0.815), and IIB (P  = 0.120) disease. PPS might allow approximately 1390 stage III patients (45.0 per cent) in the AS criterion to avoid PMRT. Conclusion PPS does not provide better risk discriminatory ability in predicting prognosis than AS in patients with node-positive HoR+/HER2+ BC after mastectomy. However, PPS is valuable in providing prognostic counselling to patients and may also guide PMRT decision-making. [ABSTRACT FROM AUTHOR]

Metagenomic analysis reveals that antibiotic-resistance genes (ARGs) are widely distributed in both human-associated and non-human-associated habitats. However, it is difficult to equally compare ARGs between samples without a standard method. Here, we constructed a comprehensive profile of the distribution of potential ARGs in bacterial tree of life and global habitats by investigating ARGs in 55 000 bacterial genomes, 16 000 bacterial plasmid sequences, 3000 bacterial integron sequences and 850 metagenomes using a standard pipeline. We found that >80% of all known ARGs are not carried by any plasmid or integron sequences. Among potential mobile ARGs, tetracycline and beta-lactam resistance genes (such as tetA , tetM and class A beta-lactamase gene) distribute in multiple pathogens across bacterial phyla, indicating their clinical relevance and importance. We showed that class 1 integrases (intI1) display a poor linear relationship with total ARGs in both non-human-associated and human-associated environments. Furthermore, both total ARGs and intI1 genes show little correlation with the degree of anthropogenicity. These observations highlight the need to differentiate ARGs of high clinical relevance. This profile is published on an online platform (ARGs-OSP, http://args-osp.herokuapp.com/) as a valuable resource for the most challenging topics in this field, i.e. the risk, evolution and emergence of ARGs. [ABSTRACT FROM AUTHOR]

Isocitrate dehydrogenase (IDH) mutant glioblastoma (GBM), accounts for ~10% GBMs, arises from lower grade diffuse glioma and preferentially appears in younger patients. Here, we aim to establish a robust gene expression-based molecular classification of IDH -mutant GBM. A total of 33 samples from the Chinese Glioma Genome Atlas RNA-sequencing data were selected as training set, and 21 cases from Chinese Glioma Genome Atlas microarray data were used as validation set. Consensus clustering identified three groups with distinguished prognostic and molecular features. G1 group, with a poorer clinical outcome, mainly contained TERT promoter wild-type and male cases. G2 and G3 groups had better prognosis differed in gender. Gene ontology analysis showed that genes enriched in G1 group were involved in DNA replication, cell division and cycle. On the basis of the differential genes between G1 and G2/G3 groups, a six-gene signature was developed with a Cox proportional hazards model. Kaplan–Meier analysis found that the acquired signature could differentiate the outcome of low- and high-risk cases. Moreover, the signature could also serve as an independent prognostic factor for IDH -mutant GBM in the multivariate Cox regression analysis. Gene ontology and gene set enrichment analyses revealed that gene sets correlated with high-risk group were involved in cell cycle, cell proliferation, DNA replication and repair. These finding highlights heterogeneity within IDH -mutant GBMs and will advance our molecular understanding of this lethal cancer. [ABSTRACT FROM AUTHOR]

Motivation: MicroRNAs (miRNAs) are endogenous non-coding small RNAs (of about 22 nucleotides), which play an important role in the post-transcriptional regulation of gene expression via either mRNA cleavage or translation inhibition. Several machine learning-based approaches have been developed to identify novel miRNAs from next generation sequencing (NGS) data. Typically, precursor/genomic sequences are required as references for most methods. However, the nonavailability of genomic sequences is often a limitation in miRNA discovery in non-model plants. A systematic approach to determine novel miRNAs without reference sequences is thus necessary. Results: In this study, an effective method was developed to identify miRNAs from non-model plants based only on NGS datasets. The miRNA prediction model was trained with several duplex structure-related features of mature miRNAs and their passenger strands using a support vector machine algorithm. The accuracy of the independent test reached 96.61% and 93.04% for dicots (Arabidopsis) and monocots (rice), respectively. Furthermore, true small RNA sequencing data from orchids was tested in this study. Twenty-one predicted orchidmiRNAs were selected and experimentally validated. Significantly, 18 of them were confirmed in the qRT-PCR experiment. This novel approach was also compiled as a user-friendly program called microRPM (miRNA Prediction Model). [ABSTRACT FROM AUTHOR]

Brassinosteroids (BRs) have been shown to enhance stress tolerance by inducing antioxidant defense systems. However, the mechanisms of BR-induced antioxidant defense in plants remain to be determined. In this study, the role of calcium (Ca2+) and maize calcium/calmodulindependent protein kinase (CCaMK), ZmCCaMK, in BRinduced antioxidant defense, and the relationship between ZmCCaMK and Ca2+ in BR signaling were investigated. BR treatment led to a significant increase in cytosolic Ca2+ concentration in protoplasts from maize mesophyll, and Ca2 + was shown to be required for BR-induced antioxidant defense. Treatment with BR induced increases in gene expression and enzyme activity of ZmCCaMK in maize leaves. Transient overexpression and silencing of ZmCCa MK in maize protoplasts demonstrated that ZmCCaMK was required for BR-induced antioxidant defense. The requirement for CCaMK was further investigated using a loss-of-function mutant of OsCCaMK, the orthologous gene of ZmCCaMK in rice. Consistent with the findings in maize, BR treatment could not induce antioxidant defense in the rice OsCCAMK mutant. Furthermore, Ca2+ was required for BR-induced gene expression and activation of ZmCCaMK, while ZmCCaMK was shown to enhance the BR-induced increase in cytosolic Ca2+ concentration. Moreover, our results also showed that ZmCCaMK and H2O2 influenced each other. These results indicate that Ca2+ works together with ZmCCaMK in BR-induced antioxidant defense, and there are two positive feedback loops between Ca2+ or H2O2 and ZmCCaMK in BR signaling in maize. [ABSTRACT FROM AUTHOR]

Rhizobia preferentially enter legume root hairs via infection threads, after which root hairs undergo tip swelling, branching, and curling. However, the mechanisms underlying such root hair deformation are poorly understood. Here, we showed that a type II small GTPase, ROP10, of Medicago truncatula is localized at the plasma membrane (PM) of root hair tips to regulate root hair tip growth. Overexpression of ROP10 and a constitutively active mutant (ROP10CA) generated depolarized growth of root hairs, whereas a dominant negative mutant (ROP10DN) inhibited root hair elongation. Inoculated with Sinorhizobium meliloti , the depolarized swollen and ballooning root hairs exhibited extensive root hair deformation and aberrant infection symptoms. Upon treatment with rhizobia-secreted nodulation factors (NFs), ROP10 was transiently upregulated in root hairs, and ROP10 fused to green fluorescent protein was ectopically localized at the PM of NF -induced outgrowths and curls around rhizobia. ROP10 interacted with the kinase domain of the NF receptor NFP in a GTP-dependent manner. Moreover, NF -induced expression of the early nodulin gene ENOD11 was enhanced by the overexpression of ROP10 and ROP10CA. These data suggest that NFs spatiotemporally regulate ROP10 localization and activity at the PM of root hair tips and that interactions between ROP10 and NF receptors are required for root hair deformation and continuous curling during rhizobial infection. [ABSTRACT FROM AUTHOR]

Background. Host genetic variation influences human immunodeficiency virus (HIV) infection and progression to AIDS. Here we used clinically well-characterized subjects from 5 pretreatment HIV/AIDS cohorts for a genome-wide association study to identify gene associations with rate of AIDS progression.Methods. European American HIV seroconverters (n = 755) were interrogated for single-nucleotide polymorphisms (SNPs) (n = 700,022) associated with progression to AIDS 1987 (Cox proportional hazards regression analysis, co-dominant model).Results. Association with slower progression was observed for SNPs in the gene PARD3B. One of these, rs11884476, reached genome-wide significance (relative hazard = 0.3; P =3. 370 × 10−9) after statistical correction for 700,022 SNPs and contributes 4.52% of the overall variance in AIDS progression in this study. Nine of the top-ranked SNPs define a PARD3B haplotype that also displays significant association with progression to AIDS (hazard ratio, 0.3; P = 3.220 × 10−8). One of these SNPs, rs10185378, is a predicted exonic splicing enhancer; significant alteration in the expression profile of PARD3B splicing transcripts was observed in B cell lines with alternate rs10185378 genotypes. This SNP was typed in European cohorts of rapid progressors and was found to be protective for AIDS 1993 definition (odds ratio, 0.43, P = .025).Conclusions. These observations suggest a potential unsuspected pathway of host genetic influence on the dynamics of AIDS progression. [ABSTRACT FROM PUBLISHER]