Abstract To explore the critical care treatment and clinical outcome of patients with severe aneurysmal subarachnoid hemorrhage (SaSAH), and to provide clinical evidence for the treatment of patients with SaSAH. 160 patients with SaSAH of Hunt and Hess (H&H) grade III or above in the neurosurgical critical care unit at ourospital between June 2016 and June 2018 were enrolled in this study. Patients were treated with brain protective bundle based on step-wised protocol under multimodal monitoring and followed up for 3 months. The incidence of various clinical complications and the clinical prognosis after discharge were statistically analyzed. Furthermore, it carried on the correlation analysis to the risk factors and the prognosis. In 160 patients with SaSAH, 127 patients had responsible aneurysms located in the anterior circulation, and the other 33 patients were located in the posterior circulation. 70 patients (43.8%) underwent transcranial clipping, 81 patients (50.6%) underwent endovascular embolization and 9 patients (5.6%) did not intervene. Patients with IV and V grades of Glasgow Outcome Scale (GOS) were considered good recovery, and those with grade I, II and III were poor prognosis. The 30-day good prognosis rate was 41.3% (66/160) and the poor prognosis rate was 58.7% (94/160). Multivariate logistic regression analysis showed that the Hunt & Hess classification correlated well with prognosis (OR: 4.367,95% CI, 2.254-8.460, P < 0.001). The clinical prognosis of patients with SaSAH is still poor. In particular, under the critical care of neurosurgery, the application of brain protective bundle based on step-wised protocol under multimodal monitoring might improve the clinical prognosis of patients with SaSAH.

OBJECTIVE: This study aimed to identify novel PITX2c mutations responsible for idiopathic atrial fibrillation. METHODS: A cohort of 210 unrelated patients with idiopathic atrial fibrillation and 200 unrelated, ethnically matched healthy individuals used as controls were recruited. The whole coding exons and splice junctions of the PITX2c gene, which encodes a paired-like homeobox transcription factor required for normal cardiovascular morphogenesis, were sequenced in 210 patients and 200 control subjects. The causative potentials of the identified mutations were automatically predicted by MutationTaster and PolyPhen-2. The functional characteristics of the PITX2c mutations were explored using a dual-luciferase reporter assay system. RESULTS: Two novel heterozygous PITX2c mutations (p.Q105L and p.R122C) were identified in 2 of the 210 unrelated patients with idiopathic atrial fibrillation. These missense mutations were absent in the 400 control chromosomes and were both predicted to be pathogenic. Multiple alignments of PITX2c protein sequences across various species showed that the altered amino acids were highly evolutionarily conserved. A functional analysis demonstrated that the mutant PITX2c proteins were both associated with significantly reduced transcriptional activity compared with their wild-type counterparts. CONCLUSION: The findings of this study associate PITX2c loss-of-function mutations with atrial fibrillation, supporting the hypothesis that dysfunctional PITX2c confers enhanced susceptibility to atrial fibrillation and suggesting potential implications for early prophylaxis and allele-specific therapy for this common arrhythmia.

OBJECTIVE: The aim of this study was to evaluate the prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation (AF). METHODS: A cohort of 136 unrelated patients with idiopathic atrial fibrillation and 200 unrelated, ethnically matched healthy controls were enrolled. The coding exons and splice junctions of the Nkx2.5 gene were sequenced in 136 atrial fibrillation patients, and the available relatives of mutation carriers and 200 controls were subsequently genotyped for the identified mutations. The functional characteristics of the mutated Nkx2.5 gene were analyzed using a dual-luciferase reporter assay system. RESULTS: Two novel heterozygous Nkx2.5 mutations (p.N19D and p.F186S) were identified in 2 of the 136 unrelated atrial fibrillation cases, with a mutational prevalence of approximately 1.47%. These missense mutations co-segregated with atrial fibrillation in the families and were absent in the 400 control chromosomes. Notably, 2 mutation carriers also had congenital atrial septal defects and atrioventricular block. Multiple alignments of the Nkx2.5 protein sequences across various species revealed that the altered amino acids were completely conserved evolutionarily. Functional analysis demonstrated that the mutant Nkx2.5 proteins were associated with significantly reduced transcriptional activity compared to their wild-type counterpart. CONCLUSION: These findings associate the Nkx2.5 loss-of-function mutation with atrial fibrillation and atrioventricular block and provide novel insights into the molecular mechanism involved in the pathogenesis of atrial fibrillation. These results also have potential implications for early prophylaxis and allele-specific therapy of this common arrhythmia.