HfO$_{2}$-based ferroelectric thin films are promising for their application in ferroelectric devices. Predicting the ultimate magnitude of polarization and understanding its switching mechanism are critical to realize the optimal performance of these devices. Here, a generalized solid-state variable cell nudged elastic band (VCNEB) method is employed to predict the switching pathway associated with domain-wall motion in (Hf, Zr)O$_{2}$ ferroelectrics. It is found that the polarization reversal pathway, where three-fold coordinated O atoms pass across the nominal unit-cell boundaries defined by the Hf/Zr atomic planes, is energetically more favorable than the conventional pathway where the O atoms do not pass through these planes. This finding implies that the polarization orientation in the orthorhombic Pca2$_{1}$ phase of HfO$_{2}$ nd its derivatives is opposite to that normally assumed, predicts the spontaneous polarization magnitude of about 70 ${\mu}$C/cm$^{2}$ that is nearly 50% larger than the commonly accepted value, signifies a positive intrinsic longitudinal piezoelectric coefficient, and suggests growth of ferroelectric domains, in response to an applied electric field, structurally reversed to those usually anticipated. These results provide important insights into the understanding of ferroelectricity in HfO$_{2}$-based ferroelectrics.
We sought to identify rare variants influencing brain imaging phenotypes in the Framingham Heart Study by performing whole genome sequence association analyses within the Trans-Omics for Precision Medicine Program.We performed association analyses of cerebral and hippocampal volumes and white matter hyperintensity (WMH) in up to 2,180 individuals by testing the association of rank-normalized residuals from mixed-effect linear regression models adjusted for sex, age, and total intracranial volume with individual variants while accounting for familial relatedness. We conducted gene-based tests for rare variants using (1) a sliding-window approach, (2) a selection of functional exonic variants, or (3) all variants.We detected new loci in 1p21 for cerebral volume (minor allele frequency [MAF] 0.005, p = 10-8) and in 16q23 for hippocampal volume (MAF 0.05, p = 2.7 × 10-8). Previously identified associations in 12q24 for hippocampal volume (rs7294919, p = 4.4 × 10-4) and in 17q25 for WMH (rs7214628, p = 2.0 × 10-3) were confirmed. Gene-based tests detected associations (p ≤ 2.3 × 10-6) in new loci for cerebral (5q13, 8p12, 9q31, 13q12-q13, 15q24, 17q12, 19q13) and hippocampal volumes (2p12) and WMH (3q13, 4p15) including Alzheimer disease- (UNC5D) and Parkinson disease-associated genes (GBA). Pathway analyses evidenced enrichment of associated genes in immunity, inflammation, and Alzheimer disease and Parkinson disease pathways.Whole genome sequence-wide search reveals intriguing new loci associated with brain measures. Replication of novel loci is needed to confirm these findings.
Background and objective We investigated the association of APOE alleles with CT-based cerebral amyloid angiopathy (CAA) markers including subarachnoid extension (SAE) and finger-like projection (FLP). Methods We included patients with acute primary supratentorial intracerebral haemorrhage (ICH) from a multicentre cohort in China. First, the association of APOE with ICH location (lobar vs non-lobar) was evaluated. Next, the relationships of APOE with SAE, FLP, and the coexistence of the two (SAE+FLP) were evaluated. Results 533 patients with supratentorial ICH were enrolled. Among them were 138 patients with lobar ICH and 395 with non-lobar ICH. Compared with the non-lobar group, APOE ε4 (OR 1.894, 95% CI 1.138 to 3.154, p=0.014) and ε2/ε4 (OR 6.098, 95% CI 1.414 to 26.293, p=0.015) were associated with lobar ICH. With regard to CAA markers, APOE ε2 was associated with SAE (OR 2.109, 95% CI 1.167 to 3.810, p=0.013), ε4 was associated with FLP and SAE+FLP (OR 3.026, 95% CI 1.353 to 6.767, p=0.007; OR 3.514, 95% CI 1.485 to 8.316, p=0.004, respectively) and ε2/ε4 was associated with all three factors (SAH: OR 7.599, 95% CI 1.764 to 32.734, p=0.006; FLP: OR 20.333, 95% CI 3.278 to 126.137, p=0.001; SAE+FLP: OR 30.568, 95% CI 4.460 to 209.503, p<0.001) after adjusting for age, and remained significant after adjusting for age and ICH volume. Conclusion In patients with spontaneous supratentorial ICH, APOE ε2 and ε4 alleles were associated with SAE and FLP, respectively, suggesting APOE allele-specific effects on CT markers of CAA and their potential mechanisms.
e16221 Background: The CARES-310 study has demonstrated that the combination of the anti-PD-1 antibody camrelizumab and the VEGFR2 tyrosine kinase inhibitor apatinib exhibits improved progression-free survival (PFS) and overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC). We conducted this study to investigate whether the addition of the anti-PD-L1 antibody adebrelimab to camrelizumab and apatinib would further improve clinical outcomes. Methods: This is a prospective, phase 1b/2 clinical trial employing the i3 + 3 dose escalation design. Eligibility includes adults with unresectable or metastatic HCC, a ECOG PS of 0 or 1, a Child-Pugh score ≤ 7, and at least one measurable lesion per RECIST v 1.1. In phase 1b, patients (pts) received adebrelimab (10 mg/kg or 20 mg/kg, I.V., D1, Q3W), camrelizumab (200mg, I.V., D1, Q3W), and apatinib (250 mg orally daily). Phase 2 is a single arm, open-label trial in the first-line setting. The primary objective were dose-limiting toxicity (DLT), maximal tolerated dose (MTD), and recommended phase II dose (RP2D). With α = 0.05 and 80% power, the pts needed for stage I and total of the Simon 2-stage design was 17 and 41 pts, respectively. Results: As of 4 February 2024, 6 HCC pts progressed after or were intolerant to first-line treatment (systemic therapy ± surgical resection) were treated in 1 dose cohorts. 1 DLT occurred (Grade 3 elevated blood bilirubin increased). The RP2D was adebrelimab (10 mg/kg), camrelizumab (200mg), and apatinib (250 mg). The most common drug-related AEs were Hypertension (83.3%) and Rash (50%); and Serum amylase increased, Itching, ALT/AST increased, and Hypothyroidism (each 33.3%). Immune-related AEs were similar to those seen with other checkpoint blockade agents. No drug-related AEs led to death. 1 pts (16.7%) discontinued due to drug-related AEs. Conclusions: The combination of Adebelimumab, Camrelizumab, and Apatinib demonstrated manageable safety for unresectable HCC. Enrollment in the phase II trial is ongoing and updated clinical data will be presented. Clinical trial information: NCT05924997 .
To investigate the feasibility and efficacy of transcanal endoscopic treatment for congenital middle ear cholesteatoma in children. Eleven children diagnosed with congenital middle ear cholesteatoma, who underwent total ear endoscopic surgery under general anesthesia, were included from the Huazhong University of Science and Technology Union Shenzhen Hospital between January 2016 and December 2020. We retrospectively analyzed their operation process and surgical complications through the surgical video; moreover, we compared the pre- and postoperative hearing outcomes. One child underwent a planned second operation to reconstruct the ossicular chain. At 6 postoperative months, all 11 children underwent reexamination. There was no significant change and a significant decrease in the mean bone and air conduction hearing thresholds, respectively ( P > .05 and P < .05); moreover, there was a significant reduction in the air–bone conduction difference ( P < .05). Further, the air–bone conduction difference was reduced to >20 dB and >10 dB in 11 and 7 children, respectively. Follow-up of the children did not reveal sensorineural deafness, facial paralysis, and other serious complications; further, there were no cases of recurrence. Transcanal endoscopic treatment for congenital middle ear cholesteatoma in children is feasible, minimally invasive, and functional.
