Efficacy and Safety of Direct Oral Anticoagulants in Patients with Atrial Fibrillation and Liver Disease: a Meta-Analysis and Systematic Review.

BACKGROUND: Liver disease is associated with increased bleeding risk. The efficacy and safety of direct oral anticoagulants (DOACs) is a subject of contention in atrial fibrillation (AF) patients with liver disease. METHODS: Electronic databases (PubMed, Embase, and Cochrane Library) were searched to retrieve studies on the efficacy and safety of DOACs versus warfarin in AF patients with liver disease from January 1980 to April 2020. A meta-analysis was conducted using a random-effects model. RESULTS: Six studies involving 41,859 patients were included. Compared with warfarin, DOACs demonstrated significant reduction in ischemic stroke (HR, 0.68; 95% CI (0.54-0.86)), major bleeding (0.74 (0.59-0.92)), and intracranial hemorrhage (ICH) (0.48 (0.40-0.58)), with no significant effect on gastrointestinal bleeding (P = 0.893) in AF patients with liver disease. Similar results were observed in regular-dose, reduced-dose, and active liver disease subgroups, albeit Asian patients had a slight reduction in major bleeding (P = 0.055). Furthermore, the pooled estimates of individual DOAC subgroups indicated that dabigatran and apixaban led to greater safety in major bleeding (P < 0.001), ICH (P < 0.001), and gastrointestinal bleeding (P < 0.005) in these patients. The same trends were observed in AF patients with cirrhosis. CONCLUSIONS: Our findings suggest that DOACs significantly reduce the risk of ischemic stroke, major bleeding, and ICH, with no significant effect on the risk of gastrointestinal bleeding in AF patients with liver disease compared with warfarin.

Resection of recurrent third branchial cleft fistulas assisted by flexible pharyngotomy.

BACKGROUND: Treatment of fistulas arising from the third branchial cleft includes endoscopic cauterization or open cervical fistulectomy. Both approaches are associated with recurrence rates of 14%-18%, and possibly greater rates when the fistula has been treated operatively beforehand. Treatment of fistulas arising from the third branchial cleft is associated with an inordinate recurrence rate. Recurrence may be multifactorial and related to incomplete resection of all of the anatomical elements of the fistula. AIM: To present a new approach that involves complete resection of the recurrent fistula by a combined therapeutic approach. METHODS: Here, 12 adult patients diagnosed with recurrent third branchial cleft fistulas underwent a combined therapy assisted by flexible fiber-optic pharyngoscopy to identify and resect the entry site of the fistula into the pyriform sinus. The fistulous opening into the pyriform sinus was identified by flexible fiber-optic pharyngoscopy. The application of intubation with a guidewire by pharyngoscopy, in addition to the removal of the partial excision of the thyroid cartilage, allowed complete resection of the opening and all parts of the fistula tract. RESULTS: All of the internal openings of the fistulas in the pharynx were found and easily identified by flexible fiber-optic pharyngoscopy. All of the 12 patients underwent complete resection of the recurrent fistula by the combined therapeutic approach. There were no postoperative complications such as parapharyngeal abscess or wound infection, injury or dysfunction of the recurrent laryngeal or superior laryngeal nerves. The pharyngeal edema had degraded, and the pharyngeal wound healed postoperatively within 1 wk. Laryngeal endoscopy and voice analysis were performed on the 14th d post-operatively. Vocal cord movements did not change. The characters of voice for jitter, shimmer, and normalized noise energy were all within normal limits. In addition, no recurrences were observed during the 13-60 mo follow-up period. CONCLUSION: It can be concluded that the proposed combined therapy is associated with excellent results, minimal morbidity, and no recurrence.

Triple versus dual oral antithrombotic therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention: a systematic review and meta-analysis.

BACKGROUND: The efficacy and safety of dual therapy (dual antiplatelet therapy [DAPT] and warfarin plus single antiplatelet [WS]) versus triple therapy (TT, DAPT plus warfarin) are still debated in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). The purpose of this study was to determine the optimal antithrombotic strategy. METHODS: Electronic databases (PubMed, Embase, Cochrane Library, CNKI and WanFang Data) were searched to retrieve studies on the efficacy and safety of TT vs. dual therapy in patients with AF undergoing PCI until August 2017. A meta-analysis was conducted using a random-effects model. The primary efficacy and safety endpoints were major adverse cardiac events (MACEs) and major bleeding events. RESULTS: Twenty-four studies involving 21,167 patients were included. The TT group had a significantly lower risk of MACEs (P=0.024) but a higher risk of major bleeding (P<0.001). In TT vs. DAPT subgroup, TT was associated with a lower risk of MI and stent thrombosis in Asian patients and a lower risk of stroke in non-Asian patients. Furthermore, TT did not decrease MACEs incidence (P=0.458) but increased the risk of major bleeding (P=0.008) relative to WS. The same trends were observed in Asian and non-Asian patients. CONCLUSION: Patients with AF undergoing PCI who received TT had significant reduction in MACEs but increased the risk of major bleeding compared with DAPT. However, WS had a similar efficacy but reduced the risk of major bleeding compared with TT. Current evidence suggests that TT might not be required and might be replaced by WS.

Aberrant Interhemispheric Connectivity in Obstructive Sleep Apnea-Hypopnea Syndrome.

OBJECTIVE: To determine the changes in interhemispheric functional coordination in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) relative to controls, using a recently introduced method of analysis: voxel-mirrored homotopic connectivity (VMHC). METHODS: Twenty-nine patients with OSAHS and twenty-six normal sex-, age-, and education-matched controls were recruited and resting-state functional magnetic resonance imaging data were obtained. We employed VMHC to analyze the interhemispheric functional connectivity differences between groups. The z-values of alterations in VMHC in brain region were correlated with clinical characteristics. RESULTS: Compared with controls, patients with OSAHS had significantly higher scores for body mass index (t = 5.749, P < 0.001), apnea-hypopnea index (AHI; t = 7.706, P < 0.001), oxygen desaturation index (t = 6.041, P < 0.001), and Epworth sleepiness scale (t = 3.711, P < 0.001), but significantly lower scores on the Rey-Osterrieth complex figure test-immediate recall (t = -3.727, P < 0.05). On the same basis, the VMHC showed significant increases in bilateral calcarine cortex and precuneus. Moreover, significant, positive correlations were found in only these areas between the AHI and the VMHC change coefficients (r = 0.399, P = 0.032; r = 0.378, P = 0.043). CONCLUSION: We found a memory defect in patients with OSAHS. The correlation between the abnormal VMHC and the AHI in patients with OSAHS suggested that AHI might be a key factor in cognitive dysfunction, which might offer new insights into the neural pathophysiology underlying OSAHS-related cognitive deficits.

Highly Efficient Glioma Targeting of Tat Peptide-TTA1 Aptamer-Polyephylene Glycol-Modified Gelatin-Siloxane Nanoparticles.

Gliomas are the most common type of intracranial malignant tumor; however, current treatment approaches are often ineffective due to limited penetration of genes or drugs through the blood-brain barrier (BBB). Here we describe the synthesis of gelatin-siloxane nanoparticles (GS NPs) as candidate gene carriers through a two-step sol-gel process. To increase the efficiency of glioma targeting, human immunodeficiency virus-derived Tat, tumor-targeting aptamer (TTA)1, and polyethylene glycol (PEG) were conjugated to the GS NPs to generate Tat-TTA1-PEG-GS NPs. In vivo imaging revealed that these modified NPs not only evaded capture by the reticulo-endothelial system, but were able to cross the BBB to reach gliomas. Our results suggest that Tat-TTA1-PEG-GS NPs are a new type of non-viral vector that can deliver therapeutic DNA or drugs for highly efficient glioma treatment.

The Resting-State Functional Connectivity of the Default Mode Networks in Patients With Obstructive Sleep Apnea-Hypopnea Syndrome.

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is normally linked to cognitive and functional dysfunctions. In this study, we explored the resting-state functional connectivity (rsFC) in the default mode network (DMN) to show the mechanism of neurophysiology in patients with OSAHS. Resting-state structural and functional Magnetic Resonance Imaging data were obtained from sixteen male moderate-to- severe patients with untreated OSAHS and 15 male matched healthy control subjects. The rsFC in the DMN was analyzed between OSAHS and healthy controls by the CONN software. Compared with the controls, the rsFC showed a significant decrease in the the medial prefrontal cortex, anterior cingulate and posterior cingulate, and showed an increase in the left inferior parietal lobule in OSAHS patients. The results indicated that the OSAHS patients presented alternatives of rsFC in the DMN compared with the controls.

Functional Connectivity in Patients With Sensorineural Hearing Loss Using Resting-State MRI.

PURPOSE: This study was undertaken to evaluate whole-brain functional connectivity changes related to auditory cortex in patients with left-sided sensorineural hearing loss (SNHL) using resting-state functional connectivity magnetic resonance imaging. METHOD: Imaging was performed in 19 patients with left-sided SNHL and 35 individuals in the control group without SNHL. Data were collected and analyzed to map functional connectivity using the left/right primary auditory cortex as the region of interest to identify global differences between patients with SNHL and the control group. RESULTS: In comparison to the control group, the SNHL group was found to have significant functional connectivity changes in the auditory system, recognition network, visual cortex, and language network. CONCLUSION: These findings suggest that functional brain alterations in unilateral SNHL patients may indicate reorganizations that occur in response to auditory deficits.

Brain structural and functional alterations in patients with unilateral hearing loss.

Alterations of brain structure and functional connectivity have been described in patients with hearing impairments due to distinct pathogenesis; however, the influence of unilateral hearing loss (UHL) on brain morphology and regional brain activity is still not completely understood. In this study, we aim to investigate regional brain structural and functional alterations in patients with UHL. T1-weighted volumetric images and task-free fMRIs were acquired from 14 patients with right-sided UHL (pure tone average ≥ 40 dB HL) and 19 healthy controls. Hearing ability was assessed by pure tone audiometry. Voxel-based morphometry (VBM) was performed to detect brain regions with changed gray matter volume or white matter volume in UHL. The amplitude of low-frequency fluctuation (ALFF) was calculated to analyze brain activity at the baseline and was compared between two groups. Compared with controls, UHL patients showed decreased gray matter volume in bilateral posterior cingulate gyrus and precuneus, left superior/middle/inferior temporal gyrus, and right parahippocampal gyrus and lingual gyrus. Meanwhile, patients showed significantly decreased ALFF in bilateral precuneus, left inferior parietal lobule, and right inferior frontal gyrus and insula and increased ALFF in right inferior and middle temporal gyrus. These findings suggest that chronic UHL could induce brain morphological changes and is associated with aberrant baseline brain activity.

Tat peptide-decorated gelatin-siloxane nanoparticles for delivery of CGRP transgene in treatment of cerebral vasospasm.

BACKGROUND: Gene transfer using a nanoparticle vector is a promising new approach for the safe delivery of therapeutic genes in human disease. The Tat peptide-decorated gelatin-siloxane (Tat-GS) nanoparticle has been demonstrated to be biocompatible as a vector, and to have enhanced gene transfection efficiency compared with the commercial reagent. This study investigated whether intracisternal administration of Tat-GS nanoparticles carrying the calcitonin gene-related peptide (CGRP) gene can attenuate cerebral vasospasm and improve neurological outcomes in a rat model of subarachnoid hemorrhage. METHOD: A series of gelatin-siloxane nanoparticles with controlled size and surface charge was synthesized by a two-step sol-gel process, and then modified with the Tat peptide. The efficiency of Tat-GS nanoparticle-mediated gene transfer of pLXSN-CGRP was investigated in vitro using brain capillary endothelial cells and in vivo using a double-hemorrhage rat model. For in vivo analysis, we delivered Tat-GS nanoparticles encapsulating pLXSN-CGRP intracisternally using a double-hemorrhage rat model. RESULTS: In vitro, Tat-GS nanoparticles encapsulating pLXSN-CGRP showed 1.71 times higher sustained CGRP expression in endothelial cells than gelatin-siloxane nanoparticles encapsulating pLXSN-CGRP, and 6.92 times higher CGRP expression than naked pLXSN-CGRP. However, there were no significant differences in pLXSN-CGRP entrapment efficiency and cellular uptake between the Tat-GS nanoparticles and gelatin-siloxane nanoparticles. On day 7 of the in vivo experiment, the data indicated better neurological outcomes and reduced vasospasm in the subarachnoid hemorrhage group that received Tat-GS nanoparticles encapsulating pLXSN-CGRP than in the group receiving Tat-GS nanoparticles encapsulating pLXSN alone because of enhanced vasodilatory CGRP expression in cerebrospinal fluid. CONCLUSION: Overexpression of CGRP attenuated vasospasm and improved neurological outcomes in an experimental rat model of subarachnoid hemorrhage. Tat-GS nanoparticle-mediated CGRP gene delivery could be an innovative strategy for treatment of cerebral vasospasm after subarachnoid hemorrhage.

[Primary mechanism of the role of dual oxidase-1 causing airway allergic diseases in human bronchial epithelium].

OBJECTIVE: To investigate the role of dual oxidase-1 (DUOX-1) inducing airway hyperresponsiveness in human bronchial epithelium. METHODS: The human bronchial epithelial cells were divided into several groups: control group, tumor necrosis factor-α (TNF-α) group, methyl-ß-cyclodextrin (M-ß-CD)+TNF-α group, desipramine (DES)+ TNF-α group, diphenylene iodonium (DPI) + TNF-α group and apocynin (APO)+TNF-α group. Fractionation was performed by sucrose gradient centrifugation and the protein DUOX-1 was measured by western blotting. The lipid raft clusters and its colocalization with DUOX-1 were confocal analysed. The intracellular reactive oxygen species (ROS) accumulation was measured by fluorescence of reactive oxygen probe of intracellular measurement. Sigmastat 3.02 software was used to analyze the data. RESULTS: (1) Detection of ROS, control group: 1.00 ± 0.00; TNF-α group: 1.95 ± 0.16; M-ß-CD+TNF-α group: 0.91 ± 0.16; DES+TNF-α group: 1.49 ± 0.20; DPI+TNF-α group: 1.03 ± 0.16; APO+TNF-α group: 1.47 ± 0.26. The difference was statistically significant (F = 3.83, P < 0.05). (2) Extracts in rafts to lipid rafts region represents the ratio of total protein, protein content DUOX-1 each group, control group: 0.21 ± 0.02; TNF-α group: 0.49 ± 0.04; M-ß-CD+TNF-α group: 0.08 ± 0.02; DES+TNF-α group: 0.09 ± 0.03; the difference was statistically significant (F = 3.96, P < 0.05). (3) DUOX-1 protein fluorescence values, control group: 1.72 ± 0.21; TNF-α group: 8.11 ± 1.23; M-ß-CD+TNF-α group: 1.51 ± 0.32; DES+TNF-α group: 1.43 ± 0.11; the difference was statistically significant (F = 4.87, P < 0.05). (4) DUOX-1 gene detection, control group: 1.00 ± 0.00 ScrRNA+TNF-α group: 1.75 ± 0.04; DUOX-1siRNA+TNF-αgroup: 1.15 ± 0.02; the difference was statistically significant (F = 4.19, P < 0.05). CONCLUSION: TNF-α can induce DUOX-1 expression increasing in lipid raft, then the DUOX-1 can be activated to increase reactive oxygen species level; acidic sphingomyelinase inhibitor desipramine can inhibit this process, the results disclose that the process will depend on the ceramide of lipid raft.

[Comparison between harmonic scalpel as major instrument and conventional operation for tonsillectomy].

OBJECTIVE: To investigate the feasibility of applying harmonic scalpel in tonsillectomy by comparing it with the conventional tonsillectomy. METHODS: Thirty-five patients were treated by harmonic scalpel assisted tonsillectomy (harmonic scalpel group) and 35 patients were treated by conventional tonsillectomy (control group). The operating time and blood loss during operation and the degree of pain and post-tonsillectomy hemorrhage as well as the time of defining were observed. RESULTS: The data of the operating time and blood loss during operation and the degree of pain in harmonic scalpel group were lower than that in the conventional group, the harmonic scalpel group had less perioperative bleeding (median 1 ml), short operation time (median 20 min), postoperative pain during 5 days with visual analogue scale was lighter (median from 5 scores down to 1 score), there was statistical difference (P < 0.01). Neither primary hemorrhage nor secondary hemorrhage occurred in harmonic scalpel group, while one primary hemorrhage and one secondary hemorrhage occurred in conventional group. No difference was found in the beginning time of defining (P > 0.05). CONCLUSION: The application of harmonic scalpel in tonsillectomy was safe, efficient and feasible, which had a nice application prospect in the field of otolaryngology.

[Functional magnetic resonance imaging in patients with long-term unilateral hearing loss].

OBJECTIVE: To evaluate the potential functional reorganization by functional magnetic resonance imaging (MRI) to measure the brain activation in responses to stimulation to healthy ears in patients with long-term unilateral hearing loss (UHL). METHODS: From June 1998 to December 2009, 23 patients with serious UHL (15 left, 8 right) were recruited along with 15 matched normal hearing subjects. Laterality index (LI) for activated voxel in primary auditory cortex (PAC) was calculated. And the activations outside auditory cortex were also evaluated. RESULTS: The data were discarded in 3 patients with left-ear UHL and 1 normal subject because of head motion. All control subjects showed contralateral dominant activation of PAC in group analysis. However, the group data of UHL patients showed that the activation was more symmetrical and the contralateral dominance diminished versus the control group. As compared with normal subjects outside PAC, heightened activation in left prefrontal cortex, bilateral inferior parietal lobule and left occipital/precuneus was found in UHL patients while reduced activation in left superior temporal gyrus was also found. CONCLUSIONS: The diminished contralateral dominance in PAC and heightened activation in non-auditory region suggest the reduction of interhemispheral inhibition and general increase in brain excitation in long-term UHL patients potentially occur as a result of functional reorganization adaptive to UHL. However, the reduced activation in superior temporal gyrus may be correlated with the deterioration of speech perception in these patients.

Enhanced brain targeting of temozolomide in polysorbate-80 coated polybutylcyanoacrylate nanoparticles.

BACKGROUND: Polybutylcyanoacrylate (PBCA) nanoparticles coated with polysorbate-80 have been extensively proposed for delivering drugs into the animal brain and have shown great potential for therapeutic applications. In this study, we made an attempt to deliver the chemotherapeutic drug, temozolomide, into the brain by using PBCA nanoparticles. The physicochemical characteristics, in vitro release, and brain targeting ability of the drug-loaded nanoparticles were investigated. RESULTS: Our results show that a significantly higher concentration of temozolomide in the form of polysorbate-80-coated PBCA nanoparticles was observed in the brain (P < 0.05) in comparison with the free drug. CONCLUSION: This study indicates that polysorbate-80 coated PBCA nanoparticles could be a feasible carrier for temozolomide delivery to the brain. It is anticipated that the developed formulation may improve on targeted therapy for malignant brain tumors in the future.

[Functional MRI in normal subjects and sudden unilateral sensorineural hearing loss patients].

OBJECTIVE: Brain activities in responses to amplitude modulation (AM) was evaluated using functional MRI (fMRI) in subjects with sudden unilateral sensorineural hearing loss (SSNHL) and those with normal hearing (NH). METHODS: Totally 25 subjects with normal hearing and 30 with SSNHL were examined with fMRI in response to AM tones of 500, 2000 and 4000 Hz respectively with the modulation frequency at 8 Hz. The fMRI was examined within 12 days after the onset of SSNHL. The AM signals were presented at 96 dB SPL binaurally. An event-related design was combined with a sparse clustered volume acquisitioning paradigm in data collection in the attempt to reduce the influence of acoustic scanner noise. SPM2 software was used for offline data analyzing. RESULTS: Brain activation in fMRI image was found mainly in the primary auditory cortex (PAC) in both subjects with NH and SSNHL NH subjects showed a clear lateralization to left cerebral hemisphere(11/16) and SSNHL patients showed a lateralization ipsilateral to the impaired ear(16/22). The activation voxel and intensity shown in BOLD were found to be decreased with increasing signal frequency in both groups. CONCLUSION: The difference in the lateralization between the two groups suggests that an adaptive process occurs shortly after the onset of SSNHL

[Dominant hemisphere and tonotopic organization of auditory functional MRI in Chinese].

OBJECTIVE: Functional MRI (fMRI) was measured in responses to stimulations of different frequencies to investigate dominant hemisphere and tonotopic organization in primary and secondary auditory cortex. METHODS: 25 healthy subjects with normal hearing were examined using tones of 0.5, 2 or 4 kHz that were amplitude modulated (AM) sinusoidally at 8 Hz. The AM signals were presented at 96 dB SPL Event-related design was combined with a sparse clustered volume acquisitioning paradigm for data collection in the attempt to reduce the influence of acoustic scanner noise. SPM2 software was used for offline data analyzing. RESULTS: Data from 9 subjects were discarded due to a large head movement during recording. In the rest of 16 subjects, activation was found mainly in the primary auditory cortex. In most of these cases, the activation area and intensity by BOLD were find to be decreased with increasing signal frequency. In a great portion of cases (6 left and 7 right hemispheres), a lateral-medial preference for low-to-high frequency response shift was clearly demonstrated in the primary auditory cortex. However, this was not clear in all other cases. No significant rule could be found in secondary auditory cortex activation. CONCLUSION: The responses to AM signals showed a clear lateralization to left cerebral hemisphere. The activated area and response intensity decreased with increasing frequency of stimulation. The activation is related to the signal frequency with high frequency AM activating more medially.

[Partial laryngectomy for ninety-eight patients with glottic carcinoma of the larynx].

OBJECTIVE: To investigate the therapeutic results after various kinds of partial laryngectomy for patients with glottic carcinoma of the larynx. METHODS: From January 1980 to Mar 2004, 98 patients with glottic carcinoma of the larynx were treated by various kinds of partial laryngectomy. The types of operation varied according to stage of the lesion: vertical or frontovertical partial laryngectomy for T1b, T2 and T1a with invasion of anterior commissura, Tuker's operation or supracricoid partial laryngectomy for T1b, T2 or those with invasion of over half of contralateral cord, and extended vertical partial laryngectomy with resection of arytenoids for T3, or with invasion of ipsilateral arytenoids cartilage without involving postcricoid mucosa or posterior commissura. Totally, vertical partial laryngectomy was carried out for 76 patients, extended vertical partial laryngectomy for 7, supracricoid partial laryngectomy for 3 and Tucker's operation for 12. One stage unilateral neck dissection was performed in 5 patients and postoperative radio-therapy was supplemented to 5 (dose 60 Gy). For laryngeal function restoration, pectoro-hyomyo-flap and cricohyoidoepi glotopexy procedures were also performed for some patients. The clinical data of these patients were retrospectively analyzed. RESULTS: The 3- and 5-year survival rate was 86.5% (64/74) and 81.7% (49/60), respectively. The total decannulation rate was 94.9% (93/98), though fifteen patients had had symptoms of aspiration. Swallowing function of all patients recovered to the normal level. The phonation of all patients was restored to various degrees and they were able to communicate socially. CONCLUSION: The 3- and 5-year survival rates of partial laryngectomy for patients with glottic carcinoma of the larynx are comparable to the results achieved by total laryngectomy, but the quality of life of the patents much better. Complete resection of the tumor and simultaneous preservation of respiratory and vocal function whenever possible by partial laryngectomy is very important for improving patients' life quality. With a suitable size and good blood supply, the sternohyoid muscle flap of unipedical and half-thickness instead of whole thickness is ideal in the reconstruction of laryngeal defect after vertical partial laryngectomy.