Non-induced Group Research Articles

Impact of timing of immunotherapy in survival among patients with advanced lung adenocarcinoma treated with first-line immunochemotherapy: A propensity score matching.

e20560 Background: Immunochemotherapy combinations have been the mainstream first-line standard treatment of advanced non-small cell lung cancer (NSCLC), wherein concurrent chemotherapy and immunotherapy are conventionally fixed to an established dosing regimen. Few studies had suggested the remarkable impact of the timing of immunotherapy on immunochemotherapy combined therapy. However, this issue has not been addressed in advanced NSCLC cohort. Methods: This study was a retrospective analysis of 532 patients with advanced lung adenocarcinoma (LUAD) without EGFR/ALK mutations who underwent immunochemotherapy as first-line systemic treatment between June 2018 to June 2022 at 3 facilities. Patients were divided into two groups (induced and non-induced) according to the different timing of immunotherapy in combined therapy, which defined induced as receiving 1 or more cycles of full-dose chemotherapy alone before concurrent immunochemotherapy. The bias between induced and non-induced groups was minimized with Propensity Score Matching (PSM). Patients outcomes, including progression-free survival (PFS) and overall survival (OS), were compared between the two groups by Kaplan-Meier survival curves and Cox regression analyses. Results: Survival analysis showed that both PFS and OS of the induced chemotherapy group patients were significantly longer than that of non-induced group (PFS: 14.63 months vs. 10.13 months, p = 0.004; OS: Not reached vs. 20.27 months, p = 0.0013). In the COX regression, after adjusting for confounders, induction chemotherapy was found to be a remarkable favorable factor for both PFS and OS (PFS: HR = 0.73, p= 0.018; OS: HR = 0.69, p= 0.034). After pretreatment features and treatment parameters were included in PSM, 104 patients were identified in each groups with matched characteristics, and moreover, the results of survival analysis remained consistent and showed significant difference between induced and non-induced group (PFS: 14.63 months vs. 10.23 months, p = 0.029; HR = 0.71, p= 0.030. OS: Not reached vs 18.27 months, p = 0.0013; HR = 0.52, p= 0.002). Conclusions: For advanced LUAD patients treated with first-line immunochemotherapy combinations, the timing of immunotherapy had significant impact on prognosis, which suggested notable benefit of induction chemotherapy before concurrent immunochemotherapy.

Ocu-miR-10a-5p promotes the chondrogenic differentiation of rabbit BMSCs by targeting BTRC-mediated Wnt/β-catenin signaling pathway.

MicroRNAs (miRNAs) play an important role in articular cartilage damage in osteoarthritis (OA). However, the biological role of miRNAs in the chondrogenic differentiation of bone marrow mesenchymal stem cell (BMSC) remains largely unclear. Rabbit bone marrow mesenchymal stem cells (rBMSCs) were isolated, cultured, and identified. Afterwards, rBMSCs were induced to chondrogenic differentiation, examined by Alcian Blue staining. Differentially expressed miRNAs were identified in rBMSCs between induced and non-induced groups by miRNA sequencing analysis, part of which was validated via PCR assay. Cell viability and apoptosis were assessed by CCK-8 assay and Hoechst staining. Saffron O staining was utilized to assess chondrocyte hyperplasia. The expression of specific chondrogenic markers, including COL2A1, SOX9, Runx2, MMP-13, Aggrecan, and BMP-2, were measured at mRNA and protein levels. The association between beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) and miR-10a-5p in the miRNA family from rabbit (ocu-miR-10a-5p) was determined by luciferase reporter assay. A total of 76 differentially expressed miRNAs, including 52 downregulated and 24 upregulated miRNAs, were identified in rBMSCs from the induced group. Inhibition of ocu-miR-10a-5p suppressed rBMSC viability and chondrogenic differentiation, as well as downregulated the expression of β-catenin, SOX9, COL2A1, MMP-13, and Runx2. BTRC was predicted and confirmed as a target of ocu-miR-10a-5p. Overexpression of BTRC rescued the promoting impacts of overexpressed ocu-miR-10a-5p on chondrogenic differentiation of rBMSCs and β-catenin expression. Taken together, our data suggested that ocu-miR-10a-5p facilitated rabbit BMSC survival and chondrogenic differentiation by activating Wnt/β-catenin signaling through BTRC.

Progression of retinal choroidal neovascularizationby latent human cytomegalovirus infection and immunological signaling among neonatal patients admitted to tertiary care hospital.

Choroidal neovascularization (CNV) is a serious condition that affects the retina, causing partial or complete blindness in people of different ages. While CNV is a common occurrence in various chorioretinopathies, research on its occurrence in neonates is limited. Human cytomegalovirus (HCMV) is a significant health threat to neonates, with a strong association with retinal angiogenesis. However, there has been limited investigation into HCMV-associated CNV progression. In this article, we extensively studied the expression of different inflammatory cytokines and chemokines during latent HCMV-associated retinal neovascularization. Our research found that HCMV-induced CNV progression was significantly prominent in the presence of AT2R-dependent angiogenesis (p < 0.001), whereas in the absence of HCMV, AT1R-dependent CCL-5-mediated angiogenesis was documented. We also observed significant increases in CCL-19, CCL-21 chemokine responses, followed by CCR-7 chemokine receptor activation (p < 0.001) in HCMV-induced CNV patients compared to HCMV non-induced CNV groups. Furthermore, significant changes in predictive chemokine markers of HCMV-induced CNV were positively correlated with HCMV viremia. These immunological alterations ultimately lead to the switching of NFκB canonical and noncanonical pathways, respectively, in HCMV-induced neonatal CNV and HCMV non-induced CNV. This clinical observation presents a novel hypothesis that ocular HCMV latency poses a noteworthy risk factor for the progression of retinal neovascularization through a distinctive immunological signaling pathway. The current study represents the first of its kind to report on this association, which may have significant implications for the clinical management of patients with ocular HCMV.

Exposure to the mixotrophic dinoflagellate Lepidodinium sp. and its cues increase toxin production of Pseudo-nitzschia multiseries

The present study examined the defense responses of toxigenic Pseudo-nitzschia species (P. multiseries) to a mixotrophic dinoflagellate, Lepidodinium sp., and its associated cues. We evaluated their responses to different predation risks, including direct physical contact and indirect interactions facilitated by cues from Lepidodinium sp. during active feeding on heterospecific prey (Rhodonomas salina), limited feeding on conspecific prey (P. multiseries) and non-feeding (autotrophic growth in f/2 medium) states. This study is the first investigation of these trophic interactions. Our results demonstrated a significant increase in cellular domoic acid (cDA) in P. multiseries when exposed to Lepidodinium sp. and its associated cues, which was 1.38 to 2.42 times higher than the non-induced group. Notably, this increase was observed regardless of Lepidodinium sp. feeding on this toxic diatom and nutritional modes. However, the most significant increase occurred when they directly interacted. These findings suggest that P. multiseries evaluates predation risk and increases cDA production as a defensive strategy against potential grazing threats. No morphological changes were observed in P. multiseries in response to Lepidodinium sp. or its cues. P. multiseries cultured in flasks of Group L+P-P showed a decrease in growth, but Group L-P and Group L+R-P did not exhibit any decrease. These results suggest a lack of consistent trade-offs between the defense response and growth, thus an increase in cDA production may be a sustainable and efficient defense strategy for P. multiseries. Furthermore, our findings indicate that P. multiseries had no significant impact on the fitness (cell size, growth and/or grazing) of Lepidodinium sp. and R. salina, which suggests no evident toxic or allelopathic impacts on these two phytoplankton species. This study enhances our understanding of the trophic interactions between toxic diatoms and mixotrophic dinoflagellates and helps elucidate the dynamics of Harmful Algal Blooms, toxin transmission, and their impact on ecosystem health.

Pre-clinical protective potentials of Carica papaya constituents in experimentally induced anemia.

Anemia is a pathological condition characterized by reduced oxygen bioavailability and/or changes in hematological parameters. This study investigated the anti-anemic activities of Carica papaya (CP) phytoconstituents in aluminium-chloride-induced anemic rats. Twenty-seven rats were randomized into nine groups of three rats as follows; group 1 was the normal (non-induced) group, 2-9 were anemic rats administered 1 mL distilled water, standard drug (3 mg/kg body weight (bw) ferrous sulphate), 100, 300 and 500 mg/kg bw of crude methanolic extract of CP (CMECP) of the leaf and 100, 300 and 500 mg/kg bw of CMECP of the seed respectively in the first stage of the study. In the second stage, thirty-three rats were randomized into eleven groups of three rats as follows; group 1 was the normal group, 2-11 were anemic rats treated with 1 mL distilled water, standard drug, 75 mg/kg bw, 150 mg/kg of alkaloid fraction of CP seed, 75 mg/kg bw, 150 mg/kg bw of flavonoid fraction of CP seed, 75 mg/kg bw and 150 mg/kg of alkaloid fraction of CP leaf, 75 mg/kg bw and 150 mg/kg bw of flavonoid fraction of CP leaf respectively. Treatment of anemic rats with CP extracts and fractions of the seed and leaf significantly reversed the hematological parameters and body weight of anemic rats in a dose independent fashion. The CMECP leaf at 100 and 500 mg/kg gave PCV of 42.50±0.50 and 47.00±0.50, while the seed gave 49.50±0.50 and 42.50±0.50 respectively after 2 weeks of treatment. However, the alkaloid and flavonoid fraction of CP presented better anti-anemic properties probably due to constituents' synergism. This study concluded that CP possesses phytoconstituents which potentiates it as a safe anti-anemic drug candidate.

Electrophysiological study prior to planned pulmonary valve replacement in patients with repaired tetralogy of Fallot.

Ventricular arrhythmias (VAs) are the most common cause of death in patients with repaired Tetralogy of Fallot (rTOF). However, risk stratifying remains challenging. We examined outcomes following programmed ventricular stimulation (PVS) with or without subsequent ablation in patients with rTOF planned for pulmonary valve replacement (PVR). We included all consecutive patients with rTOF referred to our institution from 2010 to 2018 aged ≥18 years for PVR. Right ventricular (RV) voltage maps were acquired and PVS was performed from two different sites at baseline, and if non-inducible under isoproterenol. Catheter and/or surgical ablation was performed when patients were inducible or when slow conduction was present in anatomical isthmuses (AIs). Postablation PVS was undertaken to guide implantable cardioverter-defibrillator (ICD) implantation. Seventy-seven patients (36.2 ± 14.3 years old, 71% male) were included. Eighteen were inducible. In 28 patients (17 inducible, 11 non-inducible but with slow conduction) ablation was performed. Five had catheter ablation, surgical cryoablation in 9, both techniques in 14. ICDs were implanted in five patients. During a follow-up of 74 ± 40 months, no sudden cardiac death occurred. Three patients experienced sustained VAs, all were inducible during the initial EP study. Two of them had an ICD (low ejection fraction for one and important risk factor for arrhythmia for the second). No VAs were reported in the non-inducible group (p < .001). Preoperative EPS can help identifying patients with rTOF at risk for VAs, providing an opportunity for targeted ablation and may improve decision-making regarding ICD implantation.

Contribution of atrial myofiber architecture to atrial fibrillation.

The role of fiber orientation on a global chamber level in sustaining atrial fibrillation (AF) is unknown. The goal of this study was to correlate the fiber direction derived from Diffusion Tensor Imaging (DTI) with AF inducibility. Transgenic goats with cardiac-specific overexpression of constitutively active TGF-β1 (n = 14) underwent AF inducibility testing by rapid pacing in the left atrium. We chose a minimum of 10 minutes of sustained AF as a cut-off for AF inducibility. Explanted hearts underwent DTI to determine the fiber direction. Using tractography data, we clustered, visualized, and quantified the fiber helix angles in 8 different regions of the left atrial wall using two reference vectors defined based on anatomical landmarks. Sustained AF was induced in 7 out of 14 goats. The mean helix fiber angles in 7 out of 8 selected regions were statistically different (P-Value < 0.05) in the AF inducible group. The average fractional anisotropy (FA) and the mean diffusivity (MD) were similar in the two groups with FA of 0.32±0.08 and MD of 8.54±1.72 mm2/s in the non-inducible group and FA of 0.31±0.05 (P-value = 0.90) and MD of 8.68±1.60 mm2/s (P-value = 0.88) in the inducible group. DTI based fiber direction shows significant variability across subjects with a significant difference between animals that are AF inducible versus animals that are not inducible. Fiber direction might be contributing to the initiation and sustaining of AF, and its role needs to be investigated further.

Association between Lung Microbiota Dysbiosis and Sepsis Induced Acute Respiratory Distress Syndrome

Sepsis is associated with acute respiratory distress syndrome, which has a significant impact on the prognosis of patients. Several studies have shown that the microbiota plays a significant role in sepsisinduced acute respiratory distress syndrome, but the relationship between the microbiota and sepsisinduced acute respiratory distress syndrome is not fully understood. We conducted a case-control and single-center study in 19 sepsis-induced acute respiratory distress syndrome patients and 36 sepsis-noninduced acute respiratory distress syndrome patients to investigate the clinical features and microbiota expression. There were 55 subjects enrolled, 19 of whom suffered acute respiratory distress syndrome due to sepsis. A significant increase in the abundance of Pseudomonas aeruginosa, leptospiral virus, Cytomegalovirus, Klebsiella pneumoniae, Streptococcus pneumoniae, Candida albicans, Escherichia coli, Epstein-Barr virus and Staphylococcus aureus. Besides, expressions of peripheral T lymphocytes (cluster of differentiation 3+, cluster of differentiation 4+ and cluster of differentiation 3+, cluster of differentiation 8+) was much higher in the sepsis-induced acute respiratory distress syndrome group than that in the sepsis non-induced acute respiratory distress syndrome group. The acute physiology and chronic health evaluation II scores, duration of mechanical ventilation and mortality with 28 d and 90 d were much higher in the sepsis-induced acute respiratory distress syndrome group. Patients with sepsis-induced acute respiratory distress syndrome had worse clinical outcomes and a higher expression of peripheral T lymphocytes, as well as the relative abundance of microbiota dysbiosis.

Programmed ventricular stimulation in structural heart disease: Implications of patterns of ventricular arrhythmias induced to long-term outcomes

IntroductionCurrently available data gives some credence to utility of VT induction studies in patients with stable ischemic cardiomyopathy, there are some unresolved questions as to define sensitive threshold for low-risk and the prognostic relevance of ill sustained or non-specific tachycardia on induction study. We evaluated potential ability of VT inducibility to predict likelihood of SHD (Structural heart disease) patients for subsequent arrhythmic or adverse cardiac events. Material and MethodsAll consecutive patients with syncope/documented arrhythmia who had VT induction done were included and patients with VT storm, ACS,uncontrolled HF were excluded. We studied in 4 groups-monomorphic VT, sustained polymorphicVT, ill sustainedVT/VF and no VT/VF induced. The primary-endpoints were – Sudden death, all-cause mortality and secondary-endpoints were – MACE (AICD shock, death,HF, recurrence of VT). We screened 411 patients and included 169 within inducible (n = 79) and non-inducible group (n = 90). ResultsThere were a higher number of patients with coronary artery disease, LV dysfunction, patients on amiodarone in inducible group and no difference in usage of beta-blockers. Recurrence of VT, composite of MACE was significantly higher in inducible group (p < 0.05). Mortality was not different in 3 groups compared with no VT/VF group. We found that monomorphic VT group had significantly higher MACE as compared to others and also predicted recurrence of VT and AICD shock and showed a trend towards significance for prediction of mortality. Inducible patients on AICD had mortality similar to non-inducible group. ConclusionInduction of monomorphicVT/polymorphicVT with ≤3extrastimuli is associated with a higher number of MACE events on follow up. Induction of monomorphicVT predicts recurrence of VT/ICD shock.

Activation Patterns of Functional Brain Network in Response to Action Observation-Induced and Non-Induced Motor Imagery of Swallowing: A Pilot Study.

Action observation (AO) combined with motor imagery (MI) was verified as more effective in improving limb function than AO or MI alone, while the underlying mechanism of swallowing was ambiguous. The study aimed at exploring the efficacy of AO combined with MI in swallowing. In this study, twelve subjects performed the motor imagery of swallowing (MI-SW) during magnetoencephalography (MEG) scanning, and trials were divided into three groups: the non-induced group (control group, CG), male AO-induced group (M-AIG), and female AO-induced group (F-AIG). We used event-related spectral perturbations (ERSPs) and phase locking value (PLV) to assess the degree of activation and connectivity of the brain regions during MI-SW in the three groups. The results showed that compared to CG, F-AIG and M-AIG significantly activated more brain regions in the frontoparietal, attention, visual, and cinguloopercular systems. In addition, M-AIG significantly activated the sensorimotor cortex compared to CG and F-AIG. For the brain network, F-AIG and M-AIG increased the diffusion of non-hub hot spots and cold hubs to the bilateral hemispheres which enhanced interhemispheric functional connectivity and information transmission efficiency in the MI-SW task. This study provided supporting evidence that AO induction could enhance the effect of MI-SW and supported the application of AO-induced MI-SW in clinical rehabilitation.

Nanoformulated Recombinant Human Myelin Basic Protein and Rituximab Modulate Neuronal Perturbations in Experimental Autoimmune Encephalomyelitis in Mice.

IntroductionRituximab (RTX) and recombinant human myelin basic protein (rhMBP) were proven to be effective in ameliorating the symptoms of multiple sclerosis (MS). In this study, a nanoformulation containing rhMBP with RTX on its surface (Nano-rhMBP-RTX) was prepared and investigated in comparison with other treatment groups to determine its potential neuro-protective effects on C57BL/6 mice after inducing experimental autoimmune encephalomyelitis (EAE).MethodsEAE was induced in the corresponding mice by injecting 100 μL of an emulsion containing complete Freund’s adjuvant (CFA) and myelin oligodendrocyte glycoprotein (MOG). The subjects were weighed, scored and subjected to behavioural tests. After reaching a clinical score of 3, various treatments were given to corresponding EAE-induced and non-induced groups including rhMBP, RTX, empty nanoparticle prepared by poly (lactide-co-glycolide) (PLGA) or the prepared nanoformulation (Nano-rhMBP-RTX). At the end of the study, biochemical parameters were also determined as interferon-γ (IFN-γ), myeloperoxidase (MPO), interleukin-10 (IL-10), interleukin-4 (IL-4), tumor necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-kB), brain derived neurotrophic factor (BDNF), 2’, 3’ cyclic nucleotide 3’ phosphodiesterase (CNP) and transforming growth factor beta (TGF-β) along with some histopathological analyses.ResultsThe results of the Nano-rhMBP-RTX group showed promising outcomes in terms of reducing the clinical scores, improving the behavioural responses associated with improved histopathological findings. Elevation in the levels of IL-4, CNP and TGF-β was also noticed along with marked decline in the levels of NF-kB and TNF-α.ConclusionNano-rhMBP-RTX treated group ameliorated the adverse effects induced in the EAE model. The effectiveness of this formulation was demonstrated by the normalization of EAE-induced behavioral changes and aberrant levels of specific biochemical markers as well as reduced damage of hippocampal tissues and retaining higher levels of myelination.

Comparative effectiveness of preventive treatment with dimethyl fumarate-loaded solid lipid nanoparticles and oral dimethyl fumarate in a mouse model of multiple sclerosis

BackgroundOrally administered dimethyl fumarate (DMF) presents gastrointestinal adverse effects, such as pain and diarrhea, in addition to flushing and lymphopenia. ObjectiveSolid lipid nanoparticles (SLNs) with DMF were developed for subcutaneous administration. MethodsDMF-incorporated SLNs and free DMF were tested in mice induced with experimental autoimmune encephalomyelitis (EAE). ResultsPreventive treatment of free or incorporated DMF were able to reduce the EAE clinical scores, increase the weight of the animals, reduce the lesion area (demyelination and infiltration), reduce microglial fluorescence intensity and reduce the number of microglial cells and astrocytes, when compared to untreated EAE animals. Groups that received DMF had reduced numbers of T cells, B cells and natural killer (NK) cells in the blood, when compared to the non-induced group. ConclusionsDMF incorporated in SLNs was as effective as free DMF in reducing the clinical scores of the animals, but with reduced administrations when given subcutaneously. In addition, SLN-DMF preventive treatment partially prevented a reduction in the percentages of T and B cells, in the blood, when compared to preventive treatment with free DMF (oral), which suggests reduction of lymphopenia.

Induction of Day-Time Periodic Breathing is Associated With Augmented Reflex Response From Peripheral Chemoreceptors in Male Patients With Systolic Heart Failure.

Spontaneous day-time periodic breathing (sPB) constitutes a common phenomenon in systolic heart failure (HF). However, it is unclear whether PB during wakefulness could be easily induced and what are the physiological and clinical correlates of patients with HF in whom PB induction is possible. Fifty male HF patients (age 60.8 ± 9.8 years, left ventricle ejection fraction 28.0 ± 7.4%) were prospectively screened and 46 enrolled. After exclusion of patients with sPB the remaining underwent trial of PB induction using mild hypoxia (stepwise addition of nitrogen gas to breathing mixture) which resulted in identification of inducible (iPB) in 51%. All patients underwent assessment of hypoxic ventilatory response (HVR) using transient hypoxia and of hypercapnic ventilatory response (HCVR) employing Read’s rebreathing method. The induction trial did not result in any adverse events and minimal SpO2 during nitrogen administration was ∼85%. The iPB group (vs. non-inducible PB group, nPB) was characterized by greater HVR (0.90 ± 0.47 vs. 0.50 ± 0.26 L/min/%; p <0.05) but comparable HCVR (0.88 ± 0.54 vs. 0.67 ± 0.68 L/min/mmHg; p = NS) and by worse clinical and neurohormonal profile. Mean SpO2 which induced first cycle of PB was 88.9 ± 3.7%, while in sPB mean SpO2 preceding first spontaneous cycle of PB was 96.0 ± 2.5%. There was a reverse relationship between HVR and the relative variation of SpO2 during induced PB (r = −0.49, p = 0.04). In summary, PB induction is feasible and safe in HF population using simple and standardized protocol employing incremental, mild hypoxia. Pathophysiology of iPB differs from sPB, as it relies mostly on overactive peripheral chemoreceptors. At the same time enhanced HVR might play a protective role against profound hypoxia during iPB.

PO-699-06 ELECTROPHYSIOLOGICAL STUDY PRIOR TO PLANNED PULMONARY VALVE REPLACEMENTIN PATIENTS WITH SURGICALLY REPAIRED TETRALOGY OF FALLOT

Ventricular arrhythmias (VAs) are the most common cause of death in patients with repaired Tetralogy of Fallot (rTOF). However risk stratification remains challenging. We examined outcomes following programmed ventricular stimulation (PVS) during electrophysiological studies (EPS), with or without subsequent ablation, in patients with rTOF planned for pulmonary valve replacement (PVR). All consecutive patients aged ≥18 years with rTOF referred to our institute from 2010 to 2018 for PVR were included. Right ventricular (RV) voltage maps were created and PVS performed from two different sites (apex and infundibulum), including with isoproterenol if the patient was not inducible at baseline. Catheter or surgical cryoablation was performed when patients were inducible or when anatomical isthmuses (AIs) were judged to have the potential to sustain reentrant VAs. Post-operative EPS was undertaken to guide decisions regarding implantable cardioverter-defibrillator (ICD) implantation if patients required surgical cryoablation to complete linear lesions or in cases of persistent inducibility after catheter ablation. 77 patients (36,2 +/- 14,3 years old, 71% male) were included. 18 were inducible and 22 % needed isoproterenol infusion for inducibility. Ablation was performed in 28 patients (17 inducible, 11 non-inducible with slow conduction isthmuses). 5 patients were inducible after catheter ablation, they benefited from surgical cryoablation at the time of PVR and a repeated EPS 3 months post surgery. No patients were inducible at the repeated EPS. ICDs were implanted in five patients: four inducible and one non inducible. During a follow-up of 51 +/- 35 months, 3 patients in the inducible group experienced sustained VAs (two treated by ICD shock) versus none in the non-inducible group (p<0,001). Performing systematic EPS prior to PVR can help stratifying the arrhythmic risk in the repaired TOF population. Identification of pathological isthmuses involved in reentrant VT allows targeted ablation. In our report preemptive ablation in non inducible patients with slow conducting AI seem to be safe. Finally, our protocol can guide ICD implantation.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

The effect of anesthesia depth on radiofrequency catheter ablation of ventricular tachycardia: a retrospective study

BackgroundRadiofrequency catheter ablation (RFCA) as a safe and effective method has been widely used in ventricular tachycardia (VT) patients, and with which anesthesiologists frequently manage their perioperative care. The aim of this study was to investigate the effects of different anesthetic depths on perioperative RFCA and recurrence in patients who with intractable VT and could not tolerate an awake procedure.MethodsWe reviewed electronic medical records of patients with VT who underwent RFCA by general anesthesia from January 2014 to March 2019. According to intraoperative VT induction, they were divided into two groups: non-inducible group (group N) and inducible group (group I). We constructed several multivariable regression models, in which covariates included patient characteristics, comorbidities, protopathy and bispectral index (BIS) value.ResultsOne hundred one patients were analyzed. Twenty-nine patients (28.7%) experienced VT no induction, and 26 patients (25.7%) relapsed within 1 year. Compared with group I, the proportion of patients with arrhythmogenic right ventricular cardiomyopathy in group N were higher (P < 0.05), and the recurrence rate of VT was significantly higher (51.7% vs 15.3%) (P < 0.05). The BIS value in group N was significantly lower (P < 0.01), in addition, the BIS < 40 was associated with elevated odds of VT no induction compared with a BIS > 50 (odds ratio, 6.92; 95% confidence interval, 1.47–32.56; P = 0.01). VT no induction was an independent predictor of recurrence after RFCA (odds ratio, 5.01; 95% confidence interval, 1.88–13.83; P < 0.01).ConclusionLower BIS value during VT induction in RFCA operation was associated with high risk of VT no induction, which affects postoperative outcomes. We proposed that appropriate depth of anesthesia should be maintained during the process of VT induction.

Oropharynx microbiota transitions in hypopharyngeal carcinoma treatment of induced chemotherapy followed by surgery

AimsTo analyze changes in oropharynx microbiota composition after receiving induced chemotherapy followed by surgery for hypopharyngeal squamous cell carcinoma (HPSCC) patients.MethodsClinical data and swab samples of 38 HPSCC patients (HPSCC group) and 30 patients with benign disease (control group, CG) were enrolled in the study. HPSCC group was stratified into two groups: induced chemotherapy group (IC) of 10 patients and non-induced chemotherapy group (nIC) of 28 patients. The microbiota from oropharyngeal membrane was analyzed through 16S rRNA sequencing.ResultsAlpha-diversity (Shannon and Ace indexes) and weighted UniFrac based beta-diversity severely decreased in the HPSCC group when compared with CG. In pre-operative comparisons, PCoA and NMDS analyses showed microbial structures in the IC group were more similar to CG than nIC. Both IC group and nIC group yielded significantly diverse post-operative communities in contrast to their pre-operative counterparts, evident by the decrease in genera Veillonella and Fusobacterium and increase in genera Streptococcus and Gemella. Given that post-operative oropharynx microbiota showed no difference between IC and nIC groups, the IC group showed less accumulation in anaerobic communities. The abundance of genera Fusobacterium, Parvimonas, Actinomyces were enhanced in the advanced stages (III/IV).ConclusionsOropharynx microbiota in the HPSCC group presents dysbiosis with low diversity and abundance. Induced chemotherapy is beneficial in adjusting the oropharynx microbial environment leading to fewer amounts of anaerobe accumulation after operation. Higher amounts of Fusobacterium in advanced stages (III/IV) may influence the progression of HPSCC.

Noninvasive risk factors for the prediction of inducibility on programmed ventricular stimulation in post-MI patients with ejection fraction over 40% at SCD risk, insights from the PRESERVE EF study

Abstract Funding Acknowledgements Type of funding sources: None. Background Sudden cardiac arrest (SCA) in post myocardial infarction (post-MI) patients with a relatively preserved left ventricular systolic function (LVEF≥40%) has an annual incidence of 1%, in the absence of adequate risk stratification methods and guideline recommendations for primary prevention. In the PRESERVE-EF study we used a two-step SCA risk stratification approach to detect patients at risk for major arrhythmic events. Seven noninvasive risk factors (NIRFs) were extracted from ambulatory electrocardiography (AECG). Patients with at least one NIRF present were referred for invasive programmed ventricular stimulation (PVS). Inducible patients received an ICD. Purpose To assess the performance of NIRFs extracted from 24hr AECG, based on the PRESERVE EF criteria, in predicting inducibility. Methods The PRESERVE EF study enrolled 575 patients. Two hundred and four of them had at least one NIRF and an indication for PVS, but 52 of them declined. Finally, 41 out of 152 patients who underwent PVS were inducible. For the present analysis data from these 152 patients (mean age 60 ± 10years, LVEF 49 ± 6%, 89% males) were analyzed. Chi-square test, univariate logistic regression and areas under ROC curves were calculated for the PVS inducibility endpoint. Results Age, male gender and LVEF for the PVS inducible patients group (n = 41) and the noninducible patients group (n = 111) were, respectively: 61 ± 9years vs 59 ± 10years (p = 0.310), 98% vs 86% (p = 0.048), 45 ± 4% vs 51 ± 7% (p &amp;lt; 0.001). Among NIRFs examined, LVEF ≤ 50%, nsVT≥1/24hour and presence of LPs on SAECG presented high and significant Odds Ratios (ORs) for a positive PVS study end point. A simple risk score based on cutoff points of LVEF ≤ 50%, NSVTepisode≥1/24hour and presence of LPs missed only 1 out of the 41 inducible patients and yielded: OR 14.146 (p = 0.01) with a high sensitivity 98% but low specificity 26% for a positive PVS (AUC = 0.65). Conclusion Cut off points of LVEF ≤ 50%, nsVTepisode≥1/24hour and presence of LPs were important predictors of inducibility. A simple risk score based on these predictors achieves high sensitivity but low specificity. The final decision for an ICD implantation should be based on a positive PVS, which is irreplaceable in risk stratification.

Circular RNA Circ_0005564 promotes osteogenic differentiation of bone marrow mesenchymal cells in osteoporosis

ABSTRACT Circular RNA (CircRNA) plays a potential role in bone formation. We aimed to study the circRNAs expression profiles and their functions in osteogenic differentiation of human bone marrow stromal cells (BMSCs). Firstly, we established osteogenic differentiation of BMSCs displaying increased mRNA expression of osteogenic differentiation marker (RUNX2, OPN, and OCN), increased ALP activity and protein expression, and increased mineralized nodules formation, as well as morphological alteration. Then, we employed high-throughput sequencing to analyze circRNA expression and found that 3440 and 3893 circRNAs in non-induced and induced groups, respectively. We further validated the 10 differentially expressed circRNAs with the most significant difference between induced and non-induced groups. Among these ten circRNAs, five of them with more than one miRNA binding site were used to construct a ceRNA network exhibiting 81 miRNAs and 182 target mRNAs. Furthermore, among these five circRNAs, we found only circ_0005564 significantly reduced the mRNA expression of RUNX2, OPN, and OCN. The circularity of circ_0005564 was verified. Our results showed that knockdown of circ_0005564 inhibited osteoblast differentiation in BMSCs. Taken together, our study demonstrates that circ_0005564 is a potential positive regulator of osteogenic differentiation of BMSCs.

Cognitive Function Improvement in Mouse Model of Alzheimer's Disease Following Transcranial Direct Current Stimulation.

Anodal transcranial direct current stimulation (tDCS) is a painless noninvasive method that reportedly improves cognitive function in Alzheimer’s disease (AD) by stimulating the brain. However, its underlying mechanism remains unclear. Thus, the present study investigates the cognitive effects in a 5xFAD AD mouse model using electrophysiological and pathological methods. We used male 5xFAD C57BL/6J and male C57BL/6J wild-type mice; the dementia model was confirmed through DNA sequencing. The verified AD and wild-type mice were randomly assigned into four groups of five mice each: an induced AD group receiving tDCS treatment (Stim-AD), an induced AD group not receiving tDCS (noStim-AD), a non-induction group receiving tDCS (Stim-WT), and a non-induction group not receiving tDCS (noStim-WT). In the Stim group, mice received tDCS in the frontal bregma areas at an intensity of 200 µA for 20 min. After 2 weeks of treatment, we decapitated the mice, removed the hippocampus from the brain, confirmed its neuronal activation through excitatory postsynaptic potential (EPSP) recording, and performed molecular experiments on the remaining tissue using western blots. EPSP significantly increased in the Stim-AD group compared to that in the noStim-AD, which was comparable to that in the non-induced groups, Stim-WT and noStim-WT. There were no significant differences in cyclic amp-response element binding protein (CREB), phosphorylated CREB (pCREB), and Brain-derived neurotrophic factor (BDNF) levels in the Stim-AD group compared to those in the noStim-AD group. This study demonstrated that a tDCS in both frontal lobes of a transgenic 5xFAD mouse model affects long-term potentiation, indicating possible enhancement of cognitive function.

P960Non-inducible ventricular arrhythmia soon after ventricular tachycardia ablation predicts long-term recurrence in patients with reduced ejection fraction

Abstract Introduction Radiofrequency (RF) ablation for ventricular arrhythmia in patients with reduced left ventricular ejection fraction (LVEF) is recognized to be one of the important strategies for suppressing the fatal arrhythmia events. Although, RF ablation for those patients has been performed for decades, the optimal endpoint remains unclear. Hypothesis We assessed the hypothesis that non-inducibility of any ventricular tachycardia (VT) or ventricular fibrillation (VF) immediately after VT ablation predicts long-term recurrence free rate of ventricular arrhythmia in patients who were diagnosed sustained VT with reduced LVEF. Methods From January 2014 to August 2019, we conducted a single center retrospective analysis for 127 consecutive patients with right or left ventricular arrhythmia who performed the first time RF ablation. Exclusion criteria were LVEF &amp;gt;50% and RF ablations for premature ventricular contraction or for non-sustained VT. Then 26 patients (age 69 ± 7, male 92%) were enrolled. All of the ablation procedures were performed using irrigated RF catheters and 3D mapping systems. We defined non-inducible group as the patients without monomorphic VT (clinical monomorphic VT or non-clinical monomorphic VT with any cycle length), polymorphic VT and VF by electrophysiological study (EPS) immediately after the ablation. The primary endpoint of this study was a recurrence of any sustained VT and VF during the follow up period. Results All of 26 patients were followed for a mean of 30.9 ± 22.3months.Of those patients, 7 patients were non-inducible group and 19 patients were inducible group. Age, sex, body mass index, coronary risk factors, LVEF (non-inducible:42 ± 5% vs inducible:35 ± 10%, p = 0.12), renal function and the etiology of LV dysfunction did not differ between patients with non-inducible group and inducible group (all non-significant). Catheter ablation procedural characteristics including activation mapping (non-inducible:29% vs inducible:36%, p = 1.00), entrainment mapping (14% vs 42%, p = 0.19), substrate mapping (86% vs 95%, p = 0.47), pace-mapping (86% vs 68%, p = 0.63), RF time (21 ± 13vs 18 ± 21min, p = 0.70), number of RF applications (27 ± 13vs 27 ± 32, p = 0.89), fluoroscopy time (77 ± 50vs 87 ± 42min, p = 0.59) and procedure time (309 ± 87vs 282 ± 61min, p = 0.37) did not differ between two groups. Medications before and after the VT ablation did not differ between two groups. The recurrence of any sustained VT and VF significantly lower in patients with non-inducible group than those with inducible group (Figure). Conclusion This study demonstrated that, in patients with reduced LVEF presenting sustained VT who performed RF ablation, non-inducibility of any VT and VF immediately after RF ablation predicts long-term decreased risk of recurrence of any sustained VT and VF. Not only clinical but also non-clinical VT and VF may be targeted as well at the first time VT ablation for those patients. Abstract Figure