DA Group Research Articles

The Midterm Outcomes of Endovascular Therapy for Femoropopliteal Lesions via Drug-Coated Balloon, Directional Atherectomy and Bare Metal Stent Angioplasty.

This study investigated the midterm primary patency of drug-coated balloons (DCBs), directional atherectomy plus balloon angioplasty (DA), and bare metal stent (BMS) angioplasty for the treatment of femoropopliteal lesions. This two-center retrospective cohort study included 105 patients (110 limbs) undergoing DCB, DA, and BMS angioplasty-32 patients (34 limbs), 31 patients (32 limbs), and 42 patients (44 limbs), respectively. The demographic, baseline, and procedure data were collected, and the complications and midterm outcomes (patency, amputation-free survival, and clinically driven target lesion revascularization rates) were analyzed. All three procedures achieved a 100% success rate. Significant improvements were noted in ankle brachial index, walking distance, and Rutherford classification at 30 days post-procedure (p < 0.001), with no differences or severe complications among the groups. The all-cause mortality rate during the follow-up period, was 5.5%, and amputation-free survival rates at 24 months were 97.0%, 90.6% and 90.9% in the DCB, DA, and BMS angioplasty groups, respectively. The primary patency rate for the DCB group (79.4%) exceeded those of the DA (56.2%) and BMS (52.2%) groups (p < 0.05), with no significant difference between the DA and BMS groups at 24 months. The secondary patency and clinically driven target lesion revascularization rates were similar among the three groups. A runoff number ≤1, Trans-Atlantic Intersociety Consensus (TASC) D, and severe calcification were found to be independent risk factors for primary patency. The DCB procedure demonstrated superior primary patency, compared to both BMS and DA procedures, in the treatment of femoropopliteal lesions.

Surgical management of severe planovalgus foot deformity in children with generalised joint hypermobility

BackgroundThis study aimed to evaluate the outcomes of calcaneal lengthening osteotomy (CLO) and double arthrodesis of the talonavicular and calcaneocuboid joints (DA) for correcting planovalgus foot deformity exclusively in patients with generalised joint hypermobility. MethodsWe retrospectively reviewed 29 feet in 17 consecutive patients who underwent either CLO or DA. The mean age at surgery was 11.3 ± 2.3 years, and the mean follow-up duration was 7.7 ± 3.2 years. Preoperative and final follow-up radiographs and dynamic foot-pressure measurements were analysed. ResultsBoth operations significantly improved the radiographic parameters, except for the lateral talocalcaneal angle in the CLO group. Pedobarographic study demonstrated an elevation of the medial longitudinal arch and an improved foot-pressure distribution after both surgeries. The plantar pressure in the lateral forefoot significantly increased only in the DA group, while the pressures exerted on the medial forefoot and hindfoot and the arch index improved only in the CLO group. ConclusionsBoth CLO and DA effectively improve the foot alignments of the deformity in patients with generalised joint hypermobility. However, differences were observed in the changes in the lateral talocalcaneal angle and plantar pressure distribution between the two procedures. Level of evidenceTherapeutic Level III.

Comparison of the Safety and Efficacy of Remimazolam Besylate versus Dexmedetomidine for Patients Undergoing Fiberoptic Bronchoscopy: A Prospective, Randomized Controlled Trial.

Remimazolam besylate is a novel ultra-short-acting benzodiazepine that is rapidly hydrolyzed to zolpidem propionic acid by tissue lipases. We designed this study to compare the safety and efficacy of remimazolam besylate alfentanil versus dexmedetomidine-alfentanil for fiberoptic bronchoscopy (FB). One hundred and twenty patients undergoing FB into this prospective randomized controlled trial were divided into two groups. The anesthesia induction consisted of 6 mg/kg/h of remimazolam besylate in the RA group and 0.5 μg/kg of dexmedetomidine in the DA group. 1-2 mg/kg/h of remimazolam besylate or 0.2-0.7 µg/kg/h of dexmedetomidine were administered to maintain during FB. The lowest oxygen saturation, success rate of FB, hemodynamics, time metrics, bronchoscopy feasibility, drug dose requirements, patient and bronchoscopist satisfaction scores, occurrence of intraoperative awareness, number of patients willing to repeat FB with the same sedation regimen, and occurrence and severity of adverse events. The lowest oxygen saturation during the FB was significantly higher in the RA group (P = 0.001). Compared with the variables in the DA group, peripheral oxygen saturation, systolic blood pressure, and diastolic blood pressure were significantly lower at T2 and T3 in the RA group (P < 0.05). Heart rates were significantly higher from T2 to T4 in the DA group (P < 0.05). More patients experienced bradycardia in the DA group (P = 0.041). Compared with time metrics in the DA group, the induction time, fully-alert time, and recovery room-leaving time were all significantly shorter in the RA group (P < 0.05). The bronchoscopy feasibility scores in the RA group were significantly lower at T2, whereas they were lower at T3 in the DA group (P < 0.05). Remimazolam besylate is superior to dexmedetomidine when combined with alfentanil during FB, promoting faster patients' recovery, better operative conditions and respiratory stability with similar rates of occurrence and severity of adverse events.

Direct aortic cannulation, a safe alternative to femoral artery cannulation - 17 years of type A dissection surgery experience

Aim: Optimal cannulation strategy for acute type A aortic dissection (ATAAD) surgery remains debated. Recent guidelines have advocated antegrade systemic perfusion through right axillary artery (RAX) cannulation, instead of femoral artery (FA) cannulation. However, RAX cannulation can be technically challenging and time-consuming. On the other hand, direct (ascending) aorta (DA) cannulation is a swift procedure that also ensures downstream antegrade flow. In this regard, we assessed whether DA cannulation is a safe alternative to FA cannulation. Methods: Records of all patients undergoing ATAAD surgery between 2006-2022 at the Radboud University Medical Center were retrospectively reviewed. Results: In total, 281 patients underwent surgery for ATAAD during the investigated period. Three patients were excluded due to death before the start of extracorporeal circulation and four because of RAX cannulation. Of the remaining 274 patients, 53% (N = 145) received primary FA and 47% (N = 129) DA cannulation, with a success rate of 98% for both approaches. Surgical mortality (combined in-hospital and 30-day) was 9.9% (7.8% DA group vs. 11.7% FA group, P = 0.271). New permanent neurological damage was seen in 10.9% vs. 6.9% (P = 0.248), respectively. In multivariate analysis, cannulation strategies were not significantly associated with surgical mortality nor postoperative new permanent neurological damage. Conclusion: DA cannulation offers a safe and fast alternative to FA cannulation in ATAAD surgery. There were no significant differences in mortality and neurological complications. Future studies should focus on the differences between RAX and DA cannulation strategies on postoperative outcomes in ATAAD surgery.

Venetoclax plus daunorubicin and cytarabine in newly diagnosed acute myeloid leukemia patients: A propensity score-matched analysis.

Venetoclax plus 3+7 daunorubicin and cytarabine chemotherapy (DAV) has shown safety and efficacy in eligible patients with newly diagnosed acute myeloid leukemia (AML). However, there are no direct comparisons between DAV and 3+7 daunorubicin and cytarabine chemotherapy (DA) alone. We performed a propensity score-matched analysis to compare the outcomes of DAV group with historical DA group and identify the clinical and molecular characteristics of patients who might benefit from the DAV regimen. The DAV group had a higher Complete remission (CR) rate than the DA group (90% vs. 55%, p=0.008). 25 (96%) patients in the DAV group had a higher MRD-negative CRc rate compared with 13 (62%) patients in the DA group (p=0.006). After a median follow-up duration of 19.15 (IQR 17.13-21.67) months, the DAV group had an improved overall survival (p=0.001) and event-free survival (p=0.069), but not disease-free survival (p=0.136). Collectively, DAV regimen induced high CR rates and deep MRD-negative CRc rates after one cycle of induction therapy, as well as prolonged the overall survival, in young adult patients with AML who were eligible for intensive chemotherapy. The addition of venetoclax to intensive chemotherapy should be considered in the future to achieve better survival advantages in eligible AML patients.

Should I stay or should I go: an assessment of criteria for safe day of surgery discharge of displaced supracondylar humerus fractures.

Immobilization type and in-hospital observation following surgical management of displaced supracondylar fractures are subject to surgeon preference and training. Our goal was to determine criteria for immediate discharge and optimal type of immobilization. Medical records of 661 patients with type III, IV or flexion-type displaced supracondylar humerus fractures treated at a level 1 pediatric trauma center from January 2013 to September 2019 were reviewed. Patients were separated into 'admission appropriate' (AA = 113) and 'discharge appropriate' (DA = 548) sub-cohorts. Neurovascular deficit at presentation (P < 0.001), post-operative physical exam deterioration (P < 0.001), age (P < 0.001) and post-operative immobilization modality (P = 0.02) were significantly different between AA and DA groups. When comparing patients who presented with neurologic deficit to those neurovascularly intact, there was a significant difference in whether circumferential immobilization was used post-operatively (P < 0.001), IV medication need (P < 0.001), discharge or admission (P < 0.001), neurologic decline (P < 0.001), return to ED (P = 0.008) and vascular compromise (P = 0.05). Twenty-four of the 56 (43%) patients who were AA and had no neurovascular finding on presentation had their immobilization adjusted (bivalved or loosened) to accommodate for swelling overnight. Only 1 was initially maintained in a splint or bivalved cast; the other 23 were initially maintained post-operatively in circumferential immobilization (P = 0.01). Our findings suggest that patients with intact neurovascular exams at presentation are candidates for early discharge, and splinting or bivalved casting may be preferable, especially in patients who are discharged.

Biofilm removal effect of diatom complex on 3D printed denture base resin

For patients who have difficulty in mechanical cleaning of dental appliances, a denture cleaner that can remove biofilm with dense extracellular polymeric substances is needed. The purpose of this study is to evaluate the efficacy of diatom complex with active micro-locomotion for removing biofilms from 3D printed dentures. The diatom complex, which is made by doping MnO2 nanosheets on diatom biosilica, is mixed with H2O2 to generate fine air bubbles continuously. Denture base resin specimens were 3D printed in a roof shape, and Pseudomonas aeruginosa (107 CFU/mL) was cultured on those for biofilm formation. Cleaning solutions of phosphate-buffered saline (negative control, NC), 3% H2O2 with peracetic acid (positive control, PC), denture cleanser tablet (DCT), 3% H2O2 with 2 mg/mL diatom complex M (Melosira, DM), 3% H2O2 with 2 mg/mL diatom complex A (Aulacoseira, DA), and DCT with 2 mg/mL DM were prepared and applied. To assess the efficacy of biofilm removal quantitatively, absorbance after cleaning was measured. To evaluate the stability of long-term use, surface roughness, ΔE, surface micro-hardness, and flexural strength of the 3D printed dentures were measured before and after cleaning. Cytotoxicity was evaluated using Cell Counting Kit-8. All statistical analyses were conducted using SPSS for Windows with one-way ANOVA, followed by Scheffe’s test as a post hoc (p < 0.05). The group treated with 3% H2O2 with DA demonstrated the lowest absorbance value, followed by the groups treated with 3% H2O2 with DM, PC, DCT, DCT + DM, and finally NC. As a result of Scheffe’s test to evaluate the significance of difference between the mean values of each group, statistically significant differences were shown in all groups based on the NC group. The DA and DM groups showed the largest mean difference though there was no significant difference between the two groups. Regarding the evaluation of physical and mechanical properties of the denture base resin, no statistically significant differences were observed before and after cleaning. In the cytotoxicity test, the relative cell count was over 70%, reflecting an absence of cytotoxicity. The diatom complex utilizing active micro-locomotion has effective biofilm removal ability and has a minimal effect in physical and mechanical properties of the substrate with no cytotoxicity.

Clinical features and outcomes of patients with acute myeloid leukemia: the single-center experience of 668 patients in China

ABSTRACT Objective To investigate efficacy and prognostic factors in the treatment of adult newly-diagnosed acute myeloid leukemia (AML) with or without allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Methods We retrospectively analyzed 668 patients with newly-diagnosed AML (non-M3 type) in the Department of Hematology at Shanghai Changhai Hospital from January 2012 to December 2021. Based on different induction chemotherapy regimens, patients were categorized into an IA (idarubicin, IDA + cytarabine, Ara-C) (3 + 7, regimen) group (n = 303) and a DA (daunorubicin, DNR + cytarabine, Ara-C) (3 + 7, regimen) group (n = 365) with or without allo-HSCT. Minimal residual disease (MRD), complete response (CR), overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse effects (AE) were analyzed and compared. Characteristics significantly associated with overall or progression-free survival (OS or PFS) upon univariate analysis were subsequently included in a Cox proportional hazard model. Results This study used data from 668 AML patients. After induction therapy, the CR rate in the IA group was 70.63% and ORR was 79.87%, which were significantly higher than those in the DA group (with a CR rate of 56.99% and an ORR of 70.14%) (P = 0.0002 and P = 0.0035, respectively). There were no significant differences in drug safety between the two chemotherapy regimens used in IA and DA (P > 0.05). The recurrence rate was lower in patients with an MRD < 0.001 than in patients with an MRD ≥ 0.001. A continuous negative MRD during the period is significant because it is associated with prolonged OS and PFS of AML patients. Data from 100 patients in the two groups who underwent allo-HSCT were analyzed using univariate analysis and the Cox proportional hazards model. From the multivariate analysis, MRD was found to be the only independent predictor of OS (P = 0.042; HR 1; 95%CI 0.00–0.76). Conclusion In the treatment of adult AML patients, IA regimen is associated with a high CR rate and ORR rate and does not increase treatment-related toxicity. IA regimen prolongs OS and PFS in AML patients and reduces the likelihood of leukemia cells’ subsequent infiltration into the central nervous system. There is a high correlation between the level of MRD after treatment and the patient's bone marrow recurrence. To obtain superior treatment effects for patients undergoing allo-HSCT, the MRD should be reduced to less than 0.001 before pretreatment. A negative MRD before allo-HSCT can prolong OS in patients with AML. We examined the clinical characteristics and outcomes of AML patients in China, finding novel information on prognostic factors and primary treatment of AML that may be applicable in routine clinical practice.

Safety and benefit of ambulation within 24 hours in elderly patients undergoing lumbar fusion: propensity score matching study of 882 patients

BACKGROUND CONTEXTElderly patients are less likely to recover from lumbar spine fusion (LSF) as rapidly compared with younger patients. However, there is still a lack of research on the effect of early ambulation on elderly patients undergoing LSF surgery for lumbar degenerative disorders. PURPOSETo evaluate the safety and benefit of ambulation within 24 hours in elderly patients who underwent LSF. STUDY DESIGNA retrospective study. PATIENT SAMPLEConsecutive patients (aged 65 and older) who underwent elective transforaminal lumbar interbody fusion surgery for degenerative disorders from January 2019 to October 2022. OUTCOME MEASURESOutcome measures included postoperative complications, postoperative drainage (mL), laboratory test data, length of hospital stay (LOS), readmission and reoperation within 3 months. METHODSEarly ambulation patients (ambulation within 24 hours after surgery) were propensity-score matched 1:1 to a delayed ambulation patients (ambulation at a minimum of 48 hours postoperatively) based on age, intraoperative blood loss, and number of fused segments. The incidence of postoperative adverse events (AEs, including rates of complications, readmission, and prolonged LOS) and the average LOS were used to assess the safety and benefit of early ambulation, respectively. Multivariable regression analysis was performed to assess the association between early ambulation and postoperative AEs. The risk factors for delayed ambulation were also determined using multivariable logistic analyses. RESULTSA total of 998 patients with LSF surgery were reviewed in this study. After excluding 116 patients for various reasons, 882 patients (<24 hours: N=350, 24–48 hours: N=230, and >48 hours: N= 302) were included in the final analysis. After matching, sex, BMI, preoperative comorbidities, laboratory test data and surgery-related variables were comparable between the groups. The incidence of postoperative AEs was significantly lower in the EA group (44.3% vs 64.0%, p<.001). The average postoperative LOS of the EA group was 2 days shorter than the DA group (6.5 days vs 8.5 days, p<.001). Patients in the EA group had a significantly lower rate of prolonged LOS compared with the DA group (35.1% vs 55.3%, p<.001). There was no significant difference in postoperative drainage volumes between the two groups. Multivariable analysis identified older age (odds ratio [OR] 1.07, p<.001), increased intraoperative EBL (OR 1.002, p=.001), and higher international normalization ratio (OR 10.57, p=.032) as significant independent risk factors for delayed ambulation. CONCLUSIONSAmbulation within 24 hours after LSF surgery is independently associated fewer AEs and shorter hospital stays in elderly patients. Implementing the goal of ambulation within 24 hours after LSF surgery into enhanced recovery after surgery protocols for elderly patients seems appropriate. Older age, increased intraoperative blood loss and worse coagulation function are associated with delayed ambulation.

Central blockage of sympathetic nerves inhibits the abnormal vital signs and disturbance of the gut microbiota caused by continuous light exposure

BackgroundContinuous light exposure increases sympathetic excitation in rats, leading to hypertension, left ventricular hypertrophy, and fibrosis. This study was aimed to investigate whether continuous light exposure causes destabilization of vital signs and gut microbiota (GM) in Sprague Dawley (SD) rats and whether clonidine hydrochloride (CH), a central sympathetic depressant drug, could prevent these changes. MethodsEight-week-old male SD rats were divided into three groups with different interventions for 14 weeks: control group (CG), 2-mL pure water gavaged daily while on a normal 12-h light/dark cycle; continuous illumination group (CI), 2-mL pure water gavaged daily while receiving continuous exposure to light (300 lx); and drug administration group (DA), CH (10 μg/kg) gavaged daily while receiving continuous exposure to light (300 lx). ResultsThe results showed that blood pressure, heart rate, and body weight were significantly higher in the CI group than in the CG and DA groups (P < 0.05). Moreover, the Shannon index was higher in the DA group than in the CI group (P = 0.012). The beta diversity index in the CG group was significantly higher in the CI group (P = 0.039). The pairwise comparison results of the linear discriminant analysis effect size showed that Oscillospirales were enriched in the DA group, whereas the Prevotellaceae lineage (family level) > Prevotella (genus level) > Prevotellaceae_bacterium (species level) were enriched in the CI group. The Muribaculaceae family was more abundant in the CG group than in the CI group. ConclusionSympathetic nerve inhibition restored the abnormal vital signs and GM changes under continuous light exposure.

Resting-state fMRI in patients with refractory epilepsy with and without drop attacks: exploring the connectivity of sensorimotor cortex

ObjectivePatients with multifocal or generalized epilepsies manifesting with drop attacks have severe refractory seizures and significant cognitive and behavioural abnormalities. It is unclear to what extent these features relate to network abnormalities and how networks in sensorimotor cortex differ from those in patients with refractory focal epilepsies. Thus, in this study we sought to provide preliminary data on connectivity of sensorimotor cortex in patients with epileptic drop attacks, in comparison to patients with focal refractory epilepsies. MethodsResting-state fMRI (rs-fMRI) data was available for 5 patients with epileptic drop attacks and 15 with refractory focal epilepsies undergoing presurgical evaluation. Functional connectivity was analyzed with a seed-based protocol, with primary seeds placed at the precentral gyrus, the postcentral gyrus and the premotor cortex. For each seed, the subjects’ timeseries were extracted and transformed to Z scores. Between-group analysis was then performed using the 3dttest+ + AFNI program. ResultsTwo clusters of reduced connectivity in the group with drop attacks (DA group) in relation to those with focal epilepsies were found in the between-group analysis: the precentral seed showed reduced connectivity in the surrounding motor area, and the postcentral seed, reduced connectivity with the ipsilateral posterior cingulate gyrus. In the intra-group analyses, sensorimotor and premotor networks were abnormal in the DA group, whereas patients with focal epilepsies had the usual connectivity maps with each seed. ConclusionThis pilot study shows differences in the cerebral connectivity in the sensorimotor cortex of patients with generalized epilepsies and drop attacks which should be further explored to better understand the biological bases of the seizure generation and cognitive changes in these people.

Maternal Daidzein Supplementation during Lactation Promotes Growth Performance, Immunity, and Intestinal Health in Neonatal Rabbits

The main purpose of the present research was to evaluate the effect of varying levels of DA inclusion in maternal diet, in the form of powder, on the born-weaning growth performance (days 1–30) and intestinal health of neonatal rabbits. A total of 152 delivered maternal does (3.94 ± 0.05 kg) were allocated into four groups, with thirty-eight replicates of one doe each, and fed with a control diet (CON) supplemented with different levels of powdered DA (85 mg/kg (DA85), 170 mg/kg (DA170), and 340 mg/kg (DA340)) during lactation. The results show that dietary DA increased individual body weight at days 21 and 30 (p = 0.03 and p &lt; 0.01) and showed a linear and quadratic effect on individual body weight and average daily gain (ADG) (p &lt; 0.05), although ADG was not affected by DA. The serum progesterone (P) (p = 0.05) and glutathione peroxidase (GSH-Px) (p = 0.01) concentrations of maternal rabbits were increased in all maternal DA-supplemented groups and showed a linear and quadratic effect (p &lt; 0.05), while a linear effect was observed in estrogen (E-2) (p &lt; 0.05). Interestingly, the concentrations of the serum insulin-like growth factor-1 (IGF-I) (p &lt; 0.01) and immunoglobulin (IgA and IgG) (p &lt; 0.01 and p = 0.01) in neonatal rabbits were increased in all dietary DA groups, and both showed a linear and quadratic effect (p &lt; 0.05). In addition, the serum interleukin (IL-1β) (p = 0.03) and catalase (CAT) (p = 0.04) concentrations were affected by DA supplements, but linear and quadratic effects were only observed in the catalase (CAT) of neonatal rabbits (p &lt; 0.05). Importantly, the duodenal and jejunal villus heights (p &lt; 0.04 and p = 0.01) and the ratio of villus height to crypt depth (p = 0.02 and p = 0.01) in neonatal rabbits were elevated in all DA-supplemented treatments, while a linear and quadratic effect was observed in jejunum, but a quadratic effect was observed in duodenum (p &lt; 0.05). The ileal villus height (p &lt; 0.01) was also elevated in all DA-supplemented treatments exhibiting both linear and quadratic effects (p &lt; 0.05). Moreover, the expression levels of occludin (p = 0.04), zonula occludens-1 (ZO-1) (p &lt; 0.01), IGF-1 (p = 0.03), and solute carrier family 5 member 9 (SCL5A9) (p &lt; 0.01) in jejunum were markedly elevated in the DA175 and 340 mg/kg DA-supplemented groups and were showing linear and quadratic effects (p &lt; 0.05). Finally, inflammation-related gene expression levels such as NF-κB, TLR4, and MYD88 in jejunal (p = 0.01, p = 0.04, and p &lt; 0.01) and ileal (p = 0.04, p = 0.04, and p = 0.03) epithelium were decreased in the DA170 and DA340 groups (p &lt; 0.05), while linear and quadratic effects were observed for TLR4 in jejunum and for NF-κB and TLR4 MYD88 in ileum (p &lt; 0.05). In summary, as a functional additive, maternal DA supplementation with 170 and 340 mg/kg DA during lactation can promote the growth of neonatal rabbits, which is related to improved antioxidative capacity and immunity, as well as improved intestinal health in neonatal rabbits.

Deciphering the Inhibitory Mechanism of Naphthoquinone-Dopamine on the Aggregation of Tau Core Fragments PHF6* and PHF6.

The formation of neurofibrillary tangles by abnormal aggregation of tau protein is considered to be an important pathological characteristic of tauopathies, including Alzheimer's disease and chronic traumatic encephalopathy. Two hexapeptides 275VQIINK280 and 306VQIVYK311 in the microtubule binding region, named PHF6* and PHF6, are known to be aggregation-prone and responsible for tau fibrillization. Previous experiments reported that naphthoquinone-dopamine (NQDA) could effectively inhibit the aggregation of PHF6* and PHF6 and disrupt the fibrillar aggregates into nontoxic species, displaying a dual effect on the amyloid aggregation. However, the underlying molecular mechanism remains mostly elusive. Herein, we performed all-atom molecular dynamics (MD) simulations for 114 μs in total to systematically investigate the impacts of NQDA on the oligomerization of PHF6* and PHF6. The conformational ensembles of PHF6* and PHF6 peptides generated by replica exchange MD simulations show that NQDA could effectively prevent the hydrogen bond formation, reduce the ability of peptides to self-assemble into long β-strand and large β-sheets, and induce peptides to form a loosely packed and coil-rich oligomer. The interaction analysis shows that the binding of NQDA to PHF6* is mainly through hydrophobic interactions with residue I277 and hydrogen bonding interactions with Q276; for the PHF6 peptides, NQDA displays a strong π-π stacking interaction with residue Y310, thus impeding the Y310-Y310 π-π stacking and I308-Y310 CH-π interactions. The DA group of NQDA displays a stronger cation-π interaction than the NQ group, while the NQ group exhibits a stronger π-π stacking interaction. MD simulations demonstrate that NQDA prevents the conformational conversion to β-sheet-rich aggregates and displays an inhibitory effect on the oligomerization dynamics of PHF6* and PHF6. Our results provide a complete picture of inhibitory mechanisms of NQDA on PHF6* and PHF6 oligomerization, which may pave the way for designing drug candidates for the treatment of tauopathies.

P-780 Oocyte proteome and cumulus cell transcriptome analysis reveal oocytes live in a hypoxic microenvironment underlie the arrest of human early embryos in vitro culture

Abstract Study question Can cumulus cell transcriptome analysis combined with oocyte single-cell proteomics uncover the cause of human early embryos arrest during assisted reproductive treatment? Summary answer Oocytes living in a hypoxic microenvironment underlie the arrest of human early embryos at cleavage stage in vitro culture. What is known already Preimplantation embryo developmental potential largely depends on gamete quality in assisted reproduction treatment. Human embryonic genome major activation has occurred by the eight-cell stage, up to 3 days after fertilization. Therefore, to a large extent, the development competence of embryo at cleavage stage relies on oocytes quality, which acquire during follicle development. Cumulus cell (CC) plays an essential role in transmitting signals within the ovary and supporting oocyte growth and maturation. We used whole transcriptome analysis of cumulus cells (CC) and single-cell proteomics of oocyte to gain insights into the molecular mechanisms of embryo development arrest at cleavage stage. Study design, size, duration Fifty CCs samples and eleven oocyte samples were obtained from fifty-eight couples who underwent IVF/intracytoplasmic sperm injection (ICSI) treatment. The total CCs average age was 30.18±4.51(control group) and 32.59±3.43 (DA group). The total oocyte average age was 33.13±4.83. Donated CCs were recruited between January 2018 and December 2019. Donated oocytes were recruited between September 2022 and October 2022. Participants/materials, setting, methods CCs samples were obtained from 33 patients whose rate of good-quality embryos is above 90% (as control) and 17 patients with more than 90% embryos fail to reach six-cell stage (Grade II) on day 3 (as development arrest, DA). Oocytes at GV and MI stage respectively were collected for proteomics. Differentially expressed genes were analyzed using the R package DESeq2 or DEP (filtered with q-value≤0.05 and Foldchange≥1.5). EGSEA package was used to perform pathway analysis. Main results and the role of chance RNA sequencing identified 18458 genes expressed in CCs of both groups, 31 of which were differentially expressed. CCs from patients whose embryos development arrested, contains 36 differentially expressed genes (DEGs) up-regulated and 4 DEGs down regulated. Gene ontology showed that up-regulated genes were significantly enriched with annotations related to oxidoreductase activity, mitochondrial respiratory chain complex IV and response to hypoxia. TF enrichment analysis found out that up-regulated DEGs was enriched in hypoxia-inducible factor 1 (HIF-1) induced transcription. It has been reported that HIF-1-mediated gene expression can be elicited by hypoxia, which could restrict mitochondrial biogenesis and ATP-dependent cellular processes. So, we supposed that oocytes live in an ultra-hypoxic microenvironment underlie human early embryos arrest. In consideration of the difficulty in detection of the oxygen level in antral follicles cavity, the protein level changes of oocytes in DA group were used to reflect oocyte status. There were 47 proteins up-regulated and 105 proteins down-regulated at GV stage; 55 gene up-regulated and 48 genes down-regulated at MI stage. Among these, overlap with up-regulated genes in both stages included tuberous sclerosis complex1(TSC1) and Neutral amino acid transporter A (ASCT1), which play key roles in cellular response to oxygen-glucose and hypoxia stress response. Limitations, reasons for caution Because of the lack of credible data reflecting accurately the dissolved O2 concentration adjacent to an oocyte. Determination of dissolved O2 within antral follicles is fraught with technical difficulties. We can just verify our hypothesis by single-cell proteomics of oocyte and Ultra-Low-oxygen treatment in vitro. Wider implications of the findings We provide a new hypothesis that hypoxic follicular harmed oocyte quality, causing human early embryos arrest. The DEGs we detected in CCs and oocyte could be the biomarker candidates for embryo developmental potential. Ovarian stimulation protocols for embryo development arrested patients could consider diminishing oocyte exposure time in hypoxic follicles. Trial registration number Not applicable

Geraniol ameliorates testicular damage in diabetic rats via inhibition of redox parameters and mitochondrial-mediated apoptosis

BackgroundDiabetes is a disease characterized by high levels of reactive oxygen species that trigger a series of events that culminate in programmed cell death. Terpenoids from plants used in traditional Chinese medicine have preventive and therapeutic potential. However, it is not known if geraniol, a monoterpene will prevent testicular damage in diabetic rats. Thus, this study investigated the antioxidant, and antiapoptotic effects of geraniol on testicular damage in diabetic male Wistar rats. Also, the interactions between geraniol with rat liver F1 ATPase and oxidized rat cytochrome c were investigated. MethodsA single intraperitoneal dose of streptozotocin (60 mg/kg) was used to induce diabetes in rats. Male Wistar rats were divided into 4 groups - CT (control), DA (Diabetic, 60 mg/kg streptozotocin), GE (Geraniol-treated, 60 mg/kg streptozotocin + 200 mg/kg geraniol), and GL (Glibenclamide-treated, 60 mg/kg streptozotocin + 5 mg/kg Glibenclamide). Rats were sacrificed by cervical dislocation under anesthesia after 21 days of treatment. Testicular superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), cytochrome c, caspase 9 and caspase 3, and testosterone (testes and plasma) were determined spectrophotometrically. The interactions between geraniol, and glibenclamide, with rat liver F1-ATPase (1MAB) and oxidized rat cytochrome c (5FD4) were assessed by molecular docking. ResultsThe results showed that SOD, and CAT levels were significantly (p<0.05) lowered in the DA group. Significant increases in SOD, CAT, and GSH levels were observed in the testes of rats in the GE and GL groups. Also, cytochrome c, caspase 9, and caspase 3 levels in rat testes were significantly lowered in the GE and GL groups when compared to the DA group. Furthermore, testosterone levels in the plasma and testes of rats in the GE and GL groups were significantly (p<0.05) increased in the treated groups when compared to the DA group. The binding affinities of geraniol for 1MAB (-5.4 Kcal/mol) and 5DF4 (-6.1 Kcal/mol) were comparable to that of glibenclamide (-5.5 Kcal/mol; -7.5 Kcal/mol, respectively). ConclusionThis study shows that geraniol has the potential to ebb testicular damage in diabetic rats through the inhibition of oxidative stress, caspase activation, rat liver F1-ATPase, and oxidized rat cytochrome c. This study suggests the use of geraniol-rich diet in traditional Chinese medicine.

Outcomes of different therapies in acute myeloid leukemia patients with core-binding factor.

e19036 Background: Acute myeloid leukemia (AML) with RUNX1:RUNXT1 fusion or CBFB:MYH11 fusion is defined as core-binding factor AML (CBF-AML) and has been considered to show favorable prognosis. Methods: We conducted a retrospective analysis on previously untreated CBF-AML patients who received standard-dose induction therapies between Jan 2018 and Dec 2020 in our medical center. Patients were classified into 5 groups based on the induction regimens: VA, DA, IA, HAA, and DAV. The dosage of these regimens were determined as follows: VA, venetoclax 100mg d1,200mg d2, 400mg d3-28, Azacytidine 75mg/m2 d1-7; DA, daunorubicin 60mg/m2 d1-3, cytarabine 100mg/m2 d1-7; idarubicin 8-10mg/m2 d1-3, cytarabine 100mg/m2 d1-7; HAA, homoharringtonine 2mg/m2 d1-7, cytarabine 100mg/m2 d1-7, aclarubicin 12mg/m2 d1-7; DAV, daunorubicin 60mg/m2 d1-3, cytarabine 100mg/m2 d1-7, venetoclax 100mg d4, 200mg d5, 400mg d6-11. The response rate and survival data were analysed between these groups. Results: There’s a total of 106 CBF-AML patients involved, 85(80.2%) with RUNX1:RUNXT1 fusion and 21(19.8%) with CBFB:MYH11 fusion. The most common concomitant mutation was KIT (33%), and the most frequent hotspot mutation site was D816V in exon 17. The median age was 46 years ranging from 7 to 78, and 46.2% of the patients were male.Patients were classified into 5 groups based on the induction regimens, and there were 9 in VA group, 21 in HAA group, 23 in DA group, 38 in IA group, and 15 in DAV group. The CR rate of each group was 55.6%(VA), 87.0%(DA), 65.8%(IA), 90.4%(HAA), and 100%(DAV) respectively. Among the patients who received CR, patients in DAV group showed more pronounced decreasing of fusion gene levels (median 1450 fold) than other groups, while VA group had the slightest (median 8.9 fold). As to the survival, the median follow-up time was 15.2 months, and the median overall survival (OS) were not reached in all the groups. In the RUNX1:RUNXT1 fusion subgroup, DAV group showed significantly improved OS and event-free survival (EFS) than other groups, while VA groups was the worst. The median EFS were as follows: 3.5months(VA), not reached(HAA), 10.9months(DA), 7.9months(IA), and not reached(DAV) respectively. Conclusions: Our study demonstrated a promising therapeutic results of DAV regimen, and an unsatisfactory therapeutic results of VA regimen in CBF-AML. CBF-AML patients showed significantly improved CR rate, elimination of fusion genes, OS, and EFS when received intense chemotherapy, especially DAV and HAA regimen, than VA regimen. These results indicated that intense chemotherapy may be an optimal choice for CBF-AML.

Optical coherence tomography in the diagnosis of primery neurodegenerative diseases

AbstractBackgroundThe priority task of the world community of neurologists is the early diagnosis of dementia, which is associated with an increase in life expectancy of the population. Among all dementias, Alzheimer’s disease occupies a leading position. Existing criteria for Alzheimer’s disease do not allow a diagnosis at the stage of predementia. New predictors of cognitive deficits, as such a method, scientists hope for optical coherence tomography.Method90 patients were examined, divided into 3 groups: the first group ‐ patients with Alzheimer’s disease (AD), meeting the NINCDS ADRDA criteria, the second ‐ patients with vascular dementia (VD), meeting the NINDS‐AIREN criteria. According to the criteria, each group of BA and DM consisted of 21 (70%) women and 9 (30%) men, mean age 65 years [61; 67] ∖ 66 [60; 69] years respectively. The third group included patients with open‐angle glaucoma (POAG) ‐ 20 (66.7%) women and 10 (33.3%) men, mean age 70 years [62; 76] years.ResultAccording to the results of OCT in the area of the optic disc, there were no statistically significant differences in the width of the neuroretinal rim between the groups. In the VAD group, the thickness of the peripapillary layer of nerve fibers in the upper and lower temporal quadrants was greater than in the DA and POAG groups. OCT in the macular region revealed a decrease in the thickness of the retina and the inner plexiform layer in the upper and lower quadrant of the peripheral region, as well as a decrease in the thickness of the nerve fibers, the ganglionic layer in the lower quadrant of the peripheral region in the OP and POAG groups compared with the VAD group.ConclusionBased on the data obtained, it can be concluded that in AD, degenerative changes in the retina are observed in the peripheral region, while in VD, the process is more pronounced in the foveal (central) region of the retina. In conclusion, it should be noted that a comprehensive ophthalmological examination can become one of the key and affordable methods for the early diagnosis of BA.

Targeted metabolomics analysis for serum Helicobacter pylori -positive based on LC-MS/MS.

Helicobacter pylori (H. pylori), as a harmful bacteria associated with gastric cancer, can have adverse effects on human normal flora and metabolism. However, the effects of H. pylori on human metabolism have not been fully elucidated. 13 C breathing test was used as the basis for distinguishing negative and positive groups. Serum samples were collected from the two groups for targeted quantitative metabolomics detection, and multidimensional statistics were used, including partial least squares discriminant analysis (PLS-DA), principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA), and differential metabolites were screened. Unidimensional statistics combined with multidimensional statistics were used to further screen potential biomarkers, and finally pathway analysis was performed. SPSS 21.0 software package was used for statistical analysis of experimental data. Multivariate statistical analysis such as PLS-DA, PCA and OPLS-DA was performed using Simca-P 13.0 to search for differential metabolites. This study confirmed that Helicobacter pylori caused significant changes in human metabolism. In this experiment, 211 metabolites were detected in the serum of the two groups. Multivariate statistical analysis showed that PCA of metabolites was not significantly different between the two groups. PLS-DA indicated that the serum of the two groups were well clustered. There were significant differences in metabolites between OPLS-DA groups. By setting the VIP threshold as 1 and the corresponding P value < 0.05, a total of 40 metabolites were screened in this study. P < 0.05 and| log2FC | > 0 (FC, the Fold Change) together as a unidimensional statistical filter condition. The analysis found that the expression of 15 metabolites such as Propionic acid, Acetic acid, Adipic acid increased, and the metabolism of 6 products such as DCA, 4-Hydroxyphenylpyruvic acid, Pyruvic acid decreased. P < 0.05, FDR < 0.5,|log2FC|> 1 and OPLSDA_VIP > 1 together as a condition of filter screen potential biomarkers. Four potential biomarkers were screened, which were Sebacic acid, Isovaleric acid, (DCA, Indole-3-carboxylic acid). Finally, the different metabolites were brought into the SMPDB library for the corresponding pathway enrichment analysis. The significant abnormal metabolic pathways were taurine and subtaurine metabolism, tyrosine metabolism, glycolysis or gluconeogenesis, pyruvate metabolism, etc. CONCLUSIONS: This study shows that H. pylori has an impact on human metabolism. Not only a variety of metabolites have significant changes, but also metabolic pathways are abnormal, which may be the reason for the high risk of H. pylori causing gastric cancer.

Evaluating 5-year outcomes of interlaminar devices as an adjunct to decompression for symptomatic lumbar spinal stenosis.

To assess and compare 5-year outcomes following uninstrumented spinal decompression and decompression with interlaminar device (ILD). To determine whether improvement in clinical outcomes correlated with changes in the radiological indices studied. This is because comparative literature between the above two procedures is limited past the 2-year timeframe. We conducted a retrospective review of prospectively collected data from a single surgeon across 116-patients who underwent spinal decompression with or without ILD insertion between 2007 and 2015. Patients with symptomatic LSS who met the study criteria were offered spinal decompression with ILD insertion. Patients who accepted ILD were placed in the D + ILD group (n = 61); while those opting for decompression alone were placed in the DA group (n = 55). Clinical outcomes were assessed preoperatively and up to 5-years postoperatively using the ODI, Eq.5d, VAS back and leg pain, and SF-36. Radiological indices were assessed preoperatively and up to 5-years postoperatively. Both groups showed statistically significant (p < 0.001) improvement in all clinical outcome indicators at all timepoints as compared to their preoperative status. The D + ILD group achieved significant improvement in radiological parameters namely foraminal height and posterior disc height in the immediate postoperative period that was maintained while the DA group did not. Our study found that in the management of LSS, clinical outcomes between those patients undergoing decompression alone compared to decompression with ILD showed statistically significant improvement in VAS back pain and radiological parameters namely foraminal height and posterior disc height at the 5-year mark. ILD does not predispose to increased reoperation rates.

A novel artificial intelligence based algorithm to reduce wearable cardioverter-defibrillator alarms.

The wearable cardioverter defibrillator (WCD) is an important tool in mitigating sudden cardiac death (SCD). The WCD provides patient alarms for detected arrhythmias or electrical noise/artifact. Some patients experience frequent alarms for artifact. We soughtto evaluate the effects of a novel artificial intelligence algorithm to reduce alarms related to electrical noise or artifact (advanced arrhythmia discrimination algorithm, AArD). A retrospective review of a large commercial database of prescribed WCD. Patients prescribed the WCD during the years 2017 (discrimination algorithm, DA group) or during 2019 (advanced arrhythmia discrimination algorithm, AArD) were analyzed. A total of 96,000 patients were sampled, 48,000 in the control group (using standard direct algorithm, DA) and compared to 48,000 in the intervention AArD (4000 per group per month) for 12 months. The AArD further discriminates ECG signals based on a machine-learning algorithm utilizing intensity and frequency beyond the standard DA. Outcomes regarding alarms, arrhythmias, and safety were analyzed. The AArD algorithm was associated with a significant decrease in frequency of alarms over the course of WCD use; 54% of patients in the AARD versus 27% of DA had 0 alarms (P < .001). In the entire cohort, there was a 56% relative reduction in alarms with the use of AArD. Appropriate arrhythmia treatment time was not significantly different between the groups (44 s DA vs 45 s AArD [p = ns]). A novel artificial intelligence algorithm reduces alarms without delaying appropriate therapy for VT/VF. These changes may improve compliance and quality of life in patients with a WCD.