PI Group Research Articles

Pomotrelvir and Nirmatrelvir Binding and Reactivity with SARS‐CoV‐2 Main Protease: Implications for Resistance Mechanisms from Computations

AbstractWe investigate the inhibition mechanism between pomotrelvir and the SARS‐CoV‐2 main protease using molecular mechanics and quantum mechanics/molecular mechanics simulations. Alchemical transformations where each Pi group of pomotrelvir was transformed into its counterpart in nirmatrelvir were performed to unravel the individual contribution of each group to the binding and reaction processes. We have shown that while a γ‐lactam ring is preferred at position P1, a δ‐lactam ring is a good alternative for the design of inhibitors for variants presenting mutations at position 166. For the P2 position, tertiary amines are preferred with respect to secondary amines. Flexible side chains at the P2 position can disrupt the preorganization of the active site, favouring the exploration of non‐reactive conformations. The substitution of the P2 group of pomotrelvir by that of nirmatrelvir resulted in a compound, named as C2, that presents a better binding free energy and a higher population of reactive conformations in the Michaelis complex. Analysis of the chemical reaction to form the covalent complex has shown a similar reaction mechanism and activation free energies for pomotrelvir, nirmatrelvir and C2. We hope that these findings could be useful to design better inhibitors to fight present and future variants of the SARS‐CoV‐2 virus.

Pomotrelvir and Nirmatrelvir Binding and Reactivity with SARS-CoV-2 Main Protease: Implications for Resistance Mechanisms from Computations.

We investigate the inhibition mechanism between pomotrelvir and the SARS-CoV-2 main protease using molecular mechanics and quantum mechanics/molecular mechanics simulations. Alchemical transformations where each Pi group of pomotrelvir was transformed into its counterpart in nirmatrelvir were performed to unravel the individual contribution of each group to the binding and reaction processes. We have shown that while a γ-lactam ring is preferred at position P1, a δ-lactam ring is a good alternative for the design of inhibitors for variants presenting mutations at position 166. For the P2 position, tertiary amines are preferred with respect to secondary amines. Flexible side chains at the P2 position can disrupt the preorganization of the active site, favouring the exploration of non-reactive conformations. The substitution of the P2 group of pomotrelvir by that of nirmatrelvir resulted in a compound, named as C2, that presents a better binding free energy and a higher population of reactive conformations in the Michaelis complex. Analysis of the chemical reaction to form the covalent complex has shown a similar reaction mechanism and activation free energies for pomotrelvir, nirmatrelvir and C2. We hope that these findings could be useful to design better inhibitors to fight present and future variants of the SARS-CoV-2 virus.

Sensitivity to rewards and punishments in karate athletes: an examination of the temperamental characteristics and profile of karate competitors according to the revised reinforcement sensitivity theory

BackgroundThe revised Reinforcement Sensitivity Theory (rRST) assumes the existence of three systems controlling motivation and behavior: the behavioral activation system (BAS), the behavioral inhibition system (BIS), and the fight-flight-freeze system (FFFS). This study aims to examine for the first time the features of BAS, BIS, and FFFS among karate players in comparison with athletes representing other sports disciplines (physical education students) and physically inactive people. The specific configuration of temperament traits and profiles characterizing karate players will also be found.MethodsThe cross-sectional study was performed among male karate athletes and control groups (physically active and inactive men). The study used the modified Reinforcement Sensitivity Questionnaire (rRSQ) to measure BAS, BIS, and FFFS.ResultsThe ANOVA showed that both karate competitors KS and KK scored significantly higher in BAS than the sample of PI participants. In addition, KK athletes scored significantly lower in Freeze than in PI and KS groups. Research also suggests that KK athletes presented significantly lower overall scores in FFFS than PI individuals. Furthermore, the results of K-means cluster analysis indicated the existence of two distinct patterns of temperamental traits: (1) Cluster 1 suggests avoidance tendencies (high Flight and Freeze, and low BAS, BIS, and Fight levels); while (2) the Cluster 2 describes approach tendencies (high BIS, BAS and Fight scores, and low levels of Flight and Freeze). Significantly more KK athletes were included in Cluster 2 than in Cluster 1, compared to PI, PA, and KS samples.ConclusionsThe research indicates that individuals engaged in karate, particularly those practicing Kyokushin karate, tend to exhibit a heightened sensitivity to rewards (high BAS). This finding holds significance for coaches and sports instructors, suggesting that motivating karate athletes through incentives is more effective, while the use of punishment should be minimized during training. Additionally, the study proposes that the practice of Kyokushin karate has the potential to significantly diminish the freezing response in threatening situations and enhance overall fear management by reducing levels of the Fight-Flight-Freeze System (FFFS). Consequently, the Kyokushin karate style may be considered more advantageous than the Karate Shotokan (KS) style in these aspects, despite both styles contributing to the improvement of BAS. Given that a higher BAS is linked to positive emotions, optimism, and happiness, karate training emerges as a form of health intervention, acting as a preventive measure against mental disorders and promoting overall well-being.

The Role of Platelets and Aneurysm Thrombus in the EVAR Post Implantation Syndrome

ObjectivePost implantation syndrome (PIS) is a well-defined entity with unclear etiology, complicating a number of patients with AAAs treated with EVAR. The aim of this study was to assess the platelets’ role and the influence of aneurysmal sac thrombus volumes in the development of PIS. DesignA retrospective analysis of prospectively collected data was performed and 76 patients that were treated by EVAR (2011-2013) were studied. Aneurysms with endoleak were not included in the study. Based on the criteria for SIRS (Systemic Inflammatory Response Syndrome), 17 patients (22%) developed PIS (which is considered a SIRS analogue), while 59 (78%) did not. MethodsThe two groups were compared in relation to the following parameters: baseline platelet count (PLT), decrease of platelet count (PLT drop), volume of the arterial flow before the procedure (V Flow), volume of thrombus of the aneurysm (V thromb), ratio of thrombus volume to aneurysm sac volume (V ratio) and the volume of new formed thrombus (V new). Volume flow measurements were calculated by Osirix ™ software preoperatively and in the 1st month postoperatively. Parametric and non-parametric techniques (unpaired t-test, Mann-Whitney U test) were used accordingly. ResultsBaseline platelets absolute count was greater in the PIS group (239000 ± 17000) vs. the non-PIS group (194000 ± 6900, p=0.004), and the PLT drop was larger in the PIS group (74000 ± 15600 vs. 45000 ± 5300, p=0.019). No difference was found regarding the aneurysm volumes (Vflow, Vthromb, Vratio, Vnew) between the two groups. ConclusionPlatelets, in terms of their absolute baseline count and their decrease after the procedure, seem to be an important factor in developing PIS after EVAR. Further, more tailored studies are needed to elucidate the role of platelets and flow/thrombus volumes in the development of PIS.

Pyroptosis-related pattern depicting tumor microenvironment and association with prognosis and efficacy in patients with hepatocellular carcinoma receiving combined molecular targeted therapy and immune checkpoint inhibitors: A multi-omics study.

e16194 Background: Molecular targeted therapy combined with immunotherapy is among the recommended treatment strategies for initially unresectable hepatocellular carcinoma (HCC). Pyroptosis is believed to be closely associated with immune cell infiltration in many tumors. We attempted to utilize a readily testable set of pyroptosis-related genes (PRGs) to develop genetic features predicting the efficacy of targeted combined immunotherapy in HCC, aiming to identify individuals sensitive to treatment. Methods: We conducted bioinformatics analysis on 53 PRGs using TCGA-LIHC and GTEx databases to construct PIs (Pyroptosis-Immune score). External and internal validation were performed using the GEO database and sequencing data from our center. Paired single-cell data were used to validate the predictive efficacy of PIs on the effectiveness of immune treatment. A matched cohort of 32 vs 32 individuals was established based on whether they underwent surgery after targeted combined immunotherapy. Immunohistochemistry staining analysis was conducted on pre-treatment biopsy samples, and protein expression was converted to corresponding gene expression levels. P-PIs (Pathological PIs) were calculated to verify its clinical applicability. The surgical group was assessed based on postoperative pathological efficacy, and the non-surgical group was evaluated for progression-free survival (PFS) through imaging. Results: We identified 6 PRGs closely associated with prognosis, immune cell infiltration, and the tumor microenvironment, constructing PIs. Log-Rank risk regression analysis suggested worse prognosis in the high PIs group (OS, HR = 3.44, 95% CI: 2.33-5.05, p < 0.01; PFS, HR = 2.00, 95% CI: 1.44-2.81, p < 0.01). GSE76427 dataset (n = 80; OS: HR = 1.61, 95% CI: 1.15-2.26, P < 0.01; PFS: HR = 1.44, 95% CI: 1.03-2.02, P = 0.03) and our center's sequencing data (n = 43; OS: HR = 1.53, 95% CI: 1.10-2.14, P = 0.01; PFS: HR = 1.55, 95% CI: 1.08-2.21, P = 0.02) indicated that the PIs could predict the prognosis for HCC. Single-cell sequencing data showed that tumor cells with high PI scores inhibited the function of CD8+ T cells (R = -0.33), while MDSC cells (R = 0.22), and M2 macrophage functions (R = 0.22) were enhanced. The P-PIs of operation group was higher (P = 0.01). The P-PIs in the surgical group was positively correlated with the degree of pathological remission (R = 0.95, P < 0.01). The median PFS in the non-surgical group was 8.5 months, and the P-PIs AUC was 0.76 (95% CI: 0.66-0.83). Conclusions: We developed a PIs to predict efficacy of targeted combined immunotherapy in HCC based on pre-treatment biopsy pathology. The P-PIs could potentially facilitate clinical trials aiming at personalized efficacy prediction for conversion or adjuvant treatment in HCC patients.

How does cervical sagittal profile change after the spontaneous compensation of global sagittal imbalance following one- or two-level lumbar fusion.

This study aimed to evaluate the cervical sagittal profile after the spontaneous compensation of global sagittal imbalance and analyze the associations between the changes in cervical sagittal alignment and spinopelvic parameters. In this retrospective radiographic study, we analyzed 90 patients with degenerative lumbar stenosis (DLS) and sagittal imbalance who underwent short lumbar fusion (imbalance group). We used 60 patients with DLS and sagittal balance as the control group (balance group). Patients in the imbalance group were also divided into two groups according to the preoperative PI: low PI group (≤ 50°), high PI group (PI > 50°). We measured the spinal sagittal alignment parameters on the long-cassette standing lateral radiographs of the whole spine. We compared the changes of spinal sagittal parameters between pre-operation and post-operation. We observed the relationships between the changes in cervical profile and spinopelvic parameters. Sagittal vertical axis (SVA) occurred spontaneous compensation (p = 0.000) and significant changes were observed in cervical lordosis (CL) (p = 0.000) and cervical sagittal vertical axis (cSVA) (p = 0.023) after surgery in the imbalance group. However, there were no significant differences in the radiographic parameters from pre-operation to post-operation in the balance group. The variations in CL were correlated with the variations in SVA (R = 0.307, p = 0.041). The variations in cSVA were correlated with the variations in SVA (R=-0.470, p = 0.001). Cervical sagittal profile would have compensatory changes after short lumbar fusion. The spontaneous decrease in CL would occur in patients with DLS after the spontaneous compensation of global sagittal imbalance following one- or two-level lumbar fusion. The changes of cervical sagittal profile were related to the extent of the spontaneous compensation of SVA.

Differences in mortality between patients with cardiogenic shock due to STEMI treated with PCI vs thrombolysis

Abstract Funding Acknowledgements None. Introduction STEMI is complicated with cardiogenic shock (CS) in approximately 5-10% of cases and mortality is about 40% at 30-day and 50% at 1 year worldwide. In Mexico the incidence of CS in STEMI that received revascularization therapy (PCI or thrombolysis) is between 4.4-4.8%. In our country, pharmacoinvasive strategy (PIs) is the preferred modality due to the lack of PCI centers and demographics. Purpose To demonstrate differences in total ischemia time and 30-day in-hospital mortality in patients treated with PIs or PCI. Methods This was a retrospective observational study of patients that arrived to the emergency room and coronary care unit of the National Institute of Cardiology from January 2018 to March 2023 with CS due to STEMI at presentation, who received reperfusion therapy (PCI or PIs) during the first 12 hours of symptom onset. Results We included 61 patients with CS due to STEMI at presentation, 60.7% received PIs and 39.3% underwent PCI. The prevalence of type 2 diabetes was 38%, hypertension was 28% and obesity was 10% with no significant differences between groups, however the presence of CKD differed significantly with approximately 3% in PCI group versus 0% in PIs group. 21% were smokers and 13% previous smokers. Only 8 patients (13.1%) had a previous MI, 5 patients (8.2%) had previous angioplasty and 4 patients (6.6%) had previous HF. The first medical contact (FMC) occurred at a median of 120 minutes (IQR 75-240 min) overall. For patients undergoing PIs, the FMC was 120 minutes (IQR 70-185 min), whereas for those undergoing PCI, it was 185 minutes (IQR 87-300 min). The total ischemia time was 270 minutes (IQR 180-470 min) overall, with a median of 229 minutes (IQR 163-405 min) for PIs and 396 minutes (IQR 267-592 min) for PCI. The 30-day in-hospital mortality rate was 27.9% overall, significantly lower at 18.9% in the PIs group compared to 41.7% in the PCI group (p=0.01). The average length of hospital stay was 8 days for the PIs population, slightly longer than the 6.5 days observed in the PCI group (p=0.09). Conclusion In this real-world retrospective analysis conducted in our center in a middle-income country showed that PIs impacted positively in 30-day in-hospital mortality of patients who arrived with CS due to STEMI at presentation compared to those that underwent PCI. This effect seems to be secondary to shorter ischemic times since symptom onset due to the use of a prompt reperfusion therapy.

Data-driven nonlinear turbulent flow scaling with Buckingham Pi variables

Nonlinear machine learning for turbulent flows can exhibit robust performance even outside the range of training data. This is achieved when machine-learning models can accommodate scale-invariant characteristics of turbulent flow structures. This study presents a data-driven approach to reveal scale-invariant vortical structures across Reynolds numbers that provide insights for supporting nonlinear machine-learning-based studies of turbulent flows. To uncover conditions for which nonlinear models are likely to perform well, we use a Buckingham-Pi-based sparse nonlinear scaling to find the influence of the Pi groups on the turbulent flow data. We consider nonlinear scalings of the invariants of the velocity gradient tensor for an example of three-dimensional decaying isotropic turbulence. The present scaling not only enables the identification of vortical structures that are interpolatory and extrapolatory for the given flow field data but also captures non-equilibrium effects of the energy cascade. As a demonstration, the present findings are applied to machine-learning-based super-resolution analysis of three-dimensional isotropic turbulence. We show that machine-learning models reconstruct vortical structures well in the interpolatory space with reduced performance in the extrapolatory space revealed by the nonlinearly scaled invariants. The present approach enables us to depart from labelling turbulent flow data with a single parameter of Reynolds number and comprehensively examine the flow field to support training and testing of nonlinear machine-learning techniques.

A simple method for the selection of valid spinopelvic parameters and lumbar lordosis in patients with transitional lumbosacral vertebrae

PurposeTransitional lumbosacral vertebrae (TLSV) are a congenital anomaly of the lumbosacral region that is characterized by the presence of a vertebra with morphological properties of both the lumbar and sacral vertebrae, with a prevalence of up to 36% in asymptomatic patients and 20% in adolescent idiopathic scoliosis patients. In patients with TLSV, because of these morphological changes and the different numbers of lumbar vertebrae, there are two optional reference sacral endplates that can be selected intently or inadvertently to measure the spinopelvic parameters: upper and lower endplates. The spinopelvic parameters measured using the upper and lower endplates are significantly different from each other as well as from the normative values. Therefore, the selection of a reference endplate changes the spinopelvic parameters, lumbar lordosis (LL), and surgical goals, which can result in surgical over- or under-correction. Because there is no consensus on the selection of sacral endplate among these patients, it is unclear as to which of these parameters should be used in diagnosis or surgical planning. The present study describes a standardization method for measuring the spinopelvic parameters and LL in patients with TLSV.MethodsUpper and lower endplate spinopelvic parameters (i.e., pelvic incidence [PI], sacral slope [SS], and pelvic tilt) and LL of 108 patients with TLSV were measured by computed tomography. In addition, these parameters were measured for randomly selected subjects without TLSV. The PI value in the TLSV group, which was closer to the mean PI value of the control group, was accepted as valid and then used to create an optimum PI (OPI) group. Finally, the spinopelvic parameters and LL of the OPI and control groups were compared.ResultsExcept for SS, all spinopelvic parameters and LL were comparable between the OPI and control groups. In the OPI group, 60% of the patients showed valid upper endplate parameters, and 40% showed valid lower endplate parameters. No difference was noted in the frequency of valid upper or lower endplates between the sacralization and lumbarization groups. Both the OPI and control groups showed nearly comparable correlations between their individual spinopelvic parameters and LL, except for PI and LL in the former.ConclusionsBecause PI is unique for every individual, the endplate whose PI value is closer to the normative value should be selected as the reference sacral endplate in patients with TLSV.

Efek Antidiabetes Kombinasi Ekstrak Mengkudu (Morinda citrifolia) dan Kunyit (Curcuma longa) pada Tikus yang dibuat Hiperglikemik

Background: Diabetes Mellitus is a disease characterized by hyperglycemia in a long time can cause the damage of pancreatic beta cells. Morinda citrifolia contains xeronine that can regenerate damaged pancreatic beta cells. While Curcuma longa contains curcumin which acts as an antioxidant will stabilize free radicals so it can inhibit pancreatic beta cell damage and stimulate insulin secretion.Methods: The study aim to analyze the effect of a combination of Morinda Citrifolia and Curcuma Longa in reducing blood glucose levels, increasing body weight and pancreatic histopathology in hyperglycemic mice. This type of research is an experiment with the Post Test Only Control Group. A total of 25 mice were divided into 5 groups namely PI (250 mg/dL), PII (500 mg/dL), PIII (750 mg/dL), K(+), and K(-). Blood glucose level was observed for 21 days followed by observation of pancreatic histopathology.Result: The results showed the percentage of glucose blood reduction occurred in the PI group (56.11%) and significantly different from negative controls (35.05%). There was no difference in body weight (p=0.7) and number of langerhans islet (p=0.360) in all treatment groups. The diameter of the Langerhans islet of the PI group (200.8 μm) was significantly different from the negative control (114.8 μm). (p<0.05Conclusion : The combination of Morinda citrifolia and Curcuma longa extract can reduce blood glucose levels and increase body weight but not be able to optimally repair pancreatic islet damage.

Long-Term Outcomes of Pharmacoinvasive Strategy Versus Primary Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction: A Study from Mexico City

While primary percutaneous coronary intervention (pPCI) is the treatment of choice in ST elevation myocardial infarction (STEMI), challenges may arise in accessing this intervention for certain geodemographic groups. Pharmacoinvasive strategy (PIs) has demonstrated comparable outcomes when delays in pPCI are anticipated, but real-world data on long-term outcomes are limited. The aim of the present study was to compare long-term outcomes among real world patients with STEMI undergoing either PIs or pPCI. This was a prospective registry including patients with STEMI who received reperfusion during the first 12 hours from symptom onset. The primary objective was cardiovascular mortality at 12 months according the reperfusion strategy (pPCI vs PIs); major cardiovascular events (cardiogenic shock, recurrent MI, congestive heart failure) and BARC type 3-5 bleeding events were also evaluated.A total of 799 patients with STEMI were included, 49.1% underwent pPCI and 50.9% received PIs. Patients in the PIs group presented with more heart failure on admission (Killip Kimbal >I 48.1 vs 39.7, p=0.02) and had a lower proportion of pre-existing heart failure (0.2 vs 1.8%, p=0.02) and atrial fibrillation (0.25 vs 1.2%, p=0.02). No statistically significant difference was observed in cardiovascular mortality at the 12-month follow-up (HR for PIs: 0.74, 95% CI: 0.42-1.30; log-rank p=0.30) according to the reperfusion strategy employed. The composite of major cardiovascular events (HR for PIs 0.98, 95% CI: 0.75-1.29, p=0.92) as well as BARC 3-5 bleeding rates were also comparable. A low socioeconomic status, Killip-Kimball >2, age > 60 years and admission creatinine >2.0mg/dL were predictors of the composite endpoint after multivariate analysis.In conclusion, this prospective real-world registry provides additional support that long term major cardiovascular outcomes and bleeding are not different between patients undergoing PIs versus primary PCI.

Abnormal functional connectivity of the occipital thalamus with the superior occipital gyrus is associated with mild cognitive impairment in elderly individuals with primary insomnia

AbstractStudy objectivesPrimary insomnia (PI) triggers a decline in cognitive function, and the thalamus plays an integral role in this process; however, the mechanisms are unclear. The purpose of this study was to investigate the altered functional connectivity (FC) of the thalamus in PI patients with mild cognitive impairment (MCI) and to explore the potential neural mechanisms of thalamic involvement in these patients.MethodsThis case–control study was conducted in older adults from various communities in Fuzhou, China with a PI diagnosis. These participants underwent neuropsychological assessment and were matched in a 1:2 ratio to the healthy control (HC) group and the PI group according to sex, age, and education level. Resting‐state functional magnetic resonance imaging was used to explore changes in thalamic FC in PI patients. To further compare changes in thalamic and whole‐brain FC, we further divided the PI group into cognitively normal patients and patients with MCI according to the diagnostic criteria for MCI. The relationship between abnormal FC and cognitive function was investigated.ResultsThe 28 HCs and 58 participants with PI showed significant differences in Montreal Cognitive Assessment (MoCA) scores (p = .044). In comparison to the HC group, the PI group showed enhanced FC of the occipital thalamus with the left inferior occipital gyrus, right lingual gyrus, left middle temporal gyrus, left superior marginal gyrus, left dorsolateral superior frontal gyrus, and right anterior central gyrus. The MoCA total score and the executive function, attention, and abstraction scores of PI patients with MCI (PI–MCI) were worse than those of PI patients without MCI. In comparison to the simple PI group, FC was enhanced in the PI–MCI group between the left occipital thalamus and the middle occipital gyrus, and between the right occipital thalamus and the right superior frontal gyrus, left middle frontal gyrus, right superior occipital gyrus, and orbital inferior frontal gyrus. There was a significant negative correlation between the MoCA total score and the enhanced FC between the right occipital thalamus and right superior occipital gyrus (r = −.419, p = .042).ConclusionThe early onset of cognitive impairment in patients with PI is associated with altered FC between the thalamus and the cortex. Enhanced FC between the thalamus and the visual cortex, that is, the superior occipital gyrus, which is involved in attentional processing, may play a role in the early onset of cognitive impairment in insomnia patients. Moreover, due to the fact that PI patients “overdraw” the compensatory capacity of these brain regions earlier, the PI–MCI may fall into the abyss of “decompensation” faster and face more severe cognitive impairments.

Antioxidant Properties of Pistacia vera against the Effects of Phenylhydrazine-Induced Hemolytic Anemia on Male Fertility in Mice

Objective. The reproductive system can be adversely affected by anemia, characterized by elevated free radical production and lipid peroxidation. Conversely, the pistachio is well-known for its antioxidant capabilities. In this study, a mouse model was employed to investigate the safeguarding effects of the aqueous extract of pistachio (Pistacia vera) against oxidative stress induced by phenylhydrazine (PHZ)-triggered hemolytic anemia. Materials and methods. Forty-eight male mice were distributed into six distinct experimental groups (n = 8): control, PHZ, PHZ + 20Pis, PHZ + 80Pis, PHZ + 160Pis, and 80Pis groups. The experimental groups were administered a PHZ dose of 80 mg/kg/48 hr, along with pistachio doses of 20, 80, and 160 mg/kg/day, delivered intraperitoneally. After a period of 35 days, an assessment of sperm count, motility, morphology, and viability was conducted. Additionally, sperm chromatin quality was evaluated through Chromomycin A3, aniline blue, and toluidine blue staining. Hematoxylin–eosin staining was performed to examine the total diameter of seminiferous tubes and spermatogenic cells. Hormonal levels (FSH, LH, T) and antioxidant levels were analyzed using standard kits. Results. The PHZ groups exhibited a noteworthy decrease in various sperm parameters, as well as diminished chromatin quality assays and reduced levels of sex hormones when compared to the control group. Moreover, the morphometric evaluation indicated a substantial reduction in spermatogonia cell number, spermatid count, tubule count, seminiferous diameters, and seminiferous area in the PHZ group. Notably, the Pis group demonstrated the highest concentration of antioxidant contents. Conclusion. The protective impact of P. vera extract against PHZ-induced anemia on the male reproductive system in mice may be attributed to its abundant antioxidant components, which possess therapeutic properties at elevated levels.

Investigation of the relationship between diastolic notching in uterine artery Doppler and serum salusin alpha and beta concentrations in the first trimester

Objective Studies have shown that members of the salusin family regulate the migration and proliferation of arterial smooth muscle cells and increase the tendency to atherosclerosis through fibrosis and calcification in the vascular wall. However, the effect of salusins on the uterine artery has not yet been investigated. This study was conducted to investigate whether serum salusin alpha and beta concentrations in the first trimester are associated with diastolic notching in uterine artery Doppler. Methods This non-interventional cohort study was conducted on 88 pregnant women, 44 of whom had diastolic notching on unilateral or bilateral uterine artery Doppler, and 44 of whom did not have diastolic notching on uterine artery Doppler. The uterine artery notch positive and negative groups were compared in terms of serum salusin alpha and beta concentrations. Results The two groups were similar in terms of demographic characteristics (p < 0.05). The median salusin alpha concentration was found to be 689.4 pg/ml in the uterine artery notch positive group, while it was 734.6 pg/ml in the uterine artery notch negative group (p = 0.608). The median salusin beta concentration was found to be 674.5 pg/ml in the uterine artery notch positive group, while it was 693.8 pg/ml in the uterine artery notch negative group (p = 0.453). Participants were regrouped into normal and high uterine artery resistance and compared in terms of serum salusin alpha and beta concentrations. The median salusin alpha concentration was found to be 994.5 pg/ml in the high uterine artery PI group, while it was 685.2 pg/ml in the normal uterine artery PI group (p = 0.698). The median salusin beta concentration was found to be 1,100.8 pg/ml in the high uterine artery PI group, while it was 669.1 pg/ml in the normal uterine artery PI group (p = 0.584). Conclusion Although the sample size was too small to draw a definitive conclusion, our results indicate that uterine artery diastolic notching or increased resistance in the uterine artery does not appear to be associated with serum salusin alpha or beta concentrations.

Safety and Efficacy of Hydrus and I-Stent inject combined with Phacoemulsification in Primary Open Angle Glaucoma Patients: 2 year follow up study

Aims: To compare the safety and efficacy of phacoemulsification combined with two individual kinds of trabecular bypass micro-stent device insertion. This study compares Phacoemulsification with Hydrus stent versus phacoemulsification combined with I-Stent inject W in patients with medically uncontrolled primary open-angle glaucoma (POAG). Material and Methods: A retrospective comparative case series. Results: Eighty eyes of 75 patients with 2 years completed follow-up after combined phacoemulsification with trabecular by-pass stent (s) were included. Forty eyes of 37 patients had Hydrus stent (Hydrus Group-PH) and the other 40 eyes of 38 patients had I-stent inject W (I-stent Group-Pi) insertion combined with phacoemulsification and intraocular lens implantation. Patient demographics and preoperative characteristics of the two groups studied are comparable. A post-operative decrease of 20 percentage or more in the IOP was achieved in 33 eyes (82.5%) in PH group and 30 eyes (75%) in Pi group (p=0.57). The Hydrus group (PH) had a post-operative reduction in the mean number of medications in 22 eyes (55%) in comparison to 18 eyes (45%) in the I-stent group (Pi). Second stage trabeculectomy was avoided in 31 eyes (77.5%) in the Hydrus group and 27 eyes (67.5%). There was no significant difference in rate of complications between two groups. Conclusion: Both Hydrus stent and I-stent inject W combined with phacoemulsification and intra-ocular lens implantation, are efficacious and safe for treating patients with medically uncontrolled mild and moderate primary open-angle glaucoma (POAG). The reduction in the mean IOP and in the mean number of post-operative glaucoma medications was higher for the patients in Hydrus stent group than in I-stent inject W group.

(-)-epicatechin treatment did not modify the thermogenic pathway in the gastrocnemius muscle of male rat offspring obeses by programming.

The aim of this study was to analyse the expression of genes related to the regulation of energy metabolism in skeletal muscle tissue by comparing male offspring in two age groups [at 110 and 245 postnatal days (pnd)] from a mother with obesity induced by a high-fat diet and (-)-epicatechin (Epi) administration. Four groups of six male offspring from different litters were randomly selected for the control groups [C and offspring of mothers with maternal obesity (MO)] or Epi intervention groups. We evaluated the effect of Epi on gastrocnemius tissue by analysing the mRNA and protein expression levels of Fndc5/irisin, Pgc-1α, Ucp3, and Sln. Epi significantly increased the Pgc-1α protein in the MO group of offspring at 110 pnd (p < 0.036, MO vs. MO+Epi), while at 245 pnd, Epi increased Fndc5/irisin mRNA expression in the MO+Epi group versus the MO group (p = 0.006).No differences were detected in Fndc5/irisin, Ucp3 or Sln mRNA or protein levels (including Pgc-1α mRNA) in the offspring at 110 pnd or in Pgc-1α, Ucp3, or Sln mRNA or protein levels (including Fndc5/irisin protein) at 245 pnd among the experimental groups. In conclusion, (-)-epicatechin treatment increased Fndc5/irisin mRNA expression and Pgc-α protein levels in the gastrocnemius muscle of offspring at postnatal days 110 and 245. Furthermore, it is suggested that the flavonoid effect in a model of obesity and its impact on thermogenesis in skeletal muscle are regulated by a different pathway than Fndc5/irisin.

Comparative effects of phosphorylation and acetylation on glycolysis and myofibrillar proteins degradation in postmortem muscle

The study investigated the different effects between protein phosphorylation and acetylation on glycolytic enzyme activity and myofibrillar protein degradation. Lamb longissimus thoracis lumborum muscles were homogenized and then inhibitors were added for incubation at 4 °C. Phosphatase inhibitor was added to produce a high phosphorylation level (PI group) and lysine deacetylase inhibitor was added to produce a high acetylation level (DI group). The lactate and ATP content in the PI group was inhibited compared with that in the DI group (P < 0.05). Phosphofructokinase (PFK) activity was negatively related with the phosphorylation level and was positively related with the acetylation level in the DI group (P < 0.05). The degradation of troponin T and desmin of the DI group were restrained when compared to that in the PI group (P < 0.05). Compared with initial PFK and desmin, the simulation of phosphorylation and acetylation of PFK and desmin showed different electrostatic potential at the surface and a more unstable structure. The phosphorylation level of the DI group was increased, suggesting that the changes of protein acetylation altered protein phosphorylation. In conclusion, compared with protein phosphorylation, protein acetylation had a greater effect on promoting glycolysis and inhibiting protein degradation.

Finite element analysis of five internal fixation modes in treatment of Day type Ⅱcrescent fracture dislocation of pelvis

To compare the biomechanical differences among the five internal fixation modes in treatment of Day type Ⅱ crescent fracture dislocation of pelvis (CFDP), and find an internal fixation mode which was the most consistent with mechanical principles. Based on the pelvic CT data of a healthy adult male volunteer, a Day type Ⅱ CFDP finite element model was established by using Mimics 17.0, ANSYS 12.0-ICEM, Abaqus 2020, and SolidWorks 2012 softwares. After verifying the validity of the finite element model by comparing the anatomical parameters with the three-dimensional reconstruction model and the mechanical validity verification, the fracture and dislocated joint of models were fixed with S 1 sacroiliac screw combined with 1 LC-Ⅱ screw (S 1+LC-Ⅱ group), S 1 sacroiliac screw combined with 2 LC-Ⅱ screws (S 1+2LC-Ⅱ group), S 1 sacroiliac screw combined with 2 posterior iliac screws (S 1+2PIS group), S 1 and S 2 sacroiliac screws combined with 1 LC-Ⅱ screw (S 1+S 2+LC-Ⅱ group), S 2-alar-iliac (S 2AI) screw combined with 1 LC-Ⅱ screw (S 2AI+LC-Ⅱ group), respectively. After each internal fixation model was loaded with a force of 600 N in the standing position, the maximum displacement of the crescent fracture fragments, the maximum stress of the internal fixation (the maximum stress of the screw at the ilium fracture and the maximum stress of the screw at the sacroiliac joint), sacroiliac joint displacement, and bone stress distribution around internal fixation were observed in 5 groups. The finite element model in this study has been verified to be effective. After loading 600 N stress, there was a certain displacement of the crescent fracture of pelvis in each internal fixation model, among which the S 1+LC-Ⅱ group was the largest, the S 1+2LC-Ⅱ group and the S 1+2PIS group were the smallest. The maximum stress of the internal fixation mainly concentrated at the sacroiliac joint and the fracture line of crescent fracture. The maximum stress of the screw at the sacroiliac joint was the largest in the S 1+LC-Ⅱ group and the smallest in the S 2AI+LC-Ⅱ group. The maximum stress of the screw at the ilium fracture was the largest in the S 1+2PIS group and the smallest in the S 1+2LC-Ⅱ group. The displacement of the sacroiliac joint was the largest in the S 1+LC-Ⅱ group and the smallest in the S 1+S 2+LC-Ⅱ group. In each internal fixation model, the maximum stress around the sacroiliac screws concentrated on the contact surface between the screw and the cortical bone, the maximum stress around the screws at the iliac bone concentrated on the cancellous bone of the fracture line, and the maximum stress around the S 2AI screw concentrated on the cancellous bone on the iliac side. The maximum bone stress around the screws at the sacroiliac joint was the largest in the S 1+LC-Ⅱ group and the smallest in the S 2AI+LC-Ⅱ group. The maximum bone stress around the screws at the ilium was the largest in the S 1+2PIS group and the smallest in the S 1+LC-Ⅱ group. For the treatment of Day type Ⅱ CFDP, it is recommended to choose S 1 sacroiliac screw combined with 1 LC-Ⅱ screw for internal fixation, which can achieve a firm fixation effect without increasing the number of screws.

Hard-to-treat or hard-to-catch? Clinical features and therapeutic outcomes of help-seeking foster care youths with mood disorders.

The high level of emotional problems in youths placed in foster care contrasts with the limited use of evidence-based treatments. This study aims to better characterize the clinical features and therapeutic outcomes of foster care youths with mood disorders. A secondary analysis of data collected in the context of a French-Canadian clinical research network on pediatric mood disorders in four sites was conducted to compare three groups of patients with depressive or bipolar disorder: those without exposure to child welfare intervention (WCWI, n = 181), those who received non-placement psychosocial intervention (NPI, n = 62), and those in placement interventions (PI, n = 41). We observed a very high rate of academic problems in patients in the groups NPI/PI compared to those in the WCWI group. Patients in the PI group had more disruptive behavioral disorders (OR = 6.87, 95% CI [3.25-14.52]), trauma-related disorders (OR = 3.78, 95% CI [1.6-8.94]), and any neurodevelopmental disorders (OR = 2.73, 95% CI [1.36-5.49]) compared to the other groups (NPI/WCWI). Among inpatients, the Clinical Global Impression-Improvement scale and the change in the Children Global Assessment Scale during the hospital stay did not differ across the three groups. We observed a higher prescription rate of antipsychotics in the PI group compared to the NPI/WCWI groups, but no significant difference for antidepressants and mood stabilizers. These findings support the view that, when provided with dedicated support, fostered inpatient youths can improve in a range comparable to other inpatients. Undetected neurodevelopmental disorders and academic problems are likely important contributors of the burden of mood disorders in these youths.

Favorable neuroprotective effect of intra-arterial application of edaravone dexborneol in ischemic stroke rats

ObjectiveThe aim of this study was to investigate the neuroprotective effects of intra-arterial administration of edaravone dexborneol in rats with acute ischemic stroke and determine the optimal dose. Materials and methodsFirstly, 120 male Sprague-Dawley rats (265–300 g) were selected to establish ischemic stroke models and were randomly divided into groups of sham-operation (Sham group), cerebral ischemia-reperfusion (IS group), permanent focal ischemia (PI group) and treatment (2MG group: 2 mg/kg, 4MG group: 4 mg/kg, 6MG group: 6 mg/kg) groups. There are 20 rats in each group, and ten rats in each group were randomly selected for Longa score and 2,3,5-triphenyl tetrazolium chloride staining to observe the changes in neurological function and the proportion of cerebral infarct volume in each group. Secondly, the remaining ten rats in each group were scored for Longa and tested for free radicals (hydroxyl radical; peroxynitrite; nitric oxide) and pro-inflammatory cytokines (interleukin 6; interleukin-1β; tumor necrosis factor-α). We monitored changes in the indicators in each group of rats. ResultsThere were no significant differences among the enrolled Sprague-Dawley rats concerning age, sex, and feeding conditions. Edaravone dexborneol could significantly reduce the cerebral levels of hydroxyl radical, interleukin 6, interleukin-1β, tumor necrosis factor-α, and their behavioral scores of acute ischemic stroke rats after a single dose in the carotid artery. The results suggested that 4 mg/kg might be an appropriate dose. ConclusionsA single intra-arterial administration of edaravone dexborneol can improve neurobehavioral function and alleviate cerebral injury in acute ischemic stroke rats through anti-inflammatory and free radical scavenging effects.