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Overcoming vascular immunosuppression: lack of endothelial cell (EC) responsiveness to inflammatory stimuli in the proangiogenic environment of tumors, is essential for successful cancer immunotherapy. The mechanisms through which Vascular Endothelial Growth Factor (VEGF) modulates tumor EC response to exclude T cells are not well understood. The goal was to determine the role of EC Rap1B, a small GTPase that positively regulates VEGF- angiogenesis during development, in tumor growth in vivo. Using mouse models of Rap1B deficiency, Rap1B+/- and EC-specific Rap1B KO (Rap1BiΔEC) we demonstrate that EC Rap1B restricts tumor growth and angiogenesis. More importantly, EC-specific Rap1B deletion leads to an altered tumor microenvironment with increased recruitment of leukocytes and increased activity of tumor CD8+ T cells. We find that tumor growth, albeit not angiogenesis, is restored in Rap1BiΔEC mice by depleting CD8+ T cells. Mechanistically, global transcriptome analysis indicated upregulation of the tumor cytokine, TNF-α, -induced signaling and NFκB transcriptional activity in Rap1B-deficient ECs. Functionally, EC Rap1B deletion led to upregulation of NFκB activity and enhanced Cell Adhesion Molecules (CAMs) expression in TNF-α stimulated ECs. Importantly, CAM expression was upregulated also in tumor ECs from Rap1BiΔEC mice, vs. controls. Significantly, deletion of Rap1B abrogated VEGF immunosuppressive downregulation of CAM expression, demonstrating that Rap1B is essential for VEGF-suppressive signaling. Thus, our studies identify a novel endothelial-endogenous mechanism underlying VEGF-dependent desensitization of EC to pro-inflammatory stimuli. Significantly, they identify EC Rap1 as a potential novel vascular target in cancer immunotherapy.

Previously, researchers used functional MRI to identify regional brain activations associated with sensory processing sensitivity (SPS), a proposed normal phenotype trait. To further validate SPS as a behavioral entity, to characterize it anatomically, and to test the usefulness in psychology of methodologies that assess axonal properties, the present study correlated SPS proxy questionnaire scores (adjusted for neuroticism) with diffusion tensor imaging measures. Participants (n=408) from the Young Adult Human Connectome Project that are free of neurologic and psychiatric disorders were investigated. We computed mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD) and fractional anisotropy (FA). A voxelwise, exploratory analysis showed that MD and RD correlated positively with SPS proxy scores in the right and left subcallosal and anterior ventral cingulum bundle, and the right forceps minor of the corpus callosum (peak Cohen’s D effect size = 0.269). Further analyses showed correlations throughout the entire right and left ventromedial prefrontal cortex, including the superior longitudinal fasciculus, inferior fronto-occipital fasciculus, uncinate and arcuate fasciculus. These prefrontal regions are generally involved in emotion, reward and social processing. FA was negatively correlated with SPS proxy scores in white matter of the right premotor/motor/somatosensory/supramarginal gyrus regions, which are associated with empathy, theory of mind, primary and secondary somatosensory processing. Region of interest (ROI) analysis, based-on previous fMRI results and Freesurfer atlas-defined areas, showed small effect sizes, (+0.151 to -0.165) in white matter of the precuneus and inferior frontal gyrus. Other ROI effects were found in regions of the dorsal and ventral visual pathways and primary auditory cortex. The results reveal that in a large, diverse group of participants axonal microarchitectural differences can be identified with SPS traits that are subtle and in the range of typical behavior. The results suggest that the heightened sensory processing in people who show SPS may be influenced by the microstructure of white matter in specific neocortical regions. Although previous fMRI studies had identified most of these general neocortical regions, the DTI results put a new focus on brain areas related to attention and cognitive flexibility, empathy, emotion and low-level sensory processing, as in the primary sensory cortex. Psychological trait characterization may benefit from diffusion tensor imaging methodology by identifying influential brain systems for traits.

Heart rate variability is a robust biomarker of emotional well-being, consistent with the shared brain networks regulating emotion regulation and heart rate. While high heart rate oscillatory activity clearly indicates healthy regulatory brain systems, can increasing this oscillatory activity also affect brain function? To test this possibility, we randomly assigned 106 young adult participants to one of two 5-week interventions involving daily biofeedback that either increased heart rate oscillations (Osc+ condition) or had little effect on heart rate oscillations (Osc- condition) and examined effects on brain activity during rest and during regulating emotion. While there were no significant changes in the right amygdala-medial prefrontal cortex (MPFC) functional connectivity (our primary outcome), the Osc+ intervention increased left amygdala-MPFC functional connectivity and functional connectivity in emotion-related resting-state networks during rest. It also increased down-regulation of activity in somatosensory brain regions during an emotion regulation task. The Osc- intervention did not have these effects. In this healthy cohort, the two conditions did not differentially affect anxiety, depression or mood. These findings indicate that heart rate oscillatory activity not only provides a measure of the current state of regulatory brain systems but also changes emotion network coordination in the brain.Significance StatementPeople whose breathing makes their heart rate oscillate more (leading to higher heart rate variability or HRV) generally have better regulated emotion. Thus, HRV may indicate functioning of brain networks regulating emotion and internal body states. But heart rate oscillations may not only reflect brain regulatory networks but also help shape these networks. We randomly assigned participants to practice either increasing heart rate oscillations using slow-paced breathing or decreasing them using personalized strategies. Daily practice increasing heart rate oscillations affected brain activity in emotion-related networks even during times when participants breathed no differently than the comparison group. Thus, HRV is more than just an outcome measure--it can help shape the subsequent functioning of emotion-related brain networks.

Acknowledgements: Not applicable., Funder: Fisher and Paykal Healthcare, BACKGROUND: Minimally invasive surgery is becoming more common and transfemoral transcatheter aortic valve replacement is offered to older patients with multiple comorbidities. Sternotomy is not required but patients must lie flat and still for up to 2-3 h. This procedure is increasingly being performed under conscious sedation with supplementary oxygen, but hypoxia and agitation are commonly observed. METHODS: In this randomised controlled trial, we hypothesised that high-flow nasal oxygen would provide superior oxygenation as compared with our standard practice, 2 l min-1 oxygen by dry nasal specs. This was administered using the Optiflow THRIVE Nasal High Flow delivery system (Fisher and Paykel, Auckland, New Zealand) at a flow rate of 50 l min-1 and FiO2 0.3. The primary endpoint was the change in arterial partial pressure of oxygen (pO2) during the procedure. Secondary outcomes included the incidence of oxygen desaturation, airway interventions, the number of times the patient reached for the oxygen delivery device, incidence of cerebral desaturation, peri-operative oxygen therapy duration, hospital length of stay and patient satisfaction scores. RESULTS: A total of 72 patients were recruited. There was no difference in change in pO2 from baseline using high-flow compared with standard oxygen therapy: median [IQR] increase from 12.10 (10.05-15.22 [7.2-29.8]) to 13.69 (10.85-18.38 [8.5-32.3]) kPa vs. decrease from 15.45 (12.17-19.33 [9.2-22.8]) to 14.20 (11.80-19.40 [9.7-35.1]) kPa, respectively. The percentage change in pO2 after 30 min was also not significantly different between the two groups (p = 0.171). There was a lower incidence of oxygen desaturation in the high-flow group (p = 0.027). Patients in the high-flow group assigned a significantly higher comfort score to their treatment (p ≤ 0.001). CONCLUSION: This study has demonstrated that high flow, compared with standard oxygen therapy, does not improve arterial oxygenation over the course of the procedure. There are suggestions that it may improve the secondary outcomes studied. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) 13,804,861. Registered on 15 April 2019. https://doi.org/10.1186/ISRCTN13804861.

Purpose: To determine the prevalence of keratoconus (KC) in relation to ethnicity in N. Macedonia. Methods: This was a cross-sectional, interventional retrospective study. Chart reviews were performed for all new patients attending between January 2016 and January 2020 at the Sistina Ophthalmology Hospital in Skopje. All patients were screened, KC diagnosis and classification was based on the corneal topography. Ethnicity and gender classifications were according to patients’ self-opinions. Results: A total of 2812 patients charts reviewed. The mean age was 31.71 years (SD, ±9.73), 1209 (43%) were male. 2050 (72.9%) declared themselves as Macedonians, 649 (23.1%) Albanians, 76 (2.7%) Turks and 37 (1.3%) in other ethnicities. Differences in age between the ethnic groups was statistically significant (𝑥2=90.225, pConclusion: The prevalence of KC at a refractive surgery practice in N.Macedonia is much higher compared with general population and similar to the prevalence in Middle East Asia. Nationwide screening programs are needed to diagnose the disease earlier.

BackgroundRight Heart Failure (RHF) is a severe complication that can occur after left ventricular assist device (LVAD) implantation, increasing early and late mortality. Although numerous RHF predictive scores have been developed, limited data exist on the external validation of these models.We therefore aimed at comparing existent risk score models and identifying predictors of severe RHF at our center.MethodsIn this retrospective, single center analysis, clinical, biological and functional data were collected in patients implanted with a LVAD between 2011 and 2020. Early severe RHF was defined as use of inotropes for ≥14 days, nitric oxide use for ≥48 hours or unplanned right-sided circulatory support.Risk models were evaluated for the primary outcome of RHF or RVAD implantation by means of logistic regression and receiver operating characteristic curves. ResultsAmong 92 patients implanted, 24 (26%) developed early severe RHF. The EUROMACS-RHF risk score performed the best in predicting RHF (C=0.82 - 95% CI: 0.68-0.90), compared with the other scores (Michigan, CRITT). In addition, we developed a new model, based on four variables selected for the best reduced logistic model: the INTERMACS level, the number of inotropes used, the ratio of right atrial/pulmonary capillary wedge pressure and the ratio of right ventricle/left ventricle diameters by echocardiography. This model demonstrated significant discrimination of RHF (C=0.91 - 95% CI: 0.76-0.96).ConclusionAmongst available risk scores, EUROMACS-RHF performs best to predict the occurrence of RHF after LVAD implantation. Our model’s performance compares well to the EUROMACS-RHF score, adding a more objective parameter to RV function evaluation.

PurposePostoperative atrial fibrillation is a poor prognostic factor that increases mortality rates. We have observed that patients who experienced significant pericardial effusion developed postoperative atrial fibrillation; however, little research has been conducted examining the association between postoperative atrial fibrillation and post-cardiotomy pericardial effusion.MethodsThis retrospective, single-center study included adult patients who underwent cardiovascular surgery via median sternotomy from January 2016 to December 2019. Patients who underwent routine postoperative computed tomography at 7±3 days after surgery (n = 294) were included. Pericardial effusion was measured at its thickest point. Patients were classified into groups with (n = 127) and without (n = 167) postoperative atrial fibrillation, and the association of pericardial effusion with other factors was evaluated. A possible confounder adjusted logistic regression analysis after multiple imputation was performed to obtain odds ratios for postoperative atrial fibrillation using previously published risk factors.ResultsAge, intraoperative bleeding volume, and pericardial effusion size were all significantly higher in the group with postoperative atrial fibrillation. Multivariate logistic regression after multiple imputation revealed that age, intraoperative bleeding volume, and postoperative pericardial effusion were significantly associated with postoperative atrial fibrillation.ConclusionTo our knowledge, this is the first study focusing on the relationship between post-cardiotomy pericardial effusion and postoperative atrial fibrillation. Our findings showed that post-cardiotomy pericardial effusion is associated with postoperative atrial fibrillation. However, causality remains unknown, making further studies mandatory.

PURPOSE: Results from adjuvant trials evaluating 6 cycles of epirubicin-based chemotherapy regimens suggested these programs may be more effective than 4 cycles of doxorubicin-based chemotherapy. METHODS: NSABP B-36 was a phase III clinical trial originally designed as a 2x2 factorial study comparing 6 cycles of FEC-100 (5-FU, epirubicin, cyclophosphamide) to 4 cycles of conventional AC (Adriamycin/cyclophosphamide) with celecoxib or placebo. Shortly after activation, concerns regarding increased cardiovascular risks among selective COX-2 inhibitors resulted in a decision to remove the celecoxib/placebo from the trial. Women with histologically node-negative invasive breast cancer who had undergone primary surgery with a lumpectomy or total mastectomy were eligible. Primary endpoint was disease-free survival (DFS).RESULTS: Between May 2004-July 2008, 2,722 patients were enrolled. Administration of FEC-100 did not result in improvement in DFS compared to AC (HR=1.09; 95% CI 0.92-1.29, p-value=0.31). The effect of FEC-100 compared to AC on DFS was significantly different for receptor-positive (HR=1.32, 95% CI=1.05-1.66) compared to receptor-negative patients (HR=0.86, 95% CI=0.66-1.11) (treatment-by-receptor status interaction p-value=0.02). There was no statistically significant difference in the effect of treatment on overall survival (OS) with FEC-100 compared to AC (HR=1.06; 95% CI 0.84-1.35, p-value=0.61). Overall, Grade 3 and 4 adverse events were more frequent in the FEC-100 group.CONCLUSIONS: The results of B-36 do not support use of six-cycle anthracycline-based regimens in node-negative breast cancer. Prolongation of anthracycline-based therapy with FEC-100 does not improve DFS or OS, relative to AC for 4 cycles, and was associated with expected increases in toxicity. A statistically significant interaction between treatment and hormone receptor status favoring AC in hormone-receptor-positive breast cancers is consistent with the hypothesis that optimal duration of chemotherapy may be four cycles in these patients. Late cardiac events and deaths prior to recurrence or second cancer were infrequent on both arms, but slightly higher with FEC-100.ClinicalTrials.gov: NCT00087178

Purpose To investigate the histological efficacy of ranibizumab and zoledronic acid in an experimentally induced endometriosis model as compared with danazol, buserelin acetate and dienogest. Methods Endometrial implants were introduced in 52 female Wistar albino rats, which were then randomly divided into six groups. The animals were, respectively, given dienogest, danazol, buserelin acetate, zoledronic acid, ranibizumab and 0.9% NaCl. After 4 weeks, the volumes and histopathological properties of the implants were evaluated and the implants were excised completely at the third laparotomy. A histopathological scoring system was used to evaluate the preservation of epithelia. Endometrial explants were evaluated immunohistochemically. Results Among the groups, the histological score was significantly lower in the zoledronic acid and ranibizumab groups compared with the controls (p < 0.001). There were no significant differences regarding ellipsoidal volume levels between groups (p > 0.05). However, there was a statistically significant difference regarding cell numbers according to the degree of Bcl-2, NF-kappa B, and CD31 staining (p < 0.001). There was no statistically significant difference in Bcl-2, CD31, or NF-kappa B staining in the binary comparisons between the other groups (p > 0.05). For Bcl-2 staining, the staining rate of the group treated with zoledronic acid was significantly lower compared with the dienogest and danazol groups (p < 0.05). The staining rates of CD31 and NF-kappa B were significantly lower in the zoledronic acid and ranibizumab groups compared with the controls (p < 0.05). Conclusion According to these results, zoledronic acid and ranibizumab may be putative candidates for the treatment of endometriosis., Technological and Scientific Research Council of Turkey (TUBITAK) [213S002], This study was funded by The Technological and Scientific Research Council of Turkey (TUBITAK) (213S002).

BackgroundPerioperative rehabilitation management is essential to enhanced recovery after surgery (ERAS). Limited reports, however, have focused on quantitative, detailed early activity plans for patients receiving minimally invasive esophagectomy (MIE). The purpose of this research was to estimate the effectiveness of the Tailored, Early Comprehensive Rehabilitation Program (t-ECRP) based on ERAS in the recovery of bowel and physical functions for patients undergoing MIE.MethodsIn this single-blind, 2-arm, parallel-group, randomized pilot clinical trial, patients admitted to the Affiliated Cancer Hospital of Zhengzhou University from June 2019 to February 2020 were selected and randomly assigned to an intervention group (IG) or a control group (CG). The participants in the IG received medical care based on the t-ECRP strategy during perioperative period, and participants in the CG received routine care. The recovery of bowel and physical functions, readiness for hospital discharge (RHD), and postoperative hospital stay were evaluated on the day of discharge.ResultsTwo hundred and fifteen cases with esophageal cancer (EC) were enrolled and randomized to the IG (n = 107) or CG (n = 108). The mean age was 62.58 years (SD 9.07) and 71.16% were male. For EC, 53.49% were mid-location cancers and 79.07% were classified as pathological stage II and III cancers. There were no significant differences between the two groups in terms of demographic and clinical characteristics and baseline physical functions. Participants in the IG group presented significantly shorter lengths of time to first flatus (P P = 0.024), and for up and go test (P P P ConclusionsThe t-ECRP appears to improve bowel and physical function recovery, ameliorate RHD, and shorten postoperative hospital stay for patients undergoing MIE. Clinicians should consider prescribing quantitative, detailed, and individualized early activity plans for these patients.Trial registrationClinicalTrials.gov (Identifier: NCT01998230)

This study looked at the effects of processed kola nut husks meal (PKHM) utilization as a feed ingredient on broiler chicken in a 42-day feeding trial. Kola nut pod husks were processed into a PKHM using ash treatment and rumen liquor fermentation. Three experimental diets were developed at both the starter and finisher phases, with PKHM included at 0, 4, and 8%, and dubbed diets 1, 2, and 3, respectively. In a fully randomised design, 240 Arbor Acres broiler chicks were randomly assigned to three treatments (10 birds per replicate). Except for the significantly improved (P0.05) affected by PKHM dietary inclusion. Broiler chicken carcass characteristics and relative internal organ weights remained constant (P>0.05) through diets. The serum glutathione concentration in broiler chickens fed an 8 percent PKHM inclusive diet increased significantly (P0.05) regardless of dietary treatment. Dietary PKHM inclusion of up to 8% enhanced improved feed efficiency and increased antioxidant enzyme concentration and did not affect the serum biochemical indices concentration.Statement of NoveltyKola nut husk is one of the agro-wastes that contributes to environmental deterioration due to its underutilization. The kola nut husk is underutilised in broiler production due to its chemical constitution, minimal nutritional value, and poor digestion. In this research, kola nut husk meal was ash treated and rumen liquor fermented before being integrated at varying levels in the experimental diets and the performance characteristics, antioxidant status, serum protein, enzymes and biochemical were evaluated. The findings of this study could aid in the development of an agro-waste-based, low-cost functional feed for broiler chicks that incorporates the underutilised kola nut husk and other abundant agrowastes as macro-ingredients.

Background: Mesenchymal stem cells (MSCs) from human adipose tissue and bone marrow have a great potential for use in cell therapy due to their ease of isolation, expansion, and differentiation. Our intention was to isolate and promote in vitro expansion and differentiation of MSCs from human adipose and bone marrow tissue into cells with a pancreatic endocrine phenotype and to compare the potency of these cells together.Methods and Results: MSCs were pre-induced with nicotinamide, mercaptoethanol, B-27 and b-FGF in L-DMEM for 2 days and re-induced again in supplemented H-DMEM for another 3 days. Expression of five genes in differentiated beta cells was evaluated by Real-time PCR and western blotting and the potency of insulin release in response to glucose stimulation was evaluated by insulin and C-peptide ELISA kit.Quantitative RT-PCR results showed up-regulation of four genes in differentiated beta-islet cells (Insulin, Ngn-3, Pax-4 and Pdx-1) compared with the control. Western blot analysis showed that MSCs cells mainly produced proinsulin and insulin after differentiation but nestin was more expressed in pre-differentiated stem cells. Glucose and insulin secretion assay showed that insulin levels and C-peptide secretion were significantly increased in response to 10 mM glucose.Conclusions: Our study showed that both adipose and bone marrow stem cells could differentiate into functional beta-islet cells but it seems that adipose stem cells could be a better choice for treatment of diabetes mellitus according to their more safety and potency.

Objective: the optimal management of asymptomatic, skull-based meningiomas is not well defined. The aim of this study is to compare the imaging and clinical outcomes of patients with asymptomatic, skull-based meningiomas managed either with upfront stereotactic radiosurgery (SRS) or active surveillance. Methods: this retrospective, multicenter study involved patients with asymptomatic, skull-based meningiomas. The study end-points included local tumor control and the development of new neurological deficits attributable to the tumor. Factors associated with tumor progression and neurological morbidity were also analyzed. Results: the combined unmatched cohort included 417 patients. Following propensity score matching for age, tumor volume, and follow-up 110 patients remained in each cohort. Tumor control was achieved in 98.2% and 61.8% of the SRS and active surveillance cohorts, respectively. SRS was associated with superior local tumor control (p < 0.001, HR = 0.01, 95% CI = 0.002-0.13) compared to active surveillance. Three patients (2.7%) in the SRS cohort and six (5.5%) in the active surveillance cohort exhibited neurological deterioration. One (0.9%) patient in the SRS-treated and 11 (10%) patients in the active surveillance cohort required surgical management of their meningioma during follow-up. Conclusions: SRS is associated with superior local control of asymptomatic, skull-based meningiomas as compared to active surveillance and does so with low morbidity rates. SRS should be offered as an alternative to active surveillance as the initial management of asymptomatic skull base meningiomas. Active surveillance policies do not currently specify the optimal time to intervention when meningioma growth is noted. Our results indicate that if active surveillance is the initial management of choice, SRS should be recommended when radiologic tumor progression is noted and prior to clinical progression., NA

This experiment aimed to determine the possible beneficial effects of dietary ascorbic acid (AA) on hematological indices, immune responses, and antioxidative capacity of Oncorhynchus mykiss treated with antibiotic oxytetracycline (OTC). 150 fish were divided evenly among five experimental groups (30 fish of each, in 3 replicates) receiving diets containing OTC (0 and 100 mg per kg fish weight) and AA (100, 200, 400 and 800 mg per kg fish diet) for 28 days. Treatments include group A or control (100 mg AA without OTC), group B (100 mg AA with OTC), group C (200 mg AA with OTC), group D (400 mg AA with OTC), and group E (800 mg AA with OTC). The results obtained showed that the hematological indices (red blood cells, white blood cells, hematocrit, hemoglobin and neutrophils), immunological parameters (plasma lysozyme, plasma complement and skin mucus alkaline phosphatase activities), and antioxidant enzymes activities (superoxide dismutase and catalase) were significantly decreased by OTC in O. mykiss fed control diet (P < 0.05). The results also revealed that OTC significantly increased the activity of biochemical enzymes (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase) in the plasma of O. mykiss fed control diet (P < 0.05). However, in comparison to the control diet, feeding fish with higher amounts of AA (400 and 800 mg/kg diet) significantly restored the hematological, immunological, and antioxidative responses in OTC treated groups (p < 0.05). These findings show that the dietary supplementation of AA at 400 or 800 mg/kg diet is beneficial in relieving O. mykiss from OTC-induced oxidative stress and immunosuppression.

Background: Apoptosis is upregulated in all forms of diabetes, with the mitochondria acting as a target in diabetes pathophysiology. Quercetin and vitamin E have shown usefulness in the delay of progression of diabetes-induced complications. However, their effect on the apoptotic process in diabetes mellitus is unknown. We hypothesize that quercetin treatment in diabetes may decrease the propensity for cardio-myocytic death via regulation of the mitochondria permeability transition (mPT) pore opening. Methods: Hearts from normal and streptozotocin-induced diabetic rats were used for the study. Low-ionic strength heart mitochondria were used for swelling assay, and mitochondrial lipid peroxidation (mLPO) activity was spectrophotometrically assessed. Levels of cytochrome c, caspase 3 and 9 were determined by immunohistochemistry, while lesions assessed by histology.Discussion: Diabetic heart mPT pore showed larger amplitude swelling than control, while mLPO levels was increased in diabetic rats relative to control, this resulted in cytochrome c release. This initiated increased caspase 3 and 9 activity in diabetic rats (p

Borassus flabellifer leaf extract has been used for rapid biogenic-synthesis of Zinc-Oxide nanoparticles (ZnO-NPs) due to rich source of bioactive compounds. The synthesized ZnO-NPs were preliminarily confirmed by UV-Visible spectroscopy adsorption peak range at 365nm. The XRD (X-ray diffraction) confirm purity of ZnO-NPs that were crystalline in nature. The analysis of FT-IR (Fourier-transform infrared spectroscopy) confirm the presence of following functional group such as alcohol, phenols, carboxylic acids, primary amides, secondary amides, alkyl halide. FE-SEM analysis indicated that ZnO-NPs were in spherical shape, followed by EDX analysis which confirmed the presence of Zn-element. Antimicrobial effect of ZnO-NPs was investigated using different clinical pathogens like bacteria Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Klebsiella Pneumonia, Pseudomonas aeruginosa and fungi Aspergillus flavus, Candida albicans and Penicillium expansum and which confirmed ZnO-NPs efficiency as an antimicrobial agent. Antioxidant activity were ascertained to used for several biomedical applications. The ZnO-NPs was efficiently degraded the environmental toxic dyes (methylene blue and crystal violet) under sunlight. In support of photolight-degradation, the study was progressed to understand the ZnO-dye interaction stability using molecular mechanism and it was showing efficient bonding features in the NPs environment. Overall, this investigation have great potential for being an effective and eco-friendly materials was used in environmental applications.

Introduction To evaluate the effects of combined therapy using intravitreal Aflibercept (IVA) and photodynamic therapy (PDT) on polypoidal choroidal vasculopathy related to pachychoroid disease (PPCV).Methods Patients with PPCV were treated with PDT combined with 3 IVA injections on a monthly basis, followed by pro re nata criteria. The 12-month follow-up consisted of multiple revaluations of visual acuity and SSOCT parameters of clinical activity.Results Nineteen eyes were included in the study; mean age was 65.5 years. Visual acuity improved after 12 months (0.35 ± 0.25 to 0.2 ± 0.20 logMAR, p = 0.005). Percentage of eyes with intraretinal and subretinal fluid reduced from baseline to the 12-month follow-up (from 52.6–10.5%, p = 0.12, and from 89.5–5.3% p = 0.0009, respectively). Central retinal and mean macular thicknesses reduced (258 ± 39.6 to 204.8 ± 38.8 µm p = 0.04 and 293.8 ± 32.1 to 248.1 ± 29.6 µm p = 0.017 respectively). Central choroidal and mean choroidal thicknesses also displayed a reduction (328.6 ± 54.9 to 289.8 ± 44.6 µm p = 0.001 and 314.5 ± 55.3 to 287.9 ± 47.6 µm p = 0.015 respectively). The mean number of injections was 4.6/year.Conclusion The results support the use of a combined therapy with Aflibercept and PDT in PPCV. This treatment would act in synergy, with anti-VEGF controlling exudation and PDT closing the aneurysmal vessel and reducing choroidal congestion.

Purpose To evaluate treatment outcomes of de novo metastatic nasopharyngeal carcinoma (mNPC) patients receiving taxane/gemcitabine-containing chemotherapy followed by locoregional intensity-modulated radiotherapy (IMRT) and analyze potential prognostic factors. Methods A total of 118 patients between March 2008 and November 2018 were retrospectively analyzed. All the patients were treated with taxane/gemcitabine-containing systemic chemotherapy followed by definitive locoregional IMRT. Potential prognostic factors including baseline absolute lymphocyte count (ALC) and the subdivision of metastasis were analyzed. Results The median follow-up time for the whole group was 31.5 months (range 5–138 months). Of the 118 patients, 9 (7.6%) patients experienced local regional failure and 60 (50.8%) patients had progression of distant metastasis. At the time of the last follow-up, 61 (51.7%) patients were dead. The 5-year actuarial progression free survival (PFS), overall survival (OS),distant metastasis relapse free survival (DMFS) and local regional recurrence free survival (LRFS) were 34.2%, 44%, 41.1% and 82.6%, respectively. Baseline lymphocyte count ≥ 1600/μl prior to the treatment conferred better locoregional control (5y-LRFS 96% vs. 64.7%, p p = 0.023). The multivariate analysis showed that high lymphocyte count was the most relevant predictor of superior PFS (HR = 0.236, p p = 0.04). M subdivision was found as another independent prognostic factor for OS but not for PFS. Conclusion Taxane/gemcitabine-containing chemotherapy combined with IMRT represents an effective treatment modality for mNPC. Baseline ALC is an independent significant prognostic factor for PFS and OS.

BackgroundDetermining the humoral immunogenicity of tozinameran (BNT162b2) vaccine in patients requiring chronic renal replacement therapy, and its impact on COVID-19 morbidity several months after vaccination, will guide risk assessment and subsequent changes in vaccination policy.MethodsIn a prospective post-vaccination cohort study with up to 5 months follow-up we studied outpatient dialysis and kidney transplant patients and respective healthcare teams. Outcomes were anti S1/S2 antibody response to vaccine or infection and infection rate during followup.Results175 dialysis patients (40% women, 65±15 years), 252 kidney transplant patients (33% women, 54±14 years) and 71 controls (65% women, 44±14 years) were followed. Three months or longer after vaccination we detected anti S1/S2 IgG antibodies in 80% of dialysis patients, 44% of transplant recipients and 100% of controls, whereas respective rates after infection were 94%, 75% and 100%. Predictors of non-response were older age, diabetes, history of cancer, lower lymphocyte count and lower vitamin-D levels. Factors associated with lower titers in dialysis patients were modality (hemodialysis vs peritoneal) and high serum ferritin levels. In transplant patients, hypertension and higher calcineurin or mTOR inhibitor drug levels were linked with diminished antibody response. Vaccination associated with fewer subsequent infections (HR=0.23, p10titer (pConclusionsDialysis patients, and more so kidney transplant recipients, mounted reduced antibody response to COVID-19 mRNA vaccination, and lesser humoral response associated with more infections. Measures to identify and protect non-responsive patients are urgently required.SignificanceReports on the humoral immunogenicity of SARS-CoV-2 mRNA vaccines in patients with end stage renal disease are scarce, and association with subsequent COVID-19 morbidity is unknown. In this cohort study that included 175 patients treated with dialysis, 252 kidney transplant recipients and 71 control volunteers, the proportion achieving an antibody response was time- and group-dependent, reaching 80%, 44% and 100% at 3 months post prime inoculation. Personal history of vaccination, positive antibody responses and antibody titers associated with significantly lower risk of COVID-19 infection. Thus, in patients with end stage renal disease, SARS-CoV-2 antibody testing may be warranted after vaccination, to identify non-responders at higher risk for disease.

Background: Skin blood flux (SkBF) changes caused by drinking cold water are generally associated with vagal tone and osmotic factors in the digestive system. However, the distribution and regulation of bilateral blood flow are not symmetrical but exhibit a certain laterality. The aim of this study was to analyze the laterality of skin blood flux after drinking saline (0.9%) at different temperatures by monitoring blood flux in the bilateral lower extremities.Methods: A total of 60 subjects were recruited for this study, and all subjects completed all measurements. Subjects were randomly divided into a 4 °C group, 10 °C group and 30 °C group. For every subject, skin blood perfusion of bilateral Zusanli acupoints (ST 36) was recorded simultaneously before and after drinking 500 ml of 0.9% saline using a PeriFlux System 5000. The electrogastrogram (EGG) was also monitored, and the dominant frequency of the EGG and heart rate variability were analyzed.Results: The results indicated that after drinking saline at different temperatures, the laterality index of skin blood flux at the lower extremities was different. Drinking 30 °C saline can increase the laterality index of the lower extremities. The results of wavelet analysis showed that the laterality index changes of skin blood flux were mainly reflected in the frequency interval V (0.4-1.6 Hz). Stimulation at 4 °C and 10 °C resulted in a decrease in the dominant frequency (DF) of the electrogastrogram and an increased root mean square of successive differences (RMSSD) of the RR interval. There was a weak negative correlation between the laterality index of frequency interval I or II and root mean square of successive differences.Conclusion: There was laterality of blood perfusion in the lower extremities after drinking saline at different temperatures.

BackgroundNon-invasive oxygen saturation (SpO2) measurement is a central vital sign that supports the management of COVID-19 patients. However, reports on SpO2 characteristics (patterns and dynamics) are scarce and none, to our knowledge, has analysed high resolution continuous SpO2 in COVID-19. MethodsSpO2 signal sampled at 1Hz and clinical data were collected from COVID-19 departments at the Rambam Health Care Campus (Haifa, Israel) between May 1st, 2020 and February 1st, 2021. Data from a total of 367 COVID-19 patients, totalling 27K hours of continuous SpO2 recording, could be retrieved, including 205 non-critical and 162 critical cases. Desaturations based on different SpO2 threshold definitions and oximetry derived digital biomarkers (OBMs) were extracted and compared across severity and support levels. FindingsAn absolute SpO2 threshold at 93% was the most efficient in discriminating between critical and non-critical patients without support or under oxygen support. Under no support, the non-critical group depicted a fold change (FC) of 1 {middle dot}8 times more frequent desaturations compared to the critical group. However, the hypoxic burden was 1 {middle dot}6 times more important in critical versus non-critical patients. Other OBMs depicted significant differences, notably the percentage of time below 93% SpO2 (CT93) was the most discriminating OBM. Mechanical ventilation depicted a strong effect on SpO2 by significantly reducing the frequency (1 {middle dot}85 FC) and depth (1 {middle dot}21 FC) of desaturations. OBMs related to periodicity and hypoxic burden were markedly affected up to several hours before the initiation of the mechanical ventilation. InterpretationThis is the first report investigating continuous SpO2 measurements in hospitalized patients affected with COVID-19. SpO2 characteristics differ between critical and non-critical patients and are impacted by the level of support. OBMs from high resolution SpO2 signal may enable to anticipate clinically relevant events, monitoring of treatment response and may be indicative of future deterioration. FundingThe Milner Foundation, The Placide Nicod fundation and the Technion Machine Learning and Intelligent Systems center (MLIS).

Purpose This study aims to assess the results, rebubbling rate, and graft survival after Descemet membrane endothelial keratoplasty (DMEK) with regard to the number and type of previous glaucoma surgeries. Methods This is a clinical retrospective review of 1845 consecutive DMEK surgeries between 07/2011 and 08/2017 at the Department of Ophthalmology, University of Cologne. Sixty-six eyes were included: group 1 (eyes with previous glaucoma drainage devices (GDD); n = 27) and group 2 (eyes with previous trabeculectomy (TE); n = 39). Endothelial cell loss (ECL), central corneal thickness, graft failure, rebubbling rate, and best spectacle-corrected visual acuity (BSCVA) up to 3 years after DMEK were compared between subgroups of patients with different numbers of and the two most common types of glaucoma surgeries either GDD or TE or both. Results Re-DMEK rate due to secondary graft failure was 55.6% (15/27) in group 1 and 35.9% in group 2. The mean graft survival time in group 1 was 25 ± 11 months and 31.3 ± 8.6 months in group 2 (p = 0.009). ECL in surviving grafts in group 1 was 35% (n = 13) at 6 months, 36% at 12 months (n = 8), and 27% (n = 4) at 2 years postoperatively. In group 2, ECL in surviving grafts was 41% (n = 10) at 6 months, 36% (n = 9) at 12 months, and 38% (n = 8) at 2 years postoperatively. Rebubbling rate in group 1 was 18.5% (5/27) and 35.9% (14/39) in group 2 (p = 0.079). Conclusion Eyes with previous GDD had no higher risk for an increased rebubbling rate but a higher risk for a re-DMEK due to secondary graft failure with a mean transplant survival time of about 2 years. Compared to eyes with preexisting glaucoma drainage device, eyes after trabeculectomy had less secondary graft failures and a longer mean graft survival rate.

Objective This study was aimed to compare different stenting techniques for coronary bifurcation disease (CBD). Background Percutaneous coronary intervention (PCI) remains controversial for CBD; over the years, several stent techniques for bifurcation lesions have been used. Current guidelines recommend a provisional single-stent strategy as the preferred method for coronary artery bifurcation lesions. However, several randomized controlled trials (RCT) indicated that two-stent techniques showed better clinical outcomes. Methods We systematically searched Embase, PubMed, and Web of Science to include RCTs. The primary endpoint was the major adverse cardiovascular event (MACE). Secondary outcomes were cardiac death, myocardial infarction (MI), target-lesion or target-vessel revascularization (TLR or TVR), and definite or probable stent thrombosis (ST). Finally, we used 26 RCTs and a total of 7257 individuals were randomly assigned to one of the 6 stent techniques and included in this network meta-analysis. Results In our network meta-analysis, double-kissing (DK) crush was significantly more superior to other 5 stent techniques in MACEs: OR vs. provisional 0.40 (95% CI 0.28–0.55); vs. culotte 0.40 (95% CI 0.26–0.60). DK crush ranked the most effective treatment for MACE (100%), MI (75%), ST (83%), and TLR (100%) in the rank probabilities analysis. In patients with complex bifurcation lesion defined by DEFINITION criteria, DK crush was notably more efficacious than provisional, culotte, and T-stenting/T-stenting and protrusion (TAP) in MACEs (OR vs. provisional 0.26, 95% CI 0.13–0.52) and TLR (OR vs. provisional 0.24, 95% CI 0.10–0.58). Conclusion Compared with other stenting techniques, DK crush had a lower incidence of MACEs in CBD. DK crush was significantly associated with a lower rate of MACEs in patients with complex bifurcation lesions defined by the DEFINITION criterion. Graphical abstract

The prefrontal cortex is appreciated as a key neurobiological player in human eating behavior. A special focus is herein dedicated to the dorsolateral prefrontal cortex (DLPFC), which is critically involved in executive function such as cognitive control over eating. Persons with obesity display hypoactivity in this brain area, which is linked to overconsumption and food craving. Contrary to that, higher activity in the DLPFC is associated with successful weight-loss and weight-maintenance. Transcranial direct current stimulation (tDCS) is a non-invasive neurostimulation tool used to enhance self-control and inhibitory control. The number of studies using tDCS to influence eating behavior rapidly increased in the last years. However, the effectiveness of tDCS is still unclear, as studies show mixed results and individual differences were shown to be an important factor in the effectiveness of non-invasive brain stimulation. Here, we describe the current state of research of human studies using tDCS to influence food intake, food craving, subjective feeling of hunger and body weight. Excitatory stimulation of the right DLPFC seems most promising to reduce food cravings to highly palatable food, while other studies provide evidence that stimulating the left DLPFC shows promising effects on weight loss and weight maintenance, especially in multisession approaches. Overall, the reported findings are heterogeneous pointing to large interindividual differences in tDCS responsiveness.

PURPOSE To describe the outcomes of surgical bleb revisions from a tertiary glaucoma service in Singapore. METHODS One hundred and thirty-one eyes of 129 patients who underwent surgical bleb revisions at the Singapore National Eye Centre between 2007 and 2014 were included in the study. The indications for bleb revision were: bleb-related infection (BRI), early and late bleb leak, early and late overfiltration, and bleb dysesthesia. Regression analysis was applied to elucidate risk factors. RESULTS The mean age of the patients was 66 years, 62.6% were male, and 88.5% were Chinese. The majority of the eyes had primary glaucoma (79.4%). The mean interval from the initial trabeculectomy or phaco-trabeculectomy to the bleb revision was 58.8 months. The overall success rate was 69.5%. By Kaplan-Meier survival analysis, the overall cumulative success range fell from 78.6% to 49.1% over 10 years. Eyes with early bleb leak had lower surgical success compared to eyes with late bleb leak, early overfiltration and late overfiltration (P = 0.026, log-rank test). The IOP improved significantly post-operatively for eyes with BRI, early bleb leak, late bleb leak, early overfiltration and overfiltration (P

In this research, we synthesized the Fe3O4/CuO/ZnO@MWCNT magnetic nanocomposites using water extract of Petasites hybridus rhizome, and the high performance of synthesized catalyst was confirmed by using in the solvent-free multicomponent reactions of isatoic anhydride, N-methylimidazole, alkyl bromides, activated acetylenic compounds and 2-aminoacetonitrile at ambient temperature for the production of new cyanopyrroloazepine derivatives in high yields. This catalyst could be used several times in these reactions and have main role in the yield of product. The synthesized cyanopyrroloazepines have NH groups in their structure and for this reason have good antioxidant activity. Also, employing Gram-positive and Gram-negative bacteria in the disk diffusion procedure confirmed some cyanopyrroloazepines antimicrobial effect. The results showed that synthesized cyanopyrroloazepine prevented the bacterial growth. This used process for preparation of new cyanopyrroloazepine has some improvements such as low reaction time, product with high yields, simple separation of catalyst and products.

PURPOSE Plasma F2-isoprostanes (FiP) concentration, a reliably measured, valid, systemic oxidative stress biomarker, has been associated with multiple health-related outcomes; however, associations of most individual dietary and lifestyle exposures with FiP are unclear, and there is no reported oxidative balance score (OBS) comprising multiple dietary and/or lifestyle components weighted by their associations with FiP. METHODS To investigate cross-sectional associations of dietary and lifestyle characteristics with plasma FiP concentrations, we used multivariable general linear models to compare adjusted mean FiP concentrations across categories of dietary nutrient and whole-food intakes and lifestyle characteristics in two pooled cross-sectional studies (n = 386). We also developed equal-weight and weighted OBS (nutrient- and foods-based dietary OBS, lifestyle OBS, and total OBS), and compared adjusted mean FiP concentrations across OBS tertiles. RESULTS Among men and women combined, adjusted mean FiP concentrations were statistically significantly, proportionately 28.1% higher among those who were obese relative to those who were normal weight; among those in the highest relative to the lowest total nutrient intake tertiles, FiP concentrations were statistically significantly lower by 9.8% for carotenes, 13.6% for lutein/zeaxanthin, 10.9% for vitamin C, 12.2% for vitamin E, 11.5% for glucosinolates, and 5% for calcium. Of the various OBS, the weighted OBS that combined total nutrient intakes and lifestyle exposures was most strongly associated with FiP concentrations: among those in the highest relative to the lowest total OBS, mean FiP concentrations were statistically significantly 29.7% lower (P

Over the past decades, virtual reality (VR) has found its way into biofeedback (BF) therapy programs. Using VR promises to overcome challenges encountered in traditional BF such as low treatment motivation, low attentional focus and the difficulty of transferring learnt abilities to everyday life. Yet, a comprehensive research synthesis is still missing. Hence, this scoping review aims to provide an overview over empirical studies on VR based BF regarding key outcomes, included samples, used soft- and hardware, BF parameters, mode of application and potential limitations. We systematically searched Medline, PsycINFO, Scopus, CINAHL, Google Scholar and Open Grey for empirical research. Eighteen articles met the inclusion criteria. Samples mostly consisted of healthy (44.4%) and/or adult (77.7%) participants. Outcomes were mainly anxiety (44.4%), stress (44.4%) or pain reduction (11.1%), which were reduced by the VR-BF interventions at least as much as by classical BF. Participants in VR-BF interventions showed higher motivation and involvement as well as a better user experience. Heart rate or heart rate variability were the most frequently used BF parameters (50.0%), and most VR-BF interventions (72.2%) employed a natural environment (e.g., island). Currently, there is no clear evidence that VR-BF is more effective than traditional BF. Yet, results indicate that VR-BF may have advantages regarding motivation, user experience, involvement and attentional focus. Further research is needed to assess the specific impact of VR and gamification. Also, testing a broader range of clinical and younger samples would allow more far-reaching conclusions.

PURPOSE In adolescent idiopathic scoliosis (AIS), the rib prominence is a major cosmetic concern which can be improved using thoracoplasties. We sought to determine if the use of deep drains helps minimize the development of pleural effusions after thoracoplasties. METHODS Retrospective study of 45 patients with AIS undergoing posterior spinal fusion (PSF) and thoracoplasties. RESULTS Thirty six out of 45 patients (80.0%) required placement of a deep surgical drain, and 16 out of 45 (35.6%) developed pleural effusions after PSF with concomitant thoracoplasty. Of the 16 patients who developed pleural effusion, 12 of 36 (33.3%) required a placement of a deep drain (p > 0.05). Of the total 45 patients in this cohort, 3 patients (6.7%) required chest tubes, and 4 patients (8.9%) developed surgical site infections (SSIs). We found that deep drains were associated with a lower incidence of SSI (2.8% vs 33.3%; p = 0.021). Patients who had a pleural effusion had longer ICU stays (p = 0.037) and longer requirements of nasal oxygen (p = 0.025). DISCUSSION The presence of a pleural effusion in patients with AIS undergoing PSF with thoracoplasty was associated with longer oxygen requirements and length of hospital ICU admission. Thirty six percent of patients with thoracoplasties developed pleural effusions, but deep subfascial drains did not significantly decrease the incidence of pleural effusions.

Intrauterine infections are an urgent problem of modern neonatology. One of the causes of intrauterine infective foetal lesions is physiological immunosuppression. The purpose of this study is to investigate the cytokine status in newborns infected with perinatal infections, depending on their body weight. The study examined 145 newborns. Taking into account their body weight, they were divided into 2 groups: main and secondary. The study was conducted in the immunological laboratory of the Medical Centre of Marat Ospanov West Kazakhstan Medical University in the city of Aktobe, with the determination of the level of IgM and IgG to the herpes simplex virus (HSV) types 1, 2, cytomegalovirus (CMV), and chlamydia using the MULTISKANASCENT analyser with the "Chemo" T system. The main results of this study are the predominance of the anti-inflammatory component in both normal weight and underweight infants, which is evidence of the Th-cell-mediated immune response prevalence. The applied value of this study lies in the possibility of applying its results in practice to obtain effective methods to counteract the occurrence and development of intrauterine infections.

Quantra® Hemostasis Analyzer is a Point of the care device that uses ultrasound technology to assess clot formation. In this study, we establish how Quantra® system performs compared to conventional coagulation tests at low levels of fibrinogen in the blood obtained from pregnant women. 24 mL blood was obtained from each healthy parturient. Blood was analyzed for Quantra® variables (Q): Clot time (CT), Clot stiffness (CS), platelet contribution to CS (PCS), fibrinogen contribution to CS (FCS), and conventional coagulation (CL) tests: PT, aPTT, INR, Factor VIII and fibrinogen. 6 ml blood were centrifuged to obtain pregnant plasma. 30 mL of saline was added to 10 mL of blood to simulate crystalloid resuscitation (DB) and was evaluated for Q and CL. Fractions of pregnant plasma, or nonpregnant plasma (Blood Bank) was added to DB to obtain 15% and 30% clotting factor enriched samples. 4 ml of DB was added to 4 ml of original blood (1:1) to obtain the final sample (resus). Each of the samples were analyzed for Q and CL parameters. Regression analysis and Receiving Characteristics Curves were used to study the relationship between Quantra variables and CL tests. There were remarkably high linear correlations between Fibrinogen and CS (R = 0.93, P

Purpose Major disadvantages of the percutaneous coronary intervention (PCI) are the high occurrence of repeat revascularization due to restenosis and disease progression. The current study aimed to identify indicators that can predict the risk of repeat revascularization. Methods A total of 143 patients who underwent PCI and had genetic test results were enrolled. We retrospectively reviewed their medical records after the first PCI. P2Y12 reaction units (PRU) test results were obtained by VerifyNow; 372 SNPs of NOS3, MMP3, AGT, and AGT1R gene and 380 genes related to platelet activation-related processes and clopidogrel activity were selected for analysis. Repeat revascularization and in-stent restenosis (ISR) were used as clinical outcomes, and PRU and ADP aggregation rates were used as platelet function outcomes in analysis. Results After the first PCI, the incidence of repeat revascularization at 18, 30, and 42 months was 14.1% (20/142), 17.5% (24/137), and 39.7% (31/78), respectively. In the candidate gene analysis, Rs 78830 (NOS3) was associated with both ADP aggregation rate and 18- and 30-month ISR, and rs 62275847 (AGTR1) was associated with both ADP aggregation rate and 30-month ISR. In the pathway, gene-set analysis, the linkage rs471683 and rs7785386 of GNAI1|GNAT3 were associated with PRU and ADP aggregation rate, 18-months and 30-months ISR, and repeat revascularization within 30 months. Rs1715389 of GNAI1|GNAT3 were associated with both PRU and ADP aggregation rate, 18-months and 30-months ISR, and repeat revascularization within 30 months. Rs7313458 of ITPR2 were associated with PRU and ADP aggregation rate, 18-months and 30-months ISR, and repeat revascularization within 18 months. Conclusions The genetic polymorphisms of rs78830(NOS3), rs62275874 (AGTR1), linkage rs471683 and rs7785386 (GNAI1|GNAT3), rs1715389(GNAI1|GNAT3), and rs7313458 (ITPR2) may lead to an increased risk of in-stent restenosis and revascularization after the first PCI in Chinese patients by affecting the efficacy of clopidogrel. The above six SNP may be used as potential genetic biomarkers for high risk of in-stent restenosis and revascularization after the first PCI in Chinese patients.

With more than 5500 da Vinci Surgical System (DVSS) installed worldwide, the robotic approach for general surgery, including for inguinal hernia repair, is gaining popularity in the USA. However, in many countries outside the USA, robotic surgery is performed at only a few advanced institutions; therefore, its advantages over the open or laparoscopic approaches for inguinal hernia repair are unclear. Several retrospective studies have demonstrated the safety and feasibility of robotic inguinal hernia repair, but there is still no firm evidence to support the superiority of robotic surgery for this procedure or its long-term clinical outcomes. Robotic surgery has the potential to overcome the disadvantages of conventional laparoscopic surgery through appropriate utilization of technological advantages, such as wristed instruments, tremor filtering, and high-resolution 3D images. The potential benefits of robotic inguinal hernia repair are lower rates of complications or recurrence than open and laparoscopic surgery, with less postoperative pain, and a rapid learning curve for surgeons. In this review, we summarize the current status and future prospects of robotic inguinal hernia repair and discuss the issues associated with this procedure.

To develop preoperative models as a guide to indications for neoadjuvant chemotherapy (NAC) and regional lymph node dissection (LND) before and at radical nephroureterectomy (RNU), respectively, in patients with non-metastatic upper tract urothelial carcinoma (UTUC) by incorporating the systemic immune-inflammation index (SII).This retrospective study enrolled 103 consecutive patients with UTUC undergoing RNU. The SII was calculated as neutrophils × platelets / lymphocytes. Multivariable Cox proportional hazard model was used to develop preoperative models for cancer-specific survival (CSS) and overall survival (OS). A model for predicting muscle invasion was developed using logistic regression analysis. Harrell's concordance-index (c-index) or the area under the receiver operating characteristic curve (AUC) was used to evaluate the accuracy of the models.During follow-up (median: 41 months), 26 and three patients died of UTUC and other causes, respectively. Performance status 0, clinical tumor (cT) stage ≥ 3, and SII 520 were independent adverse prognosticators for CSS, and one point was assigned to each prognosticator. Risk score models comprising the sum of the points stratified patients into three risk groups (0, 1, and 2-3; P 0.001 for CSS and OS) with respective c-indices of 0.843 and 0.820. SII 677 and ≥ cT3 were independently associated with muscle invasion. A model based on these variables predicted muscle invasion with AUC of 0.804.Preoperative SII is significantly associated with worse survival outcomes and muscle invasion in patients with non-metastatic UTUC. Our preoperative predictive models may serve as a guide to indications for NAC and LND.

Purpose Tumor mutational burden (TMB) is a surrogate biomarker of neo-antigens and high TMB status is associated with favorable response to immune-checkpoint inhibitors (ICIs). This study aimed to elucidate the association between TMB and the outcome of definitive radiotherapy in patients with cervical cancer. Materials and methods TMB and treatment outcome were retrospectively analyzed in patients with newly diagnosed cervical cancer treated with definitive radiotherapy available with somatic mutation data of pre-treatment tumors obtained using a commercially available gene panel. Results The study enrolled 98 patients (median follow-up period, 61 months). The median TMB was 9.5 mutations per megabase (range, 3.0–35.5 mutations per megabase). After dichotomization based on this median value, the 5-year overall survival (OS) for TMB-high patients was significantly worse than that of TMB-low patients (61.1% vs. 82.2%). Multivariate analysis identified high TMB status as a significant prognostic factor for worse OS, along with advanced stage, para-aortic lymph node involvement, and absence of concurrent chemotherapy. Conclusion These data indicate that TMB is a potential prognostic factor for worse survival in patients with cervical cancer treated with definitive radiotherapy, thereby providing a rationale for treatment of TMB-high cervical cancers with a combination of ICIs plus radiotherapy. Secondary abstract This retrospective study of 98 patients demonstrates for the first time that tumor mutational burden (TMB) is an independent prognostic factor for worse overall survival of patients treated with definitive radiotherapy, providing a rationale for treatment of TMB-high cervical cancers with a combination of immune-checkpoint inhibitors plus radiotherapy.

PURPOSE Growing evidence proved the efficacy of multi-parametric MRI (mpMRI) and prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-guided targeted biopsy (TB) in prostate cancer (PCa) diagnosis, but there is no direct comparison between mpMRI-TB and PSMA PET/CT-TB. Gastrin-releasing peptide receptor (GRPR) is highly expressed in PCa, which can compensate for the unstable expression of PSMA in PCa. Therefore, we designed a study to compare the efficiency of mpMRI-TB, dual-tracer (GRPR and PSMA) PET/CT-TB, systematic biopsy, and combined biopsy for the diagnosis of prostate cancer. METHODS One hundred twelve suspicious PCa patients were enrolled from September 2020 to June 2021. Patients with anyone of positive dual-tracer PET/CT or mpMRI underwent TB, and all enrolled patients underwent systematic biopsy (SB) after TB. The primary outcome was the detection rates of PCa in different biopsy strategies. Secondary outcomes were the performance of three imaging methods, omission diagnostic rates, and upgrading and downgrading of biopsy samples relative to those of prostatectomy specimens in different biopsy strategies. McNemar's tests and Bonferroni correction in multiple comparisons were used to compare the primary and secondary outcomes. RESULTS In 112 men, clinically significant PCa (grade group[GG] ≥ 2) accounted for 34.82% (39/112), and nonclinically significant PCa (GG = 1) accounted for 4.46% (5/112). 68 Ga-PSMA PET/CT-TB achieved higher PCa detection rate (69.77%) and positive ratio of biopsy cores (0.44) compared with SB (39.29% and 0.12) and mpMRI-TB (36.14% and 0.23), respectively (P

Purpose PI3K/AKT pathway alterations are frequent in hormone receptor-positive (HR+) breast cancers. IPATunity130 Cohort B investigated ipatasertib–paclitaxel in PI3K pathway-mutant HR+ unresectable locally advanced/metastatic breast cancer (aBC). Methods Cohort B of the randomized, double-blind, placebo-controlled, phase 3 IPATunity130 trial enrolled patients with HR+ HER2-negative PIK3CA/AKT1/PTEN-altered measurable aBC who were considered inappropriate for endocrine-based therapy (demonstrated insensitivity to endocrine therapy or visceral crisis) and were candidates for taxane monotherapy. Patients with prior chemotherapy for aBC or relapse 2, days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). Results Overall, 146 patients were randomized to ipatasertib–paclitaxel and 76 to placebo–paclitaxel. In both arms, median investigator-assessed PFS was 9.3 months (hazard ratio, 1.00, 95% CI 0.71–1.40) and the objective response rate was 47%. Median paclitaxel duration was 6.9 versus 8.8 months in the ipatasertib–paclitaxel versus placebo–paclitaxel arms, respectively; median ipatasertib/placebo duration was 8.0 versus 9.1 months, respectively. The most common grade ≥ 3 adverse events were diarrhea (12% with ipatasertib–paclitaxel vs 1% with placebo–paclitaxel), neutrophil count decreased (9% vs 7%), neutropenia (8% vs 9%), peripheral neuropathy (7% vs 3%), peripheral sensory neuropathy (3% vs 5%) and hypertension (1% vs 5%). Conclusion Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered HR+ HER2-negative aBC. The ipatasertib–paclitaxel safety profile was consistent with each agent’s known adverse effects. Trial registration NCT03337724.

Whether surgical revascularization can prevent recurrent hemorrhage in hemorrhagic moyamoya disease (HMD) patients remains a matter of debate. This study mainly aims at the comparison of treatment effect between surgical revascularization and conservative treatment of adult HMD patients. We retrospectively enrolled 322 adult HMD patients, including 133 in revascularization group and 189 in conservative group. The revascularization group included patients who underwent combined (n = 97) or indirect revascularization alone (n = 36). Ninety-two and forty-one patients underwent unilateral and bilateral revascularization respectively. The modified Rankin scale (mRS) was used to assess the functional status. The comparison was made based on initial treatment paradigm among two categories: (1) revascularization vs. conservative, (2) unilateral vs. bilateral revascularization. The rebleeding rate was significantly lower in revascularization group than that in conservative group (14.3% vs. 27.0%, P = 0.007). As for the functional outcomes, the average mRS was significantly better in revascularization group (1.7 ± 1.5) than that in conservative group (2.8 ± 1.9) (P

INTRODUCTION Large tumors may prove unsuitable for surgical cure or other local therapies due to their size, involvement of critical structures, prior non-ablative treatment failure, or coexisting disease burden. This study was performed to assess the safety and feasibility of percutaneous cryoablation for treatment of large tumors exceeding 6 cm in size, and to highlight the key technical considerations inherent to such cases. MATERIALS AND METHODS This single-institution retrospective study identified 77 patients (42 male, 35 female; median age 55 years) who underwent 96 cryoablation procedures for treatment of 78 tumors (mean diameter 9.8 ± 3.6 cm) from 2008 through 2020. Technical success, procedure-related complications, mortality, oncologic outcomes, and procedural logistics were evaluated. Technical success was defined as ice ball extension at least 5 mm beyond the tumor margins. RESULTS Intentional subtotal ablations were performed in 32% of cases due to tumor encroachment on vulnerable structures or as part of staged/combined therapies. Of the 68% of cases that were planned for complete ablation, the technical success rate was 100%. Major complications occurred after 19/96 (20%) procedures, with hemorrhage and acute kidney injury each occurring in 6/96 (6%). Post-procedural myositis occurred in 24/96 (25%) cases and was not considered a major complication in the absence of acute kidney injury. Local recurrence occurred in 2/23 (8.7%) of patients undergoing ablation for cure or local control at a median follow-up duration of 13 months. CONCLUSION Percutaneous cryoablation may be used to treat large (> 6 cm) tumors with a high degree of technical success and an acceptable safety profile.

BACKGROUND Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) is widely used in patients with gastric outlet obstruction (GOO). Recurrence of obstruction symptoms caused by stent migration is the major reason for reintervention in EUS-GE. To solve this problem, we proposed developing a double anchor lock (DAL) fixing stent method for EUS-GE. The safety and efficacy of the DAL fixing stent method were evaluated in this study. METHODS Sixteen Bama miniature pigs were randomly divided into an experimental group (n = 8) and a control group (n = 8). A gastric outlet obstruction model was established for all the pigs. The experimental group was treated with the DAL fixing stent method for EUS-GE, while the control group was treated with EUS-GE. Three-month stent migration rate, remission rate of GOO, re-occlusion intervention rate, weight change, and incidence of procedure-related complications of EUS-GE were analyzed and estimated in the two groups. RESULTS EUS-GE was successfully completed in every subject in both groups. Symptoms of digestive tract obstruction can be relieved in all animals. The stent existence rate in the 3 months was higher in the experimental group than in the control group (87.5% vs. 12.5%, P = 0.012). Except for one animal in the experimental group in which there was pneumoperitoneum due to a stent insertion failure, no animal experienced bleeding or perforation. CONCLUSION The DAL fixing stent method, which can effectively prevent stent migration, is safe and simple. EUS-GE can effectively relieve the symptoms of digestive tract obstruction.

Acute coronary syndrome (ACS) may lead to adverse remodelling and impaired cardiac function. Limited data exists on the effect of culprit coronary artery lesion site and impact on longitudinal cardiac remodelling. The present study included a total of 299 patients suffering from ACS treated with percutaneous coronary intervention (PCI). All patients had two echocardiographic examinations. The first echocardiography was median 2(IQR: 1;3) days following PCI, while the follow-up echocardiography (FUE) was median 257(IQR: 96;942) days following the first. Patients were grouped based on coronary artery PCI location; left anterior descending artery (LAD), right coronary artery (RCA) or circumflex artery (Cx). Patients with multiple lesions were excluded. Mean age was 63 ± 11 years and 77% were male. At FUE, mean left ventricular ejection fraction was 42 ± 9% and global longitudinal strain (GLS) was - 13 ± 4%. PCI treatment was allocated as 168 LAD lesions, 95 RCA lesions, and 36 Cx lesions. Linear regression analysis showed that patients with a LAD lesion displayed worsening in E/A (mean ∆ = 0.05, β = - 0.196, p = 0.001) and a larger increase in LVEDV (mean ∆ = 33.18 mL, β = 0.135, p = 0.012). Meanwhile patients with Cx lesion were significantly associated with a larger decrease in E/e' (mean ∆ = 2.6, β = - 0.120, p = 0.028). Patients with Cx lesion were observed to have elevated E/e' at baseline, which normalized at FUE. The present study suggests that culprit coronary artery lesion has a differential impact on myocardial remodelling. This information may potentially aid in understanding the pathophysiological differences in cardiac structure and function amongst patients with ACS.

BACKGROUND Pancreaticoduodenectomy (PD) remains the cornerstone of managing pancreatic ductal adenocarcinoma (PDAC) of the pancreas head/neck, but it is associated with high morbidity. We hypothesize that, in absence of pancreatectomy-specific morbidity (PSM), minimally invasive PD (MIPD) provides improved short-term outcomes compared to open PD (OPD). METHODS NSQIP pancreatectomy-targeted database 2014-2019 was utilized. PSM was defined as the occurrence of delayed gastric emptying (DGE) and/or post-operative pancreatic fistula (POPF). The cohort was divided into No-PSM and PSM groups. Propensity score match was applied in each group to compare outcomes of MIPD vs. OPD. RESULTS 8,121 patients were selected. Patients were divided into No-PSM (N = 6267) and PSM (N = 1854) groups. In No-PSM group, we matched 1656 OPD to 552 MIPD patients. MIPD had longer operations (423 vs. 359 min; p

During the COVID-19 pandemic lasting now for well more than a year, nearly 247 million cases have been diagnosed and over 5 million deaths have been recorded worldwide as of November 2021. The devastating effects of the SARS-CoV-2 virus on the immune system lead to the activation of signaling pathways involved in inflammation and the production of inflammatory cytokines. SARS-CoV-2 displays a great deal of homology with other coronaviruses, especially SARS-CoV and MERS-CoV which all display similar components which may serve as targets, namely the Spike (S) protein, the main protease (MPro) which is a chymotrypsin-like protease (CLPro) and RNA-directed RNA polymerase (RdRp). Natural constituents found in traditional herbal medicines, dietary supplements and foods demonstrate activity against SARS-CoV-2 by affecting the production of cytokines, modulating cell signaling pathways related to inflammation and even by direct interaction with targets found in the virus. This has been demonstrated by the application of fluorescence resonance energy transfer (FRET) experiments, assays of cytopathic effect (CPE) and in silico molecular docking studies that estimate binding strength. Glycyrrhizin, flavonoids such as quercetin, kaempferol and baicalein, and other polyphenols are the most common constituents found in Traditional Chinese Medicines that modulate inflammation and cell signaling pathways, and bind viral targets demonstrating valuable effects against SARS-CoV-2. However, the bioavailability of these natural products and their dependence on each other in extracts make it difficult to assess their actual utility in the treatment of COVID-19. Therefore, more can be learned through rational drug design based on natural products and from well-designed clinical trials employing specific doses of standardized combinations.

Purpose There is an ongoing debate whether vegetarian (VG) and especially vegan (VN) diets are nutritionally adequate in early childhood. Hence, the Vegetarian and Vegan Children Study (VeChi Diet Study) aimed to assess the food and nutrient intake of VG and VN infants. Methods The study examined the diets of 1–3-year-old VG, VN, and omnivorous (OM) children (n = 430). Dietary intake was assessed via a 3-day weighed dietary record and compared between groups using ANCOVA. Lifestyle data were collected using a questionnaire. Here, the results of micronutrient and fatty acid intakes are presented. Results Most nutrient intakes (with and without supplements) differed significantly between VN children and the two other groups, with a more favourable overall micronutrient intake in VN, followed by VG children, [e.g., the highest intake of vitamin E (8.3 mg/d vs. VG 7.4 mg/d and OM 5.1 mg/d), vitamin B1 (569 µg/d vs. VG 513 µg/d and OM 481 µg/d), folate (143 µg/d vs. VG 116 µg/d and OM 108 µg/d), magnesium (241 mg/d vs. VG 188 mg/d and OM 164 mg/d), and iron (8.9 mg/d vs. VG 7.3 mg/d and OM 6.0 mg/d)] as well as fat quality [highest intake of polyunsaturated fatty acids (8.7 E% vs. VG 6.9 E% and OM 4.5 E%) and lowest intake of saturated fatty acids (9.1 E% vs. VG 11.9 E% and OM 14.0 E%)]. In contrast, OM children had the highest intake of vitamin B2 (639 µg/d vs. VG 461 µg/d and VN 429 µg/d), calcium (445 mg/d vs. VG 399 mg/d and VN 320 mg/d), iodine (47 µg/d vs. VG 33 µg/d and VN 31 µg/d), and DHA (35.4 mg/d vs. VG 16.6 mg/d and VN 18.4 mg/d). Without supplementation, OM children had the highest average vitamin B12 intake (1.5 µg/d vs. VG 0.6 µg/d and VN 0.2 µg/d), whereas VN children had the highest average vitamin B12 intake with supplementation (73.8 µg/d vs. VG 1.3 µg/d and OM 1.7 µg/d). Without supplementation, none of the groups’ median intakes met the harmonised Average Requirement (h-AR) for vitamin D and iodine. Moreover, VG and VN children did not achieve h-ARs for vitamin B2, vitamin B12, and iron—if a low absorption of iron is anticipated; VN children also did not do so for calcium. Conclusion In early childhood, VN and VG diets can provide most micronutrients in desirable amounts and a preferable fat quality compared to an OM diet. Special focus should be paid to (potentially) critical nutrients, particularly vitamin D, iodine, and DHA for all children regardless of diet, as well as vitamin B2, vitamin B12, calcium, and iron for VG and VN children. Trail registration This study was registered with the German Clinical Trials Register (DRKS00010982) on (September 2, 2016).

Steroids are critical for various physiological processes and used to treat inflammatory conditions. Steroids act by two distinct pathways. The genomic pathway is initiated by the steroid binding to nuclear receptors while the non-genomic pathway involves plasma membrane receptors. It has been proposed that steroids might also act in a more indirect mechanism by altering biophysical properties of membranes. Yet, little is known about the effect of steroids on membranes, and steroid-membrane interactions are complex and challenging to characterise. The focus of this review is to outline what is currently known about the interactions of steroids with phospholipid bilayers and illustrate the complexity of these systems using cortisone and progesterone as the main examples. The combined findings from current work demonstrate that the hydrophobicity and planarity of the steroid core does not provide a consensus for steroid-membrane interactions. Even small differences in the substituents on the steroid core can result in significant changes in steroid-membrane interactions. Furthermore, steroid-induced changes in phospholipid bilayer properties are often dependent on steroid concentration and lipid composition. This complexity means that currently there is insufficient information to establish a reliable structure–activity relationship to describe the effect of steroids on membrane properties. Future work should address the challenge of connecting the findings from studying the effect of steroids on phospholipid bilayers to cell membranes. Insights from steroid-membrane interactions will benefit our understanding of normal physiology and assist drug development.

BACKGROUND: Non-vestibular schwannomas are relatively rare, with trigeminal and jugular foramen schwannomas being the most common. This is a heterogenous group which requires detailed investigation and careful consideration to management strategy. The optimal management for these tumours remains unclear, and there are several controversies. The aim of this paper is to provide insight into the main principles defining management and surgical strategy, in order to formulate a series of recommendations. METHODS: A task force was created by the EANS skull base section committee along with its members and other renowned experts in the field to generate recommendations for the surgical management of these tumours on a European perspective. To achieve this, the task force performed an extensive systematic review in this field and had discussions within the group. This article is the third of a three-part series describing non-vestibular schwannomas (IX, X, XI, XII). RESULTS: A summary of literature evidence was proposed after discussion within the EANS skull base section. The constituted task force dealt with the practice patterns that exist with respect to preoperative radiological investigations, ophthalmological assessments, optimal surgical and radiotherapy strategies and follow-up management. CONCLUSION: This article represents the consensually derived opinion of the task force with respect to the treatment of non-vestibular schwannomas. For each of these tumours, the management paradigm is shifting towards the compromise between function preservation and progression free survival.

PURPOSE: To identify the genetic causes of multiple morphological anomalies of the flagella (MMAF) and oligoasthenoteratozoospermia (OAT). METHODS: Whole-exome sequencing (WES) was performed on the proband to identify pathogenic mutation for infertility. Western blotting and immunofluorescence analysis detected the expression level and localization of adenylate kinase 7 (AK7). RESULTS: We identified a novel homozygous missense mutation (NM_152327: c.1846G > A; p.E616K) in AK7 in two brothers with MMAF and OAT from a consanguineous family by WES. Western blotting and immunofluorescence experiments determined that the expression level of AK7 decreased in the sperm from the proband. The proband and his wife underwent two cycles of intracytoplasmic sperm injection (ICSI) treatment but got unfavorable outcomes. CONCLUSION: This study could provide precise genetic diagnosis for the patient and expand the spectrum of AK7 mutations.

Children with heart disease often experience symptoms and medically intense end-of-life care. Our study explored bereaved parents' perceptions of a "good death" via a mail survey to 128 parents of children with heart disease who died in two centers. Parental perceptions of end-of-life circumstances were assessed by closed-ended questions including level of agreement with the question: "would you say your child experienced a good death?" and open-ended comments were contributed. Medical therapies at end-of-life and mode of death were retrieved through chart review. Of 50 responding parents, 44 (response rate: 34%) responded to the "good death" question; 16 (36%) agreed strongly, 15 (34%) agreed somewhat, and 30% disagreed (somewhat: 7, 16%; strongly: 6, 14%). Half the children were on mechanical support and 84% intubated at death. Of children with cardiopulmonary resuscitation (CPR) at end-of-life, 71% of parents disagreed with the "good death" question compared with 22% of parents whose child died following discontinuation of life-sustaining therapy or comfort measures (OR 9.1, 95% CI 1.3, 48.9, p