High Responder Groups Research Articles

Acute vasoreactivity testing for severe pulmonary hypertension associated with lung disease

Abstract Background Pulmonary hypertension results in clinical deterioration and increases mortality risk in patients with lung disease (LD), including chronic obstructive pulmonary disease, interstitial lung disease and combined pulmonary fibrosis and emphysema. Though acute vasoreactivity testing predicts long term-survival of patients with pulmonary arterial hypertension (PAH), its clinical impact for patients with pulmonary hypertension associated with LD (LD-PH) remains unknown. Purpose The purpose of this study is to clarify the clinical impact of acute vasoreactivity testing using inhaled nitric oxide for severe LD-PH. Methods We retrospectively reviewed 65 consecutive patients with LD-PH between January 2014 and December 2022; 48 patients (73 [68–78] years; males, 81%; median follow-up period 23 [7–35] months) with severe pulmonary hypertension who underwent acute vasoreactivity testing were included. We divided the patients based on a median pulmonary vascular resistance (PVR) response (−15%) in acute vasoreactivity testing into the high-responder (PVR response ≦−15%) and the low-responder (PVR response >−15%) groups. Results Acute vasoreactivity testing significantly decreased mean pulmonary arterial pressure (mPAP) (from 41 [34–48] to 36 [31–40] mmHg, P<0.01) and PVR (from 10.7 [8.3–13.8] to 8.9 [6.6–11.4] Wood units, P<0.01). The high-responder group had better long-term survival than the low-responder group (P = 0.03). Univariate Cox regression analysis showed that the prognostic factors for better survival included younger age, high-responder to acute vasoreactivity testing, and PAH-specific therapy (P <0.01, 0.04, 0.03, respectively). There were correlations between the PVR response at acute vasoreactivity testing and improvement in mPAP (R=0.40, P=0.03) or PVR (R = 0.47, P <0.01) with PAH-specific therapy. Conclusions PVR response at acute vasoreactivity testing was associated with better long-term survival and haemodynamic improvement with PAH-specific therapy. Acute vasoreactivity testing may be useful to predict the responders to PAH-specific therapy and long-term survival in patients with severe LD-PH.

Combinatorial Genomic Biomarkers Associated with High Response in IgE-Dependent Degranulation in Human Mast Cells.

Mast cells are the major effector cells that mediate IgE-dependent allergic reactions. We sought to use integrated network analysis to identify genomic biomarkers associated with high response in IgE-mediated activation of primary human mast cells. Primary human mast cell cultures derived from 262 normal donors were categorized into High, Average and Low responder groups according to their activation response profiles. Transcriptome analysis was used to identify genes that were differentially expressed in different responder cultures in their baseline conditions, and the data were analyzed by constructing a personalized perturbed profile (PEEP). For upregulated genes, the construction of PEEP for each individual sample of all three responder groups revealed that High responders exhibited a higher percentage of "perturbed" samples whose PEEP values lay outside the normal range of expression. Moreover, the integration of PEEP of four selected upregulated genes into distinct sets of combinatorial profiles demonstrated that the specific pattern of upregulated expression of these four genes, in a tandem combination, was observed exclusively among the High responders. In conclusion, this combinatorial approach was useful in identifying a set of genomic biomarkers that are associated with high degranulation response in human mast cell cultures derived from the blood of a cohort of normal donors.

Serum IgG Immunoglobulin Levels are Associated with Reduced PCR Detection of Mycoplasma bovis in Naturally Infected American Bison (Bison bison).

Mycoplasma bovis (M. bovis) is an important pathogen of American bison (Bison bison), associated with high morbidity and mortality epizootics of respiratory and reproductive disease. Despite the significant negative impact on bison health, little is known about the kinetics of disease and the host immune response to infection. To address these questions, a cohort of bison calves was created and serially sampled 5 times, once every 2-3 mo, over a 12-mo period. At each sampling period nasal swab samples were collected and tested by PCR for the presence of M. bovis. Serum samples were also collected and assessed for M. bovis-specific antibodies using both a commercial and an in-house ELISA. Overall, 19/41 bison (46.3%) had positive PCR tests, and 31/41 (75.6%) were seropositive. Over the course of the study, the frequency of PCR-positive nasal swabs and the ELISA scores decreased, although serum samples remained positive for at least 6 mo following the final positive PCR test. Bison were grouped according to results from the in-house ELISA into high-responder (n=7), low-responder (n=5), and seronegative (n=7) groups. M. bovis-specific IgG antibody levels were significantly elevated in the high-responder group compared to the low-responder and seronegative groups. The differences were statistically significant for 3/5 sampling periods. A trend toward increased IgG2 levels was observed in the high-responder group. High total IgG responses correlated with a decline in positive PCR tests from nasal swabs. These data provide evidence that a strong humoral response is beneficial and is probably involved in the clearance of M. bovis from bison.

Effect of Periodontal Treatment on Reducing Chronic Inflammation in Systemically Healthy Patients With Periodontal Disease

BackgroundWe determined the effects and an accurate marker of periodontal treatment on serum interleukin (IL)-6 and high-sensitivity C-reactive protein (HsCRP) levels in systemically healthy individuals with periodontal disease. MethodsThis multicenter study included systemically healthy individuals with periodontal disease who received initial periodontal treatment and had no periodontal treatment history. Periodontal parameters, including periodontal inflamed surface area, masticatory efficiency, and periodontal disease classification; serum IL-6 and HsCRP levels; and serum immunoglobulin (Ig)G titers against periodontal pathogens were evaluated at baseline and after treatment. Subjects were classified as low or high responders (group) based on periodontal inflamed surface area changes. ResultsThere were 153 participants. Only periodontal inflamed surface area changes were markedly different between low and high responders. Periodontal treatment (time point) decreased both serum IL-6 and HsCRP levels. The interaction between group and time point was remarkable only for serum IL-6 levels. Changes in serum immunoglobulin (Ig)G titers against periodontal pathogens were not associated with IL-6 changes in high responders. We analyzed the indirect effect of serum anti-Porphyromonas gingivalis type 2 IgG titer changes using mediation analysis and found no significance. However, the direct effect of group (low or high responder) on IL-6 changes was considerable. ConclusionsPeriodontal treatment effectively decreased serum IL-6 levels, independent of periodontal pathogen infection, in systemically healthy individuals with periodontal disease.

Does the decrease in E2 levels between the trigger of ovulation and embryo transfer affect the reproductive outcome in IVF-ICSI cycles?

This study aimed to evaluate the effect of the rate of decline in serum estradiol (E2) levels between hCG injection and the day of embryo transfer (ET) on the success of assisted reproductive technology (ART) in women with infertility of different etiologies. Women 20-45 years of age who underwent a standard GnRH antagonist or long agonist protocol and fresh ET during day 3 of their first ART cycle were included. Group 1 was diagnosed with low ovarian reserve, group 2 comprised high ovarian responders, and group 3 consisted of normal responders. Both groups were divided into four subgroups according to the decrease in E2 levels between the day of hCG injection and the day of ET. Subgroup A patients had a decrease of <20%, subgroup B a decrease of 20-40%, subgroup C a decrease of 41-60%, and subgroup D a decrease >60%. The primary outcome measure was the effect of an E2 decline, based on the measurement of E2 on the day of hCG administration and day of ET, on the implantation rate. The secondary outcome was the change in E2 values in these three groups. The study was conducted on 1.928 women. Of these, 639 were poor responders (group 1), 502 were high responders (group 2), and 787 women had a normal ovarian response (group 3). Patients with a 60% decrease in their E2 levels on the ET day after hCG had a lower live birth rate (LBR) and higher miscarriage rate (MCR), except normoresponders, in whom a similar decline was significant only with respect to MCR. We indicate that high ovarian responders who underwent fresh ET cycles with a 60% decrease in their E2 levels on the ET day after human chorionic gonadotropin had lower LBRs and higher miscarriage. However, in normoresponder women, this decline was only significant in miscarriage.

Predicting responses to cognitive behavioral therapy in obsessive-compulsive disorder based on multilevel indices of rs-fMRI

ObjectiveThis study aimed to identify neuroimaging predictors to predict the response of cognitive behavioral therapy (CBT) in patients with obsessive-compulsive disorder (OCD) based on indices of resting-state functional magnetic resonance imaging (rs-fMRI). MethodsFifty patients with OCD were enrolled and allocated to either high or low responder groups after CBT using a 50 % response rate as the delineator. The pre-treatment amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo), and degree centrality (DC) in each cerebrum region, defined by automated anatomical labeling atlas, were extracted. Least absolute shrinkage and selection operator and logistic regression were used to select features and establish models. ResultsThe combination of multilevel rs-fMRI indices achieved the best performance, with a cross-validation area under the receiver operating characteristic curve (AUC) of 0.900. In this combined model, an increase of interquartile range (IQR) in fALFF of right inferior orbital frontal gyrus (IOFG), and ReHo of left hippocampus and superior occipital gyrus (SOG) corresponded to a 26.52 %, 38.67 % and 24.38 % increase in the possibility to be high responders of CBT, respectively. ALFF of left thalamus and ReHo of left putamen were negatively associated with the response to CBT, with a 14.30 % and 19.91 % decrease per IQR increase of the index value. ConclusionThe combination of ALFF, fALFF and ReHo achieved a better predictive performance than separate index. Pre-treatment ALFF of the left thalamus, fALFF of the right IOFG, ReHo of the left hippocampus, SOG and putamen can be used as predictors of CBT response.

Intravenous immunoglobulin therapy in children with severe atopic dermatitis.

Children with severe atopic dermatitis (AD) can benefit from intravenous immunoglobulin (IVIG) therapy. This study aimed to identify the efficacy and safety of IVIG therapy in children with severe AD. Twenty pediatric AD patients were enrolled in this study. Patients with an Investigator's Global Assessment score of 0 or 1 or a reduction of 2 points after treatment were defined as high-responders (HRs), otherwise, they were defined as low-responders (LRs). Twelve patients (60%) achieved an excellent treatment response after 2months, while eight (40%) had a low response. The Scoring Atopic Dermatitis index had improved significantly at 2months post-treatment compared with baseline (p < 0.001). Baseline total serum IgE levels and eosinophil counts were elevated in all subjects and decreased significantly at 2months post-treatment (p=0.004 and 0.021, respectively). Baseline IgE levels were significantly higher in the HR group compared with the LR group (p=0.020). The treatment was well tolerated. Fever was the most common adverse event and occurred in five patients (25%). In conclusion, IVIG could be a safe and effective therapy for children with severe AD and may be more effective in patients with higher IgE levels. Further studies are needed to investigate the different therapeutic responses in patients with different AD phenotypes.

Antibody and T-Cell Subsets Analysis Unveils an Immune Profile Heterogeneity Mediating Long-term Responses in Individuals Vaccinated Against SARS-CoV-2.

Based on the fact that coronavirus disease 2019 (COVID-19) is still spreading despite worldwide vaccine administration, there is an imperative need to understand the underlying mechanisms of vaccine-induced interindividual immune response variations. We compared humoral and cellular immune responses in 127 individuals vaccinated with either BNT162b2, mRNA-1273, or ChAdOx1-nCoV-19 vaccine. Both mRNA vaccines induced faster and stronger humoral responses as assessed by high spike- and RBD-specific antibody titers and neutralizing efficacy in comparison to ChAdOx1-nCoV-19 vaccine. At 7 months postvaccination, a decreasing trend in humoral responses was observed, irrespective of the vaccine administered. Correlation analysis between anti-S1 IgG and interferon- (IFN-) production unveiled a heterogeneous immune profile among BNT162b2-vaccinated individuals. Specifically, vaccination in the high-responder group induced sizable populations of polyfunctional memory CD4 helper T cells (TH1), follicular helper T cells (TFH), and T cells with features of stemness (TSCM), along with high neutralizing antibody production that persisted up to 7 months. In contrast, low responders were characterized by significantly lower antibody titers and memory T cells and a considerably lower capacity for interleukin-2 and IFN- production. We identified that long-term humoral responses correlate with the individuals ability to produce antigen-specific persistent memory T-cell populations.

Role of FSHR gene (rs6165) polymorphism in ovarian stimulation by exogenous FSH of Iraqi infertile women

Background: Exogenous FSH has been dispensed to induce follicular growth both when monofollicular development was required and when multifollicular growth was desired to generate multiple mature oocytes. Methods: 210 infertile women and 50 healthy women aged less than 34 years were recruited in present study, the infertile women were separated to three groups based on treatment response (poor ,moderate and high ) responder groups. Results: The outcomes indicated that poor responder group displayed higher levels of FSH and LH also lower levels of AMH,E2,AFC. Conclusion: Polymorphism of FSHR gene(rs6165) was linked to poor response to FSH treatment of Iraqi infertile women.

P-691 Assessment of ovarian vascularity by three-dimensional vaginal power Doppler on day seven of menstrual cycle to predict the number of eggs collected in antagonist cycle

Abstract Study question Could ovarian vascularity indices on day 2 and 7 of stimulation, measured by 3-dimensional (3D) vaginal power Doppler, predict after controlled ovarian stimulation? Summary answer Ovarian vascularity index (VI) on day 7 may be an indicator of poor (&amp;lt;three mature eggs collected) ovarian responses to gonadotropins. What is known already Poor and/or hyper ovarian responses to gonadotropins may be related to cycle cancellation during controlled ovarian stimulation (COS). In this context, gonadotropin dose is often individualized using patient features that predict ovarian response (such as age, antral follicular count (AFC) and anti-Müllerian hormone (AMH)). In parallel, ovarian vascularity color doppler is a valuable evaluation method to predict the ovarian hyperstimulation syndrome and the growth/maturity of Graafian follicles. The aim of the present study is to estimate the utility of 3-dimensional vaginal power Doppler and ovarian vascular flow indices in the prediction of the number of mature occytes collected after COS. Study design, size, duration A prospective study was conducted on 296 couples undergoing intracytoplasmic sperm injection cycle at Al Hadi Laboratory and Medical center, Beirut, Lebanon. It was performed between January 2020 and dec 2021. Couples were categorized into poor responders group (3 or less metaphase II (MII) eggs collected) (36.1%), high responders group (16 or more MII eggs collected) group ( 6.7%), and normal responders group (more than 3 and less than 16 MII eggs collected) (57,2%). Participants/materials, setting, methods On the second and seventh day of the menstrual cycle, ovarian volume and vascularity parameters (vascularity index (VI), flow index (FI), and vascularity flow index (VFI)) were measured using the 3D power Doppler and the Virtual Organ Computer-Aided Analysis. On day 2 , the antral follicle count was evaluated and a blood sample for AMH testing was collected. Women included in the study have undergone COS using GnRH antagonist protocol. Main results and the role of chance Mean age was 35,88+/- 6 year , day2 VI and day2 VFI correlates with the number of egg collected (p = 0.014 and 0.045 respectively). 9 parameters were used to predict poor and high ovarian responses (Age, AMH, AFC, day2 VI, day2 FI , day2 VFI , day7 VI, day7 FI and day7 VFI) in a Receiver operator characteristics (ROC) curve model . Ovarian day7 FI significantly predicted poor ovarian response to gonadotropins (p = 0.038) with an area under the curve of 0.679. AFC predicted also poor ovarian response to gonadotropins (p = 0.006) . In parallel, AFC significantly predicted high ovarian response to gonadotropins (p = 0.002) and AUC (0.778) while all other 3D doppler parameters couldn’t predict high responders. Limitations, reasons for caution It will be necessary to perform a prospective analysis on a broad sample size to validate these findings. In addition, it will be interesting to assess the impact of ovarian vascularity on pregnancy outcomes. Wider implications of the findings Assessing ovarian vascularity during ovarian stimulation can help reduce the rate of cycle cancellation. In addition, more studies are welcomed in the field to unravel the mechanisms behind altered ovarian vascularity and to test the possibility of restoring normal ovarian physiology. Trial registration number Not Applicable

O-010 The One-and-Done Approach: does higher dosing of gonadotropins in predicted high and low responders increase the incidence of multiple live births from one ART-stimulation cycle?

Abstract Study question Does higher gonadotropin dosing in predicted high and low responders lead to a higher reproductive potential from one ART-cycle? Summary answer Higher gonadotropin dosing may double the incidence of more than one child birth from one ART-stimulation cycle in predicted high responders. What is known already Several studies have been conducted to address individualization of the gonadotropin starting dose, one of them being the OPTIMIST-trial. This trial investigated whether an individualized gonadotropin starting dose improved cumulative live birth rates (cLBR) and treatment safety. There was no difference in cLBR between the standard and adjusted starting dose groups, yet a statistically significant decrease in the occurrence of ovarian hyper-stimulation syndrome (OHSS) in predicted high responders. The discussion arose if the higher dosed patients that achieved a live birth (LB) could have had supernumerary useable frozen embryos left, potentially resulting in multiple live births from one stimulation cycle. Study design, size, duration Predicted high and low responders (based on AFC) that achieved a LB in the OPTIMIST trial were included. Predicted high responders received either the standard (150 IU) or a reduced dosage gonadotropins (100 IU). Predicted low responders received a higher dose (225/450 IU) or the standard gonadotropin dose (150 IU). All known subsequent frozen embryo transfers after the 1st LB were analyzed for the chance of a second live birth from the same stimulation cycle. Participants/materials, setting, methods 527 women had a LB in the OPTIMIST trial during the study period or thereafter from embryos obtained from the last stimulation cycle during the study period. Except for 23 women, data was collected regarding the return of these patients for a renewed child wish. Multiple imputation was performed (10 imputations, 20 iterations). Odds ratio (OR) with 95% confidence interval (CI) were calculated and adjusted for confounders if necessary. Main results and the role of chance Of the 504 women, 340 women had remaining frozen embryos. The incidence of at least two live births from one stimulation cycle was twice as high in the standard dosage arm (150 IU) of the predicted high responder group (21,5% versus 10,8%, OR 2.27 [95% CI, 1.19 – 4.31]. The incidence of at least two live births in the predicted low responder group did not differ (7,1% versus 6,2% for the higher versus the standard dosed group respectively, OR 1.04 [95% CI, 0.31 – 3.46]). After excluding 149 women with frozen embryos that did not return for their renewed child wish (resulting in a total of 355 women), the comparison showed that the incidence of at least two live births from one stimulation was 30.1% versus 15.0% for the 150 IU versus 100 IU high responder groups, OR 2.43 [95% CI, 1.25 - 4.74]. In the low responder group, 11,8% versus 9,0% had a second live birth in the 225/450 IU versus the 150 IU group (OR 1.60 [95% CI 0.43– 5.98]). More information on the number of embryos used for a second child and gonadotropin dose adjustments is currently obtained. Limitations, reasons for caution Not all women had returned for or used all their frozen embryos, which may lead to selection bias. The potential benefit of the one-and-done strategy needs to be balanced against higher safety risks and the clinical relevance should be interpreted with caution. Wider implications of the findings To date, no study investigated the total number of live births from one IVF/ICSI stimulation cycle in relation to the FSH dosage administered. These results stress the need for additional research to advice the clinician on choosing an appropriate starting dose which balances the reproductive potential and treatment safety risks. Trial registration number not applicable

Antiplatelet response to clopidogrel is associated with a haplotype in CYP2C19 gene in Pakistani patients

Clopidogrel, an antiplatelet drug, is frequently prescribed to patients diagnosed with ischemic diseases such as those suffering from acute coronary syndromes or ischemic stroke. Despite the drug being effective in majority of the patients, some still experience ischemic events early in the treatment which might be due to poor platelet inhibition. This study aims to investigate the association of cytochrome P450 2C19 (CYP2C19) loss-of-function polymorphisms, haplotypes as well as a wide range of clinical and demographic variables with platelet aggregation phenotypes to clopidogrel in a Pakistani cohort. The study comprised of a total of 120 patients diagnosed with cardiovascular diseases and were treated with clopidogrel. Antiplatelet response to clopidogrel was monitored by Helena AggRAM (HL-2-1785P) and patients with maximal platelet aggregation more than 50% were categorized as low responders and those with less than 50% as high responders. Our results show that 56.6% of patients were homozygous for the CYP2C19 wild-type allele, 38.3% of patients possessed one copy of the CYP2C19*2 allele and 5% of patients possessed both CYP2C19*2 alleles. No CYP2C19*3 allele was found in our patient cohort. There was no statistically significant difference between the high and low responder groups to clopidogrel in terms of extensive, intermediate and poor metabolizer genotypes. However, haplotype (H1), leukocyte count, random blood glucose, and history of diabetes mellitus was associated with the antiplatelet response to clopidogrel. The prevalence of clopidogrel resistance in our population was in line with that reported for other regional and global populations.

Circulating miRNAs in girls with abdominal obesity: miR-221-3p as a biomarker of response to weight loss interventions.

SummaryBackgroundRecent studies have associated several microRNAs (miRNAs) with childhood obesity and energy homeostasis, suggesting that an individual miRNA profile could be used as an early predictor to estimate the response to weight loss interventions in the design of precision nutrition.ObjectiveTo investigate associations between the expression of circulating adiposity‐related miRNAs and the response to a weight loss intervention.MethodsA total of 51 Spanish girls (age 7–16 years) with abdominal obesity underwent 8 weeks of a multidisciplinary intervention for weight loss. Participants were stratified into two groups in accordance with changes in body mass index (BMI) standard deviation score: low‐responders (LR) and high‐responders (HR). The expression of 39 circulating miRNAs (c‐miRNAs) was evaluated in plasma of all subjects before the intervention.ResultsSix miRNAs were differentially expressed between LR and HR. However, after adjustment for Tanner stage, the association was maintained only for miR‐126‐3p and miR‐221‐3p with a higher expression in HR group compared to LR group. After the intervention, miR‐221‐3p expression decreased in all subjects with a significant difference in the change within groups. However, changes in miR‐126‐3p levels were not significant. The expression of miR‐221‐3p was positively correlated with body weight, BMI and waist circumference, and negatively correlated with quantitative insulin sensitivity check index.ConclusionsBioinformatic analysis evidenced that miR‐221‐3p participates in several obesity‐related pathways, and more interestingly, this miRNA targets several candidate genes to childhood obesity according to DisGeNet database. Thus, miR‐221‐3p could be used for predicting the response to a multidisciplinary intervention for weight loss in young girls.

Abstract 13127: Concordance in Nutrient Biomarker and Cardiometabolic Risk Factors Between Child-Parent Dyads Participating in a Family-Based Childhood Weight Management Intervention

Introduction: Children are at elevated risk for developing obesity/cardiometabolic abnormalities when their parents have these conditions. Little is known about diet quality and subsequent impact on cardiometabolic risk factors (CMRFs) in child-parent dyads. Objective: To determine the concordance between nutrient biomarkers and CMRF changes in children (age 7-12 years; BMIz &gt;85%tile) and their parents, who participated in a 1-year randomized controlled trial designed to evaluate the effects of adding an enhanced program to standard care. Methods: Pre-post intervention changes in nutrient biomarkers (plasma carotenoids; RBC fatty acid profiles) and CMRFs (BMI, blood pressure, and plasma glucose, insulin, lipid profile, inflammatory markers and adipokine concentrations) were evaluated in 226 child-parent dyads. Based on percent change in children’s BMIz score, they were grouped into high ( &gt; -8%), medium (0 to -8%) and low ( &gt; 0%) responders. Spearman’s correlation coefficients were calculated to determine association between 1-year change in nutrient biomarkers and CMRFs within child-parent dyad groups. Results: There were positive associations in beta-carotene, and RBC SFA, MUFA, PUFA n-6, PUFA n-3 and trans fatty acid concentrations in child-parent dyads, regardless of group ( r= 0.25 to 0.83, p&lt;0.05). Significant positive child-parent associations were observed for systemic (TNFa, IL-1, IL-6) and vascular (E- and P-selectin, thrombomodulin) inflammatory markers (r= 0.32 to 0.83, p&lt;0.05), and adiponectin (r=0.47, p=0.001), but not other CMRFs. In the high responder group, there was a positive association between improvements in child’s BMIz scores and parental BMI (r=0.32, p=0.01). This dyad also had the most favorable improvements in nutrient biomarkers (increases in carotenoids, and decreases in SFA and trans fatty acids) and CMRFs (decreases in blood pressure, and LDL-C, TG and hsCRP concentrations). Conclusions: Our finding of concordance in child-parent dyad changes in nutrient biomarkers and selected CMRFs after a 1-year intervention, especially in the high responder group, suggests parallel dietary changes and highlights the importance of parental engagement in the effectiveness of childhood obesity interventions.

Investigation of oxidative stress status in cumulus cells in patıents with in vitro fertilization

The negative impact of oxidative stress on oocytes obtained from in vitro fertilization (IVF) patients is a challenge for the optimization of live birth rates. In this study, it is aimed to investigate whether oxidant/antioxidant parameters have a predictive value in terms of determining the count and quality of oocytes. Catalase (CAT), glutathione-S-transferase (GST), arylesterase (ARE) enzyme activities, and malondialdehyde (MDA) levels were analysed in cumulus cells of poor responder (n = 28, oocyte count ≤ 4), normo responder (n = 48, 5 ≤ oocyte count ≤ 14), and high responder (n = 26, oocyte count ≥ 15) patient groups continuing IVF treatment. The cumulus cell GST enzyme activity were statistically significantly increased in the high responders group compared to the poor responder and the normo responder’s groups (p < 0.001 and p = 0.002, respectively). The cumulus cell MDA levels were significantly decreased in the high responder group compared to the poor responder group (p = 0.008). The cumulus cell CAT (p = 0.175) and ARE (p = 0.124) enzyme activities were examined but no statistically significant difference found between the groups. The significant increase in GST enzyme activity and significant decrease in MDA levels in the high responder group indicate that oxidative stress has an effect oocyte status and quality.

P–688 Assessment of ovarian vascularity by three-dimensional vaginal power Doppler on day two of menstrual cycle to predict the number of mature eggs collected

Abstract Study question Could ovarian vascularity indices, measured by 3-dimensional (3D) vaginal power Doppler, predict the number of mature oocytes collected after controlled ovarian stimulation? Summary answer Ovarian vascularity index (VI) may be an indicator of poor (&amp;lt;three mature eggs collected) and high (&amp;gt;ten mature eggs collected) ovarian responses to gonadotropins. What is known already Poor and/or hyper ovarian responses to gonadotropins may be related to cycle cancellation during controlled ovarian stimulation (COS). In this context, gonadotropin dose is often individualized using patient features that predict ovarian response (such as age, antral follicular count (AFC) and anti-Müllerian hormone (AMH)). In parallel, ovarian vascularity color doppler is a valuable evaluation method to predict the ovarian hyperstimulation syndrome and the growth/maturity of Graafian follicles. The aim of the present study is to estimate the utility of 3-dimensional vaginal power Doppler and ovarian vascular flow indices in the prediction of the number of mature occytes collected after COS. Study design, size, duration A prospective study was conducted on 200 couples undergoing intracytoplasmic sperm injection cycle at Al Hadi Laboratory and Medical center, Beirut, Lebanon. It was performed between January 2020 and July 2020. Couples were categorized into poor responders group (3 or less metaphase II (MII) eggs collected) (n = 43), high responders group (10 or more MII eggs collected) group (n = 66), and normal responders group (more than 3 and less than 10 MII eggs collected) (n = 66). Participants/materials, setting, methods On the second day of the menstrual cycle, ovarian volume and vascularity parameters (vascularity index (VI), flow index (FI), and vascularity flow index (VFI)) were measured using the 3D power Doppler and the Virtual Organ Computer-Aided Analysis. On the same day, the antral follicle count was evaluated and a blood sample for AMH testing was collected. Women included in the study have undergone COS using GnRH antagonist protocol. Main results and the role of chance Receiver operator characteristics (ROC) curve model was used to predict the number of mature eggs collected. 7 parameters were used to predict poor and high ovarian responses (Age, AMH, AFC, ovarian volume, VI, FI and VFI). Ovarian VI significantly predicted poor ovarian response to gonadotropins (p = 0.033 and area under the curve (AUC)=0.668). Subsequently, the cut off value was 0.0025 with 84% sensitivity and 83.3% specificity. In parallel, ovarian VI significantly predicted high ovarian response to gonadotropins (p = 0.036 and AUC (0.778)) with a cut off value 0.0375 and with 77.8% sensitivity and 78.3% specificity. Furthermore, VFI significantly predicted high ovarian response to gonadotropins (p = 0.045; AUC=0.677). Limitations, reasons for caution It will be necessary to perform a prospective analysis on a broad sample size to validate these findings. In addition, it will be interesting to assess the impact of ovarian vascularity on pregnancy outcomes. Wider implications of the findings: Assessing ovarian vascularity prior to ovarian stimulation can help reduce the rate of cycle cancellation. In addition, more studies are welcomed in the field to unravel the mechanisms behind altered ovarian vascularity and to test the possibility of restoring normal ovarian physiology. Trial registration number Not applicable

Cannabidiol Modulates the Motivational and Anxiety-Like Effects of 3,4-Methylenedioxypyrovalerone (MDPV) in Mice.

3,4-Methylenedioxypyrovalerone (MDPV) is a new psychoactive substance (NPS) and the most widespread and life-threatening synthetic cathinone of the “bath salts”. Preclinical research has proven the cocaine-like psychostimulant effects of MDPV and its potential for abuse. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid that has emerged as a new potential treatment for drug addiction. Here, we tested the effects of CBD (20 mg/kg) on MDPV (2 mg/kg)-induced conditioned place preference and MDPV (0.05 and 0.075 mg/kg/infusion) self-administration paradigms. In addition, we assessed the effects of the co-administration of CBD and MDPV (3 and 4 mg/kg) on anxiety-like behaviour using the elevated plus maze (EPM). CBD mitigated the MDPV-induced conditioned place preference. On the contrary, CBD administration throughout the MDPV (0.075 mg/kg/infusion) self-administration increased drug-seeking and taking behaviours, but only in the high-responders group of mice. Furthermore, CBD exerted anxiolytic-like effects, exclusively in MDPV-treated mice. Taken together, our results indicate that CBD modulation of MDPV-induced motivational responses in mice varies depending on the requirements of the learning task, resulting in a complex response. Therefore, further research attempting to decipher the behavioural and molecular interactions between CBD and MDPV is needed.

Association between Venom Immunotherapy and Changes in Serum Protein-Peptide Patterns.

Venom immunotherapy (VIT) is administered to allergic patients to reduce the risk of dangerous systemic reactions following an insect sting. To better understand the mechanism of this treatment and its impact on the human organism, we analysed serum proteomic patterns obtained at five time-points from Hymenoptera-venom-allergic patients undergoing VIT. For statistical analyses, patients were additionally divided into two groups (high responders and low responders) according to serum sIgG4 levels. VIT was found to be associated with changes in seven proteins: the fibrinogen alpha chain, complement C4-A, complement C3, filamin-B, kininogen-1, myosin-9 and inter-alpha-trypsin inhibitor heavy chain H1. The number of discriminative m/z (mass-to-charge ratio) features increased up to the 90th day of VIT, which may be associated with the development of immunity after the administration of increased venom doses. It may also suggest that during VIT, there may occur processes involved not only in protein synthesis but also in protein degradation (caused by proteolytic venom components). The results are consistent with measured serum sIgG4 levels, which increased from 2.04 mgA/I at baseline to 7.25 mgA/I at 90 days. Moreover, the major proteomic changes were detected separately in the high responder group. This may suggest that changes in protein–peptide profiles reflect the actual response to VIT.

Serum IgG Profiling of Toddlers Reveals a Subgroup with Elevated Seropositive Antibodies to Viruses Correlating with Increased Vaccine and Autoantigen Responses.

PurposeThe human antibody repertoire forms in response to infections, the microbiome, vaccinations, and environmental exposures. The specificity of such antibody responses was compared among a cohort of toddlers to identify differences between seropositive versus seronegative responses.MethodsAn assessment of the serum IgM and IgG antibody reactivities in 197 toddlers of 1- and 2-years of age was performed with a microfluidic array containing 110 distinct antigens. Longitudinal profiling was done from years 1 to 2. Seropositivity to RNA and DNA viruses; bacteria; live attenuated, inactive, and subunit vaccines; and autoantigens was compared. A stratification was developed based on quantitative variations in the IgG responses. Clinical presentations and previously known genetic risk alleles for various immune system conditions were investigated in relation to IgG responses.ResultsIgG reactivities stratified toddlers into low, moderate, and high responder groups. The high group (17%) had elevated IgG responses to multiple RNA and DNA viruses (e.g., respiratory syncytial virus, Epstein-Barr virus, adenovirus, Coxsackievirus) and this correlated with increased responses to live attenuated viral vaccines and certain autoantigens. This high group was more likely to be associated with gestational diabetes and an older age. Genetic analyses identified polymorphisms in the IL2RB, TNFSF4, and INS genes in two high responder individuals that were associated with their elevated cytokine levels and clinical history of eczema and asthma.ConclusionSerum IgG profiling of toddlers reveals correlations between the magnitude of the antibody responses towards viruses, live attenuated vaccines, and certain autoantigens. A low responder group had much weaker responses overall, including against vaccines. The serum antibody screen also identifies individuals with IgG responses to less common infections (West Nile virus, parvovirus, tuberculosis). The characterization of the antibody responses in combination with the identification of genetic risk alleles provides an opportunity to identify children with increased risk of clinical disease.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10875-021-00993-w.

Individual characteristics associated with the magnitude of heat acclimation adaptations

PurposeThe magnitude of heat acclimation (HA) adaptations varies largely among individuals, but it remains unclear what factors influence this variability. This study compared individual characteristics related to fitness status and body dimensions of low-, medium-, and high responders to HA.MethodsTwenty-four participants (9 female, 15 male; maximum oxygen uptake [dot{{V}}O2peak,kg] 52 ± 9 mL kg−1 min−1) completed 10 daily controlled-hyperthermia HA sessions. Adaptations were evaluated by heat stress tests (HST; 35 min cycling 1.5 W kg−1; 33 °C, 65% relative humidity) pre- and post-HA. Low-, medium-, and high responder groups were determined based on tertiles (n = 8) of individual adaptations for resting rectal temperature (Tre), exercise-induced Tre rise (ΔTre), whole-body sweat rate (WBSR), and heart rate (HR).ResultsBody dimensions (p > 0.3) and dot{{V}}O2peak,kg (p > 0.052) did not differentiate low-, medium-, and high responders for resting Tre or ΔTre. High WBSR responders had a larger body mass and lower body surface area-to-mass ratio than low responders (83.0 ± 9.3 vs 67.5 ± 7.3 kg; 249 ± 12 vs 274 ± 15 cm2 kg−1, respectively; p < 0.005). Conversely, high HR responders had a smaller body mass than low responders (69.2 ± 6.8 vs 83.4 ± 9.4 kg; p = 0.02). dot{{V}}O2peak,kg did not differ among levels of responsiveness for WBSR and HR (p > 0.3).ConclusionIndividual body dimensions influenced the magnitude of sudomotor and cardiovascular adaptive responses, but did not differentiate Tre adaptations to HA. The influence of dot{{V}}O2peak,kg on the magnitude of adaptations was limited.