Low Sensitivity Group Research Articles

Pre-anesthetic brain network metrics as predictors of individual propofol sensitivity

Background and ObjectiveNumerous factors, including demographic characteristics, have been implicated in modulating individual sensitivity to propofol; however, substantial inter-individual differences persist even after accounting for these factors. This study thus aimed to explore whether pre-anesthesia brain functional network metrics correlate with an individual's sensitivity to propofol. MethodsA total of 54 subjects, including 30 patients and 24 healthy volunteers, were enrolled. Propofol was administered via a target-controlled infusion device, and anesthesia depth was monitored using a bispectral index monitor. Sensitivity to propofol was quantified using the induction time, measured from infusion onset to the bispectral index, which reached 60. Brain functional network metrics indicative of functional integration and segregation, centrality, and network resilience were computed from pre-anesthetic 60-channel EEG recordings. Linear regression analysis and machine learning predictive models were applied to evaluate the contribution of pre-anesthesia network metrics in predicting individual sensitivity to propofol. ResultsOur analysis results revealed that subjects could be categorized into high- or low-sensitivity groups based on their induction time. Individuals with low sensitivity exhibited a greater network degree, clustering coefficient, global efficiency, and betweenness centrality, along with reduced modularity and assortativity coefficient in the alpha band. Furthermore, alpha band network metrics were significantly correlated with individual induction time. Leveraging these network metrics as features enabled the classification of individuals into high- or low-sensitivity groups with an accuracy of 94%. ConclusionsUsing a clinically relevant endpoint that signifies the level of anesthesia suitable for surgical procedures, this study underscored the robust correlation between pre-anesthesia alpha-band network metrics and individual sensitivity to propofol in a cohort that included both patients and healthy volunteers. Our findings offer preliminary insights into the potential utility of pre-anesthetic brain status assessment to predict propofol sensitivity on an individual basis, which may help to develop a more accurate personalized anesthesia plan.

Relationship between texture perception and oral function: A preliminary study in young, healthy adults.

Oral frailty, characterised by reduced oral function, is associated with systemic health issues in older adults. Although the criteria for diminished oral function often focus on motor and secretory abilities, texture perception also plays a crucial role in health due to its impact on food intake and palatability. This study aimed to explore the relationship between thickness discrimination ability (TDA) and oral motor and secretory functions in healthy young individuals. Twenty-eight adults were assessed for texture perception using eight concentrations of aqueous xanthan gum solutions to determine TDA scores. Measurements of occlusal force, masticatory performance, tongue pressure, stimulated salivary flow rate and tongue-lip motor function were conducted. Spearman's correlation analysis was used to evaluate the relationship between TDA scores and oral functions. Participants were divided into high-sensitivity and low-sensitivity groups based on their TDA scores to compare oral function test results. The TDA scores varied among the participants, with higher scores correlating with higher masticatory performance (r = 0.41, p < .05). Masticatory performance in the high-sensitivity group was significantly higher than in the low-sensitivity group (211.9 ± 59.2 mg/dL vs. 157.9 ± 43.0 mg/dL, p = .013), with no significant differences in other oral functions. Masticatory performance was correlated with TDA, suggesting a link between the selection function of mastication and thickness discrimination. These findings highlight the potential relevance of texture perception in oral function and indicate the need for further exploration, particularly in older adults with declining oral health.

Prefrontal-Limbic Circuitry Is Associated With Reward Sensitivity in Nonhuman Primates

BackgroundAbnormal reward sensitivity is a risk factor for psychiatric disorders, including eating disorders such as overeating and binge-eating disorder, but the brain structural mechanisms that underlie it are not completely understood. Here, we sought to investigate the relationship between multimodal whole-brain structural features and reward sensitivity in nonhuman primates. MethodsReward sensitivity was evaluated through behavioral economic analysis in which monkeys (adult rhesus macaques; 7 female, 5 male) responded for sweetened condensed milk (10%, 30%, 56%), Gatorade, or water using an operant procedure in which the response requirement increased incrementally across sessions (i.e., fixed ratio 1, 3, 10). Animals were divided into high (n = 6) or low (n = 6) reward sensitivity groups based on essential value for 30% milk. Multimodal magnetic resonance imaging was used to measure gray matter volume and white matter microstructure. Brain structural features were compared between groups, and their correlations with reward sensitivity for various stimuli was investigated. ResultsAnimals in the high sensitivity group had greater dorsolateral prefrontal cortex, centromedial amygdaloid complex, and middle cingulate cortex volumes than animals in the low sensitivity group. Furthermore, compared with monkeys in the low sensitivity group, high sensitivity monkeys had lower fractional anisotropy in the left dorsal cingulate bundle connecting the centromedial amygdaloid complex and middle cingulate cortex to the dorsolateral prefrontal cortex, and in the left superior longitudinal fasciculus 1 connecting the middle cingulate cortex to the dorsolateral prefrontal cortex. ConclusionsThese results suggest that neuroanatomical variation in prefrontal-limbic circuitry is associated with reward sensitivity. These brain structural features may serve as predictive biomarkers for vulnerability to food-based and other reward-related disorders.

The relationship between noise sensitivity and the perception of floor impact noise

Noise sensitivity is a factor that determines how an individual perceives how uncomfortable a sound is, and noise sensitivity is believed to affect the annoyance response to floor impact noise in dwellings. In this study, we conducted a survey using the Weinstein Noise Sensitivity Scale given to subjects who participated in an evaluation of annoyance to floor impact noise and investigated the relationship with the results of the annoyance judgments. As with previous research, it is predicted that the reaction to annoyance to floor impact sound varies greatly depending on the listener’s noise sensitivity and that a reaction of “annoy” is more likely to occur in the high sensitivity group, while a “annoy” judgment is less likely to occur in the low sensitivity group.

Particle perception: Defining sensory thresholds for grittiness of upcycled apple pomace powders

Recent years have seen increased interest in environmentally-friendly and sustainable foods, including upcycled ingredients. However, some of these ingredients can contribute to grittiness or graininess, which could in turn impact consumer acceptance. To explore this topic, the current study used apple pomace powder (APP), a nutrient-rich byproduct from apple juice and cider processing to yield new knowledge on particle perception in upcycled foods. Seven APPs with particle sizes of average hydrated diameter Dv(90): 166, 208, 320, 363, 471, 569, 642 μm were incorporated into fruit yogurts. Napping® was successfully used as a preliminary step to threshold testing to inform selection of threshold testing methodology and an appropriate particle size range. The Ascending Forced Choice Method of Limits was applied to a consumer panel (N = 71) for threshold determination. The group threshold, was 259 μm (Dv(90)). The current study demonstrated that by reducing the particle size, it is possible to use APP in a smoother product, such as yogurt, without introducing grittiness. However, a great deal of individual variability was noted with some participants able to detect the smallest particle sizes (166 μm) and some not able to detect even the largest particle sizes (642 μm). Participants were clustered into groups using agglomerative hierarchical cluster analysis and high (44 %), medium (31 %) and low (25 %) particle sensitivity groups were observed. The diversity of particle size detection thresholds in the population presents both an opportunity and challenge for product developers seeking to avoid gritty or grainy textures and should be further studied.

High expression of IL6 and decrease in immune cells in COVID-19 patients combined with myocardial injury.

Myocardial injury, as a serious complication of coronavirus disease-2019 (COVID-19), increases the occurrence of adverse outcomes. Identification of key regulatory molecules of myocardial injury may help formulate corresponding treatment strategies and improve the prognosis of COVID-19 patients. Gene Set Enrichment Analysis (GSEA) was conducted to identify co-regulatory pathways. Differentially expressed genes (DEGs) in GSE150392 and GSE169241 were screened and an intersection analysis with key genes of the co-regulatory pathway was conducted. A protein-protein interaction (PPI) network was constructed to screen for key regulatory genes. Preliminarily screened genes were verified using other datasets to identify genes with consistent expression. Based on the hierarchical cluster, we divided the patients from GSE177477 into high- and low-risk groups and compared the proportion of immune cells. A total of 267 COVID-19 patients from the Zhejiang Provincial Hospital of Chinese Medicine from December 26, 2022, to January 11, 2023, were enrolled to verify the bioinformatics results. Univariate and multivariate analyses were performed to analyze the risk factors for myocardial injury. According to high-sensitivity troponin (hsTnI) levels, patients with COVID-19 were divided into high- and low-sensitivity groups, and interleukin 6 (IL6) expression and lymphocyte subsets were compared. Patients were also divided into high and low groups according to the IL6 expression, and hsTnI levels were compared. Interleukin signaling pathway and GPCR ligand binding were shown to be co-regulatory pathways in myocardial injury associated with COVID-19. According to the hierarchical cluster analysis of seven genes (IL6, NFKBIA, CSF1, CXCL1, IL1R1, SOCS3, and CASP1), patients with myocardial injury could be distinguished from those without myocardial injury. Age, IL6 levels, and hospital stay may be factors influencing myocardial injury caused by COVID-19. Compared with COVID-19 patients without myocardial injury, the levels of IL6 in patients with myocardial injury increased, while the number of CD4+ T cells, CD8+ T cells, B cells, and NK cells decreased (P<0.05). The hsTnI levels in COVID-19 patients with high IL6 levels were higher than those in patients with low IL6 (P<0.05). The COVID-19 patients with myocardial injury had elevated IL6 expression and decreased lymphocyte counts. IL6 may participate in myocardial injury through the interleukin signaling pathway.

A brain-wide genome-wide association study of candidate quantitative trait loci associated with structural and functional phenotypes of pain sensitivity.

Individual pain sensitivity is modulated by the brain's structural and functional features, but its heritability remains unclear. This paper conducted a brain-wide genome-wide association study (GWAS) to explore the genetic bases of neuroimage phenotypes of pain sensitivity. In total, 432 normal participants were divided into high and low pain sensitivity groups according to the laser quantitative test threshold. Then, the brain's gray matter density (GMD) features correlated with pain sensitivity were identified. Next, GWAS was performed on each GMD phenotype using quality-controlled genotypes. Based on the heatmap and hierarchical clustering results, the right insula was identified for further refined analysis in terms of subregions GMD and resting-state functional connectivity (rs-FC) phenotypes. The results indicate that the right insula GMD in the high sensitivity group is significantly lower than that in the low sensitivity group. Also, the TT/TC group at locus rs187974 has lower right insula GMD than the CC group. Further, loci at gene CYP2D6 may lead to a variation of rs-FC between the right insula and left putamen. In conclusion, our study suggests that the right insula and multiple candidate loci may be importantly involved in pain sensitivity modulation, which may guide the future development of precision pain therapeutics.

Differences in protein expression, at the basal state and at 2h of insulin infusion, in muscle biopsies from healthy Arab men with high or low insulin sensitivity measured by hyperinsulinemic euglycemic clamp.

Skeletal muscle is the main site for insulin-dependent glucose disposal. The hyperinsulinemic euglycemic clamp (HIEC) is the gold standard for the assessment of insulin sensitivity (IS). We have previously shown that insulin sensitivity, measured by HIEC, varied widely among a group of 60 young healthy men with normoglycemia. The aim of this study was to correlate the proteomic profile of skeletal muscles to insulin sensitivity. Muscle biopsies from 16 subjects having the highest (M ≥ 13; n = 8, HIS) and lowest (M ¾ 6, n = 8, LIS) IS were obtained at baseline and during insulin infusion after stabilization of the blood glucose level and glucose infusion rate at the end of the HIEC. The samples were processed using a quantitative proteomic analysis approach. At baseline, 924 proteins were identified in the HIS and LIS groups. Among the 924 proteins detected in both groups, three were suppressed and three were increased significantly in the LIS subjects compared with the HIS subjects. Following insulin infusion, 835 proteins were detected in both groups. Among the 835 proteins, two showed differential responsiveness to insulin; ATP5F1 protein was decreased, and MYLK2 was higher in the LIS group compared with that in the HIS group. Our data suggest that alteration in mitochondrial proteins and an increased number of proteins involved in fast-twitch fiber correlate to insulin sensitivity in healthy young Arab men. These results suggest a change in a small number of differentially expressed proteins. A possible reason for this small change could be our study cohorts representing a homogeneous and healthy population. Additionally, we show differences in protein levels from skeletal muscle in low and high insulin sensitivity groups. Therefore, these differences may represent early events for the development of insulin resistance, pre-diabetes, and type 2 diabetes.

Predicting Rectal Cancer Response to Total Neoadjuvant Treatment Using an Artificial Intelligence Model Based on Magnetic Resonance Imaging and Clinical Data.

To develop a model for predicting response to total neoadjuvant treatment (TNT) for patients with locally advanced rectal cancer (LARC) based on baseline magnetic resonance imaging (MRI) and clinical data using artificial intelligence methods. Baseline MRI and clinical data were curated from patients with LARC and analyzed using logistic regression (LR) and deep learning (DL) methods to predict TNT response retrospectively. We defined two groups of response to TNT as pathological complete response (pCR) versus non-pCR (Group 1), and high sensitivity [tumor regression grade (TRG) 0 and TRG 1] versus moderate sensitivity (TRG 2 or patients with TRG 3 and a reduction in tumor volume of at least 20% compared to baseline) versus low sensitivity (TRG 3 and a reduction in tumor volume <20% compared to baseline) (Group 2). We extracted and selected clinical and radiomic features on baseline T2WI. Then we built LR models and DL models. Receiver operating characteristic (ROC) curves analysis was performed to assess predictive performance of models. Eighty-nine patients were assigned to the training cohort, and 29 patients were assigned to the testing cohort. The area under receiver operating characteristics curve (AUC) of LR models, which were predictive of high sensitivity and pCR, were 0.853 and 0.866, respectively. Whereas the AUCs of DL models were 0.829 and 0.838, respectively. After 10 rounds of cross validation, the accuracy of the models in Group 1 is higher than in Group 2. There was no significant difference between LR model and DL model. Artificial Intelligence-based radiomics biomarkers may have potential clinical implications for adaptive and personalized therapy.

Increased self-reported sensitivity to environmental stimuli and its effects on perception of air quality and well-being.

In previous studies, negative associations were found between increased environmental sensitivity and general well-being as well as positive perception of air quality. However, only a few studies with partly inconsistent results examined this relation under exposure. They tried to determine whether people with increased environmental sensitivity react to real environmental conditions with changes in current well-being and perception of air quality. Pooled data from two single-blinded randomized controlled trials with different exposure levels were analyzed. Participants were exposed to different levels of volatile organic compounds (VOC) and carbon dioxide (CO₂) in the front part of a former in-service wide-body airplane inserted in a low-pressure chamber. Three exposure groups were created depending on the VOC/CO₂ levels: low, medium and high. Subjects repeatedly answered questions about their current mental well-being and about perception of air quality and odor intensity. Based on self-reported data the participants were classified into groups with low and higher environmental sensitivity. Data were evaluated using a 2 (environmental sensitivity) x 3 (exposure) ANCOVA with repeated measures. 503 individuals (221 females) participated (mean age: 42.8±14.5 years). Thereof, 166 individuals were assigned to the group with higher environmental sensitivity; they reported poorer psychological well-being regarding vitality (F (1,466)=16.42, p&lt;.001***, partial η²=0.034) and vigilance (F (1,467)=7.82, p=.005**, partial η²=0.016) and rated the pleasantness of air quality (F (1,476)=7.55, p=.006**, partial η²=0.016) and air movement (F (1,474)=5.11, p=.024*, partial η²=0.011) worse than people in the low sensitivity group. Exposure levels showed no effects. No systematic differences between men and women were found. Increased environmental sensitivity shared common variance with negative affectivity, another person-related variable. Its explanatory power was higher for evaluations of the environment whereas no differences between the concepts in explaining current psychological well-being were found. Even a slightly elevated level of environmental sensitivity led to worse ratings of the environment with no clear relation to the real environment. Consequently, environmental sensitivity should be considered as a confounding factor in environmental exposure studies. The independency from real exposure levels is in line with the results from previous studies showing that the differences in environmental ratings are probably also driven by psychological factors.

High Sensitivity: Factor structure of the highly sensitive person scale and personality traits in a high and low sensitivity group. Two gender—matched studies

Sensory Processing Sensitivity (SPS) is a heritable personality related trait which includes sensitivity to a variety of stimuli, emotional, cognitive, and behavioural reactions such as strong positive and negative emotional responses, deep cognitive processing of stimuli, and empathic behaviour. Two studies are reported. Study 1 investigated the factor structure of the Highly Sensitive Person scale (HSP) and gender differences in HSP. Study 2 described differences in Big Five personality traits between two HSP groups. Study 1 comprised a sample of adults, mostly university students, matched on gender (N men = 548, N women = 548; total N = 1096). Study 2 was based on a sample consisting of a High (N = 164) and Low (N = 164) HSP group also matched on gender (N men = 82 and N women = 82 in both groups; total N = 328). There were no age differences between men and women in the two samples. Results from Study 1 showed a correlated three-factor solution: The first factor reflected excitability, easily aroused, negative emotional reactivity, frustration, avoidance of upsetting situations and childhood shyness. Factor 2 comprised low sensory threshold and sensory discomfort. Factor 3 captured intensity of aesthetic reactions, preoccupation with details in the environment, and socio-emotional sensitivity. Gender differences were found, women had elevated HSP scores on all scales, also when controlled for personality traits. Study 2 showed that the highly sensitive individuals had a unique personality trait profile compared to low sensitives. They had higher scores on neuroticism, agreeableness, openness, and lower scores on conscientiousness. There were no differences in extraversion i.e., there was no tendency towards introversion among the high sensitives.

Whole-exome sequencing reveals genetic variations in humans with differential sensitivity to sevoflurane：A prospective observational study

BackgroundThe anesthesia sensitivity is heterogeneous both in animals and humans, while the underlying molecular mechanism has not yet been determined. Here, for the first time, we conducted a prospective observational study to test whether genetic variations contribute to the differential sensitivity to sevoflurane in humans. MethodsFive hundred patients who underwent abdominal surgeries were included. The end-tidal sevoflurane concentration (ETsevo) was adjusted to maintain Bispectral index (BIS) value between 40 and 60. The mean ETsevo from 20 min after endotracheal intubation to 2 h after the beginning of surgery was calculated for each patient. These patients were further divided into high sensitivity group (mean - SD, H group) and low sensitivity group (mean + SD, L group) to investigate the genetic variants related to the differential sensitivity to sevoflurane by whole-exome sequencing (WES) and genome-wide association study (GWAS) in karyocyte from peripheral blood. ResultsThe mean ETsevo of these 500 patients was 1.60% ± 0.34%. After pairing, 55 patients from H group and 59 patients from L group were selected for WES (ETsevo of H group: 1.06% ± 0.13% vs. ETsevo of L group: 2.17% ± 0.16%, P < 0.001), respectively. Finally, FAT atypical cadherin 2 (FAT2, SNP rs174272, rs174271, and rs174261), acireductone dioxygenase 1 (ADI1, SNP rs117278), NEDD4 E3 ubiquitin protein ligase (NEDD4, SNP rs70048, rs70049, and rs70056), and FAD dependent oxidoreductase domain containing 2 (FOXRED2, SNP rs144281) were found to be associated with sevoflurane sensitivity. ConclusionsGenetic variations may contribute to the differential sensitivity to sevoflurane among humans.

Tear Neuromediators in Subjects with and without Dry Eye According to Ocular Sensitivity.

To investigate differences of tear neuromediators between subjects with and without dry eye (DE) depending on the ocular sensitivity. Thirty-one subjects with DE and 29 subjects without DE were recruited in this study. The eyes were stimulated by exposure to an irritating product applied to the periocular region. Both DE and non-DE subjects were divided into the high sensitivity and low sensitivity groups based on the degree of ocular sensitivity to ocular irritation. Baseline tear film break-up time (TBUT) and corneal staining score were examined, and tear samples were collected. The concentrations of the tear neuromediators, including nerve growth factor (NGF), serotonin, calcitonin gene-related peptide (CGRP), substance P, neuropeptide Y, and vasoactive intestinal peptide were measured using the enzyme-linked immune sorbent assay. The baseline neuromediator concentrations were compared between subjects with and without DE based on ocular sensitivity. In both DE and non-DE subjects, baseline TBUT was significantly lower in the high sensitivity group than in the low sensitivity group. In the high sensitivity group, baseline tear NGF levels were higher in subjects with DE than in those without DE. In the low sensitivity group, baseline levels of tear CGRP were lower in subjects with DE than in those without DE. Tear neuromediators associated with DE had differences in their concentrations depending on ocular sensitivity. In patients with DE, tear NGF levels increased with high ocular sensitivity to ocular irritation, whereas tear CGRP levels decreased with low ocular sensitivity.

Machine learning–based prediction of heat pain sensitivity by using resting-state EEG

The development of quantitative, objective signatures or predictors to evaluate pain sensitivity is crucial in the clinical management of pain and in precision medicine. This study combined multimodal (neurophysiology and psychometrics) signatures to classify the training dataset and predict the testing dataset on individual heat pain sensitivity.Healthy individuals were recruited in this study. Individual heat pain sensitivity and psychometric scores, as well as the resting-state electroencephalography (EEG) data, were obtained from each participant. Participants were divided into low-sensitivity and high-sensitivity subgroups according to their heat pain sensitivity. Psychometric data obtained from psychometric measurements and power spectral density (PSD) and functional connectivity (FC) derived from resting-state EEG analysis were subjected to feature selection with an independent t test and were then trained and predicted using machine learning models, including support vector machine (SVM) and k-nearest neighbor.In total, 85 participants were recruited in this study, and their data were divided into training (n = 65) and testing (n = 20) datasets. We identified the resting-state PSD and FC, which can serve as brain signatures to classify heat pain as high-sensitive or low-sensitive. Using machine learning algorithms of SVM with different kernels, we obtained an accuracy of 86.2%-93.8% in classifying the participants into thermal pain high-sensitivity and low-sensitivity groups; moreover, using the trained model of cubic SVM, an accuracy of 80% was achieved in predicting the pain sensitivity of an independent dataset of combined PSD and FC features of resting-state EEG data.Acceptable accuracy in classification and prediction by using the SVM model indicated that pain sensitivity could be achieved, leading to considerable possibilities of the use of objective evaluation of pain perception in clinical practice. However, the predictive model presented in this study requires further validation by studies with a larger dataset.

Classification of sound environment based on subjective response with speech privacy in open plan offices

To implement pleasant open plan offices (OPOs) in the preference aspect based on the subjective responses of the workers, we proposed novel acoustic environment design classification criteria for speech privacy-related parameters. To this end, we created acoustic stimuli through computer simulations and surveyed the related preference responses of test participants. Then, we selected classification criteria based on the survey response results. First, field measurements were performed in two typical OPOs, and a computer simulation model was built. Twelve different sound stimuli were generated by changing the material absorption coefficient conditions for the ceiling and floor inside an office. The investigation of the noise sensitivity and satisfaction of each sound source according to the individuals indicated that the A-weighted sound pressure level at 4 m (Lp,A,S,4m) and spatial decay rate of speech (D2,S) were the major acoustical parameters that determined OPO satisfaction, with Lp,A,S,4m considered first in the OPO design stage. The Lp,A,S,4m class interval was set to 2 dB, and a new four-level classification criteria was proposed, in which the participant response rates of satisfaction were divided according to the change of Lp,A,S,4m into 25% intervals: A (≤ 46 dB), B (46 dB ≤x≤ 48 dB), C (48 dB ≤x≤ 50 dB), and D (≥50 dB). A large difference of two or more satisfaction classes was observed between the high and low noise sensitivity groups for the same Lp,A,S,4m, confirming that the noise sensitivity of workers influences the preferences for OPOs. The proposed classification criteria are expected to be applicable to the design of comfortable OPOs in the future.

Food Neophobia, Odor and Taste Sensitivity, and Overall Flavor Perception in Food

Smell, which allows us to gather information about the hedonic value of an odor, is affected by many factors. This study aimed to assess the relationship among individual factors, odor sensitivity, and enjoyment, and to evaluate how overall flavor perception and liking in actual food samples are affected by odor sensitivity. A total of 749 subjects, from four different Italian regions, participated in the study. The olfactory capabilities test on four odors (anise, banana, mint, and pine), as well as PROP (6-n-prpyl-2-thiouracil) status and food neophobia were assessed. The subjects were clustered into three groups of odor sensitivity, based on the perceived intensity of anise. The liking and intensity of the overall flavor were evaluated for four chocolate puddings with increasing sweetness (C1, C2, C3, and C4). The individual variables significantly affected the perceived intensity and liking of the odors. Even if all of the odor sensitivity groups perceived the more intensely flavored samples as the C1 and C4 chocolate puddings, the high-sensitivity group scored the global flavor of all of the samples as more intense than the low-sensitivity group. The low-sensitive subjects evaluated the liking of the sweeter samples with higher scores than the moderate-sensitive subjects, whereas the high-sensitive subjects gave intermediate scores. In conclusion, odor sensitivity plays a pivotal role in the perception and liking of real food products; this has to be taken into account in the formulation of new products, suitable for particular categories with reduced olfactory abilities.

The Preventive Value of Acupoint Sensitization for Patients with Stable Angina Pectoris: A Randomized, Double-Blind, Positive-Controlled, Multicentre Trial.

Background Acupoint sensitization is considered an important factor in the efficacy of acupoint therapy. This study aimed to evaluate the efficacy of acupressure in the prevention of stable angina pectoris using acupoints with different pressure-pain sensitivities. Methods A total of 202 patients were enrolled and randomly assigned to a high-sensitivity group (HSG) (n = 109) in which patients received acupressure at the five acupoints with the highest sensitivity to pain and a low-sensitivity group (LSG) (n = 93) in which patients received acupressure at the five acupoints with the lowest sensitivity to pain. The duration of acupressure treatment was 4 weeks, and the patients were evaluated at baseline, week 4, and week 8. The primary outcome was a change in the frequency of angina attacks from baseline. The secondary outcomes included nitroglycerin consumption, the Canadian Cardiovascular Society classification, and the Seattle Angina Questionnaire score. Adverse events such as bleeding and subcutaneous haemorrhage were recorded in both groups. Results The effect of acupressure compared with baseline on the prevention of angina pectoris in HSG was better than that in LSG at week 4 (incidence rate ratio (IRR): 0.691 and 95% confidence interval (CI): [0.569, 0.839]) and week 8 (IRR: 0.692 and 95% CI: [0.569, 0.839]). No significant difference between groups was found in the frequency of nitroglycerin consumption at week 4 (odds ratio (OR) = 0.863 and 95% CI: [0.147, 5.077]) or week 8 (OR = 1.426 and 95% CI: [0.211, 9.661]). Two themes in the questionnaire showed significantly different changes from baseline between the two groups. Scores on the angina frequency (AF) subscale had changed more from the baseline in the HSG at week 8 than in the LSG (mean difference (MD) = 3.807 and 95% CI: [0.673, 6.942]). Scores on the treatment satisfaction (TS) subscale had also changed more in the HSG than in the LSG at week 4 (MD = 3.651 and 95% CI: [0.327, 7.327]) and week 8 (MD = 4.220 and 95% CI: [0.347, 7.346]). One patient in the LSG reported bruising at the acupoint. No unexpected safety problems arose. Conclusions This study showed that acupressure at acupoints with high sensitivity to pain may effectively reduce the frequency of stable angina pectoris episodes. This trial is registered with NCT03975140.

Metabolomics and Whole-Exome Sequencing in Patients with Differential Sensitivity to Sevoflurane: A Protocol for a Prospective Observational Trial.

Introduction: Different sensitivity to volatile anesthetics in Drosophila, nematodes and mice is related to mutation of energy metabolism genes. In clinical practice, we find that the end-tidal sevoflurane concentration (ETsevo) differs among patients at the same depth of anesthesia, indicating that the sensitivity to sevoflurane varies among patients. However, the underlying mechanism remains unclear. The sensitivity of an anesthetic is associated with the postoperative outcomes of patients and the mechanism of action of volatile anesthetics. We therefore propose this protocol to determine whether differences in metabolite profile and genetic variations contribute to patients’ sensitivity to volatile anesthetics. Methods and Analysis: This is a single-centre, prospective observational study. 720 patients undergoing abdominal surgery were included. General anesthesia was induced with inhaled sevoflurane, a bolus of sufentanil (0.2–0.4 μg/kg) and cis-atracurium (0.2–0.3 mg/kg). The end-tidal sevoflurane concentration (ETsevo) was adjusted to maintain a BIS (bispectral index) value between 40–60. The mean ETsevo from 20 min after endotracheal intubation to 2 h after the beginning of surgery (steady state) was calculated for each patient. Patients were further divided into a high-sensitivity group (mean ETsevo – SD) and a low-sensitivity group (mean ETsevo + SD) to investigate the sensitivity to sevoflurane. Cases were paired from the high-sensitivity group (group H) and low-sensitivity group (group L) according to age, sex, body mass index (BMI), ASA physical status classification, vital signs, BIS, ephedrine use, sufentanildose, and cis-atracurium dose at anesthesia induction and steady state. Differences in metabolite levels, single nucleotide polymorphisms (SNPs) and protein-coding gene sequence variations between group H and group L will be determined through plasma metabolomics, whole-exome sequencing (WES), genome-wide association study (GWAS), and bioinformatics analyses. These results will be analysed to determine the reasons for the differential sensitivity to sevoflurane in humans. Ethics and Dissemination: This prospective observational study protocol has received ethical approval from the Ethical Committee of West China Hospital of Sichuan University on May 19, 2017 (Approval No. 78). Informed consent will be obtained before patient enrolment. The results will be submitted to international peer-review journals. Trial Registration Number: ChiCTR1800014327.

Sy-1365, a Potent and Selective CDK7 Inhibitor, Exhibits Anti-Tumor Activity in Preclinical Models of Hematologic Malignancies, and Demonstrates Interactions with the BCL-XL/BCL2 Mitochondrial Apoptosis Signaling Pathway in Leukemia

Introduction: The transcriptional kinase CDK7 has been implicated in the pathogenesis of multiple malignancies, including hematologic malignancies, and may play important roles in regulation of oncogenic transcriptional dependencies and in regulation of the mitochondrial apoptosis machinery in tumors. SY-1365, a selective inhibitor of CDK7, was developed to exploit tumor dependencies driven by CDK7 and is in clinical development in patients with advanced solid tumors. We have previously reported that SY-1365 selectively induces apoptosis in leukemic cells relative to non-malignant cells in vitro, and demonstrates anti-tumor activity in AML xenografts. Here we report that SY-1365 has potent inhibitory activity against a broad panel of hematologic malignancies in vitro and ex vivo, induces regressions in AML xenografts using a clinically relevant dosing regimen, and demonstrates synergy with the BCL2 inhibitor venetoclax in AML cells in vitro.Methods: SY-1365 dose-response curves were measured using the ATP-lite assay in a panel of 85 leukemia and lymphoma cell lines in vitro, and in a panel of 226 patient-derived tumor samples from 5 leukemic indications cultured ex vivo. In vivo tumor inhibitory activity was evaluated using once weekly (QW) and twice weekly (BIW) dosing regimens in ML-2 and Kasumi-1 AML xenografts. Growth-rate (GR) adjusted dose response curves were used to classify cell lines into low and high sensitivity groups, and were evaluated relative to RNA expression data to identify markers predictive of sensitivity to SY-1365. Synergy between SY-1365 and venetoclax was evaluated in vitro using KG-1 AML cells.Results: In 42 leukemia lines, SY-1365 had a median IC50 of 11nM (range 1-79nM), with 48% (20/42) demonstrating particularly low IC50s (<10nM). In 43 lymphoma lines, the median IC50 was 6nM (range 1-39nM), with 59% (27/46) demonstrating low IC50s (<10nM). Similarly, SY-1365 demonstrated potent inhibitory activity against patient-derived leukemia samples cultured ex vivo (median IC50 of 28nM), with 82% (185/226) of the samples showing IC50 below 100nM and 8% (19/226) under 10nM. Furthermore, analysis of growth rate (GR) in hematologic tumor cell lines showed that <10nM SY-1365 induced cytotoxicity (GR<0) in 19% (8/42) of leukemia and 21% (9/43) of lymphoma lines. To evaluate SY-1365 anti-tumor activity in vivo, 2 AML cell lines that demonstrate cytotoxic responses to SY-1365 in vitro (Kasumi-1 and ML-2) were grown as subcutaneous xenografts in mice. QW and BIW dosing of 40mg/kg SY-1365 induced tumor regressions in Kasumi-1 xenografts, and BIW dosing induced tumor stasis in ML-2 xenografts. Tumor growth inhibition was detected with a 20mg/kg BIW dosing regimen in both models. Comparison of SY-1365 sensitivity with RNA expression in hematologic tumor cell lines revealed that lower expression of BCL2L1, which encodes the mitochondrial apoptosis inhibitor BCL-XL, was highly predictive of sensitivity in leukemia cell lines (Accuracy=89%, FDR<0.05); no such relationship was observed in lymphoma lines. Considering the established role of BCL2 and the mitochondrial apoptosis pathway in leukemia, we reasoned that BCL-XL low-expressing leukemias, in addition to being sensitive to SY-1365, would also be reliant on BCL2 for survival. Indeed, in vitro combination studies demonstrated synergistic inhibitory activity of SY-1365 with the BCL2 inhibitor venetoclax in KG-1 AML cells. A potential synergistic interaction with SY-1365 and venetoclax is currently being explored in vivo with AML xenografts.Conclusions: SY-1365 shows potent in vitro inhibitory activity in multiple hematological indications and can induce AML xenograft tumor regression in mice. In vitro exploratory biomarker and tumor cell inhibitory combination studies in AML suggest a role for mitochondrial apoptosis signaling in mediating sensitivity to SY-1365 and support the evaluation of a combination with venetoclax. SY-1365 is currently being assessed in a phase 1 trial in adult patients with advanced solid tumors (NCT03134638). The results described here support the potential for additional exploration in patients with hematological malignancies. DisclosuresHodgson:Syros Pharmaceuticals: Employment, Equity Ownership. Johannessen:Syros Pharmaceuticals: Employment, Equity Ownership. Rajagopal:Syros Pharmaceuticals: Employment, Equity Ownership. Hu:Syros Pharmaceuticals: Employment, Equity Ownership. Orlando:Syros Pharmaceuticals: Employment, Equity Ownership. Eaton:Syros Pharmaceuticals: Employment, Equity Ownership. McKeown:Syros Pharmaceuticals: Employment. Tyner:Takeda Pharmaceutical Company: Research Funding; Agios Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Gilead: Research Funding; Janssen Pharmaceutica: Research Funding; Syros: Research Funding; Aptose Biosciences: Research Funding; Seattle Genetics: Research Funding; Constellation Pharmaceuticals: Research Funding; Genentech: Research Funding; Array Biopharma: Research Funding; AstraZeneca: Research Funding; Leap Oncology: Consultancy. Sprott:Syros Pharmaceuticals: Employment, Equity Ownership. Fritz:Syros Pharmaceuticals: Employment, Equity Ownership. Di Tomaso:Syros Pharmaceuticals: Employment.

Individual Lymphocyte Sensitivity to Steroids as a Reliable Biomarker for Clinical Outcome after Steroid Withdrawal in Japanese Renal Transplantation.

Recently, steroid reduction/withdrawal regimens have been attempted to minimize the side effects of steroids in renal transplantation. However, some recipients have experienced an increase/resumption of steroid administrations and acute graft rejection (AR). Therefore, we investigated the relationship between the individual lymphocyte sensitivity to steroids and the clinical outcome after steroid reduction/withdrawal. We cultured peripheral blood mononuclear cells (PBMCs) isolated from 24 recipients with concanavalin A (Con A) in the presence of methylprednisolone (MPSL) or cortisol (COR) for four days, and the 50% of PBMC proliferation (IC50) values and the PBMC sensitivity to steroids were calculated. Regarding the experience of steroid increase/resumption and incidence of AR within one year of steroid reduction/withdrawal, the IC50 values of these drugs before transplantation in the clinical event group were significantly higher than those in the event-free group. The cumulative incidence of steroid increase/resumption and AR in the PBMC high-sensitivity groups to these drugs before transplantation were significantly lower than those in the low-sensitivity groups. These observations suggested that an individual’s lymphocyte sensitivity to steroids could be a reliable biomarker to predict the clinical outcome after steroid reduction/withdrawal and to select the patients whose dose of steroids can be decreased and/or withdrawn after transplantation.