Sensitive Measure Research Articles

Diabetes worsens the adverse association between myocardial diffuse fibrosis and left ventricular strain

Abstract Background Heart failure is a common cardiovascular complication to diabetes. Increased fibrosis of the myocardium has been suggested to be a mechanism, however, no convincing clinical evidence has so far been presented. A better understanding of how myocardial tissue characteristics influence functional aberration in diabetes could aid diagnosis, risk assessment and guide treatment. Native T1 is a CMR marker of diffuse fibrosis with diagnostic and prognostic value (1,2), and feature tracking (CMR-FT) strain is a sensitive measure of myocardial systolic function. In this study, we evaluated the association of CMR markers of fibrosis with markers of systolic function in individuals with and without diabetes. Purpose To understand the relationship between native T1 and myocardial strain and how diabetes may affect this. Methods Participants from the UK Biobank population imaging study were included. Left ventricular global longitudinal strain (GLS) was derived using a semi-automated batch processing software tool. Native T1 was derived from segmentation of the entire short axis slice using an automated quality control tool, excluding scans with predicted dice score of <0.7. Multivariable linear models were used with the strain metrics as the outcome variable and native T1 and diabetes as the exposure variables. These models were adjusted for age, sex, BMI, ethnicity, smoking and alcohol status, prevalent hypertension hypercholesterolaemia and coronary artery disease. The effect of interaction between diabetes and native T1 on GLS was examined by introducing an interaction term. Results In total 41,533 participants were included, of which 1957 had diabetes – see Table 1 for baseline characteristics. The average GLS measured for those with diabetes was -17% and was -18% for those without. The average native T1 in those with diabetes was 935ms and 933ms for those without on the background of greater prevalence of cardiovascular risk factors in those with diabetes. In model adjusted for all relevant co-variates, individuals with diabetes had worse GLS measured compared to those without diabetes (β-coefficient: 0.51, p value <0.001). Increasing fibrosis (native T1) was associated with worsening GLS (β-coefficient: 0.005, p value <0.001) in all participants. However, in those with diabetes, increasing native T1 was associated with a greater decline in GLS compared to those without diabetes (interaction term β-coefficient: 0.005, p value <0.001), with a relative impairment seen within normal ranges for native T1 - see Figure 1. Conclusion(s) This is the largest study of its kind to demonstrate a dose dependent relationship between increasing native T1, representing potential myocardial fibrosis, and myocardial strain, representing cardiac dysfunction. Our findings indicate that increased fibrosis alone does not explain the higher risk of HF in diabetes, other mechanisms, perhaps intracellular, might be at play.

Right ventricular global longitudinal strain by cardiac magnetic resonance feature tracking is associated with outcome in patients with a systemic right ventricle

Abstract Introduction It is well known, that patients with a systemic (sub-aortic) right ventricle (sRV) for congenitally-corrected transposition of the great arteries (TGA) or with complete TGA after atrial switch operation are more threatened to develop RV dysfunction, relevant supra- and ventricular tachycardia and have a reduced life expectancy. While the randomized, placebo-controlled, double-blinded, multi-centre SERVE trial to investigate the effect of phosphodiesterase-5 inhibitor tadalafil in sRV patients showed negative results on the primary end-point RV endsystolic volume (RVESV), aim of this sub-analysis was to evaluate RV global longitudinal strain (GLS), a more sensitive measure of RV function, by cardiac magnetic resonance (CMR) feature tracking (FT) over time, for treatment effect and to investigate whether RV GLS predicts clinical outcome in sRV patients. Methods CMR volumetric RV and FT parameters were analysed (blinded for patient and assessment time and treatment) at baseline and compared to follow-up (FU) after 3 years, or after 1 year in case of withdrawal of the study drug. FT was performed using appropriate software. Treatment effect was analysed using ANCOVA with baseline values and FU-time as covariates. Values of > 4th quartile of RV GLS were used as cut-off for Kaplan-Meier analysis on the primary outcome, defined as a composite of all-cause death, clinically relevant arrhythmias and hospitalisation for heart failure. Results CMR exams were available for 78 patients at baseline (40±11 years, 33% females) and for 71 patients at FU. No treatment effect of tadalafil compared to the placebo was discovered for RV GLS (p=0.26), RVESVi (p=0.63) and RV ejection fraction (RVEF, p=0.6). Over a 3 years FU-time, RV GLS mildly increased (p=0.0023, figure 1). During FU, 14 patients experienced a clinical outcome: 1 death, 4 hospitalisations for heart failure, and 12 clinically relevant arrhythmic events. An RV GLS > -13.4% was associated with adverse clinical outcome (p=0.003, figure 2). Conclusion In patients with a systemic RV, treatment with Tadalafil had no effect on CMR-derived RV global longitudinal strain compared to placebo. RV GLS changed significantly over the 3 years FU-time. A RV GLS value of > -13.4% is associated with adverse clinical outcome in these patients.Figure 1Figure 2

Impact of Experimentally Induced Pain on Logical Reasoning and Underlying Attention-Related Psychophysiological Mechanisms

Background. Pain is known to negatively impact attention, but its influence on more complex cognitive abilities, such as logical reasoning, remains inconsistent. This may be due to compensatory mechanisms (e.g., investing additional resources), which might not be detectable at the behavioral level but can be observed through psychophysiological measures. In this study, we investigated whether experimentally induced pain affects logical reasoning and underlying attentional mechanisms, using both behavioral and electroencephalographic (EEG) measures. Methods. A total of 98 female participants were divided into a pain-free control group (N = 47) and a pain group (N = 51). Both groups completed the Advanced Progressive Matrices (APM) task, with EEG recordings capturing task-related power (TRP) changes in the upper alpha frequency band (10–12 Hz). We used a mixed design where all participants completed half of the APM task in a pain-free state (control condition); the second half was completed under pain induction by the pain group but not the pain-free group (experimental condition). Results. Logical reasoning performance, as measured by APM scores and response times, declined during the experimental condition, compared to the control condition for both groups, indicating that the second part of the APM was more difficult than the first part. However, no significant differences were found between the pain and pain-free groups, suggesting that pain did not impair cognitive performance at the behavioral level. In contrast, EEG measures revealed significant differences in upper alpha band power, particularly at fronto-central sites. In the pain group, the decrease in TRP during the experimental condition was significantly smaller compared to both the control condition and the pain-free group. Conclusions. Pain did not impair task performance at the behavioral level but reduced attentional resources, as reflected by changes in upper alpha band activity. This underscores the importance of incorporating more sensitive psychophysiological measures alongside behavioral measures to better understand the impact of pain on cognitive processes.

Consciousness Under the Spotlight: The Problem of Measuring Subjective Experience.

The study of consciousness is considered by many one of the most difficult contemporary scientific endeavors and confronts several methodological and theoretical challenges. A central issue that makes the study of consciousness so challenging is that, while the rest of science is concerned with problems that can be verified from a "third person" view (i.e., objectively), the study of consciousness deals with the phenomenon of subjective experience, only accessible from a "first person" view. In the present article, we review early (starting during the late 19th century) and later efforts on measuring consciousness and its absence, focusing on the two main approaches used by researchers within the field: objective (i.e., performance based) and subjective (i.e., report based) measures of awareness. In addition, we compare the advantages and disadvantages of both types of awareness measures, evaluate them according to different methodological considerations, and discuss, among other issues, the possibility of comparing them by transforming them to a common sensitivity measure (d'). Finally, we explore several new approaches-such as Bayesian models to support the absence of awareness or new machine-learning based decoding models-as well as future challenges-such as measuring the qualia, the qualitative contents of awareness-in consciousness research.

Waist-height ratio highlights detrimental risk for olanzapine associated weight gain earlier than body mass index.

The objective of the current study was to compare the level of sensitivity of body mass index (BMI) or waist-height ratio (WHtR) in identifying physically determinable adiposity levels that are considered to be landmarks for commencing intervention to prevent more sinister cardio-metabolic risks among schizophrenia patients receiving olanzapine. The study was a descriptive crossectional one among patients with schizophrenia recieving olanzapine and healthy volunteers as controls. Key measurement of anthropological parameters were compared between the population. Our findings revealed significantly higher rates of abnormal body mass index (BMI) (X2=17.06, p=0.000036; OR=4.58, CI=2.16-9.74) and abnormal waist-height ratio (WHtR) (X2=35.57, p=2.46E-9; OR=6.37, CI=3.39-12.00) among the schizophrenia patients compared to the healthy volunteers. Notably, BMI identified 43.3 % of the schizophrenia patients as having concerning weight changes, whereas WHtR identified 64.7 %, indicating that WHtR is a more sensitive measure. This discrepancy means that an additional 21.4 % of schizophrenia patients would benefit from weight management guidance based on WHtR rather than BMI. Our results underscore the critical importance of WHtR in assessing adiposity among schizophrenia patients treated with olanzapine, highlighting its value as a tool for monitoring and managing cardiometabolic risks in this population.

Comparison of protective effects of teneligliptin and luseogliflozin on pancreatic β-cell function: randomized, parallel-group, multicenter, open-label study (SECRETE-I study)

AimsThe aim of this study is to directly compare the effects of SGLT2 inhibitors and DPP-4 inhibitors on β-cell function in patients with type 2 diabetes.Materials and methodsWe conducted a 26-week, randomized, open-label, parallel-group study, including a 1-2 week drug washout period, in patients with type 2 diabetes with HbA1c ≥7.0% and <9.0% and BMI ≥20 kg/m2 despite treatment with a drug naïve or other than DPP-4 inhibitors or SGLT2 inhibitors. A total of 103 subjects were randomly assigned to receive once daily oral luseogliflozin (L) or teneligliptin (T). The primary endpoint was the effect of L vs. T on the change in logarithmus naturalis (Ln) disposition index (DI) (DI 0-120min; combining measures of insulin secretion and sensitivity) from baseline to week 25-26 (post intervention), which was calculated by conducting an oral glucose tolerance test.ResultsLn DI 0-120min were improved in both groups: -0.46 ± 0.68 to -0.20 ± 0.59 (p=0.03) in L group and -0.26 ± 0.60 to -0.05 ± 0.62 (p=0.01) in T group. The change in Ln serum proinsulin/C-peptide ratio, a marker of β-cell dysfunction, was reduced in L group (1.63 ± 0.63 to 1.56 ± 0.68, p=0.16), but rather increased in T group (1.70 ± 0.75 to 1.90 ± 0.51, p=0.01), with significant difference between the two groups (-0.27; p=0.004).ConclusionsImprovement of disposition index in subjects with obese type 2 diabetes was comparable between luseogliflozin and teneligliptin. On the other hand, it is likely that alleviation of β-cell dysfunction is more effective with luseogliflozin compared to tenegliptin.Clinical trial registrationhttps://rctportal.niph.go.jp/en, identifier jRCTs061190008.

Discrimination of mnemonic similarity is associated with short-term and long-term memory precision.

Remembering specific memories with precision relies on the differentiation of similar memory contents - a process commonly referred to as pattern separation and behaviorally operationalized as lure discrimination in the mnemonic similarity task. Although pattern separation is typically investigated in the context of long-term memory (LTM), recent research extends these findings to short-term memory (STM) within a mixture model framework, emphasizing the distinction between memory quality and quantity. According to this framework, pattern separation is associated with memory precision across STM and LTM, regardless of the overall memory likelihood. However, these associations among memory quality measures may persist without the mixture model assumption. In an alternative model, a unitary memory strength measure quantified as a discrimination score (d') may also capture the association between pattern separation and memory quality, as pattern separation has been previously linked with strength-based memory performance. We tested these possibilities based on individual differences among 132 participants who underwent tasks measuring mnemonic pattern separation and STM/LTM quality. We found that behavioral estimates of pattern separation are significantly correlated with STM and LTM precision, irrespective of the likelihood of STM/LTM recall success. However, these associations are absent when considering the correlation between pattern separation and memory strength under a unitary model framework. By leveraging individual differences to constrain our understanding of cognitive models, our data unravel the intricate relationship between pattern separation and memory quality across timescales. These findings may therefore contribute to identifying sensitive behavioral measures for detecting subtle memory deficits in older adults or clinical populations.

Corneal nerve loss in adolescents with obesity and acanthosis nigricans.

Obesity and related metabolic abnormalities in adults are associated with peripheral neuropathy. Acanthosis nigricans (AN) is associated with insulin resistance, fatty liver, hyperlipidemia and glucose intolerance, all of which are risk factors for neuropathy. The aim of this study was to investigate if obese adolescents with AN have evidence of small nerve fiber damage. Adolescents with obesity with and without AN underwent body composition analysis, assessment of vibration perception threshold (VPT), monofilament sensitivity and corneal confocal microscopy (CCM) to quantify corneal nerve fiber density (CNFD), branch density (CNBD), length (CNFL) and inferior whorl length (IWL). Forty-six participants with obesity with (n = 31) and without (n = 15) AN aged 15(14-17) years were compared to 20 healthy controls aged 13(12-14) years. There was no difference in VPT, monofilament sensitivity and CCM measures between adolescents with obesity and controls. However, adolescents with AN had a significantly higher weight (P = 0.022), fat% (P = 0.029) and fat-muscle ratio (P = 0.012) with a lower CNFD (P = 0.045) compared to those with obesity without AN. Adolescents with obesity and acanthosis nigricans have a higher fat mass and small nerve fibre loss, indicative of a sub-clinical neuropathy.

Impact of Keratoconus on Contrast Sensitivity

Objective: Keratoconus (KC) disrupts corneal shape, leading to irregular astigmatism and increased higher-order aberrations (HOA), ultimately affecting visual quality. While visual acuity (VA) remains the standard, its limitations in early KC diagnosis are recognized. This study aimed to evaluate the impact of KC on contrast sensitivity function (CSF), a potentially more sensitive measure of visual performance.Material and Methods: A case-control design compared CSF in KC patients (n=7) to healthy controls (n=16). All subjects achieved the best-corrected visual acuity (BCVA) of 6/9 or better (logMAR ≤0.10). Corneal topography was measured using Tomey TMS-5 to confirm KC diagnosis. CSF was assessed with the Functional Acuity Contrast Test (FACT).Results: KC eyes exhibited significantly reduced CSF across all spatial frequencies compared to controls (p-value<0.05). Row A of the FACT chart (representing the lowest spatial frequency, 1.5 cpd) demonstrated the most prominent difference (t (21)=-3.073, p-value=0.003).Conclusion: Our findings reveal that KC patients, despite achieving good BCVA, demonstrate measurable deficits in CSF. This suggests CSF measurement with FACT may be a valuable tool for the early diagnosis and monitoring of KC, potentially offering a more sensitive and comprehensive assessment of visual function compared to BCVA alone.

Development of a Diabetes Dietary Quality Index: Reproducibility and Associations with Measures of Insulin Resistance, Beta Cell Function, and Hyperglycemia

Aims: Various dietary risk factors for type 2 diabetes have been identified. A short assessment of dietary patterns related to the risk for type 2 diabetes mellitus may be relevant in clinical practice given the largely preventable nature of the disease. The aim of this study was to investigate the reproducibility of a short food frequency questionnaire based on available knowledge of diabetes-related healthy diets. In addition, we aimed to investigate whether a Diabetes Dietary Quality Index based on this questionnaire was related to metabolic risk factors, including measures of beta cell function and insulin sensitivity. Methods: A short food frequency questionnaire was composed by selecting fourteen questions (representing eight dietary factors) from existing food frequency questionnaires on the basis of their reported relationship with diabetes risk. Healthy participants (N = 176) from a Dutch family study completed the questionnaire and a subgroup (N = 123) completed the questionnaire twice. Reproducible items from the short questionnaire were combined into an index. The association between the Diabetes Dietary Quality index and metabolic risk factors was investigated using multiple linear regression analysis. Measures of beta cell function and insulin sensitivity were derived from a mixed meal test and an euglycemic–hyperinsulinemic and modified hyperglycemic clamp test. Results: Our results show that this new short food frequency questionnaire is reliable (Intraclass Correlations ranged between 0.5 and 0.9). A higher Diabetes Dietary Quality index score was associated with lower 2 h post-meal glucose (β −0.02, SE 0.006, p < 0.05), HbA1c (β −0.07, SE 0.02, p < 0.05), total cholesterol, (β −0.02, SE 0.07, p < 0.05), LDL cholesterol, (β −0.19, SE 0.07, p < 0.05), fasting (β −0.4, SE 0.16, p < 0.05) and post-load insulin, (β −3.9, SE 1.40, p < 0.05) concentrations and the incremental AUC of glucose during MMT (β −1.9, SE 0.97, p < 0.05). The scores obtained for the oral glucose insulin sensitivity-derived mixed meal test were higher in subjects who scored higher on the Diabetes Dietary Quality index (β 0.89, 0.39, p < 0.05). In contrast, we found no significant associations between the Diabetes Dietary Quality index and clamp measures of beta cell function. Conclusions: We identified a questionnaire-derived Diabetes Dietary Quality index that was reproducible and inversely associated with a number of type 2 diabetes mellitus and metabolic risk factors, like 2 h post-meal glucose, Hba1c and LDL, and total cholesterol. Once relative validity has been established, the Diabetes Dietary Quality index could be used by health care professionals to identify individuals with diets adversely related to development of type 2 diabetes.

Investigating the effects of artificial baroreflex stimulation on pain perception: A comparative study in no-pain and chronic low back pain individuals.

The autonomic nervous system (ANS) and pain exhibit a reciprocal relationship, where acute pain triggers ANS responses, whereas resting ANS activity can influence pain perception. Nociceptive signalling can also be altered by 'top-down' processes occurring in the brain, brainstem and spinal cord, known as 'descending modulation'. By employing the conditioned pain modulation (CPM) paradigm, we previously revealed a connection between reduced low-frequency heart rate variability and CPM. Individuals with chronic pain often experience both ANS dysregulation and impaired CPM. Baroreceptors, which contribute to blood pressure and heart rate variability regulation, may play a significant role in this relationship, although their involvement in pain perception and their functioning in chronic pain have not been sufficiently explored. In the present study, we combined artificial 'baroreceptor stimulation' in both pressure pain and CPM paradigms, seeking to explore the role of baroreceptors in pain perception and descending modulation. In total, 22 individuals with chronic low back pain (CLBP) and 29 individuals with no-pain (NP) took part in the present study. We identified a differential modulation of baroreceptor stimulation on pressure pain between the groups of NP and CLBP participants. Specifically, NP participants perceived less pain in response to baroreflex activation, whereas CLBP participants exhibited increased pain sensitivity. CPM scores were associated with baseline measures of baroreflex sensitivity in both CLBP and NP participants. Our data support the importance of the baroreflex in chronic pain and a possible mechanism of dysregulation involving the interaction between the ANS and descending pain modulation. KEY POINTS: Baroreflex stimulation has different effects on pressure pain in participants with chronic pain compared to matched individuals with no-pain. Baroreceptor activation decreases pain in participants with no-pain but increases pain perception in participants with chronic pain. Baroreflex sensitivity is associated with conditioned pain modulation in both groups of chronic pain and no-pain participants. The reactivity of the baroreflex during autonomic stress demonstrated a positive correlation with Pain Trait scores in participants with chronic back pain.

Endpoints and Design for Clinical Trials in USH2A-Related Retinal Degeneration: Results and Recommendations From the RUSH2A Natural History Study.

To evaluate functional and structural assessments as endpoints for clinical trials for USH2A-related retinal degeneration. People with biallelic disease-causing variants in USH2A, visual acuity ≥ 20/80, and visual field ≥ 10° diameter were enrolled in a 4-year, natural history study. Participants underwent static perimetry, microperimetry, visual acuity, fullfield stimulus testing (FST), and optical coherence tomography annually. Rates of change estimated from mixed-effects linear models and percentages of eyes with changes exceeding the coefficient of repeatability (CoR) or thresholds conforming with U.S. Food and Drug Administration (FDA) guidelines were evaluated. Rates of change were generally more sensitive to change than proportions of eyes exceeding a threshold such as the CoR. Baseline ellipsoid zone area ≥ 3mm2 was necessary to detect change. Mean sensitivity and volumetric hill of vision measures on static perimetry had similar properties and were the most sensitive to changes of the continuous measures. The highest 4-year proportions of eyes exceeding the CoR were from FST testing (47%) and microperimetry (32%). Specification of loci as functional transition points (FTPs) resulted in 45% (static perimetry) and 46% (microperimetry) at 4years, meeting FDA guidelines for progression. Rate of change of mean sensitivity on static perimetry was a sensitive perimetric continuous measure. Percentages of within-eye change were largest with FST testing and microperimetry. FTPs appear to be particularly sensitive to change. These results affect clinical trial design for USH2A-related retinal degeneration. Analyses of natural history data from the Rate of Progression in USH2A-Related Retinal Degeneration (RUSH2A) study can inform eligibility criteria and endpoints for clinical trials.

Arsenic K-edge and Thallium L3-edge XANES, with XFM imaging and LA-ICP-MS to determine oxidation states and distribution in sphalerite

XANES, XFM imaging and LA-ICP-MS were employed to reveal the localisation of elements and the oxidation states of As and Tl in highly banded MVT sphalerite from Wiesloch, Germany. Arsenic K-edge and Tl L3-edge XANES spectra were retrieved, and results were compared to reference standards that represented different oxidation states. Fingerprinting analyses indicated As3+ and Tl+ in the Wiesloch sphalerite. Substitution mechanisms are provided that include the coupled incorporation of As and Tl in sphalerite, and a two-step series of reactions that creates and consumes vacant cation sites to better accommodate the larger size of Tl+ in tetrahedral coordination. XANES spectra also revealed a different edge position for As in Porgera (Papua New Guinea) pyrite and XFM imaging showed As localised entirely in the pyrite, rather than the adjacent sphalerite. A pH sensitive measure of redox in sphalerite-pyrite coprecipitated mineral assemblages is therefore suggested.

Impacts on study design when implementing digital measures in Parkinson's disease-modifying therapy trials.

Parkinson's Disease affects over 8.5 million people and there are currently no medications approved to treat underlying disease. Clinical trials for disease modifying therapies (DMT) are hampered by a lack of sufficiently sensitive measures to detect treatment effect. Reliable digital assessments of motor function allow for frequent at-home measurements that may be able to sensitively detect disease progression. Here, we estimate the test-retest reliability of a suite of at-home motor measures derived from raw triaxial accelerometry data collected from 44 participants (21 with confirmed PD) and use the estimates to simulate digital measures in DMT trials. We consider three schedules of assessments and fit linear mixed models to the simulated data to determine whether a treatment effect can be detected. We find at-home measures vary in reliability; many have ICCs as high as or higher than MDS-UPDRS part III total score. Compared with quarterly in-clinic assessments, frequent at-home measures reduce the sample size needed to detect a 30% reduction in disease progression from over 300 per study arm to 150 or less than 100 for bursts and evenly spaced at-home assessments, respectively. The results regarding superiority of at-home assessments for detecting change over time are robust to relaxing assumptions regarding the responsiveness to disease progression and variability in progression rates. Overall, at-home measures have a favorable reliability profile for sensitive detection of treatment effects in DMT trials. Future work is needed to better understand the causes of variability in PD progression and identify the most appropriate statistical methods for effect detection.

6711 Single Nuclei RNA-seq To Map Adipose Cellular Populations And Senescent Cells In Response To A Lifestyle Or Senolytic Intervention In Older Adults With Obesity: A Double-Blind, Placebo-Controlled, Randomized Trial

Abstract Disclosure: A. Aslamy: None. G. Connolly: None. J. Nie: None. S. Espinoza: None. M. Serra: None. N. Musi: None. It is well established that obese and older individuals are at significantly increased risk for diabetes and metabolic syndrome. However, the underlying molecular mechanisms by which increased adiposity and aging predisposes individuals to metabolic disease are not well understood. Recent data suggests that variations in adipocyte cellular populations and subpopulations influence whole body metabolism. Particularly, an increased burden of adipocyte senescent cells (cells that are in a state of replicative arrest) have been implicated in metabolic diseases. To investigate the relationship between adipose molecular signatures and cellular senescence on metabolic outcomes, we will use a novel, high-throughput, high-resolution methodology called single nuclei RNA sequencing (SnRNA-seq) to develop a transcriptomic atlas of human adipose tissue and analyze molecular profiles before and after interventions of lifestyle vs. senolytic vs. placebo. We will recruit a cohort of older obese participants (≥65 years of age; BMI = 30-39.9 kg/m2; n = 72), and conduct a double-blinded, placebo-controlled, randomized trial in which we obtain adipose biopsies to analyze cellular/molecular profiling via snRNA-seq as it relates to phenotypic measures of insulin sensitivity, glucose tolerance, beta cell function, and hepatic lipid content compared to cohorts of younger lean (18-30 years of age; BMI = 18.5-24.9 kg/m2; n = 24) and older lean (≥65 years of age; BMI = 18.5-24.9 kg/m2; n = 24) participants. Older obese participants will be randomized to one of three groups for a 10-week period: lifestyle (diet- and exercise-induced weight loss of 8-10% of body mass), senolytic (dasatinib and quercetin), or placebo. Repeat adipose biopsies and metabolic testing will be analyzed before and after intervention to assess potential changes in gene expression and associated phenotypic measures. Inclusion criteria for the older obese participants are the following: ≥65 years of age, BMI 30-39.9 kg/m2, any sex, race and ethnic group, sedentary (≤1.5h of exercise per week), and nondiabetic. Exclusion criteria include history of diabetes, participation in structured exercise >1.5h per week, chronic inflammatory/neurologic/autoimmune/pulmonary disorders, GI or heart disease, use of anti-arrhythmic or weight altering medications, smoking/alcohol use, previous bariatric surgery, and use of/allergy to senolytic agents. Preliminary snRNA-seq analyses of adipose biopsies from our pilot study with non-diabetic participants identified cells with elevated expression of positive regulators of senescence (CDKN1A, CDKN2A, ARG2); notably, one subpopulation of senescent adipocytes, termed NewA1, was increased with higher BMI. Overall, the findings from this study may help us gain better understanding of the aging process and identify potential molecular targets for prevention of metabolic disease. Presentation: 6/1/2024

Noise sensitivity: from systematic review to improving its measurement

Noise sensitivity is known to be the most influential non-acoustic factor affecting noise annoyance. While there is general consensus within the international research community as to how noise annoyance should be measured, it is not true for noise sensitivity. Either single-item rating scales are used or full-fledged questionnaires. Few of these instruments have been validated across different languages, and some of them have never been psychometrically evaluated. Even though noise sensitivity has been studied for many decades, there is no systematic review of what noise sensitivity is. The present research program started out by conducting a systematic review of the instruments available to measure noise sensitivity. Next, an online survey will be carried out to evaluate and compare existing noise-sensitivity questionnaires on a large sample while considering versions in different languages. Finally, on the basis of both the systematic review and the questionnaire evaluation, a resulting measure of noise sensitivity will be assessed in the laboratory by relating it to both noise annoyance and physiological measurements. The relevance of the proposed work is thus to designate a reliable, yet economic method to measure noise sensitivity in future surveys. [Research funded by Fondation pour l'Audition (grant FPA RD-2022-6)]

Smoking-Related Increases in Alcohol Outcomes and Preliminary Evidence for the Protective Effect of a Functional Nicotine Receptor Gene (CHRNA5) Variant on Alcohol Consumption in Individuals Without Alcohol Use Disorder.

Alcohol and nicotine interact with the nicotinic acetylcholine receptor system to alter reward-related responses, thereby contributing to the co-use and misuse of these drugs. A missense polymorphism rs16969968 (G>A) in the CHRNA5 gene has shown a strong association with nicotine-related phenotypes. However, less is known about the impact of this variant on alcohol-related phenotypes. We assessed the main and interactive effect of smoking and rs16969968 polymorphism on alcohol consumption using the Alcohol Use Disorders Identification Test (AUDIT), Timeline Follow Back (TLFB), and Lifetime Drinking History (LDH) in 980 healthy adults without alcohol use disorder. We further examined the effect of the rs16969968 polymorphism on acute alcohol consumption using a free-access i.v. alcohol self-administration (IV-ASA) human laboratory paradigm in a subset of 153 nonsmoking participants. Subjective alcohol responses, alcohol sensitivity, and expectancy measures were compared between genotype groups (GG; AA/AG). We observed a significant association of smoking with AUDIT, TLFB, and LDH measures across genotype groups, with smokers showing higher scores compared with nonsmokers. Additionally, we found an association between genotype and TLFB-total drinks in the IV-ASA subset, with the GG group showing higher scores than AA/AG group. Relatedly, the alcohol negative expectancy score was significantly lower in the GG group than the AA/AG group. Our findings underscore the association of smoking with alcohol measures. We found preliminary evidence for the protective effect of the functional CHRNA5 polymorphism on alcohol consumption and its association with increased negative alcohol expectancies, which highlights the substantial heterogeneity in alcohol responses.

New and Emerging Drug and Gene Therapies for Friedreich Ataxia.

The life shortening nature of Friedreich Ataxia (FRDA) demands the search for therapies that can delay, stop or reverse its relentless trajectory. This review provides a contemporary position of drug and gene therapies for FRDA currently in phase 1 clinical trials and beyond. Despite significant scientific advances in the specificity of both compounds and targets developed and investigated, challenges remain for the advancement of treatments in a limited recruitment population. Currently therapies focus on reducing oxidative stress and improving mitochondrial function, modulating frataxin controlled metabolic pathways and gene replacement and editing. Approval of omaveloxolone, the first treatment for individuals with FRDA aged 16 years and over, has created much excitement for both those living with FRDA and those that care for them. The process of approval of omaveloxolone by the US Food and Drug Administration highlighted the importance of sensitive outcome measures and the significant role of data from natural history studies.

Cognition Assessment in Virtual Reality (CAVIR): Associations with neuropsychological performance and activities of daily living in patients with mood or psychosis spectrum disorders

BackgroundMore ecologically valid tools are needed to better capture daily-life cognitive impairments in patients with mood or psychosis spectrum disorders in clinical settings and cognitive treatment trials. We developed the Cognition Assessment in Virtual Reality (CAVIR) test, which assesses daily-life cognitive skills in an immersive virtual reality kitchen scenario. This study investigated the validity and sensitivity of CAVIR, including its association with activities of daily living (ADL) ability. Methods70 symptomatically stable patients with mood or psychosis spectrum disorders and 70 healthy controls completed CAVIR and standard neuropsychological tests and were rated for clinical symptoms, functional capacity, and subjective cognition. In addition, patients' ADL ability was evaluated with the Assessment of Motor and Process Skills (AMPS). ResultsHigher global CAVIR performance correlated moderately with better global neuropsychological test scores (rs(138) = 0.60, p < 0.001) and showed a weak to moderate association with better ADL process ability in patients (r(45) = 0.40, p < 0.01), also after adjusting for sex and age (ps ≤ 0.03). In comparison, neuropsychological performance, interviewer- and performance-based functional capacity, and subjective cognition were not significantly associated with ADL process ability (ps ≥ 0.09). Further, CAVIR was sensitive to cognitive impairments in patients and was able to differentiate between patients with and without the ability to undertake regular employment. LimitationsThe modest sample size and concomitant medication. ConclusionOur results indicate that CAVIR is a sensitive measure of daily-life cognitive skills in patients with mood or psychosis spectrum disorders.

THE IMPACT OF COGNITIVE STIMULATION IN OLDER ADULTS WITH DEMENTIA

This study evaluated the impact of a cognitive stimulation program on older adults diagnosed with dementia. The sample comprised 22 participants aged 73-95, randomly assigned to an experimental group (N = 12) and a control group (N = 10). While no statistically significant decreases were observed in the studied dimensions, clinically relevant gains were noted: 41.70% in cognition, 41.60% in quality of life, and 8.3% in functional skills. Although no therapeutic interventions have successfully reversed dementia, healthcare providers reported improvements in participants’ social interactions, behaviors, and engagement in daily institutional routines. These observations suggest tangible benefits from program participation. It’s important to note that staff working closely with these patients daily observed these improvements despite the lack of statistically significant results. This discrepancy highlights the potential limitations of relying solely on quantitative measures to assess such interventions’ effectiveness. In conclusion, the cognitive stimulation program shows promise as a potential tool for slowing dementia-associated degenerative processes, particularly in areas that standard quantitative assessments may not fully capture. Further research with larger sample sizes and more sensitive measures may be warranted to fully understand the program’s impact.