Delta Scores Research Articles

α-Synuclein Oligomers in Skin Biopsies Predict the Worsening of Cognitive Functions in Parkinson’s Disease: A Single-Center Longitudinal Cohort Study

α-synuclein oligomers within synaptic terminals of autonomic fibers of the skin reliably discriminate Parkinson’s disease (PD) patients from healthy controls. Nonetheless, the prognostic role of oligomers for disease progression is unknown. We explored whether α-synuclein oligomers evaluated as proximity ligation assay (PLA) score may predict the worsening of cognitive functions in patients with Parkinson’s disease. Thirty-four patients with PD and thirty-four healthy controls (HC), matched 1:1 for age and sex, were enrolled. Patients with PD underwent baseline skin biopsy and an assessment of cognitive domains including Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clock Drawing Test, and Frontal Assessment Battery. At the last follow-up visit available, patients were either cognitively stable (PD-CS) or cognitively deteriorated (PD-CD). α-synuclein oligomers were quantified as PLA scores. Differences between groups were assessed, controlling for potential confounders. The relationship between skin biopsy measures and cognitive changes was explored using correlation and multivariable regression analyses. The discrimination power of the PLA score was assessed via ROC curve. To elucidate the relationship between skin biopsy and longitudinal cognitive measures, we conducted multivariable regression analyses using delta scores of cognitive tests (Δ) as dependent variables. We found that PD-CD had higher baseline PLA scores than PD-CS (p = 0.0003), and they were correctly identified in the ROC curve analysis (AUC = 0.872, p = 0.0003). Furthermore, ANCOVA analysis with Bonferroni correction, considering all groups (PD-CS, PD-CD, and HC), showed significant differences between PD-CS and PD-CD (p = 0.003), PD-CS and HC (p = 0.002), and PD-CD and HC (p < 0.001). In the regression model using ΔMMSE as the dependent variable, the PLA score was found to be a significant predictor (β = −0.441, p = 0.016). Similar results were observed when evaluating the model with ΔMoCA (β = −0.378, p = 0.042). In conclusion, patients with Parkinson’s disease with higher α-synuclein burden in the peripheral nervous system may be more susceptible to cognitive decline.

Preoperative multifidus and psoas major muscle quality and patient-reported outcomes after anterolateral lumbar interbody fusion: predictors for preoperative disability and back pain improvement

To investigate associations between preoperative lumbar multifidus muscle (LMM) and psoas major muscle (PMM) qualities and pre- and postoperative patient-reported outcomes (PROs) after anterolateral lumbar interbody fusion (A-LLIF). A retrospective review was conducted of patients with A-LLIF between L1 and S1 during 2017-2022 at a single institution who had at least approximately1 year of follow-up and preoperative MRI available. Preoperative MRI was analyzed using 2 image analysis platforms (AMBRA and ImageJ). Parameters studied included cross-sectional area (CSA) and fat infiltration (FI) indices. Pearson correlation and multiple linear regression analyses were used to study relationships between muscle quality and pre- and postoperative PROs. Subanalyses were performed for LMM CSA percentiles and stratification of previous surgery. One hundred patients met the inclusion criteria (mean [SD] age, 65.3 [11.0] years; 57% women, 43% men) during a mean (SD) follow-up period of 1.29 (0.20) years. In total, 207 surgical levels were analyzed. Smaller LMM CSA was significantly associated with greater preoperative disability and preoperative back pain (p<0.04 [ImageJ]). There were no statistically significant confounding factors. Patients with greater LMM CSA and previous lumbar procedures (n=42) had more improvement in visual analog scale for lower back pain delta scores (p=0.02 [ImageJ]; p=0.04 [AMBRA]). Neither LMM FI indices nor PMM morphology influenced PROs. Significant associations were found between LMM CSA and preoperative disability and back pain. Compared to A-LLIF patients with larger LMM (CSA > 12 cm2), those with LMM CSA <5 cm2 had significantly greater preoperative disability and back pain.

Internal Consistency of the DELTA Scale Assessing Psychotic-Like Experiences

Abstract: This study’s objective was to conduct a reliability generalization meta-analysis of the DELTA scale capturing Disintegration, i.e., proneness to psychotic-like experiences and behaviors. Eligible studies applied various versions of the DELTA scale; 573 α coefficients nested in 76 reports were identified. The pooled effect of all included α coefficients was calculated by applying a 4-level meta-analytic random-effects model. Test length, sample type, demographic sample characteristics (mean age, share of females), language, the proportion of reverse-keyed items, publication status, documentation quality of reliability estimates (reported vs. post hoc computed reliabilities), and DELTA score M and SDs were tested as moderators. The model yielded an average Cronbach’s α for DELTA and its facets of .86 (95% CI [.84, .88]), with medium and long DELTA versions reaching .96 (95% CI [.94, .96]) and .97 (95% CI [.95, .98]), respectively. Moderators explaining the heterogeneity among α coefficients were as follows: test length (expectedly, higher reliability estimates for longer tests), mean scores and SD of the DELTA scores (lower α estimates for larger means and lower SDs), and language (highest α estimates for the German language). Overall, the DELTA scales used in past research showed high-reliability estimates.

The Effects of a Multi-Ingredient Dietary Supplement on Recovery from Delayed-Onset Muscle Soreness

Introduction: The purpose of this investigation was to determine the effects of multi-ingredient dietary supplement on indices of muscle recovery on delayed-onset muscle soreness (DOMS). Methods: In a randomized, placebo-controlled trial, healthy exercise-trained subjects (n=24) consumed the treatment (i.e., Caraflame®: Retinyl Palmitate (Vit. A) 3.3 mg, Sodium Butyrate 175 mg, and Beta-Caryophyllene 30 mg or placebo (i.e., Maltodextrin 1000mg) daily over a 14-day period. Subjects completed the DOMS protocol and were assessed for changes in pain (visual analog scale (VAS) and a pressure algometer), strength (1-RM), and inflammatory markers (Interleukin-1b, Interleukin-6 and C-reactive protein). A dependent samples t-test was used to determine differences between groups with regard to the delta score. A p-value of P&lt;0.05 was used to determine significance. Results: All subjects were physically active, healthy adults (Mean±SD – Age 23.5±7, Height 170±12.7 cm, Body Mass 71.0±19.57 kg, % body fat 24.3±10.6). A statistically significant difference was found for the assessment of pain threshold via VAS. Subjects in the treatment group exhibited a higher pain threshold two days post-DOMS (i.e., delta score data). No significant differences between groups for arm circumference, 1-RM, pain assessed by algometer, or arm circumference between the groups. Furthermore, there were no significant differences between groups for inflammatory markers (CRP, IL-6, and IL-1b). Conclusions: Based on this preliminary investigation, two weeks of a multi-ingredient dietary supplement may decrease the subjective perception of delayed-onset muscle soreness in exercise-trained adults.

The Effects of a Novel Taurine-L-Malic Acid Complex on Indices of Recovery after an Exercise Protocol Inducing Delayed-Onset Muscle Soreness

Introduction: The purpose of this investigation was to determine the effects of a novel dietary supplement (Maltor™) on indices of muscle recovery after a delayed-onset muscle soreness (DOMS) protocol. Methods: In a double-blind, placebo-controlled, crossover trial, subjects consumed the treatment (i.e., 5 g. Maltor™ – a complex of taurine and L-malic acid in an approximately 2:1 ratio) and placebo (i.e.,1 g of sodium citrate and 4 g of maltodextrin) daily over 14 days. Subjects were instructed to consume the treatment or placebo for 14 days. After 14 days of consumption, subjects performed a DOMS protocol based on their 1-RM. Inflammatory markers, arm circumference, strength, subjective and objective measures of pain were assessed 24hr, 48hr and 72hrs after DOMS protocol. Results: A statistically significant difference was found for the assessment of pain threshold via the pressure algometer (p=0.5). Subjects in the treatment group exhibited a higher pain threshold two days post-DOMS (i.e., delta score data). We found no significant differences between groups for arm circumference, 1-RM (p=0.66), pain assessed by VAS (0.94), or arm circumference (p=0.91) between the groups. Furthermore, there were no significant differences between groups for Interleukin-6 (p=0.85) and C-reactive protein (p=0.48), key markers of inflammation. Conclusions: Based on this preliminary investigation, two weeks of consuming taurine-L-malic acid complex may diminish delayed-onset muscle soreness in exercise-trained males as assessed by an algometer (i.e., assessment of pain threshold).

Arthroscopic Margin Convergence Repair Without Suture Anchors Improves Clinical Outcomes for Full- and Partial-Thickness Rotator Cuff Tears

To evaluate the clinical outcome scores of an arthroscopic margin convergence technique without the use of suture anchors to repair different types of rotator cuff tears and to determine whether the type or extent of the tear has an effect on clinical outcome scores after this procedure. Patients receiving arthroscopic margin convergence repair without suture anchors for rotator cuff tears from 2013 to 2018 were retrospectively analyzed. Arthroscopically determined partial- or full-thickness rotator cuff tears with a minimum follow-up period of 20 months were included. Outcomes were assessed using the American Shoulder and Elbow Surgeons (ASES) shoulder score; University of California, Los Angeles (UCLA) shoulder score; and visual analog scale (VAS) score. A 2-tailed distribution paired t test was used to determine statistical significance (P < .05) between preoperative scores and scores at final follow-up. Correlation tests and linear regression analysis were used to determine the correlation between various clinical variables and outcomes. A cohort-specific minimal clinically important difference analysis was performed for each outcome score, calculated as one-half of the standard deviation of the delta score. A total of 38 patients were included for analysis: 12 with partial-thickness tears and 26 with full-thickness tears. The mean postoperative follow-up period was 33.9 months (range, 22.2-94.5 months), with a minimum follow-up period of 22 months. The mean age of the patients was 62 ± 15.1 years. The minimal clinically important difference values for the ASES, UCLA, and VAS scores were 9.68, 2.92, and 1.13, respectively. There were significant improvements in the ASES (from 29.3 ± 18.3 preoperatively to 93.7 ± 8.3 postoperatively, P= .001), UCLA (from 14.3 ± 6.2 to 32.8 ± 2.6, P= .001), and VAS (from 7.37 ± 1.8 to 0.63 ± 1.02, P= .001) clinical outcome scores. However, patients with either Patte stage 3 retraction (P= .033 for ASES score and P=.020 for UCLA score) or U-shaped tears (P= .047 for ASES score and P= .050 for UCLA score) had significantly lower clinical outcome scores than patients with less severe retraction or differently shaped tears. The arthroscopic margin convergence technique without the use of suture anchors may be a suitable option in patients with partial- or full-thickness rotator cuff tears. Level IV, therapeutic case series.

Can mental fatigue affect perception of barbell velocity in resistance training?

Perception of Velocity (PV) is the ability to estimate single repetition velocity during resistance training (RT) exercises. The main purpose of the study was to evaluate the effects of Mental Fatigue (MF) on the accuracy of barbell PV. The secondary aims were to evaluate whether MF affected RT performance and ratings of perceived exertion (RPE; OMNI-RES) in the back squat. Twenty-four (14 Females, 10 Males) resistance-trained participants underwent 2 familiarization sessions and 1RM test for the back squat. In two separate sessions, PV was tested for light, medium, and heavy loads in 2 conditions in random order: at rest (REST) and in MF condition (POST-MF) induced by previous incongruent Stroop color-word task. MF and Motivation were assessed through visual analog scales (VAS; 0-100) before and after the Stroop task. For each load subjects performed 2 repetitions and reported the RPE value. Mean propulsive velocity (Vr) of the barbell was recorded with a linear encoder, while the perceived velocity (Vp) of the subjects was self-reported using the Squat-PV scale. The PV accuracy was calculated through the delta score (ds: Vp-Vr). Following the Stroop task MF increased significantly (p<0.001; F (1, 23)=52.572), while motivation decreased (p<0.05; F (1, 23)=7.401). Ds, Vr, and RPE did not show significant differences between conditions (p>0.05) for the three loads analyzed. MF induced by previous demanding cognitive task did not affect PV accuracy. Furthermore, subjects maintained unchanged both RT performance and RPE values associated with each load, even when mentally fatigued.

Does Fatigue Affect the Perception of Velocity Accuracy During Resistance Training?

Romagnoli, R and Piacentini, MF. Does fatigue affect the perception of velocity accuracy during resistance training? J Strength Cond Res 38(7): 1243-1247, 2024-The purpose of this study was to investigate whether perception of barbell velocity (PV) is affected by fatigue induced by 2 different training protocols. Twenty-two subjects were randomly divided into 2 groups: 10% velocity loss group (VL10) and repetitions to failure group (EX). Both protocols included 5 sets at 75% 1 repetition maximum but differed in the number of repetitions performed (Reps). Perception of barbell velocity was assessed in the back squat exercise during a test with 3 blinded loads (heavy, medium, light) 1 day rested (REST) and 1 day immediately following 1 of the 2 designated training protocols (POST). The accuracy of the PV was analyzed by calculating the delta score (ds), that is, the difference between perceived velocity (Vp) and real velocity of the barbell (Vr). During training, each group performed significantly different Reps per set (VL10: 3.9 ± 1.4; EX: 13.8 ± 6.3, p < 0.001) and consequently reported different levels of perceived exertion and repetitions in reserve ( p < 0.001). Real velocity and ds did not change between REST and POST-VL10 conditions at all loads. Although a significant decrease in Vr was found at light and medium loads ( p < 0.05) between REST and POST in the EX-Group, no significant differences were detected in the ds. These results demonstrate that Vp is a stable parameter on which practitioners can base their training despite different levels of fatigue.

Clustering patients with late-life depression by blood glutathione-dependent enzymatic activities for stratification of a heterogeneous group

IntroductionWe have previously found significant alterations in activities of glutathione dependent enzymes in blood cells of patients with late-life depression (LLD) compared with age-matched controls.ObjectivesThe revealing subgroups of LLD patients by glutathione-metabolism enzymes’ activities in blood cells using cluster analysis.Methods LLD patients (n=101) of 60-86 age (69 patients with recurrent depression (RD), 23 with bipolar disorder (BD) and 9 patients with a single depressive episode (DE)) were assessed by Hamilton depression rating scale (HAMD-17), and Hamilton Anxiety Rating Scale (HARS). Activity levels of glutathione reductase (GR) and glutathione S-transferase (GST) were determined in patients’ platelets (-pl) and erythrocytes (-er). The control group consisted of 51 peoples 55-84 years old without mental pathology. Cluster analysis module of the STATISTICA software was used for clustering the patients by baseline blood parameters.Results Three clusters of patients were obtained: C1, n=39, C2, n=31, C3, n=31, differing significantly in all biochemical parameters (Kruskal-Wallis test, p&lt;0.001), except GST. When compared with control group by Mann-Whitney test, GST-pl, GST-er, and GR-er were significantly decreased in C1; GST-er was significantly increased in C2; GST-pl, GR-pl, and GR-er were significantly decreased in C3. Several significant correlations were found between the measured parameters and scores by HDRS or HAMD-17. In C1, baseline activity of GST-er correlated with total scores by HAMD-17 (R=0.335, p=0.043) after treatment. In C2, baseline activity of GR-er correlated with total scores by HARS (R=-0.376, p=0,037) after treatment and GR-pl correlated with delta scores by HAMD-17 under the treatment (R=0.484, p=0.006). No significant correlations were found in C3. Patients with BD distributed significantly unevenly between C1, C2, and C3, with significantly more BD patients clustering in C1 (61%) compared with C2 and C3 (Yetes-corrected Chi-square =7.73, p=0.0054), whereas patients with RD and DE distributed evenly.Conclusions Patterns of activity levels for glutathione-dependent enzymes in patients with BD differ from those in patients with RD and DE. Significant correlations of the measured biochemical parameters with scores by HDRS or HAMD-17 assessed after the treatment and evidenced for the treatment efficacy seem to be promising biomarkers for further evaluation of the treatment efficacy in heterogeneous group of LLD patients using the proposed approach to their stratification into subgroups.Disclosure of InterestNone Declared

Abstract 5141: Autoantibody profiling for predictive biomarkers for immune-related adverse events and clinical benefit in rare tumors treated with anti-PD-1 therapy

Abstract Background: Immune checkpoint inhibitors (ICIs) have changed the cancer treatment paradigm; however, with high frequency of immune-related adverse events (irAEs) and limited response rates in select patients. This underscores the unmet need for the development of biomarkers predictive for the development of irAEs and ICI response. Herein, we conducted autoantibody (AAb) profiling to assess baseline (BL) AAb associations with clinical benefit (CB) and irAEs in patients (pts) with rare tumors (RT) treated with programmed cell death protein 1 (anti-PD-1) therapy. Methods: AAbs against 1168 antigens were analyzed using the SeroTag antibody discovery technology. The study included 41 pts with RT who received anti-PD-1 therapy. We conducted a Significance Analysis of Microarray (SAM) to analyze the association between BL AAbs with irAEs and CB (defined as pts achieving complete response (CR), partial response (PR), or stable disease (SD) for ≥4 months by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1). AAb biomaker candidates were discovered based on filtering for SAM hits with p &amp;lt; 0.05 and a delta score |D| &amp;gt;2. Results: Table 1 outlines patients’ demographics. CB and irAEs were observed in 34% and 39% of patients, respectively. Eighteen BL AAbs were significantly associated with CB such as DNA ligase III (LIG3) and small nuclear ribonucleoprotein polypeptide (SNRPA) (p = 0.002 and p = 0.003, respectively). Likewise, 13 BL AAbs showed significant associations with any-grade irAEs, particularly AAbs to breast cancer 2 (BRCA2) DNA repair associated antigen and chromatin-modifying protein 4A (CHMP4A) (p = 0.001 and p = 0.003, respectively). Conclusion: The predictive potential of autoantibodies as biomarkers is promising. Further evaluation in larger cohorts is needed for validation of our findings and understanding the underlying mechanism. Table 1. Patients’ demographics Total patients n=41 Median age in years (range) 66 (35-84) Male n=19 Female n=22 Tumor type Carcinoma of unknown primary n=13 Squamous cell carcinoma of the skin n=9 Small cell malignancies of non-pulmonary origin n=7 Adrenocortical carcinoma n=6 Vascular sarcoma n=5 Other rare histology n=1 Clinical benefit CR, PR, or SD ≥ 4 months n=14 SD &amp;lt;4 months or progressive disease (PD) n=23 Not evaluable n=4 irAEs Yes n=16 No n=25 Citation Format: Mohamed H. Derbala, Joud Hajjar, Bettzy Stephen, Serdar A. Gurses, Evan Kwiatkowski, Petra Budde, Hans-Dieter Zucht, Manuel Bräutigam, Ann-Sophie Schubert, Behnaz Ahangarianabhari, Enedelia Rodriguez, Mohamed Gouda, Lilibeth Castillo, Abdulrazzak Zarifa, Jeffrey A. How, Justin T. Moyers, David S. Hong, Funda Meric-Bernstam, Aung Naing. Autoantibody profiling for predictive biomarkers for immune-related adverse events and clinical benefit in rare tumors treated with anti-PD-1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5141.

Efficacy of Intervention of Participation and Executive Functions (I-PEX) for Adults Following Traumatic Brain Injury: A Preliminary Pilot Randomized Controlled Trial

Background Participation restrictions following traumatic brain injury are associated with executive function (EF) deficits (EFDs). The subacute recovery phase’s specific characteristics (enhanced brain plasticity and impaired self-awareness) and contextual factors (inpatient setting) warrant adjusting cognitive rehabilitation protocols. The Intervention of Participation and Executive Functions (I-PEX) was designed to improve EFDs during subacute inpatient rehabilitation. Objective To investigate the I-PEX’s preliminary efficacy to improve EFDs during the performance of complex daily activities and enhance self-awareness, cognitive self-efficacy, participation, and quality of life postdischarge. Methods A pilot pre-, post-, and follow-up double-blind randomized controlled trial with 25 participants randomly allocated to the I-PEX (n = 13) or treatment-as-usual (n = 12) group. Cognitive assessments were administered pre- and postintervention, and quality of life and participation questionnaires 1-month postdischarge. Data analysis included repeated measures analysis of variance mixed design and independent t-tests, extracting effect sizes. Results Significant group-by-time interaction effect with a medium effect size was found for the primary outcome measure; EFs manifested in complex daily activities, indicating a larger improvement for the experimental group. The group effect was not significant. The experimental group’s mean delta score (pre–post improvement) was significantly higher (1.75 ± 2.89; t(23) = 2.52, P = .019), with a large effect size (d = 1.012, 95% confidence interval [0.166-1.840]). We found no significant group and interaction effects for EFs, self-awareness, and cognitive self-efficacy or no significant differences in participation or quality of life postdischarge. Conclusions Results provide initial evidence for the I-PEX efficacy in treating EFDs in the subacute phase and could help determine effect size for future studies. Clinical Trial Registry Number: ClinicalTrial.gov NCT04292925.

Enhanced Skin Assessment Methodology to Detect Early Tissue Damage and Prevent Pressure Injuries.

The purpose of this study was to evaluate a skin assessment technique, subepidermal moisture (SEM) assessment, to assess, identify, and prevent pressure injuries (PIs) in critically ill adults. This was a retrospective, descriptive, comparative research study. The sample comprised 69 critically ill adults; their mean age was 58.8years (SD 18.1years). The majority were male (n=40, 58%), 29 (42%) were African American (AA), and 36 (52%) were White. The study setting was a surgical trauma intensive care unit (STICU) in a southern US Gulf Coast academic level I trauma hospital. Data were collected from September to November 2021. We conducted a retrospective medical record review of subjects who had undergone SEM assessment. We also collected demographic and pertinent clinical information, including Braden Scale cumulative scores and subscale scores, documented PI prevention interventions, and PI occurrence and characteristics if developed within 7days of SEM measurement. We also evaluated whether PI prevention interventions were appropriate. To examine nurse perception of the SEM device, we conducted a web-based survey of nurses providing care in our facility's STICU. Comparison of responses was done using Fisher's test or Chi-square test, and the mean responses from groups were compared using t test. Thirty-five (57%) subjects had a sacral SEM delta ≥0.6; 14 (40%) were AA; 20 (57%) were White; and 11 (31%) had a hospital-acquired PI (HAPI) or present-on-admission (POA) PI. Among the 14 HAPI and POA PI subjects with sacral SEM delta, 11 (79%) had sacral SEM delta ≥0.6. Among 26 AA subjects with sacral SEM delta, 5 had a HAPI or POA PI, and of those, 4 (80%) had sacral SEM delta ≥0.6. A significant and negative correlation was observed between cumulative Braden Scale scores on day 2 and sacral SEM delta (r =-0.28, P =.03) and R heel delta (r =-0.29, P =.03) scores, indicating higher PI risk. Of the 35 patients with a sacral SEM delta ≥0.6, 24 (69%) subjects did not have appropriate PI prevention interventions. Nurses (n=13) indicated that the SEM device was easy to use and helped them perform an accurate skin assessment on patients with darker skin tones. This study demonstrates that SEM technology is beneficial to address racial disparities in skin assessment, enhance skin assessment accuracy beyond existing PI care, improve the accuracy of risk assessment, and promote appropriate location-specific PI prevention interventions.

Abstract B001: Does deep intronic splicing in breast cancer susceptibility genes contribute to breast cancer?

Abstract Breast cancer (BC) is the most common cancer and leading cause of cancer mortality in women. Average lifetime BC risk for a woman in the United States is 13%. However, pathogenic variants in BC susceptibility genes such as BRCA1/2, ATM, and RAD51C, or high polygenic risk scores substantially increase BC risk. Women with a family history of BC and/or ovarian cancer, BC &amp;lt; age 40, or BC and second primary tumor are considered high-risk with an increased likelihood of having a pathogenic variant in a BC susceptibility gene. Yet, more than 60% of women with high-risk BC test negative for coding variants. In these women, possible causal variation could be non-coding in deep intronic or regulatory regions, or cryptic structural variants (SV). To determine whether deep intronic splicing contributes to BC in high-risk women testing negative for pathogenic coding variants in BC genes, we analyzed the intronic sequences of 649 BRCA1/BRCA2 negative individuals with high-risk BC. The samples had undergone targeted capture sequencing of exons and introns of more than 100 target genes including ATM and RAD51C. From the 649 samples, we identified three intronic splicing variants in ATM and RAD51C in 10 samples (1.5%) that had SpliceAI delta scores &amp;gt;0.5 suggesting changes to splicing. One splicing donor gain variant, RAD51C c.145+246A&amp;gt;T, was found exclusively in women of self-reported African ancestry at a frequency of 0.047. In gnomAD, the variant was found exclusively in individuals of African ancestry at a frequency of 0.012. A 1.3-fold enrichment in variant frequency was observed in AFR women under 65 with breast cancer compared to age-matched cancer free controls in the All of Us dataset. Using lymphoblastoid-cell derived RNA from carriers of RAD51C c.145+246A&amp;gt;T, we performed RT-PCR and cDNA amplification targeting the exons surrounding the variant and observed a lengthened exon. Targeted amplicon sequencing also confirmed the presence of intronic sequence in the variant cDNA. The introduced intronic sequence contains a UGA stop codon 12 bp from the end of the exon which could led to loss of RAD51C function. We have created minigene vectors in the RHCglo background and are performing minigene splicing assays to validate the splicing changes in ATM due to intronic variants. Gene functional assays and association studies will be conducted to determine the functional effects and risk conferred by these variants. Understanding the level of contribution of deep intronic splicing in known BC susceptibility genes is critically important, as results impact sequencing offered to patients, and if positive, their medical management. Citation Format: Mwangala P. Akamandisa, Bradley Wubbenhorst, Kurt D'Andrea, Heather Symecko, Rhonda Gillette, Payal D. Shah, Angela R. Bradbury, Kara N. Maxwell, Susan M. Domchek, Katherine L. Nathanson. Does deep intronic splicing in breast cancer susceptibility genes contribute to breast cancer? [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B001.

Influence of pathogenic filaggrin variants on dupilumab treatment in atopic dermatitis

BackgroundPathogenic variants in filaggrin (FLG) are associated with an increased risk of atopic dermatitis (AD). ObjectiveTo evaluate the influence of FLG variants on the effectiveness of dupilumab treatment in AD. MethodsThis prospective observational study included adult AD patients treated with dupilumab from the BioDay Registry. FLG was analysed with smMIP targeted sequencing. Novel mutations were confirmed by Sanger sequencing. Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Numeric Rating Scale (NRS) pruritus, Dermatology Quality of Life Index (DLQI) and Patient Oriented Eczema Measure (POEM) were assessed at baseline, week 16 and 52. ResultsGenetic analysis of 285 included patients showed bi-allelic pathogenic variants (FLG-/-) in n=41 (14%), mono-allelic pathogenic variants (FLG-/+) in n=64 (23%) and wild-type alleles (FLG+/+) in n=180 (63%). Three novel pathogenic variants were found. We observed no clinically relevant differences in EASI, IGA, NRS pruritus, DLQI and total POEM scores for patients with and without pathogenic FLG variants at all time points. The FLG-/- group showed significantly higher POEM flaking and dryness scores at week 16 (p<0.001 and p=0.002, respectively) and 52 (p<0.001 and p=0.016, respectively) compared to FLG+/+, and also significant differences compared with FLG-/+, while differences in delta scores were non-significant. ConclusionThis study suggests that the effectiveness of dupilumab treatment in AD patients was not influenced by pathogenic FLG variants. However, patients with bi-allelic pathogenic FLG variants tended to have a drier skin before and during dupilumab treatment compared to patients with mono-allelic pathogenic variants or wild-type alleles.

Patients Aged 40 Years and Older Demonstrate Durable and Comparable Results to Patients Aged Less Than 40 Years After Primary Hip Arthroscopy for Femoroacetabular Impingement Syndrome: A Propensity Matched Study at Minimum 10-Year Follow-Up

To compare clinical outcomes and rates of secondary surgery, including revision hip arthroscopy and conversion to total hip arthroplasty (THA), after primary hip arthroscopy for femoroacetabular impingement syndrome (FAIS) in patients ≥40 years of age at minimum 10-year follow-up compared with a propensity-matched control group of patients <40 years. A retrospective cohort study was performed for patients who underwent primary hip arthroscopy for FAIS between January 2012 and February 2013. Patients ≥40 years old were propensity matched in a 1:1 ratio by sex and body mass index to patients <40 years old. Patient-reported outcomes (PROs) including Hip Outcome Score for Activities of Daily Living and Sports-Specific subscales, modified Harris Hip, International Hip Outcome Tool-12, and Visual Analog Scale for Pain and Satisfaction were collected. Rates of minimal clinically important difference (MCID) and patient-acceptable symptomatic state (PASS) achievement at 10 years were evaluated and compared between groups. Rates of secondary surgery including revision hip arthroscopy and conversion to THA were evaluated. Gross survivorship between cohorts was evaluated using a Kaplan-Meier curve. Fifty-three patients aged ≥40 (age 48.3 ± 5.8 years) were successfully matched to 53 patients aged <40 (age: 28.9 ± 7.2, <0.001). There were no other preoperative group differences regarding patient demographics, characteristics, or radiographic findings. Both groups demonstrated significant improvement regarding all PROs at a minimum of 10 years' follow-up (P < .001 for all). No significant difference was noted between cohorts regarding any delta (preoperative to 10-year postoperative) scores (P > .05 for all). High rates of MCID and PASS achievement were achieved in both cohorts, with no significant differences in any PRO measure (P > .05 for all). No significant differences in rates of complications (age ≥40: 2.0%, age <40: 7.7%, P= .363), rates of revision (age ≥40: 7.5%, age <40: 9.4%, P= .999), orconversion to THA (age ≥40: 13.2%, age <40: 3.8%, P= .161) were identified. On Kaplan-Meier analysis, no significant difference (P=.321) was demonstrated in overall gross survivorship between cohorts. Patients with age≥40 with FAIS undergoing primary hip arthroscopy demonstrated durable and comparable 10-year PRO and rates of MCID and PASS achievement compared with a propensity-matched cohort of age <40 counterparts. Level III, retrospective comparative prognostic trial.

Relevance of multidimensional dyspnea assessment in the context of pulmonary rehabilitation.

Objectives: While dyspnea is the main symptom in chronic obstructive pulmonary disease (COPD), it is often inadequately evaluated in pulmonary rehabilitation (PR), as it is typically measured using only the impact dimension (ID). However, dyspnea is a multidimensional construct including perception (PD) and emotional (ED) domains. Our work aimed to study the complementarity of dyspnea dimensions and their respective ability to identify different evolutions during PR. Methods: 145 people with COPD attending PR were included in this retrospective study. Dyspnea scores from the modified Medical Research Council scale (ID) and the Multidimensional Dyspnea Profile questionnaire (PD/ED), exercise capacity, quality of life at the start (T1) and the end of PR (T2) were collected from existing databases/medical files. The evolution of each dyspnea dimension was evaluated using the delta score between T2-T1. PR response was defined using the minimal clinically important difference. Results: Our results show that each dyspnea dimension was associated with different health-outcomes. Positive correlations were found between PD-ED at baseline and between their T2-T1 delta score (ρ = 0.51; ρ = 0.41 respectively, p < .01), but there was no significant correlation between ID-PD or -ED (p > .05). 51% of the patients did not respond on ID, but 85% of them nonetheless responded on either PD or ED. Finally, 92% of patients responded on at least one dimension after PR. Discussion: Our study emphasizes the significance of assessing each dimension of dyspnea independently and complementary, as dimensions are associated with different elements and evolve differently under PR effects. This approach is crucial to identifying weak points and allows professionals to focus on program elements that most effectively address the specific dimension causing problems.

Longitudinal analysis of culture of patient safety survey results in surgical departments.

There is a need for improved methodologies on how to longitudinally analyze, interpret and learn from the Surveys on Patient Safety Culture™ (SOPS), developed by the Agency for Healthcare Research and Quality (AHRQ). Typically, SOPS quantify results by the percentage of positive responses, but this approach may miss insights from neutral or negative feedback. The SOPS were distributed every two years from 2011 to 2022 to all hospital staff at one academic institution from perioperative services. Differences between rates of "positive" and "negative" scores ("Delta"), and "neutral" responses over time were calculated. The coefficient of determination (R 2) was used to assess the correlation strength of the positive scores as the primary outcomes provided by the SOPS and Delta values over time. Finally, we evaluated patterns (crossing and converging [indicating "worrisome" patterns] vs. diverging [suggesting "desirable" pattern] vs. stable [suggesting "neutral" pattern]) of the longitudinal scores. A total of 1,035 responses were analyzed [51 and 40 survey items for SOPS v1 and v2 (2022 only), respectively]. Comparing the R 2 values of the positive only scores to the Delta scores demonstrated a change in effect size for "Nonpunitive Response to Error" (R 2 = 0.290 vs. 0.420). Of the 13 specific categories measured through SOPS, plotting negative vs. positive values elucidated 2 crossing, 2 converging and 2 diverging patterns indicating both a decrease in positive responses and an increase in negative responses rather than neutral. Longitudinal analysis of the SOPS using the directional measures, Delta and pattern trends can provide organizations with additional key insights regarding culture of patient safety.

Associations between NIH‐Toolbox Flanker test and the Picture Sequence Memory Test and multimodal Alzheimer’s disease biomarkers in cognitively unimpaired individuals

AbstractBackgroundAlzheimer’s disease (AD) pathologic changes start years before cognitive symptoms appear; however, some early cognitive changes can be detected. We aimed to investigate the association between performance changes in two NIH‐Toolbox tests, Flanker test and Picture Sequence Memory Test (PSMT), and baseline AD biomarkers in cognitively unimpaired (CU) individuals.MethodWe studied 356 ALFA+ participants (mean [SD] age = 60.8 [4.72] years). The rate of cognitive change after 3 years was measured through delta scores (Follow‐up ‐ Baseline). Biomarker data included cerebrospinal fluid (CSF) β‐amyloid (Aβ) 42/40 ratio, phosphorylated‐tau‐181 (p‐tau), neurofilament light (NfL), and neuroimaging (MRI‐based cortical thickness AD signature, hippocampal volumes, and FDG‐PET‐SUVR (fluorodeoxyglucose ‐ positron emission tomography ‐ standardized uptake value ratio) metaROI) measures (Table 1). CSF Aβ40, Aβ42 and NfL were measured with the exploratory NTK robust immunoassays, while CSF p‐tau181 was measured using the electrochemiluminescence Elecsys® Phospho‐Tau (181P) CSF immunoassays (Roche Diagnostics International Ltd). AT groups were defined according to published cut‐offs (A+ Aβ 42/40 &lt;0.071; T+: p‐tau &gt; 24 pg/ml) (Milà‐Alomà et al., 2020). Baseline biomarker levels were used as predictors of cognitive change in linear models. Interactions and stratified analyses were also explored.ResultAT groups significantly differed in the change in the Flanker Test (p = 0.002), driven by poorer performance in A+T+ vs A‐T‐ groups (p = 0.001) (Figure1). Higher cortical thickness predicted better longitudinal cognitive performance in the Flanker Test in the whole group (p = 0.020; β = 0.983). We found a significant interaction between AT group and FDG‐PET‐SUVR (p = 0.042), and the right hippocampal volume (p = 0.001), but no significant associations were observed in analyses stratified by AT (Figure2A). A negative association between right hippocampal volume and Flanker test change was observed in A+T‐ (p = 0.026) and A+T+ (p = 0.029) (Figure2B). No associations were observed between the PSMT and AD biomarkers (Figure 1).ConclusionOur findings support the hypothesis that executive function show a steeper decline than episodic memory in CU individuals with evidence of pathologic AD biomarkers levels. We observed a negative association between executive change and neuroimaging neurodegeneration markers in A+T‐ and A+T+ groups. This is in accordance with previous studies that found non‐linear associations in incipient AD pathology.

Domain‐specific subtle cognitive decline associations with cerebrospinal fluid and plasma β‐amyloid and p‐tau Alzheimer’s disease biomarkers in cognitively unimpaired individuals

AbstractBackgroundPresence of Alzheimer’s disease (AD) core pathology, β‐amyloid (Aβ) and p‐tau, has been proven to impact cognitive function even in cognitively unimpaired (CU) individuals. Although the Aβ and p‐tau (AT) effect has been mainly associated with memory function, recent evidence (Tideman, P., 2022. Neurology) suggested that Aβ levels were associated independently of p‐tau with the cross‐sectional performance in executive functioning. The aim of the present study was to explore specific associations of cerebrospinal fluid (CSF) and plasma Aβ and p‐tau baseline levels with the longitudinal change in several cognitive domains in a sample of CU individuals at increased risk of AD.MethodWe analyzed the associations of baseline CSF Aβ42/40, and p‐tau181 as well as plasma Aβ42/40, and p‐tau231 levels, with domain‐specific cognitive changes 3 years after baseline in 337 CU participants from the ALFA+ study. We defined AT groups (A‐T‐, A+T‐, and A+T+) using CSF levels, and the A‐T‐ group’s baseline performance served as reference to compute z‐scores for Visual Processing, Semantic Fluency, Executive Functioning, Episodic Memory, and Attentional Processing. Delta scores were computed by subtracting baseline from follow‐up scores and then compared among AT groups by means of ANCOVAs. Multiple linear regressions were performed on the whole sample using CSF Aβ42/40, p‐tau181 and plasma Aβ42/40, p‐tau231 as predictors of change in cognitive function.ResultA+T+ individuals showed a significant decline in Executive Function (p = 0.005, Cohen’s d = 0.716), and Attentional Processing (p = 0.032, Cohen’s d = 0.563), but not in Episodic Memory (p = 0.334) when compared with A‐T‐ individuals. In the whole sample, CSF Aβ42/40 was associated independently of p‐tau181 with a decline in Semantic Fluency (β = 6.284, p = 0.013), Attentional Processing (β = 3.828, p = 0.020), and Episodic Memory (β = 3.513, p = 0.004). Plasma p‐tau231 levels were associated with a decline in Semantic Fluency (β = ‐0.413, p = 0.045). CSF p‐tau181 and plasma Aβ42/40 were not associated with cognitive changes.ConclusionExecutive Function and Attentional Processing were more sensitive than Episodic Memory in capturing the early subtle cognitive changes in CU individuals with underlying AD pathology. Attentional Processing was the only cognitive domain associated both with the status of AD biomarkers and with the effect of CSF Aβ levels independently of p‐tau.

BIO-RSA vs metal augmented baseplate in shoulder osteoarthritis with multiplanar glenoid deformity: a comparative study of radiographic findings and patient outcomes.

Reverse shoulder arthroplasty (RSA) requiring extensive reaming to address severe glenoid bone loss increases the risk of glenoid medialization and baseplate failure. We hypothesized that i) metal augmented baseplate prevents the medialization of the joint line and preserves glenoid bone stock similarly to BIO-RSA; ii) bone graft viability and healing in BIO-RSA patients become compromised over time. Eighty-one patients (83 shoulders) underwent glenoid lateralization with bone (BIO-RSA group, 44) or metal augmented baseplate (MIO-RSA group, 39) and a minimum follow-up of 24 months were included. The orientation and direction of glenoid erosion was identified and recorded using computerized 3D planning. Active range of motion, and the Western Ontario Osteoarthritis of the Shoulder (WOOS) index were assessed before arthroplasty and at the last follow-up visits. Radiographic changes around the glenoid and humeral components were assessed. Healing and thickness of bone graft were evaluated by predefined criteria. Postoperative global glenoid inclination (β angle) and retroversion were also measured. Delta scores of active anterior elevation were higher in the MIO-RSA group (p= 0.027). The differences in the other planes of shoulder motion and in WOOS index scores between the groups were not significant. Preoperative glenoid retroversion was higher in BIO-RSA patients, glenoid inclination was similar in both groups. Type B2 and B3 glenoids had a posterior-central (91%) and posterior-superior (90%) erosion with a mean posterior humeral head subluxation of 76% and 78%, respectively. The direction of erosion in Type E2 and E3 glenoids was posterior-superior, with a mean posterior humeral head subluxation of 74%. The rate of high position of the glenosphere was higher in the BIO-RSA group (p = 0.022), while the values of β angle and postoperative retroversion were similar in the two groups. BIO-RSA group showed radiolucent lines < 2mm around the bone graft in 16 patients (36.4%) and decreased thickness in 15 (34.1%). Incomplete baseplate seating was found in 4 MIO-RSA patients (10%). We found higher rate of humerus condensation lines in MIO-RSA patients (p= 0.01) and higher rate of cortical thinning and tuberosity resorption in the BIO-RSA group (p= 0.027 and p = 0.004, respectively). Metal augmented glenoid is a suitable alternative to BIO-RSA to preserve bone and prevent the medialization of the joint line in arthritic glenoid with multiplanar glenoid deformity. Bone and metal augmentation provided satisfactory clinical outcomes. Bone graft resorption in BIO-RSA patient raise concern about the risk of baseplate loosening and requires further long term studies.