Subset Scores Research Articles

529 - Worsening of itch before flaring in patients with moderate-to-severe atopic dermatitis treated with abrocitinib: a post hoc analysis of the phase 3 JADE REGIMEN trial

Abstract Background Patients with atopic dermatitis (AD) often experience a disease course that fluctuates in severity over time, with periods of remission interrupted by flares. Abrocitinib, an oral, once-daily Janus kinase-1 selective inhibitor is approved for the treatment of patients with moderate-to-severe AD. In the phase 3 JADE REGIMEN (NCT03627767) trial, patients achieved an initial response with abrocitinib 200 mg, which was maintained with continued treatment with abrocitinib 200 mg, reduced-dose treatment with abrocitinib 100 mg, or placebo (treatment withdrawal). Following an initial efficacy response, over the 40-week maintenance period some patients across all treatment groups, but predominantly those who switched to placebo, experienced flares, defined as ≥50% loss of Eczema Area and Severity Index response at week 12 and Investigator’s Global Assessment score ≥2, and received rescue therapy. The utility of itch response as a predictor of an upcoming flare in these patients has not yet been determined. Objective To assess itch response before flaring in patients treated with abrocitinib who experienced a flare during the maintenance period of JADE REGIMEN. Methods In JADE REGIMEN, patients aged ≥12 years with moderate-to-severe AD who responded to abrocitinib 200 mg during open-label induction for 12 weeks were randomly assigned 1:1:1 to receive abrocitinib 200 mg, abrocitinib 100 mg, or placebo for up to 40 weeks (maintenance period). Patients who experienced a flare during maintenance received rescue treatment with abrocitinib 200 mg plus topical medicated therapy in an open-label 12-week period. This post hoc analysis evaluated mean itch scores in subsets of patients who did or did not experience flares during the maintenance period. Itch was assessed using the Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD; © 2016 Pfizer Inc. All rights reserved.) itch numerical rating scale (NRS) item which asked patients, “How itchy was your skin over the past 24 hours?” on a scale from 0 (not itchy) to 10 (extremely itchy). PSAAD scores were collected daily via an e-diary during the screening period and from day 1 through the end of study. Daily itch scores were analyzed at baseline (day of randomization to maintenance treatment groups), from 14 days prior to flaring (from day –14 to day –1), and on the day of flare (day 0) in patients who experienced a flare, and at baseline through 274 days post-randomization in patients who did not experience a flare. Results Of 1233 patients treated with abrocitinib 200 mg in the open-label induction period, 798 (65%) achieved response at week 12 and were randomized to abrocitinib 200 mg (n=266), abrocitinib 100 mg (n=265), or placebo (n=267) in the maintenance period. Across all treatment groups, 442 (55%) patients did not experience a flare and 356 (45%) patients experienced a flare during maintenance. Among patients who did not experience a flare, mean PSAAD itch NRS score remained consistently around 2, with a mean score of 1.5 on day 1 of randomization and 2.1 on day 274 post-randomization. Among patients who experienced a flare, mean PSAAD itch NRS score at baseline was 1.8, which increased to 4.4 on day –14 (14 days before flaring) and continued to increase up to the day of flare (day 0 mean score: 6.4). Conclusions After a successful initial response with abrocitinib, mean itch scores remained stable over time among patients who did not flare. Patients who experienced a flare had worsening of itch from 2 weeks before until the onset of flare. Monitoring of itch may predict onset of flares in patients with moderate-to-severe AD and help inform treatment management or optimization to achieve disease control.

NegotiAge: Development and pilot testing of an artificial intelligence-based family caregiver negotiation program.

Family caregivers of people with Alzheimer's disease experience conflicts as they navigate health care but lack training to resolve these disputes. We sought to develop and pilot test an artificial-intelligence negotiation training program, NegotiAge, for family caregivers. We convened negotiation experts, a geriatrician, a social worker, and community-based family caregivers. Content matter experts created short videos to teach negotiation skills. Caregivers generated dialogue surrounding conflicts. Computer scientists utilized the dialogue with the Interactive Arbitration Guide Online (IAGO) platform to develop avatar-based agents (e.g., sibling, older adult, physician) for caregivers to practice negotiating. Pilot testing was conducted with family caregivers to assess usability (USE) and satisfaction (open-ended questions with thematic analysis). Development: With NegotiAge, caregivers progress through didactic material, then receive scenarios to negotiate (e.g., physician recommends gastric tube, sibling disagrees with home support, older adult refusing support). Caregivers negotiate in real-time with avatars who are designed to act like humans, including emotional tactics and irrational behaviors. Caregivers send/receive offers, using tactics until either mutual agreement or time expires. Immediate feedback is generated for the user to improve skills training. Pilot testing: Family caregivers (n = 12) completed the program and survey. USE questionnaire (Likert scale 1-7) subset scores revealed: (1) Useful-Mean 5.69 (SD 0.76); (2) Ease-Mean 5.24 (SD 0.96); (3) Learn-Mean 5.69 (SD 0.74); (4) Satisfy-Mean 5.62 (SD 1.10). Items that received over 80% agreements were: It helps me be more effective; It helps me be more productive; It is useful; It gives me more control over the activities in my life; It makes the things I want to accomplish easier to get done. Participants were highly satisfied and found NegotiAge fun to use (91.7%), with 100% who would recommend it to a friend. NegotiAge is an Artificial-Intelligent Caregiver Negotiation Program, that is usable and feasible for family caregivers to become familiar with negotiating conflicts commonly seen in health care.

An Assessment of the One-Month Effectiveness of Telehealth Treatment for Opioid Use Disorder Using the Brief Addiction Monitor.

Telehealth treatment with medication for opioid use disorder (teleMOUD) was made possible with regulations following the COVID-19 pandemic that permitted prescribing buprenorphine without an in-person visit. This study evaluates the self-reported outcomes of patients treated by teleMOUD using the Brief Addiction Monitor (BAM), a 17-question tool that assesses drug use, cravings, physical and psychological health, and psychosocial factors to produce 3 subset scores: substance use, risk factors, and protective factors. Patients treated by a teleMOUD provider group operating in >30 states were asked to complete an app-based version of BAM at enrollment and at 1 month. Patients who completed both assessments between June 2022 and March 2023 were included. A total of 2556 patients completed an enrollment BAM and 1447 completed both assessments. Mean number of days from baseline BAM to follow-up was 26.7 days. Changes were significantly different across most questions. The substance use subscale decreased from mean 2.6 to 0.8 (P < .001), the risk factors subscale decreased from mean 10.3 to 7.5 (P < .001), and the protective factors subscale increased from mean 14.3 to 15.0. (P < .001). Substance use and risk factor subscale changes were significant across all sex and age groups, while protective factors subscale did not improve for those <25 and >54 years. Patient reports of at least 1 day of illegal use or misuse decreased, including marijuana (28.1% vs 9.0%), cocaine/crack (3.9% vs 2.6%), and opioids (49.8% vs 10.5%). Among patients treated by teleMOUD who completed assessments at enrollment and 1 month, there was improvement in drug use, risk factor, and protective factor scores.

Modified-Weight Healthy Eating Index-2015 Scores Are More Strongly Associated With Mortality Risk Than Standard Scores

BackgroundVarious diet quality scores are consistently and similarly associated with mortality risk. Emerging evidence suggests that individual diet quality components are differentially associated with mortality risk, but it is unclear whether or not modified weights reflective of relative component differences would strengthen mortality associations. ObjectiveThis study examined whether Healthy Eating Index 2015 (HEI-2015) scores with modified (vs standard) component weights are differentially associated with mortality risk. DesignThis was a longitudinal analysis of the National Health and Nutrition Examination Survey III (1988-94) with 23 years of mortality follow-up. The HEI-2015 and modified-weight scores were calculated from one 24-hour recall. The a priori Key Facets HEI was a subset score equivalently weighting fruits, vegetables, whole grains, and seafood and plant proteins. In the least absolute shrinkage and selection operator regression-weighted HEI, components were assigned weights reflecting relative mortality risk associations. Participants/settingAnalyses included 10,789 US adults (aged 20 years and older) who were not pregnant and without prior diabetes, cancer, cardiovascular disease, or chronic kidney disease diagnoses. Main outcome measuresAll-cause and cardiovascular disease mortality risk were the primary outcomes examined. Statistical analyses performedThree energy-adjusted HEI scores were assigned to quintiles; covariate-adjusted sex-stratified Cox models with age as the timescale assessed associations between and trends across quintiles of HEI scores and all-cause and cardiovascular disease mortality risk. ResultsModified-weight HEI scores were associated with 23% to 38% reduced all-cause mortality risk in the highest vs lowest quintile, whereas comparisons were only significant for women (Key Facets P = 0.02 and least absolute shrinkage and selection operator regression-weighted P = 0.001; for men P = 0.06 on both scores), trends across quintiles of modified-weight scores were significant for men and women. The HEI-2015 was not significantly associated with all-cause mortality risk, and none of the scores were associated with cardiovascular disease mortality risk. ConclusionsOnly modified-weight HEI scores were associated with reduced all-cause mortality risk. Findings suggest modified diet quality weighting schemes warrant further examination to determine their replicability.

Synergistic disruption of BTK and BCL-2 causes apoptosis while inducing ferroptosis in double-hit lymphoma

Double-hit lymphoma (DHL) is an aggressive subset of Diffuse Large B-cell Lymphoma (DLBCL) with poor outcomes and without satisfying treatment options. BTK inhibitor monotherapy is ineffective to suppress aggressive lymphoma. Hence, combination with other potential agents is warranted. Here, we demonstrated the second generation of BTK inhibitor, zanubrutinib, and a BCL-2 inhibitor, navitoclax, worked in synergistic manner to suppress DHL. Comprehensive in silico approach by interrogating single-cell to bulk-level profiling was employed along with in vitro and in vivo validation in DHL cell lines. Ablation of BTK enhanced sensitivity to navitoclax and suppressed proliferation of DHL cells. Combination of second generation of BTK inhibitor with navitoclax synergistically suppressed DLBCL cells with higher synergy score in DHL subset. The drug combination triggered apoptosis and ferroptosis, with the latter being characterized by reactive oxygen species (ROS) accumulation, extensive lipid peroxidation, and depletion of reduced glutathione. Moreover, ablation of BTK sensitized DHL cells to ferroptosis. Mechanistically, disruption of BTK and BCL-2 triggered ferroptosis by downregulating NRF2 and HMOX1, while deactivating GPX4. Combination of zanubrutinib and navitoclax effectively suppressed tumor growth in vivo. Our data suggest that zanubrutinib and navitoclax synergistically suppressed DHL by inducing apoptosis and ferroptosis.

Declining Gait Speed is associated with Deteriorating Executive Performance in people with Mild Cognitive Impairment

AbstractBackgroundThe Motoric Cognitive Risk Syndrome has highlighted the link between cognitive and motor performance, and the associated incremental higher risk of developing dementia. There is considerable debate regarding what aspects of cognition (working memory, executive function, attention) are most associated with gait changes. This study investigates the relationship between mobility scores and cognitive profiles in individuals with Mild Cognitive Impairment (MCI) specifically with regard to executive performance and amnestic/non‐amnestic profiles.MethodParticipants diagnosed with MCI, (Clinical Dementia Rating scale global score of ≤0.5, sum of boxes score ≤4.0), attending a regional specialist memory service had a three‐meter Timed Up and Go (TUG) gait assessment and multi‐domain neuropsychiatric assessment undertaken. Amnestic neuropsychiatric profile was defined as Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) delayed memory subset score &lt;1SD i.e. ≤16th centile below norm for age/ education. Executive function performance was assessed using the Executive Interview (EXIT‐25) where higher scores reflect poorer executive performance.ResultData was reviewed for 161 patients with MCI; 53% (86/161) women. 80% (129/161) had an amnestic neuropsychiatric profile, mean age 73.8 ±7.2 (51‐94). 20% (32/161) had non‐amnestic MCI, mean age 74 ±7.07 (60‐87). There was no significant difference in TUG results between amnestic and non‐amnestic MCI patients (11.2 ±3.3 vs 10.7 ±3.1 p = NS). There was a significant increase in TUG values with worsening executive function performance [EXIT‐25 score 0–9 (88/161) mean TUG = 10.5 ±3.3 seconds vs EXIT‐25 score 10–14 (43/161) mean TUG = 11.9 ±2.8 seconds vs EXIT‐25 score 15–25 (30/161) mean TUG = 12.1 ±3.9 seconds; p = 0.021] which persisted after controlling for age, gender and other relevant cofactors.ConclusionReflective of the importance of frontal lobe integration to the respective tasks, subtle differences in gait performance are associated with executive function performance regardless of predominant amnestic or non‐amnestic MCI profile.

Fat mass index as a screening tool for the assessment of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is replacing hepatitis B as the leading cause of chronic liver disease in China. The purpose of this study is to select good tools to identify NAFLD from the body composition, anthropometry and related routine clinical parameters. A total of 5076 steelworkers, aged 22–60 years, was included in this study. Body fat mass was measured via bioelectrical impedance analysis (BIA) and fat mass index (FMI) was derived. Ultrasonography method was used to detect hepatic steatosis. Random forest classifier and best subset regression were used to select useful parameters or models that can accurately identify NAFLD. Receiver operating characteristic (ROC) curves were used to describe and compare the performance of different diagnostic indicators and algorithms including fatty liver index (FLI) and hepatic steatosis index (HSI) in NAFLD screening. ROC analysis indicated that FMI can be used with high accuracy to identify heavy steatosis as determined by ultrasonography in male workers [area under the curve (AUC) 0.95, 95% CI 0.93–0.98, sensitivity 89.0%, specificity 91.4%]. The ability of single FMI to identify NAFLD is no less than that of combination panels, even better than the combination panel of HSI. The best subset regression model that including FMI, waist circumference, and serum levels of triglyceride and alanine aminotransferase has moderate accuracy in diagnosing overall NAFLD (AUC 0.83). FMI and the NAFLD best subset (BIC) score seem to be good tools to identify NAFLD in Chinese steelworkers.

Association of pain and clinical factors on disability and quality of life in systemic sclerosis: A cross-sectional study from Turkish League Against Rheumatism Network.

In this study, we aimed to evaluate the factors associated with disability and quality of life (QoL) in Turkish patients with systemic sclerosis (SSc). Between January 2018 and January 2019, a total of 256 SSc patients (20 males, 236 females; mean age: 50.9±12.4 years; range, 19 to 87 years) who were diagnosed with SSc were included in the study. Disability and health-related QoL (HRQoL) were evaluated by the Health Assessment Questionnaire (HAQ), scleroderma HAQ (SHAQ), Duruöz Hand Index (DHI), and Short Form-36 (SF-36). Linear regression analysis methods were used to describe factors associated with disability and QoL of the patients. All disability scores were higher and HRQoL scores were lower in diffuse cutaneous SSc patients compared limited cutaneous SSc, and differentiations were significant (p=0.001 and p=0.007). In multiple regression, pain (VAS) was the strongest predictor for high disability and low QoL scores (p<0.001) as HAQ (β=0.397, 0.386, 0.452), SHAQ (β=0.397, 0.448, 0.372), DHI (β=0.446, 0.536, 0.389), PCS (β=-0.417,-0.499, -0.408) and MCS (β=-0.478, -0.441, -0.370) in combined, lcSSc and dcSSc patients respectively. The factors associated with high disability and low QoL scores were forced vital capacity for HAQ (β=-0.172, p=0.002) and SF-36 PCS (β=0.187, p=0.001); disease duration for HAQ (β=0.208, p<0.001), DHI (β=0.147, p=0.006), and SF-36 PCS (β=-0.134, p=0.014); 6-minute walk test for HAQ (β=-0.161, p=0.005) and SF-36 PCS (β=0.153, p=0.009); and modified Rodnan skin score for SHAQ (β=0.250, p<0.001) and DHI (β=0.233, p<0.001) in SSc patients. Diffusing capacity of the lungs for carbon monoxide for HAQ (β=-0.189, p=0.010) and SHAQ (β=-0.247, p=0.002); erythrocyte sedimentation rate for DHI (β=0.322, p<0.001); age for SF-36 PCS (β=-0.221, p=0.003) and body mass index for SF-36 PCS (β=-0.200, p=0.008) and MCS (β=-0.175, p=0.034) were the other variables associated with high disability or low QoL scores in SSc subsets. Clinicians should consider the management of the pain and its sources as a key to improve better functional state and quality of daily life in SSc.

Association between white matter microstructure and cognitive function in patients with methamphetamine use disorder.

Methamphetamine use disorder (MUD) has been associated with broad neurocognitive impairments. While the cognitive impairments of MUD have been demonstrated, the neuropathological underpinnings remain inadequately understood. To date, the published human diffusion tensor imaging (DTI) studies involving the correlation between diffusion parameters and neurocognitive function in MUD are limited. Hence, the present study aimed to examine the association between cognitive performance and white matter microstructure in patients with MUD. Forty-five patients with MUD and 43 healthy controls (HCs) completed their demographic information collection, cognitive assessments, and DTI imaging. DTI images were preprocessed to extract fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) of various fiber tracts. Univariate tests were used to examine group differences in cognitive assessments and DTI metrics. Linear regression was used to examine the relationship between these two metrics. The results revealed that patients with MUD had lower subset scores of the MATRICS Consensus Cognitive Battery (MCCB), which reflects five cognitive domains: processing speed, attention, verbal learning, visual learning, problem-solving. Patients with MUD also had significantly higher AD, MD, and RD values of the left superior longitudinal fasciculus than HCs. Furthermore, the RD value of the left superior longitudinal fasciculus was a significant predictor of processing speed and problem-solving ability, as shown by the digit-symbol coding test and NAB-Mazes scores, respectively. Findings extended our understanding of white matter microstructure that is related to neurocognitive deficits in MUD and provided potential targets for the prevention and treatment of this chronic disorder.

1062 GAIT SPEED AND EXECUTIVE PERFORMANCE IN PEOPLE WITH MILD COGNITIVE IMPAIRMENT

Abstract Introduction The Motoric Cognitive Risk Syndrome has highlighted the link between cognitive and motor performance, and the associated incremental higher risk of developing dementia. There is considerable debate regarding what aspects of cognition (working memory, executive function, attention) are most associated with gait changes. This study investigates the relationship between mobility scores and cognitive profiles in individuals with Mild Cognitive Impairment (MCI) specifically with regard to executive performance and amnestic/non-amnestic profiles. Method Participants diagnosed with MCI, (Clinical Dementia Rating scale global score of ≤0.5, sum of boxes score ≤ 4.0), attending a regional specialist memory service had a three-meter Timed Up and Go (TUG) gait assessment and multi-domain neuropsychiatric assessment undertaken. Amnestic neuropsychiatric profile was defined as Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) delayed memory subset score &amp;lt; 1SD i.e. ≤16th centile below norm for age/education. Executive function performance was assessed using the Executive Interview (EXIT-25) where higher scores reflect poorer executive performance. Results Data was reviewed for 161 patients with MCI; 53% (86/161) women. 80% (129/161) had an amnestic neuropsychiatric profile, mean age 73.8 ± 7.2 (51–94). 20% (32/161) had non-amnestic MCI, mean age 74 ± 7.07 (60–87). There was no significant difference in TUG results between amnestic and non-amnestic MCI patients (11.2 ± 3.3 vs 10.7 ± 3.1 p = NS). There was a significant increase in TUG values with worsening executive function performance [EXIT-25 score 0–9 (88/161) mean TUG = 10.5 ± 3.3 seconds vs EXIT-25 score 10–14 (43/161) mean TUG =11.9 ± 2.8 seconds vs EXIT-25 score 15–25 (30/161) mean TUG = 12.1 ± 3.9 seconds; p = 0.021] which persisted after controlling for age, gender and other relevant cofactors. Discussion Reflective of the importance of frontal lobe integration to the respective tasks, subtle differences in gait performance are associated with executive function performance regardless of predominant amnestic or non-amnestic MCI profile.

The correlation between proteoglycan 2 and neuropsychiatric systemic lupus erythematosus

The proposed pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) mainly includes ischemia and neuroinflammation mechanisms. Protein encoded by Proteoglycan 2 (PRG2) mRNA is involved in the immune process related to eosinophils, also being found in the placenta and peripheral blood of pregnant women. We evaluated the correlation between PRG2 and NPSLE for the first time and found that PRG2 protein was overexpressed in the serum of patients with NPSLE and correlated with the SLE disease activity index (SLEDAI) subset scores of psychosis. Moreover, we investigated the correlation between hippocampal PRG2 level and hippocampally dependent learning and memory ability in MRL/lpr mice, and discovered that the number of PRG2+GFAP+ astrocytes in the cortex and hypothalamus and the number of PRG2+IBA-1+ microglia in the hippocampus and cortex significantly increased in the MRL/lpr mice. These data provided a reference for the follow-up exploration of the role of PRG2 in SLE or other diseases.

The Influence of Caffeine Consumption and the Polymorphisms of DRD2 and ADORA2A Genes on Fine Motor Task Performance

Caffeine is the most commonly used psychoactive drug and has been associated with increased attention, focus and motor activity through adenosine receptor (ADORA2A) antagonism. ADORA2A and DRD2 are co‐localized in the central nervous system and blocking the adenosine receptor has been show to act as a dopamine receptor (DRD2) agonist which influence focus and motor tasks. Finally, single nucleotide polymorphisms of ADORA2A varies in response to caffeine which may influence the dopamine response.PURPOSEThe purpose of this study was to determine the influence of caffeine as well as the effects of the adenosine (ADORA2A) and dopamine (DRD2) polymorphisms during unilateral and bilateral motor tasks.METHODSThirty‐four subjects (age: 18‐23) were recruited and gave informed consent to participate in the study. An oral bolus of caffeine (CAF), 5mg•kg‐1, or placebo (PLA), maltodextrin, was given in a double‐blind, randomized, and counterbalanced design 60 min prior to testing. The Purdue Pegboard Test (PPT) was used to assess the unilateral movements by placing pegs with the right hand and left hand; this was coded for dominant and non‐dominant. Bilateral movements were also assessed with PPT by placing pegs with both hands and during a peg/washer/collar assembly task. Buccal cells were obtained using a 0.9% NaCl mouth rinse, spun down, and lysed via proteinase k. DNA was extracted using QiAmp Mini spin columns with amplification and allelic discrimination for ADORA2A (rs5751876) and DRD2 (rs1800497) obtained via One‐Step qPCR. All samples were run in duplicate with negative and positive controls. Data was analyzed using a 2 (condition) x 2 (SNP) with repeated measures for each subset of the PPT and a 2 (condition) x 2 (ADORA2A) x 2 (DRD2) with repeated measures to for each subset to find the interaction of ADORA2A and DRD2, p&lt;0.05)RESULTSFor the ADORA2A SNP, the main effect of caffeine demonstrated a significant increase in performance for each unilateral task from placebo to caffeine trials, dominant hand (16.4+1.6 to 17.4, p&lt;0.01), non‐dominant hand, (15.8+1.8 to 16.0, p&lt;0.05) and combined (45.5+4.3 to 46.2, p&lt;0.05). No difference was found for the bilateral movements. ADORA2A interaction effects demonstrated that TT genotype scored better under the caffeine condition, 15.8+1.9 to 16.2+ 0.8 for placebo and caffeine respectively. For DRD2, there were no significant differences in the main effects or interaction effects. The 3‐way ANOVA, condition x ADORA2A x DRD2, demonstrated no significant differences for the main effects or interaction effects.DISCUSSIONA bolus of caffeine improved performance for the test subset scores that involved unilateral movements but had no influence on scores for bilateral movements. The reduction in performance could be due to slower reaction times or neural coupling to coordinate movements between the limbs during bilateral movements. The increased performance in the non‐dominant hand for the TT genotype may be due to the increased sensitivity of this specific SNP to caffeine. While not significant, variations in responses to caffeine were observed when assessing task performance by grouped ADORA2A/DRD2 polymorphisms and the possible combinations. One grouping, TC/CC:AG/AA, demonstrated negative response to caffeine, whereas two other groupings (TT:GG, TC/CC:GG) demonstrated positive responses to caffeine. Further research and an increased sample size will help demonstrate the specific SNP interactions.

A distinct cognitive profile in individuals with 3q29 deletion syndrome.

3q29 deletion syndrome is associated with mild to moderate intellectual disability as well as comorbid psychopathology such as ADHD, anxiety, ASD and schizophrenia. A greater understanding of specific profiles that could increase risk for psychopathology is necessary in order to best understand and support individuals with 3q29 deletion syndrome. The goal of this study was to thus carefully outline the strengths and weaknesses of these individuals. A second goal was to ask whether the cognitive impact of the deletion predicted psychopathology in other domains. We systematically evaluated cognitive ability, adaptive behaviour and psychopathology in 32 individuals with the canonical 3q29 deletion using gold-standard instruments and a standardised phenotyping protocol. Mean full scale IQ was 73 (range 40-99). Verbal subtest score (mean 80, range 31-106) was slightly higher and had a greater range than non-verbal subtest score (mean 75, range 53-98). Spatial ability was evaluated in a subset (n=24) and was lower than verbal and non-verbal ability (mean 71, range 34-108). There was an average 14-point difference between verbal and non-verbal subset scores; 60% of the time the verbal subset score was higher than the non-verbal subset score. Study subjects with a verbal ability subtest score lower than the non-verbal subtest score were four times more likely to have a diagnosis of intellectual disability (suggestive, P value 0.07). The age at which a child first spoke two-word phrases was strongly associated with measures of verbal ability (P value 2.56e-07). Cognitive ability was correlated with adaptive behaviour measures (correlation 0.42, P value 0.02). However, although group means found equivalent scores, there was, on average, a 10-point gap between these skills (range -33 to 33), in either direction, in about 50% of the sample, suggesting that cognitive measures only partially inform adaptive ability. Cognitive ability scores did not have any significant relationship to cumulative burden of psychopathology nor to individual neurodevelopmental or psychiatric diagnoses. Individuals with 3q29 deletion syndrome have a complex pattern of cognitive disability. Two-thirds of individuals with the deletion will exhibit significant strength in verbal ability; this may mask deficits in non-verbal reasoning, leading to an overestimation of overall ability. Deficits in verbal ability may be the driver of intellectual disability diagnosis. Cognitive ability is not a strong indicator of other neurodevelopmental or psychiatric impairment; thus, individuals with 3q29 deletion syndrome who exhibit IQ scores within the normal range should receive all recommended behavioural evaluations.

Randomised single centre double-blind placebo controlled phase II trial of Tocovid SupraBio in combination with pentoxifylline in patients suffering long-term gastrointestinal adverse effects of radiotherapy for pelvic cancer: The PPALM study

BackgroundPreclinical data suggest that combined gamma-tocotrienol with pentoxifylline ameliorates radiotherapy-induced gastrointestinal damage. AimTo test whether gastrointestinal symptoms arising after radiotherapy, and persisting after maximal medical therapy, can be improved using Tocovid SupraBio 200 mg and pentoxifylline 400 mg orally twice daily for one year. Patients stratified by severity of symptoms, and randomised to active treatment or matched placebo were assessed after 12 months. The primary end point was improvement in gastrointestinal symptoms measured using the Inflammatory Bowel Disease Questionnaire, bowel subset score. Changes in bio-markers of fibrosis were assessed. Results62 patients, median age 66, 34(55%) treated for prostate, 21(34%) gynaecological, 6(10%) anal and one(1%) rectal cancer were recruited; 40(65%) randomised to treatment, 22(35%) to placebo, 39 months (median) after radiotherapy completion. Gamma tocotrienol was not detected in serum in 41% of treated patients, despite good compliance with study medication. Treatment was completed in 28(70%) and 17(77%) patients in the treatment and placebo groups respectively. No improvement in symptom scores nor in quality of life was identified. Thirteen serious adverse events occurred. A transient ischaemic attack, was possibly related to pentoxifylline, others were assessed as unlikely to be related to treatment. Levels of EGF, PDGF and FGF were significantly reduced and consistent trends in reduced inflammation were seen during treatment but were not sustained once treatment ended. SummaryThis single centre study closed prematurely and therefore data interpretation is of necessity limited. No clinical benefit was demonstrated. However, biochemical data suggest that this intervention does have anti-inflammatory and anti-fibrotic effects.

The Alteration of Circulating Lymphocyte Subsets During Tacrolimus Therapy in Neuromyelitis Optica Spectrum Disorder and Its Correlation With Clinical Outcomes.

ObjectivesWe aimed to explore the alteration of circulating lymphocyte subsets before and after tacrolimus (TAC) therapy in neuromyelitis optica spectrum disorder (NMOSD) and its correlation with clinical outcomes.MethodsAnti-aquaporin-4 antibody (AQP4-ab)-positive patients with NMOSD treated with TAC were followed and clinically evaluated at 0, 3, 6, and 12 months after initiation of TAC. Flow cytometry was employed to detect the proportion of various whole blood lymphocyte subsets at every time point. Correlation analysis was further performed to explore the association between annualized relapse rate (ARR), the Expanded Disability Status Scale (EDSS) score, and the proportion of circulating lymphocyte subsets before and after TAC therapy.ResultsA total of 13 eligible patients with NMOSD were included. The proportion of CD19+CD24hiCD38hi/CD19+ and CD19+CD5+CD1dhi/CD19+ lymphocyte subsets increased significantly after TAC therapy (p = 0.010 and p < 0.001). The proportion of CD19+BAFFR+, CD19+IFN-γ+, and CD19+IL-10+ subsets decreased significantly after TAC therapy (p = 0.015, 0.018, and 0.042, respectively). There was a negative correlation between CD4+CD25hi subset and EDSS score (p = 0.016, r = −0.652).ConclusionPossibly through increasing regulatory B and suppressing BAFFR+ B and interferon (IFN)-γ+ B subsets, TAC could decrease relapse. EDSS score may be correlated with some lymphocyte subsets after TAC therapy.

Affective and somatic symptom clusters in depression and their relationship to treatment outcomes in the STAR*D sample

BackgroundThe heterogenous nature of depression continues to stymie efforts to identify biomarkers or predict treatment response. Efforts leveraging large datasets to define more uniform subtypes of depression or subgroups of depressed patients have considered only small subsets of symptoms. We aimed to understand how inclusion of more diverse complaints would impact data-emergent symptom and patient clusters. MethodsWe applied principal components analysis to baselineInventory of Depressive Symptomatology data from 1491 patients with major depressive disorder to derive naturally co-occurring symptom subsets before utilizing k-means clustering to divide patients into groups based on standardized residuals of each symptom subset score. We evaluated the clinical utility of our approach by comparing how cluster membership impacted response to citalopram. ResultsPrinicpal components analysis identified nine naturally co-occurring symptom subsets: core affective symptoms, appetite/weight loss, anxiety, somatic symptoms, insomnia, negative intrusive thoughts, leaden paralysis/mood quality, diurnal mood variation, and irritability. Cluster analysis identified two patient groups, differing significantly in 7 of 9 c symptom subsets. Patients distinguished by the prominence of somatic versus core affective symptoms exhibited less reduction in depression severity with citalopram treatment. LimitationsResults depend not only on raw data, but also parameter selection, and interpretation. Replication is indicated. ConclusionsFindings are consistent with previous reports linking somatic symptoms to treatment resistance and demonstrating that SSRIs are most effective in treating affective symptoms. A novel distinction between physical somatic symptoms and psychic anxiety highlights the utility of assessing a broad spectrum of symptoms when exploring heterogeneity in depression and the need for treatments targeting physical somatic symptoms specifically.

Younger age and early puberty are associated with cognitive function decline in children with Cushing disease.

To investigate the effect of hypercortisolism on the developing brain we performed clinical, cognitive, and psychological evaluation of children with Cushing disease (CD) at diagnosis and 1 year after remission. Prospective study of 41 children with CD. Children completed diverse sets of cognitive measures before and 1 year after remission. Neuropsychological evaluation included the Wechsler Intelligence Scale, California Verbal Learning Test, Trail Making Test, the combined subset scores of Wide Range Achievement Test and Woodcock-Johnson Psychoeducational Battery Test of Achievement, and the Behavioral Assessment System for Children. Comprehensive cognitive evaluations at baseline and 1 year following cure revealed significant decline mostly in nonverbal skills. Decrements occurred in most of the various indices that measure all aspects of cognitive function and younger age and early pubertal stage largely contributed to most of this decline. Results indicated that age at baseline was associated with positive regression weights for changes in scores for verbal, performance, and full intelligence quotient (IQ) scores and for subtests arithmetic, picture completion, coding, block design, scores; indicating that older age at baseline was associated with less of a deterioration in cognitive scores from pre- to posttreatment. Our findings suggest that chronic glucocorticoid excess and accompanying secondary hormonal imbalances followed by eucortisolemia have detrimental effects on cognitive function in the developing brain; younger age and pubertal stage are risk factors for increased vulnerability, while older adolescents have cognitive vulnerabilities like that of adult patients affected with CD.

Machine Learning Based Models To Predict Functional Improvement in Stroke Patients During Inpatient Rehabilitation

<h3>Research Objectives</h3> To build a predictive model and find demographic and clinical factors associated with functional improvement in acute stroke survivors using Natural Language Processing (NLP) and Machine Learning (ML). <h3>Design</h3> Retrospective study of clinical and demographic factors and outcomes. <h3>Setting</h3> Acute stroke patients admitted to Memorial Hermann/TIRR inpatient rehabilitation facilities. <h3>Participants</h3> A convenience sample that includes individuals admitted from 2017-2019 and excludes individuals with multiple stroke or pre-stroke neurological conditions. It documents 421 male and 382 female with median age of 69 and racial breakdown of 43% Caucasian, 28% African American, and 18% Asian. Right and left laterality are equal. Bilateral stroke noted in 73 clients. One-quarter of patients had intracerebral hemorrhage and the rest had ischemic stroke. <h3>Interventions</h3> N/A. <h3>Main Outcome Measures</h3> We developed a novel model using gradient-boosting tree algorithm, CatBoost, and utilized Shapley values to estimate the contribution of each predictor to significant functional improvement (SFI). SFI was defined as an increase by a minimum of two points on at least 5 FIM (Functional Independence Measure) subset scores from admission to discharge. We analyzed 229 Independent variables including demographics, stroke characteristics, severity on the NIHSS, Initial FIM scores at admission, NLP vectorized clinical notes, history of hypertension, smoking, diabetes, and hyperlipidemia. <h3>Results</h3> Our model achieved an area under receiver operator curve of 0.89 showing better performance compared to commonly used ML and statistical models. Based on Shapely values, age, presenting symptoms, stroke laterality, initial NIHSS, case mix index score and inpatient therapy time have a more pronounced role in predicting functional improvement. <h3>Conclusions</h3> ML models carry the high potential to analyze large multidimensional data on stroke patients undergoing inpatient rehabilitation. They may help clinicians better predict functional improvement for patients undergoing rehabilitation. <h3>Author(s) Disclosures</h3> The authors declare no conflict of interest.

Brief Report: Improving Fellow Performance of the Pharmacology Section of the American Society of Clinical Oncology In-Training Exam.

Though the electronic medical record has streamlined the process for ordering chemotherapy and reduced medical error, it has come at the cost of potentially hindering medical oncology fellows' acquisition of basic principles of chemotherapy administration. Recognizing the need for improving fellow knowledge and comfort level in chemotherapy prescription, we created an anticancer therapeutics curriculum for fellows at the University of North Carolina (UNC). The curriculum, which was comprised of a self-assessment, review session, and chemotherapy writing workshop, was offered voluntarily to all UNC fellows planning to take the medical oncology boards. We distributed a pre-intervention and post-intervention survey. In total, 11 of 18 fellows participated. After our interventions, there were statistically significant improvements in comfortability with calculating a dose of chemotherapy (p = 0.002), writing orders (p = 0.004), and taking the American Society of Clinical Oncology (ASCO) In-Training Exam (ITE) (p = 0.002). Furthermore, we saw a 4% overall improvement in pharmacology subset scores on the ITE compared to the prior year. Overall, our study suggested that the addition of a chemotherapy competency curriculum led to improved outcomes on the ASCO ITE, improved comfortability in chemotherapy administration, and hopefully improved patient care.

The MINT Sprint: Exploring a Fast Administration Procedure with an Expanded Multilingual Naming Test.

The present study examined if time-pressured administration of an expanded Multilingual Naming Test (MINT) would improve or compromise assessment of bilingual language proficiency and language dominance. Eighty Spanish-English bilinguals viewed a grid with 80 MINT-Sprint pictures and were asked to name as many pictures as possible in 3 min in each language in counterbalanced order. An Oral Proficiency Interview rated by four native Spanish-English bilinguals provided independent assessment of proficiency level. Bilinguals also self-rated their proficiency, completed two subtests of the Woodcock-Muñoz, and a speeded translation recognition test. We compared scores after 2 min, a first-pass through all the pictures, and a second-pass in which bilinguals were prompted to try to name skipped items. The MINT Sprint and a subset score including original MINT items were highly correlated with Oral Proficiency Interview scores for predicting the degree of language dominance - matching or outperforming all other measures. Self-ratings provided weaker measures (especially of degree of balance - i.e., bilingual index scores) and did not explain any unique variance in measuring the degree of language dominance when considered together with second-pass naming scores. The 2-min scoring procedure did not improve and appeared not to hamper assessment of absolute proficiency level but prompting to try to name skipped items improved assessment of language dominance and naming scores, especially in the nondominant language. Time-pressured rapid naming saves time without significantly compromising assessment of proficiency level. However, breadth of vocabulary knowledge may be as important as retrieval speed for maximizing the accuracy in proficiency assessment.