Compassion Versus Accuracy: Lenient Scoring of the Spatial Orientation Items on the Mini-mental State Exam Lowers Sensitivity.

The Mini-mental State Examination (MMSE) is a commonly used screening tool for cognitive impairment. Lenient scoring of spatial orientation errors (SOEs) on the MMSE is common and negatively affects its diagnostic utility. We examined the effect of lenient SOE scoring on MMSE classification accuracy in a consecutive case series of 103 older adults (age 60 or above) clinically referred for neuropsychological evaluation. Lenient scoring of SOEs on the MMSE occurred in 53 (51.4%) patients and lowered the sensitivity by 7% to 18%, with variable gains in specificity (0% to 11%) to psychometrically operationalized cognitive impairment. Results are consistent with previous reports that lenient scoring is widespread and attenuates the sensitivity of the MMSE. Given the higher clinical priority of correctly detecting early cognitive decline over specificity, a warning against lenient scoring of SOEs (on the MMSE and other screening tools) during medical education and in clinical practice is warranted.

Central Sleep Apnea in Patients With Coronary Heart Disease Taking P2Y12 Inhibitors.

ABSTRACT: Central sleep apnea (CSA) is common in patients with heart failure. Recent studies link ticagrelor use with CSA. We aimed to evaluate CSA prevalence in patients with coronary heart disease (CHD) and whether ticagrelor use is associated with CSA. We reviewed consecutive patients with CHD who underwent a polysomnography (PSG) test over a 5-year period from 3 sleep centers. We sampled patients who were on ticagrelor or clopidogrel during a PSG test at a 1:4 ticagrelor:clopidogrel ratio. Patients with an active opioid prescription during PSG test were excluded. Age, left ventricle (LV) dysfunction, and P2Y12 inhibitor use were included in a multivariate logistic regression. A total of 135 patients were included with 26 on ticagrelor and 109 on clopidogrel (age 64.1 ± 11.4, 32% male). High CSA burden (12%) and strict CSA (4.4%) were more common in patients on ticagrelor than in those on clopidogrel (27% vs. 8.3% and 10.0% vs. 1.8%). Ticagrelor use (vs. clopidogrel) was associated with high CSA burden (OR 3.53, 95% CI 1.04-12.9, P = 0.039) and trended toward significance for strict CSA (OR 6.32, 95% CI 1.03-51.4, P = 0.052) when adjusting for age and LV dysfunction. In an additional analysis also adjusting for history of atrial fibrillation, ticagrelor use and strict CSA became significantly associated (OR 10.0, 95% CI 1.32-117, P = 0.035). CSA was uncommon in patients with CHD undergoing sleep studies. Ticagrelor use (vs. clopidogrel) was associated with high CSA burden and trended toward significance for strict CSA.

Replicating the classification accuracy of the Verbal Paired Associates and Visual Reproduction recognition trials as embedded performance validity tests.

OBJECTIVE: This study was designed to replicate previous research on the clinical utility of the Verbal Paired Associates (VPA) and Visual Reproduction (VR) subtests of the WMS-IV as embedded performance validity tests (PVTs) and perform a critical item (CR) analysis within the VPA recognition trial. METHOD: Archival data were collected from a mixed clinical sample of 119 adults (MAge = 42.5, MEducation = 13.9). Classification accuracy was computed against psychometrically defined criterion groups based on the outcome of various free-standing and embedded PVTs. RESULTS: Age-corrected scaled scores ≤ 6 were specific (.89-.98) but had variable sensitivity (.36-.64). A VPA recognition cutoff of ≤ 34 produced a good combination of sensitivity (.46-.56) and specificity (.92-.93), as did a VR recognition cutoff of ≤ 4 (.48-.53 sensitivity at .86-.94 specificity). Critical item analysis expanded the VPA's sensitivity by 3.5%-7.0% and specificity by 5%-8%. Negative learning curves (declining output on subsequent encoding trials) were rare but highly specific (.99-1.00) to noncredible responding. CONCLUSIONS: Results largely support previous reports on the clinical utility of the VPA and VR as embedded PVTs. Sample-specific fluctuations in their classification accuracy warrant further research into the generalizability of the findings. Critical item analysis offers a cost-effective method for increasing confidence in the interpretation of the VPA recognition trial as a PVT. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Delayed esophageal anastomotic complication and ramucirumab therapy: A case report.

Current NCCN guidelines for second-line therapy in recurrent or metastatic esophago-gastric cancers recommend the use of VEGF inhibitors such as ramucirumab. VEGF inhibitors have been shown to be associated with gastrointestinal perforation in clinical trials and late colorectal anastomotic leaks in a few case reports. Here, we present a case of late esophageal anastomotic leak in a patient receiving ramucirumab. Case information was obtained from our institution's electronic medical records. The patient was found to have T4N1M0, poorly differentiated invasive adenocarcinoma and subsequently received neoadjuvant chemoradiation followed by hybrid Ivor-Lewis esophagectomy 6 weeks later. He recovered well with no leak or perioperative complications. The patient had disease progression 9 months postoperatively on CT and PET imaging. Sixteen months after surgery he began paclitaxel and ramucirumab and 16 weeks after ramucirumab initiation, he was found to have an esophago-pulmonary fistula in the region of the anastomosis. Biopsies were negative for recurrence at the anastomosis. He died one week later from progressive pneumonia despite stenting. In conclusion, this is the only known report of delayed esophageal anastomotic complication associated with ramucirumab. VEGF inhibitor therapies such as bevacizumab have been associated with late (greater than 3 months postoperative) colorectal anastomotic complications including fistulas and leaks. Risk factors that have been associated are perioperative radiotherapy and history of early postoperative leak. These findings raise concern whether VEGF inhibitor therapy should be used in post-esophagectomy patients with recurrence if these rare but catastrophic events are likely to be terminal.

Do executive functions differentiate Iranian children with attention-deficit/hyperactivity disorder with and without comorbid obesity?

OBJECTIVE: To compare multiple dimensions of executive function between children with attention-deficit/hyperactivity disorder (ADHD) with and without comorbid obesity. METHOD: Participants were 90 Iranian children (ages 8-13, 50% female) who were equally dispersed across three study groups: typically developing (TD), ADHD with obesity (ADHD+O), and ADHD without obesity (ADHD-O). Study participants were administered a comprehensive battery of Iranian-adapted "cool" executive function tasks including Digit Span from the Wechsler Intelligence Scale for Children-Fifth Edition (WISC-V), Victoria Stroop Test (VST), Wisconsin Card Sorting Test (WCST), Tower of London, and dot-probe task (i.e., a task of attentional bias). Parents completed the Children's Scale for Future Thinking Questionnaire, which assesses future-oriented cognition (e.g., saving, planning, episodic foresight, delay of gratification), aligning more with "hot" executive functions. Groups were compared using multivariate and post-hoc univariate general linear models. RESULTS: Significant group effects were observed for all executive function variables, broadly with the gradient pattern of TD > ADHD-O > ADHD+O. ADHD+O had poorer performances than ADHD-O for WISC-V Digit Span (d = -0.84), WCST Categories Completed (d = -0.55) and Perseverative Responses (d = 1.15), VST Interference Errors (d = 0.83) and Interference Time (d = 1.38), and Dot-Probe Task (d = 0.84). Relative to the ADHD-O group, ADHD+O had also poorer parent-reported Prospective Memory (d = -0.62), Episodic Foresight (d = -0.63), and Delay of Gratification (d = -0.54). CONCLUSIONS: Children with ADHD-O have poorer executive functioning than those without obesity. We observed stronger effects for "cool" rather than "hot" domains of executive function, though this could be due to the former being performance-based and the latter parent-reported.

Accelerated long-term forgetting of recall and recognition memory in people with epilepsy.

PURPOSE: Persons with epilepsy (PWE) report memory deficits as one of the most distressing aspects of their disorder. Recently, a long-term memory deficit known as Accelerated Long-Term Forgetting (ALF) has been described in PWE. ALF is characterized by the initial retention of learned information, followed by an accelerated rate of memory decay. However, the rate of ALF varies widely across literature and it is unclear how it impacts different memory retrieval types. The current study aimed to capture the time course of ALF on both free recall and recognition memory using a movie-based task in PWE. METHODS: A sample of 30 PWE and 30 healthy comparison (HC) subjects watched a nature documentary and were tested on their recall and recognition of the film's content immediately after viewing and at delays of 24 hours, 48 hours, and 72 hours. Participants also rated the confidence they had in their recognition memory trial responses. RESULTS: For recall, PWE exhibit ALF at 72 hours (ß = -19.840, SE = 3.743, z(226) = -5.301, p < 0.001). For recognition, PWE had decreased performance compared to controls at the 24-hour (ß = -10.165, SE = 4.174, z(224) = -3.166, p = 0.004), 48-hour (ß = -8.113, SE = 3.701, z(224) = -2.195, p = 0.044), and 72-hour (ß = -10.794, SE = 3.017, z(224) = -3.295, p = 0.003) delays. The PWE group showed positive correlations (tau = 0.165, p < 0.001) between confidence ratings and accuracy, with higher confidence reflecting successful recognition. PWE were 49% less likely to answer either retrieval type correctly at 72 hours (OR 0.51, 95% CI [0.35, 0.74], p < 0.001). Left hemispheric seizure onset decreased the odds of successful retrieval by 88% (OR 0.12, 95% CI [0.01, 0.42], p = 0.019). CONCLUSIONS: These findings provide evidence of ALF in PWE, with a differential impact on recall and recognition memory. This further supports the call to include ALF assessments in standard memory evaluations in PWE. Additionally, identifying the neural correlates of ALF in the future will be important in developing targeted therapies to alleviate the burden of memory impairment for PWE.

Replicating a Meta-Analysis: The Search for the Optimal Word Choice Test Cutoff Continues.

This study was designed to expand on a recent meta-analysis that identified ≤42 as the optimal cutoff on the Word Choice Test (WCT). We examined the base rate of failure and the classification accuracy of various WCT cutoffs in four independent clinical samples (N = 252) against various psychometrically defined criterion groups. WCT ≤ 47 achieved acceptable combinations of specificity (.86-.89) at .49 to .54 sensitivity. Lowering the cutoff to ≤45 improved specificity (.91-.98) at a reasonable cost to sensitivity (.39-.50). Making the cutoff even more conservative (≤42) disproportionately sacrificed sensitivity (.30-.38) for specificity (.98-1.00), while still classifying 26.7% of patients with genuine and severe deficits as non-credible. Critical item (.23-.45 sensitivity at .89-1.00 specificity) and time-to-completion cutoffs (.48-.71 sensitivity at .87-.96 specificity) were effective alternative/complementary detection methods. Although WCT ≤ 45 produced the best overall classification accuracy, scores in the 43 to 47 range provide comparable objective psychometric evidence of non-credible responding. Results question the need for designating a single cutoff as "optimal," given the heterogeneity of signal detection environments in which individual assessors operate. As meta-analyses often fail to replicate, ongoing research is needed on the classification accuracy of various WCT cutoffs.

Univariate and Multivariate Base Rates of Score Elevations, Reliable Change, and Inter-Rater Discrepancies in the BRIEF-A Standardization Samples.

The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) is a standardized rating scale of subjective executive functioning. We provide univariate and multivariate base rates (BRs) for scale/index scores in the clinical range (T scores ≥65), reliable change, and inter-rater information not included in the Professional Manual. Participants were adults (ages = 18-90 years) from the BRIEF-A self-report (N = 1,050) and informant report (N = 1,200) standardization samples, as well as test-retest (n = 50 for self, n = 44 for informant) and inter-rater (n = 180) samples. Univariate BRs of elevated T scores were low (self-report = 3.3%-15.4%, informant report = 4.5%-16.3%). Multivariate BRs revealed the common occurrence of obtaining at least one elevated T-score across scales (self-report = 26.5%-37.3%, informant report = 22.7%-30.3%), whereas virtually none had elevated scores on all scales. Test-retest scores were highly correlated (self = .82-.94; informant = .91-.96). Inter-rater correlations ranged from .44 to .68. Significant (p < .05) test-retest T-score differences ranged from 7 to 12 for self-report, from 6 to 8 for informant report, and from 16 to 21 points for inter-rater T-score differences. Applications of these findings are discussed.

Multivariate models provide an effective psychometric solution to the variability in classification accuracy of D-KEFS Stroop performance validity cutoffs.

ObjectiveThe study was designed to expand on the results of previous investigations on the D-KEFS Stroop as a performance validity test (PVT), which produced diverging conclusions. Method The classification accuracy of previously proposed validity cutoffs on the D-KEFS Stroop was computed against four different criterion PVTs in two independent samples: patients with uncomplicated mild TBI (n = 68) and disability benefit applicants (n = 49). Results Age-corrected scaled scores (ACSSs) ≤6 on individual subtests often fell short of specificity standards. Making the cutoffs more conservative improved specificity, but at a significant cost to sensitivity. In contrast, multivariate models (≥3 failures at ACSS ≤6 or ≥2 failures at ACSS ≤5 on the four subtests) produced good combinations of sensitivity (.39-.79) and specificity (.85-1.00), correctly classifying 74.6-90.6% of the sample. A novel validity scale, the D-KEFS Stroop Index correctly classified between 78.7% and 93.3% of the sample. Conclusions A multivariate approach to performance validity assessment provides a methodological safeguard against sample- and instrument-specific fluctuations in classification accuracy, strikes a reasonable balance between sensitivity and specificity, and mitigates the invalid before impaired paradox.

Charge Radii of

Nuclear charge radii of ^{55,56}Ni were measured by collinear laser spectroscopy. The obtained information completes the behavior of the charge radii at the shell closure of the doubly magic nucleus ^{56}Ni. The trend of charge radii across the shell closures in calcium and nickel is surprisingly similar despite the fact that the ^{56}Ni core is supposed to be much softer than the ^{48}Ca core. The very low magnetic moment µ(^{55}Ni)=-1.108(20) µ_{N} indicates the impact of M1 excitations between spin-orbit partners across the N,Z=28 shell gaps. Our charge-radii results are compared to ab initio and nuclear density functional theory calculations, showing good agreement within theoretical uncertainties.

Psychometric properties of the Behavior Rating Inventory of Executive Function, second edition (BRIEF2) self-report form in Iranian adolescents.

BACKGROUND: This study investigated the psychometric properties of a Persian translation of the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF2) Self-Report form. METHOD: Participants were 589 typically developing adolescents (336 girls and 253 boys), ages 11-18 years old (M = 15.16; SD = 2.04), in Iran. They completed the Persian version of the BRIEF2 Self-Report form and Teenage Executive Functioning Inventory (TEXI). The Persian translated BRIEF2 psychometric properties were examined via internal consistency, test-retest reliability, convergent validity via associations with TEXI scores, and internal structure using structural equation modeling (SEM) to evaluate fit of the three-factor structure from the original English version BRIEF2. RESULTS: Findings indicated the Persian version of BRIEF2 Self-Report form yielded scores with robust reliability, with internal consistency ranging from .87 to .93 and test-retest correlations ranging from .89 to .96, and adequate convergent validity, with correlations with the TEXI ranging from .48 to .79. SEM revealed that a three-factor solution was the best fitting model for the seven subscales of the Persian BRIEF2. CONCLUSION: These findings support the clinical use of the Persian BRIEF2 in Iranian adolescents, including the interpretation of the BRIEF2 three-factor structure, as well as the multidimensional nature of executive functions.

Pharmacokinetic and toxicodynamic concepts in idiosyncratic, drug-induced liver injury.

INTRODUCTION: Idiosyncratic drug-induced liver injury (IDILI) causes morbidity and mortality in patients and leads to curtailed use of efficacious pharmaceuticals. Unlike intrinsically toxic reactions, which depend on dose, IDILI occurs in a minority of patients at therapeutic doses. Much remains unknown about causal links among drug exposure, a mode of action, and liver injury. Consequently, numerous hypotheses about IDILI pathogenesis have arisen. AREAS COVERED: Pharmacokinetic and toxicodynamic characteristics underlying current hypotheses of IDILI etiology are discussed and illustrated graphically. EXPERT OPINION: Hypotheses to explain IDILI etiology all involve alterations in pharmacokinetics, which lead to plasma drug concentrations that rise above a threshold for toxicity, or in toxicodynamics, which result in a lowering of the toxicity threshold. Altered pharmacokinetics arise, for example, from changes in drug metabolism or from transporter polymorphisms. A lowered toxicity threshold can arise from drug-induced mitochondrial injury, accumulation of toxic endogenous factors or harmful immune responses. Newly developed, interactive freeware (DemoTox-PK; https://bit.ly/DemoTox-PK) allows the user to visualize how such alterations might lead to a toxic reaction. The illustrations presented provide a framework for conceptualizing idiosyncratic reactions and could serve as a stimulus for future discussion, education, and research into modes of action of IDILI.

The Common H202D Variant in GDF-15 Does Not Affect Its Bioactivity but Can Significantly Interfere with Measurement of Its Circulating Levels.

BACKGROUND: There is growing interest in the measurement of growth differentiation factor 15 (GDF-15) in a range of disorders associated with cachexia. We undertook studies to determine whether a common histidine (H) to aspartate (D) variant at position 202 in the pro-peptide (position 6 in the mature peptide) interfered with its detection by 3 of the most commonly used immunoassays. METHODS: Three synthetic GDF-15-forms (HH homo-, HD hetero-, and DD-homodimers) were measured after serial dilution using Roche Elecsys®, R&D QuantikineTM ELISA, and MSD R&D DuoSet® immunoassays. GDF-15 concentrations were measured by the Roche and the MSD R&D immunoassays in 173 genotyped participants (61 HH homozygotes, 59 HD heterozygotes, and 53 DD homozygotes). For the comparative statistical analyses of the GDF-15 concentrations, we used non-parametric tests, in particular Bland-Altman difference (bias) plots and Passing-Bablok regression. The bioactivity of the 2 different homodimers was compared in a cell-based assay in HEK293S-SRF-RET/GFRAL cells. RESULTS: The Roche assay detected H- and D-containing peptides similarly but the R&D reagents (Quantikine and DuoSet) consistently underreported GDF-15 concentrations in the presence of the D variant. DD dimers had recoveries of approximately 45% while HD dimers recoveries were 62% to 78%. In human serum samples, the GDF-15 concentrations reported by the R&D assay were a median of 4% lower for HH, a median of 36% lower for HD, and a median of 61% lower for DD compared to the Roche assay. The bioactivities of the HH and DD peptides were indistinguishable. CONCLUSIONS: The D variant of GDF-15 substantially affects its measurement by a commonly used immunoassay, a finding that has clear implications for its interpretation in research and clinical settings.

FRAGLER: A Fragment Recycler Application Enabling Rapid and Scalable Modular DNA Assembly.

Rapid and flexible plasmid construct generation at scale is one of the most limiting first steps in drug discovery projects. These hurdles can partly be overcome by adopting modular DNA design principles, automated sequence fragmentation, and plasmid assembly. To this end we have designed a robust, multimodule golden gate based cloning platform for construct generation with a wide range of applications. The assembly efficiency of the system was validated by splitting sfGFP and sfCherry3C cassettes and expressing them in E. coli followed by fluorometric assessment. To minimize timelines and cost for complex constructs, we developed a software tool named FRAGLER (FRAGment recycLER) that performs codon optimization, multiple sequence alignment, and automated generation of fragments for recycling. To highlight the flexibility and robustness of the platform, we (i) generated plasmids for SarsCoV2 protein reagents, (ii) automated and parallelized assemblies, and (iii) built modular libraries of chimeric antigen receptors (CARs) variants. Applying the new assembly framework, we have greatly streamlined plasmid construction and increased our capacity for rapid generation of complex plasmids.

Critical item (CR) analysis expands the classification accuracy of performance validity tests based on the forced choice paradigm-Replicating previously introduced CR cutoffs within the Word Choice Test.

OBJECTIVE: This study was designed to replicate previous research on critical item analysis within the Word Choice Test (WCT). METHOD: Archival data were collected from a mixed clinical sample of 119 consecutively referred adults (Mage = 51.7, Meducation = 14.7). The classification accuracy of the WCT was calculated against psychometrically defined criterion groups. RESULTS: Critical item analysis identified an additional 2%-5% of the sample that passed traditional cutoffs as noncredible. Passing critical items after failing traditional cutoffs was associated with weaker independent evidence of invalid performance, alerting the assessor to the elevated risk for false positives. Failing critical items in addition to failing select traditional cutoffs increased overall specificity. Non-White patients were 2.5 to 3.5 times more likely to Fail traditional WCT cutoffs, but select critical item cutoffs limited the risk to 1.5-2. CONCLUSIONS: Results confirmed the clinical utility of critical item analysis. Although the improvement in sensitivity was modest, critical items were effective at containing false positive errors in general, and especially in racially diverse patients. Critical item analysis appears to be a cost-effective and equitable method to improve an instrument's classification accuracy. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

[Formula: see text]Multivariate base rates of score elevations on the BRIEF2 in children with ADHD, autism spectrum disorder, or specific learning disorder with impairment in reading.

There is a paucity of research examining multivariate base rates (MBRs) of elevated scores in pediatric rating scales of cognition. We present novel MBR information on the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF2) for several clinical groups: Attention-Deficit/Hyperactivity Disorder Combined Presentation (ADHD-C); ADHD Inattentive Presentation (ADHD-I); Autism Spectrum Disorder (ASD); and Specific Learning Disorder with impairment in Reading (SLD-R). Participants included children diagnosed as having ADHD-C (n = 350), ADHD-I (n = 343), ASD (n = 390), or SLD-R (n = 240). Cumulative MBRs (e.g., the % of a sample having one or more elevated scores) were examined for each BRIEF2 form (Parent, Teacher, and Self-Report) and at three T-score cutoffs (T ≥ 60, T ≥ 65, and T ≥ 70). The MBR of obtaining at least one elevated score was common across clinical groups and forms at T ≥ 60 (ADHD-C = 90.5-98.1%; ADHD-I = 83.9-98.7%; ASD = 90.3-96.9%, SLD-R = 60.0-78.4%), T ≥ 65 (ADHD-C = 66.7-97.2%; ADHD-I = 77.5-94.9%; ASD = 77.3-92.7%; SLD-R = 38.5-64.0%), and T ≥ 70 (ADHD-C = 52.4-89.4%; ADHD-I = 64.8-84.2%; ASD = 54.5-83.2%; SLD-R = 26.9-44.1%). MBRs appeared to differ as a function of group (ADHD-C > ADHD-I > ASD > SLD-R) and form (Parent > Teacher > Self-Report) though future research with well-defined samples is needed to investigate this. We provide novel MBR information to enhance clinical interpretation of BRIEF2 data.

Effectiveness of a Self-Management Program to Improve Cognition and Quality of Life in Epilepsy: A Pragmatic, Randomized, Multicenter Trial.

BACKGROUND AND OBJECTIVES: We conducted a multisite, pragmatic replication trial at 4 New England epilepsy centers to determine the effectiveness of Home-Based Self-Management and Cognitive Training Changes Lives (HOBSCOTCH) in a real-world setting and to assess feasibility of a virtual intervention. METHODS: HOBSCOTCH is an 8-session intervention addressing cognitive impairment and quality of life (QoL) for people with epilepsy (PWE). Participants were recruited from epilepsy centers in 4 states and block-randomized into the following groups: in-person HOBSCOTCH (H-IP), virtual HOBSCOTCH (H-V), and waitlist control. Outcome measures were assessed for all groups at baseline, 3 months, and 6 months; intervention groups received long-term follow-up at 9 and 12 months. RESULTS: A total of 108 participants were recruited, of whom 85 were included in this analysis (age at baseline 47.5 ± 11.5 years; 68% female). Participants completing the in-person intervention (H-IP) had a 12.4-point improvement in QoL score compared with controls (p < 0.001). Pairwise comparisons found a 6.2-point treatment effect for subjective cognition in the H-IP group (p < 0.001). There were no meaningful group differences in objective cognition or health care utilization at any time points and the treatment effect for QoL diminished by 6 months. The virtual intervention demonstrated feasibility but did not significantly improve outcomes compared with controls. Within-group analysis found improvements in QoL for both H-V and H-IP. DISCUSSION: This study replicated the effectiveness of the HOBSCOTCH program in improving QoL for PWE. The study was conducted prior to the COVID-19 pandemic, but the distance-delivered intervention may be particularly well-suited for the current environment. Future research will explore modifications designed to improve the efficacy of H-V and the sustainability of HOBSCOTCH's treatment effect. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov (NCT02394509). CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in-person HOBSCOTCH delivery improved subjective measures of cognition in persons with epilepsy.

Harnessing secretory pathway differences between HEK293 and CHO to rescue production of difficult to express proteins.

Biologics represent the fastest growing group of therapeutics, but many advanced recombinant protein moieties remain difficult to produce. Here, we identify metabolic engineering targets limiting expression of recombinant human proteins through a systems biology analysis of the transcriptomes of CHO and HEK293 during recombinant expression. In an expression comparison of 24 difficult to express proteins, one third of the challenging human proteins displayed improved secretion upon host cell swapping from CHO to HEK293. Guided by a comprehensive transcriptomics comparison between cell lines, especially highlighting differences in secretory pathway utilization, a co-expression screening of 21 secretory pathway components validated ATF4, SRP9, JUN, PDIA3 and HSPA8 as productivity boosters in CHO. Moreover, more heavily glycosylated products benefitted more from the elevated activities of the N- and O-glycosyltransferases found in HEK293. Collectively, our results demonstrate the utilization of HEK293 for expression rescue of human proteins and suggest a methodology for identification of secretory pathway components for metabolic engineering of HEK293 and CHO.

Cardio-ankle vascular index of increased arterial wall stiffness is associated with neurocognitive impairment in well-controlled HIV.

OBJECTIVES: HIV-associated neurocognitive disorders (HAND) remain prevalent in people living with HIV (PLWH) despite widespread use of combined antiretroviral therapy (ART). Vascular disease contributes to the pathogenesis of HAND, but traditional vascular risk factors do not fully explain the relation between vascular disease and HAND. A more direct measure of vascular dysfunction is needed. This cross-sectional study tested whether the cardio-ankle vascular index (CAVI), a novel method to assess arterial stiffness, is associated with HAND among PLWH. METHODS: Participants included 75 non-diabetic adults with well-controlled HIV from an outpatient HIV clinic. We assessed the relation between CAVI and neurocognitive impairment (NCI). The latter was primarily characterized by the Frascati criteria and secondarily (post hoc) using the Global Deficit Score (GDS). Logistic regression models tested whether high CAVI (≥ 8) was independently associated with NCI when controlling for potential confounders. RESULTS: Participants (Mage  = 45.6 ± 8.3 years; 30.1% male) had few traditional cardiovascular disease (CVD) risk factors (hypertension, n = 7; dyslipidaemia, n = 34; body mass index ≥ 25 kg/m2 , n = 12; smoking history, n = 13; 2.2% mean 10-year risk of CVD or stroke). Twelve (16%) participants had high CAVI, which was independently associated with meeting Frascati criteria for NCI [n = 39, odds ratio (OR) = 7.6, p = 0.04], accounting for age, education, gender, income, CD4 nadir, recent CD4 and traditional CVD risk factors. High CAVI was also associated with NCI as reflected by higher GDS (OR = 17.4, p = 0.02). CONCLUSIONS: Cardio-ankle vascular index is a promising measure of vascular dysfunction that may be independently associated with NCI in relatively healthy PLWH. Larger studies should test the utility of CAVI in predicting NCI/decline in PLWH.