Selenylated Analogs of Tacrine: Synthesis, in Silico and in Vitro Studies of Toxicology and Antioxidant Properties.

We present our results on the synthesis and preliminary in silico and in vitro studies of the toxicology and antioxidant properties of selenylated analogs of Tacrine. Initially, we synthesized 2-aminobenzonitriles containing an organic selenium moiety, resulting in sixteen compounds with various substituents linked to the portion derived from diorganyl diselenide. These compounds were then used as substrates in reactions with cyclic ketones, in the presence of 1.4 equivalents of trifluoroboroetherate as a Lewis acid, to synthesize selenylated analogs of Tacrine with yields ranging from 20% to 87%. In silico studies explored computational parameters related to antioxidant activity and hepatotoxicity. In vitro studies elucidated the antioxidant effects of Tacrine and its selenium hybrid (TSe) in neutralizing ABTS radicals, scavenging DPPH radicals, and reducing iron ions. Additionally, the acute oral toxicity of one synthesized compound was evaluated.

Effect of processing speed and memory performance on classification accuracy of the dot counting test in a mixed neuropsychiatric sample.

OBJECTIVE: This study examined the impact of impairment in two specific cognitive abilities, processing speed and memory, on Dot Counting Test (DCT) classification accuracy by evaluating performance validity classification accuracy across cognitively unimpaired, single-domain impairment, and multidomain impairment subgroups within a mixed clinical sample. METHOD: Cross-sectional data were analyzed from 348 adult outpatients classified as valid (n = 284) or invalid (n = 64) based on four independent criterion performance validity tests (PVTs). Unimpaired (n = 164), single-domain processing speed impairment (n = 24), single-domain memory impairment (n = 53), and multidomain processing speed and memory impairment (n = 43) clinical subgroups were established among the valid group. Both the traditional DCT E-score and unrounded E-score were examined. RESULTS: Overall, the DCT demonstrated acceptable to excellent classification accuracy across the unimpaired (area under the curve [AUC] traditional E-score=.855; unrounded E-score=.855) and single-domain impairment groups (traditional E-score AUCs = .690-.754; unrounded E-score AUCs = .692-747). However, it did not reliably discriminate the multidomain processing speed and memory impairment group from the invalid performers (traditional and unrounded E-scores AUC = .557). CONCLUSIONS: Findings support the DCT as a non-memory-based freestanding PVT for use with single-domain cognitive impairment, with traditional E-score ≥17 (unrounded E-score ≥16.95) recommended for those with memory impairment and traditional E-score ≥19 (unrounded ≥18.08) with processing speed impairment. Moreover, results replicated previously established optimal cutoffs for unimpaired groups using both the traditional (≥14) and unrounded (≥13.84) E-scores. However, the DCT did not reliably discriminate between invalid performance and multidomain cognitive impairment, indicating caution is warranted when using the DCT with patients suspected of greater cognitive impairment.

Protein and Amino Acid Adequacy and Food Consumption by Processing Level in Vegans in Brazil.

Importance: Major concerns regarding individuals who adhere to a vegan diet are whether they meet protein and essential amino acid recommendations and how reliant they are on ultraprocessed foods. Objectives: To investigate whether individuals who adhere to a vegan diet meet protein and essential amino acid recommendations and, as secondary objectives, to determine ultraprocessed food intake and potential factors associated with inadequate protein intake in this population. Design, Setting, and Participants: This cross-sectional survey study was conducted between September 2021 and January 2023 in Brazil among male and female adults (aged 18 years or older) who adhered to a vegan diet recruited from social media platforms. Exposure: Adherence to a vegan diet and unprocessed and minimally processed foods and ultraprocessed food consumption. Main Outcomes and Measures: Protein and essential amino acid intake and food consumption by processing level were assessed using a 1-day food diary. Nutrient adequacy ratios were calculated by dividing nutrient intake by its recommendation (using scores truncated at 1) for each participant and then finding the mean across participants for each nutrient. The mean adequacy ratio was the mean of all nutrient adequacy ratios. Results: Of 1014 participants who completed the survey, 774 individuals (median [IQR] age, 29 [24-35] years; 637 female [82.3%]) were confirmed as adhering to a vegan diet and provided adequate food recalls, among whom 558 individuals reported body weight and so had relative protein and amino acid intake values available. The median (IQR) body mass index (calculated as weight in kilograms divided by height in meters squared) of participants was 22.6 (20.3-24.8). The nutrient adequacy ratio of protein was 0.93 (95% CI, 0.91-0.94); for essential amino acids, ratios ranged from 0.90 (95% CI, 0.89-0.92) for lysine to 0.98 (95% CI, 0.97-0.99) for phenylalanine and tyrosine. The mean adequacy ratio for protein and all amino acids was 0.95 (95% CI, 0.94-0.96). The median intake level was 66.5% (95% CI, 65.0%-67.9%) of total energy intake for unprocessed and minimally processed food and 13.2% (95% CI, 12.4%-14.4%) of total energy intake for ultraprocessed food. Adjusted logistic regression models showed that consuming protein supplements (odds ratio [OR], 0.06 [95% CI 0.02-0.14]; P < .001) or textured soy protein (OR, 0.32 [95% CI, 0.17-0.59]; P < .001) was associated with decreased odds of inadequate protein intake. Higher ultraprocessed food intake levels were also associated with decreased odds of inadequate protein intake (eg, fourth vs first quartile of intake: OR, 0.16 [95% CI, 0.07-0.33]; P < .001), and higher unprocessed and minimally processed protein intake levels were associated with increased odds of inadequate protein intake (eg, fourth vs first quartile of intake: OR, 12.42 [95% CI, 5.56-29.51]; P < .001). Conclusions and Relevance: In this study, most individuals who adhered to a vegan diet attained protein and essential amino acid intake recommendations, largely based their diet of unprocessed and minimally processed food, and had a significantly lower proportion of ultraprocessed food intake compared with previous reports. Participants consuming less ultraprocessed food were more likely to have inadequate protein intake, suggesting a significant reliance on ultraprocessed proteins for this population.

The temperature dependence of the Hildebrand solubility parameters of selected hydrocarbon polymers and hydrocarbon solvents: a molecular dynamics investigation.

CONTEXT: To determine the miscibility of liquids at high temperatures using the concept of Hildebrand solubility parameter δ , the current practice is to examine the difference in δ between two liquids at room temperature, assuming that δ is not sensitive to temperature. However, such an assumption may not be valid for certain polymer blends and solutions. Therefore, a knowledge of the δ values of the liquids of interest at high temperatures is desirable. The determination of δ at high temperatures, especially for high-molecular-weight polymers, is impossible, as polymers have vapor pressures of zero. To this end, molecular dynamics (MD) simulations provide a practical means for determining δ over a wide range of temperatures. In this work, we study the temperature dependence of δ of five hydrocarbon polymers: polyethylene (PE), isotactic and atactic polypropylene (i-PP and a-PP), polyisobutylene (PIB), and polyisoprene (PI) in five hydrocarbon solvents: n-pentane, n-hexane, n-dodecane, isobutene, and cyclohexane. The polymers are modeled as monodisperse chains with 100 repeat units. The average δ values of PE, i-PP, a-PP, PIB, and PI at 300 K are determined as 18.6, 14.9, 14.6, 14.3, and 16.4 MPa1/2, respectively, in a good agreement with experimental data. The δ values of these polymers at various temperatures are also determined. The temperature dependence of δ is fitted to two linear equations, one above and the other below the polymer's glass transition temperature Tg. The δ values are more sensitive to temperature at T ≥ Tg. The Tg values of the polymers, determined based upon their specific volumes and δ values agree with the experiment qualitatively. The determination of the temperature dependence of δ has a great potential for industrial applications, such as determining miscibility, developing polymeric organogelators as flocculants and oil spill treating agents, and identifying potential solvents and ideal processing temperatures. METHODS: The MD simulations are performed using the GROMACS 2022.3 package with optimized potential for liquid simulations-all atom (OPLS-AA) force field parameters. All polymers are built as extended chains using CHARMM-GUI Polymer Builder.

Alcohol Use Disorder and Chronic Pain: An Overlooked Epidemic.

Alcohol use disorder (AUD) and chronic pain disorders are pervasive, multifaceted medical conditions that often co-occur. However, their comorbidity is often overlooked, despite its prevalence and clinical relevance. Individuals with AUD are more likely to experience chronic pain than the general population. Conversely, individuals with chronic pain commonly alleviate their pain with alcohol, which may escalate into AUD. This narrative review discusses the intricate relationship between AUD and chronic pain. Based on the literature available, the authors present a theoretical model explaining the reciprocal relationship between AUD and chronic pain across alcohol intoxication and withdrawal. They propose that the use of alcohol for analgesia rapidly gives way to acute tolerance, triggering the need for higher levels of alcohol consumption. Attempts at abstinence lead to alcohol withdrawal syndrome and hyperalgesia, increasing the risk of relapse. Chronic neurobiological changes lead to preoccupation with pain and cravings for alcohol, further entrenching both conditions. To stimulate research in this area, the authors review methodologies to improve the assessment of pain in AUD studies, including self-report and psychophysical methods. Further, they discuss pharmacotherapies and psychotherapies that may target both conditions, potentially improving both AUD and chronic pain outcomes simultaneously. Finally, the authors emphasize the need to manage both conditions concurrently, and encourage both the scientific community and clinicians to ensure that these intertwined conditions are not overlooked given their clinical significance.

Isolation of nucleic acids using liquid-liquid phase separation of pH-sensitive elastin-like polypeptides.

Extraction of nucleic acids (NAs) is critical for many methods in molecular biology and bioanalytical chemistry. NA extraction has been extensively studied and optimized for a wide range of applications and its importance to society has significantly increased. The COVID-19 pandemic highlighted the importance of early and efficient NA testing, for which NA extraction is a critical analytical step prior to the detection by methods like polymerase chain reaction. This study explores simple, new approaches to extraction using engineered smart nanomaterials, namely NA-binding, intrinsically disordered proteins (IDPs), that undergo triggered liquid-liquid phase separation (LLPS). Two types of NA-binding IDPs are studied, both based on genetically engineered elastin-like polypeptides (ELPs), model IDPs that exhibit a lower critical solution temperature in water and can be designed to exhibit LLPS at desired temperatures in a variety of biological solutions. We show that ELP fusion proteins with natural NA-binding domains can be used to extract DNA and RNA from physiologically relevant solutions. We further show that LLPS of pH responsive ELPs that incorporate histidine in their sequences can be used for both binding, extraction and release of NAs from biological solutions, and can be used to detect SARS-CoV-2 RNA in samples from COVID-positive patients.

Implante transcateter da válvula aórtica (TAVI) em pacientes com valva aórtica bicúspide versus tricúspide: um estudo retrospectivo comparativo / Transcatheter aortic valve implantation (TAVI) in patients with bicuspid versus tricuspid aortic valve: a comparative retrospective study

INTRODUÇÃO: A válvula aórtica bicúspide (BAV) ocorre em até 6% dos pacientes com estenose aórtica importante. Sua presença pode refletir um desafio para TAVI uma vez que pacientes com BAV podem possuir maiores diâmetros do anel valvar, calcificação acentuada dos folhetos e dilatação da aorta ascendente. O número crescente de TAVI nessa população torna imperativo um aprofundamento na investigação de seus resultados e desfechos clínicos. MÉTODOS: Retrospectivo, unicêntrico e observacional. Realizamos uma revisão de banco de dados e selecionamos pacientes submetidos a TAVI no período de novembro de 2020 a janeiro de 2024. O objetivo deste estudo é avaliar a incidência e resultados imediatos na população com BAV comparativamente aos pacientes com valva tricúspide. Para isso, foram coletados dados clínicos e demográficos, bem como informações sobre complicações e desfechos intrahospitalares após TAVI em ambas as populações, segundo o VARC 3. A análise dos dados foi realizada utilizando estatística descritiva e comparativa (Teste T de Student), com intuito de verificar se há diferenças significativas em desfechos entre as populações. RESULTADOS: De um total de 174 pacientes, 33 deles apresentaram BAV, resultando em uma incidência de 18,96%. A análise estatística não evidenciou diferença significativa nos dados de base de ambas as populações. Média de idade entre o grupo BAV (75,84 ± 8,19 anos) e o grupo tricúspide (78,61 ± 6,32 anos), com um p-valor não significativo de p 0,243. O STS score médio foi de 3,14 ± 1,86% no grupo BAV e 3,47 ± 1,97% no grupo tricúspide; p 0,12. Em relação ao procedimento, houve diferença significativa na necessidade de pré-dilatação entre os grupos, sendo necessária em 25 dos 33 casos de bicúspide (75,75%) e 71 dos 141 casos de tricúspide (50,35%) (p 0,008). Porém, não foi evidenciada diferença significativa no gradiente ventrículo esquerdo e aorta pós-procedimento de 4,53 ± 3,04 vs 5,33 ± 4,46; p 0,233, de bicúspide e tricúspide respectivamente; nem no tempo de permanência hospitalar pós procedimento 2,63 ± 2,11 vs 3,03 ± 4,29; p 0,439. Não foi observado também diferença significativa em relação a necessidade de marcapasso definitivo, refluxo paravalvular ou complicações hemorrágicas e vasculares. CONCLUSÃO: Com base nos resultados, não foi observada diferença significativa nos desfechos entre os pacientes com BAV e tricúspide. Estes achados sugerem que a TAVI é um tratamento seguro e eficaz para pacientes com BAV. No entanto, são necessários estudos adicionais com amostras mais amplas para confirmar esses resultados.

Assessing pain in persons with opioid use disorder: Approaches, techniques and special considerations.

Pain and opioid use disorder (OUD) are inextricably linked, as the former can be a risk factor for the development of the latter, and over a third of persons with OUD suffer concomitant chronic pain. Assessing pain among people with OUD is challenging, because ongoing opioid use brings changes in pain responses and most pain assessment tools have not been validated for this population. In this narrative review, we discuss the fundamentals of pain assessment for populations with OUD. First, we describe the biological, psychological and social aspects of the pain experience among people with OUD, as well as how opioid-related phenomena may contribute to the pain experience in this population. We then review methods to assess pain, including (1) traditional self-reported methods, such visual analogue scales and structured questionnaires; (2) behavioural observations and physiological indicators; (3) and laboratory-based approaches, such as quantitative sensory testing. These methods are considered from a perspective that encompasses both pain and OUD. Finally, we discuss strategies for improving pain assessment in persons with OUD and implications for future research, including educational strategies for multidisciplinary teams. We highlight the substantial gaps that persist in this literature, particularly regarding the applicability of current pain assessment methods to persons with OUD, as well as the generalizability of the existing results from adjacent populations on chronic opioid therapy but without OUD. As research linking pain and OUD evolves, considering the needs of diverse populations with complex psychosocial backgrounds, clinicians will be better equipped to reduce these gaps.

An Intricate Network Involving the Argonaute ALG-1 Modulates Organismal Resistance to Oxidative Stress.

Cellular response to redox imbalance is crucial for organismal health. microRNAs are implicated in stress responses. ALG-1, the C. elegans ortholog of human AGO2, plays an essential role in microRNA processing and function. Here we investigated the mechanisms governing ALG-1 expression in C. elegans and the players controlling lifespan and stress resistance downstream of ALG-1. We show that upregulation of ALG-1 is a shared feature in conditions linked to increased longevity (e.g., germline-deficient glp-1 mutants). ALG-1 knockdown reduces lifespan and oxidative stress resistance, while overexpression enhances survival against pro-oxidant agents but not heat or reductive stress. R02D3.7 represses alg-1 expression, impacting oxidative stress resistance at least in part via ALG-1. microRNAs upregulated in glp-1 mutants (miR-87-3p, miR-230-3p, and miR-235-3p) can target genes in the protein disulfide isomerase pathway and protect against oxidative stress. This study unveils a tightly regulated network involving transcription factors and microRNAs which controls organisms' ability to withstand oxidative stress.

Empirically derived symptom profiles in adults with attention-Deficit/hyperactivity disorder: An unsupervised machine learning approach.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with various cognitive, behavioral, and mood symptoms that complicate diagnosis and treatment. The heterogeneity of these symptoms may also vary depending on certain sociodemographic factors. It is therefore important to establish more homogenous symptom profiles in patients with ADHD and determine their association with the patient's sociodemographic makeup. The current study used unsupervised machine learning to identify symptom profiles across various cognitive, behavioral, and mood symptoms in adults with ADHD. It was then examined whether symptom profiles differed based on relevant sociodemographic factors. METHODS: Participants were 382 adult outpatients (62% female; 51% non-Hispanic White) referred for neuropsychological evaluation for ADHD. RESULTS: Employing Gaussian Mixture Modeling, we identified two distinct symptom profiles in adults with ADHD: "ADHD-Plus Symptom Profile" and "ADHD-Predominate Symptom Profile." These profiles were primarily differentiated by internalizing psychopathology (Cohen's d = 1.94-2.05), rather than by subjective behavioral and cognitive symptoms of ADHD or neurocognitive test performance. In a subset of 126 adults without ADHD who were referred for the same evaluation, the unsupervised machine learning algorithm only identified one symptom profile. Group comparison analyses indicated that female patients were most likely to present with an ADHD-Plus Symptom Profile (χ2 = 5.43, p < .001). CONCLUSION: The machine learning technique used in this study appears to be an effective way to elucidate symptom profiles emerging from comprehensive ADHD evaluations. These findings further underscore the importance of considering internalizing symptoms and patients' sex when contextualizing adult ADHD diagnosis and treatment.

From taboo to treatment: The emergence of psychedelics in the management of pain and opioid use disorder.

The rise of psychedelics in contemporary medicine has sparked interest in their potential therapeutic applications. While traditionally associated with countercultural movements and recreational use, recent research has shed light on the potential benefits of psychedelics in various mental health conditions. In this review, we explore the possible role of psychedelics in the management of chronic pain and opioid use disorder (OUD), 2 critical areas in need of innovative treatment options. Pain control remains a significant clinical challenge, particularly for individuals with OUD and those who receive long-term opioid therapy who develop marked tolerance to opioid-induced analgesia. Despite the magnitude of this problem, there is a scarcity of controlled studies investigating pain management alternatives for these populations. Drawing from preclinical and human evidence, we highlight the potential of psychedelics to act on shared neurobiological substrates of chronic pain and OUD, potentially reversing pain- and opioid-induced neuroadaptations, such as central sensitization. We elaborate on the multifaceted dimensions of the pain experience (sensory, affective and cognitive) and their intersections that overlap with opioid-related phenomena (opioid craving and withdrawal), hypothesizing how these processes can be modulated by psychedelics. After summarizing the available clinical research, we propose mechanistic insights and methodological considerations for the design of future translational studies and clinical trials, building on a shared clinical and neurobiological understanding of chronic pain and OUD. Our intention is to provide timely perspectives that accelerate the development and exploration of novel therapeutics for chronic pain and OUD amidst the escalating opioid crisis.

Efficacy of topiramate in reducing second-generation antipsychotic-associated weight gain among children: A systematic review and meta-analysis.

AIMS: To conduct a systematic review and meta-analysis with the aim of synthesizing existing data on the efficacy and safety of topiramate as an adjunctive treatment for reducing second-generation antipsychotic (SGA)-associated weight gain in children aged 4-18 years. METHODS: We conducted a comprehensive search of PubMed, Embase, PsychNet and Web of Science from time of their inception up to 12 February 2024, including randomized controlled trials that compared SGA treatment with and without topiramate co-administration in children. The primary outcomes were changes in body weight and body mass index (BMI). Heterogeneity was assessed using I2 statistics. RESULTS: This systematic review included five randomized trials, totalling 139 participants (43.9% female; mean [SD] age 11.9 [3.5] years). Four of these trials were included in the meta-analysis, comprising 116 subjects. We found that topiramate was significantly effective both in reducing SGA-associated weight gain, with a mean difference of -2.80 kg (95% confidence interval [CI] -5.28 to -0.31; p = 0.037, I2 = 86.7%) and a standardized mean difference (SMD) of -1.33 (95% CI -2.14 to -0.51; p = 0.014, I2 = 31.7%), and in reducing BMI change compared to placebo (SMD -1.90, 95% CI -3.09 to -0.70; p = 0.02, I2 = 0%). Sedation risk was lower with topiramate than with placebo (odds ratio 0.19, 95% CI 0.11-0.32; p < 0.01, I2 = 0%). No significant differences were found in dropouts, any other side effects, and metabolic parameters, such as triglycerides, total cholesterol, low-density lipoprotein, high-density lipoprotein, and glucose. None of the included studies reported assessments on cognitive side effects. CONCLUSION: This meta-analysis suggests that topiramate is an effective and safe option for mitigating SGA-associated weight gain in children.

Extraskeletal chondroma of the toe in a child with DICER1 tumor predisposition syndrome: support for a dominant negative mechanism.

DICER1 tumor predisposition syndrome is a pleiotropic disorder that gives rise to various mainly pediatric-onset lesions. We report an extraskeletal chondroma (EC) of the great toe occurring in a child who, unusually, carries a germline "hotspot" missense DICER1 variant rather than the more usual loss-of-function (LOF) variant. No heterozygous LOF allele was identified in the EC. We demonstrate this variant impairs 5p cleavage of precursor-miRNA (pre-miRNA) and competes with wild-type (WT) DICER1 protein for pre-miRNA processing. These results suggest a mechanism through which a germline RNase IIIb variant could impair pre-miRNA processing without complete LOF of the WT DICER1 allele.

Vestigial organs alter fossil placements in an ancient group of terrestrial chelicerates.

Vestigial organs provide a link between ancient and modern traits and therefore have great potential to resolve the phylogeny of contentious fossils that bear features not seen in extant species. Here we show that extant daddy-longlegs (Arachnida, Opiliones), a group once thought to possess only one pair of eyes, in fact additionally retain a pair of vestigial median eyes and a pair of vestigial lateral eyes. Neuroanatomical gene expression surveys of eye-patterning transcription factors, opsins, and other structural proteins in the daddy-longlegs Phalangium opilio show that the vestigial median and lateral eyes innervate regions of the brain positionally homologous to the median and lateral eye neuropils, respectively, of chelicerate groups like spiders and horseshoe crabs. Gene silencing of eyes absent shows that the vestigial eyes are under the control of the retinal determination gene network. Gene silencing of dachshund disrupts the lateral eyes, but not the median eyes, paralleling loss-of-function phenotypes in insect models. The existence of lateral eyes in extant daddy-longlegs bears upon the placement of the oldest harvestmen fossils, a putative stem group that possessed both a pair of median eyes and a pair of lateral eyes. Phylogenetic analysis of harvestman relationships with an updated understanding of lateral eye incidence resolved the four-eyed fossil group as a member of the extant daddy-longlegs suborder, which in turn resulted in older estimated ages of harvestman diversification. This work underscores that developmental vestiges in extant taxa can influence our understanding of character evolution, placement of fossils, and inference of divergence times.

A Systematic Prospective Comparison of Fluid Volume Evaluation across OCT Devices Used in Clinical Practice.

Objective: Treatment decisions in neovascular age-related macular degeneration (nAMD) are mainly based on subjective evaluation of OCT. The purpose of this cross-sectional study was to provide a comparison of qualitative and quantitative differences between OCT devices in a systematic manner. Design: Prospective, cross-sectional study. Subjects: One hundred sixty OCT volumes, 40 eyes of 40 patients with nAMD. Methods: Patients from clinical practice were imaged with 4 different OCT devices during one visit: (1) Spectralis Heidelberg; (2) Cirrus; (3) Topcon Maestro2; and (4) Topcon Triton. Intraretinal fluid (IRF), subretinal fluid (SRF), and pigment epithelial detachment (PED) were manually annotated in all cubes by trained human experts to establish fluid measurements based on expert-reader annotations. Intraretinal fluid, SRF, and PED volume were quantified in nanoliters (nL). Bland-Altman plots were created to analyze the agreement of measurements in the central 1 and 6 mm. The Friedman test was performed to test for significant differences in the central 1, 3, and 6 mm. Main Outcome Measures: Intraretinal fluid, SRF, and PED volume. Results: In the central 6 mm, there was a trend toward higher IRF and PED volumes in Spectralis images compared with the other devices and no differences in SRF volume. In the central 1 mm, the standard deviation of the differences ranged from ± 3 nL to ± 6 nL for IRF, from ± 3 nL to ± 4 nL for SRF, and from ± 7 nL to ± 10 nL for PED in all pairwise comparisons. Manually annotated IRF and SRF volumes showed no significant differences in the central 1 mm. Conclusions: Fluid volume quantification achieved excellent reliability in all 3 retinal compartments on images obtained from 4 OCT devices, particularly for clinically relevant IRF and SRF values. Although fluid volume quantification is reliable in all 4 OCT devices, switching OCT devices might lead to deviating fluid volume measurements with higher agreement in the central 1 mm compared with the central 6 mm, with highest agreement for SRF volume in the central 1 mm. Understanding device-dependent differences is essential for expanding the interpretation and implementation of pixel-wise fluid volume measurements in clinical practice and in clinical trials. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Comparing embedded performance validity indicators within the WAIS-IV Letter-Number sequencing subtest to Reliable Digit Span among adults referred for evaluation of attention-deficit/hyperactivity disorder.

Objectives: This study investigated the Wechsler Adult Intelligence Scale-Fourth Edition Letter-Number Sequencing (LNS) subtest as an embedded performance validity indicator among adults undergoing an attention-deficit/hyperactivity disorder (ADHD) evaluation, and its potential incremental value over Reliable Digit Span (RDS). Method: This cross-sectional study comprised 543 adults who underwent neuropsychological evaluation for ADHD. Patients were divided into valid (n = 480) and invalid (n = 63) groups based on multiple criterion performance validity tests. Results: LNS total raw scores, age-corrected scaled scores, and age- and education-corrected T-scores demonstrated excellent classification accuracy (area under the curve of .84, .83, and .82, respectively). The optimal cutoff for LNS raw score (≤16), age-corrected scaled score (≤7), and age- and education-corrected T-score (≤36) yielded .51 sensitivity and .94 specificity. Slightly lower sensitivity (.40) and higher specificity (.98) was associated with a more conservative T-score cutoff of ≤33. Multivariate models incorporating both LNS and RDS improved classification accuracy (area under the curve of .86), and LNS scores explained a significant but modest proportion of variance in validity status above and beyond RDS. Chaining LNS T-score of ≤33 with RDS cutoff of ≤7 increased sensitivity to .69 while maintaining ≥.90 specificity. Conclusions: Findings provide preliminary evidence for the criterion and construct validity of LNS as an embedded validity indicator in ADHD evaluations. Practitioners are encouraged to use LNS T-score cutoff of ≤33 or ≤36 to assess the validity of obtained test data. Employing either of these LNS cutoffs with RDS may enhance the detection of invalid performance.

Exploring Subfactors of Adult Cognitive Disengagement Syndrome and Impact on Neuropsychological Performance.

OBJECTIVE: This study investigated subfactors of cognitive disengagement syndrome (CDS; previously referred as sluggish cognitive tempo) among adults referred for neuropsychological evaluation of attentiondeficit/hyperactivity disorder (ADHD). METHOD: Retrospective analyses of data from 164 outpatient neuropsychological evaluations examined associations between CDS subfactors and self-reported psychological symptoms and cognitive performance. RESULTS: Factor analysis produced two distinct but positively correlated constructs: "Cognitive Complaints'' and "Lethargy." Both correlated positively with symptom reports (rs = 0.26-0.57). Cognitive Complaints correlated negatively with working memory, processing speed, and executive functioning performance (rs = -0.21 to -0.37), whereas Lethargy correlated negatively only with processing speed and executive functioning performance (rs = -0.26 to -0.42). Both predicted depression symptoms, but only Cognitive Complaints predicted inattention symptoms. Both subfactors demonstrated modest to nonsignificant associations with cognitive performance after accounting for estimated premorbid intelligence and inattention. CONCLUSION: Findings indicate a bidimensional conceptualization of CDS, with differential associations between its constituent subfactors, reported symptoms, and cognitive performance.

An Open-Label Phase I Study of Metformin and Nelfinavir in Combination With Bortezomib in Patients With Relapsed and Refractory Multiple Myeloma.

BACKGROUND: In preclinical models, combining a GLUT4 inhibitor with an oxidative phosphorylation inhibitor shows synergistic therapeutic potential against multiple myeloma (MM). Thus, this study evaluated the safety and tolerability of repurposing metformin, a complex I inhibitor, and nelfinavir, a GLUT4 inhibitor, in combination with bortezomib for the treatment of relapsed/refractory MM that had progressed on all standard of care therapies. MATERIALS AND METHODS: This trial utilized a 3 + 3 dose escalation design with 3 dose levels planned for up to a maximum of 6 (21-day) cycles. Metformin and nelfinavir were administered for 14 of 21 days, and subQ bortezomib was administered to a portion of patients on days 1, 8, and 15. The primary objective was to determine the maximal tolerated dose, and the secondary objective was to evaluate the safety and overall response rate (ORR) of this combination. RESULTS: Nine patients were accrued with a median age of 65 (range: 42-81) and received a median of 7 prior lines of therapy (Range: 5-12). The first 3 patients received only metformin (500 mg BID) and nelfinavir (1250 mg BID) at the first dose level, with 1 patient experiencing an unconfirmed minimal response (MR) in the first cycle, 1 experiencing progressive disease after 1 cycle of treatment and 1 patient going off treatment prior to assessing response but with signs of progressive disease. Given the limited therapeutic activity, the upfront addition of bortezomib (1.3 mg/m2) was utilized for the subsequent 6 patients accrued. Three of these 6 patients went off study due to progressive disease, 1 patient achieved an unconfirmed partial response after 1 cycle of treatment but reported progressive disease in the subsequent cycle, 1 patient went off study to enter hospice, and the remaining patient experienced stable disease (SD) after receiving 6 cycles of clinical trial treatment. The study was closed before accrual to the next dose level was started. CONCLUSION: This is the first study to evaluate the safety and efficacy of this repurposed drug combination in this very difficult-to-treat population of relapsed and refractory MM. This was an overall negative study with no ORR observed. Fortunately, 1 patient experienced an SD response, allowing this combination to stabilize their disease until another novel therapy on a clinical trial was available.

The impact of cannabis on non-medical opioid use among individuals receiving pharmacotherapies for opioid use disorder: a systematic review and meta-analysis of longitudinal studies.

Background: The relationship between cannabis use and the risk of returning to using opioids non-medically during treatment for opioid use disorder (OUD) remains unclear.Objective: We sought to quantify the impact of cannabis use on the risk of non-medical opioid use among people receiving pharmacotherapies for OUD.Methods: A comprehensive search was performed using multiple databases from March 1 to April 5 of 2023. Eligible studies longitudinally assessed the association between cannabis use and non-medical opioid use among people with OUD receiving treatment with buprenorphine, methadone, or naltrexone. We utilized a random-effects model employing the restricted maximum likelihood method. A sensitivity analysis was conducted to understand potential differences between each OUD treatment modality.Results: A total of 10 studies were included in the final meta-analysis. There were 8,367 participants (38% female). The average follow-up time across these studies was 9.7 months (SD = 3.77), ranging from 4 to 15 months. The pharmacotherapies involved were methadone (76.3%) buprenorphine (21.3%), and naltrexone (2.4%). The pooled odds ratio did not indicate that cannabis use significantly influenced non-medical opioid use (OR: 1.00, 95% CI: 0.97-1.04, p = .98). There is evidence of moderate heterogeneity and publication bias.Conclusion: There was no significant association between cannabis use and non-medical opioid use among patients receiving pharmacotherapies for OUD. These findings neither confirm concerns about cannabis increasing non-medical opioid use during MOUD, nor do they endorse its efficacy in decreasing non-medical opioid use with MOUD. This indicates a need for individualized approaches for cannabis use and challenges the requirement of cannabis abstinence to maintain OUD pharmacotherapies.

Demonstration of a scalable process for remediation of petroleum-impacted soil using electron beam irradiation.

Petroleum-impacted soils pose several hazards and require fast, effective, and versatile remediation techniques. Electron beam irradiation provides a novel means of heating soil and inducing non-equilibrium chemical reactions and has previously been applied to environmental remediation. In this work a scalable process for remediation of petroleum-impacted soils using a 100 kW, 3 MeV industrial electron beam is investigated. The process involves conveying impacted soil through a beam at a controllable rate to achieve a desired dose of approximately 1000 kGy. Reductions to less than 1% Total Petroleum Hydrocarbon (TPH) content from an initial TPH of 3.3% were demonstrated for doses of 710-1370 kGy. These reductions were achieved in in conditions equivalent to 4 m3 per hour, demonstrating the applicability of this technique to remediation sites. TPH reduction appeared to be temperature-dependent but not heavily dependent on dose rate, with reductions of 96% achieved for a dose of 1370 kGy and peak temperature of 540 °C. The performance of the process at high dose rates suggests that it can be incorporated into remediation of sites for which a high rate of material processing is required with a relatively small device footprint.