Biological impact of iberdomide in patients with active systemic lupus erythematosus.

OBJECTIVES: Iberdomide is a high-affinity cereblon ligand that promotes proteasomal degradation of transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). Pharmacodynamics and pharmacokinetics of oral iberdomide were evaluated in a phase 2b study of patients with active systemic lupus erythematosus (SLE). METHODS: Adults with autoantibody-positive SLE were randomised to placebo (n=83) or once daily iberdomide 0.15 mg (n=42), 0.3 mg (n=82) or 0.45 mg (n=81). Pharmacodynamic changes in whole blood leucocytes were measured by flow cytometry, regulatory T cells (Tregs) by epigenetic assay, plasma cytokines by ultrasensitive cytokine assay and gene expression by Modular Immune Profiling. RESULTS: Iberdomide exhibited linear pharmacokinetics and dose-dependently modulated leucocytes and cytokines. Compared with placebo at week 24, iberdomide 0.45 mg significantly (p<0.001) reduced B cells, including those expressing CD268 (TNFRSF13C) (-58.3%), and plasmacytoid dendritic cells (-73.9%), and increased Tregs (+104.9%) and interleukin 2 (IL-2) (+144.1%). Clinical efficacy was previously reported in patients with high IKZF3 expression and high type I interferon (IFN) signature at baseline and confirmed here in those with an especially high IFN signature. Iberdomide decreased the type I IFN gene signature only in patients with high expression at baseline (-81.5%; p<0.001) but decreased other gene signatures in all patients. CONCLUSION: Iberdomide significantly reduced activity of type I IFN and B cell pathways, and increased IL-2 and Tregs, suggesting a selective rebalancing of immune abnormalities in SLE. Clinical efficacy corresponded to reduction of the type I IFN gene signature. TRIAL REGISTRATION NUMBER: NCT03161483.

Lessons Learned about the Need for Early Screening for Depression during the First Months of the COVID-19 Pandemic in the United States.

A nationwide survey assessed the prevalence and pandemic-related risk factors of major depressive disorder (MDD) at the initial onset of the COVID-19 pandemic. Findings showed a significant increase in the prevalence of MDD (22.7%) compared to the pre-pandemic 12-month estimate (10.4%). Specific pandemic-related concerns, along with significant increases in stress, loneliness, fatigue, and substance use behaviors are noted for those with the provisional diagnosis of MDD. Early screening and detection for potential MDD cases can reduce the severity and duration of maladaptive symptoms, decreasing the risk for future depression episodes and the potential loss of quality of life and productivity.

Neuropsychological functioning in opioid use disorder: A research synthesis and meta-analysis.

BACKGROUND: Research has demonstrated that patients with opioid use disorders (OUD; including both opioid abuse and/or dependence) have poorer neuropsychological functioning compared to healthy controls; however, the pattern and robustness of the findings remain unknown. OBJECTIVES: This study meta-analyzed the results from previous research examining the neuropsychological deficits associated with opioids across 14 neurocognitive domains. METHOD: Articles comparing patients with OUD to healthy controls were selected based on detailed inclusion/exclusion criteria and variables of interest were coded. In total, 61 studies were selected for the analyses. These consisted of 2580 patients with OUD and 2102 healthy control participants (15.9% female). Drug-related variables were analyzed as potential moderators. RESULTS: The largest effect size difference in neuropsychological performance was observed in complex psychomotor ability. With the exception of the motor and processing speed domains, which showed no group differences, small-to-medium effect sizes were associated with all neurocognitive domains examined. Meta-regression revealed that increases in the length of abstinence were associated with decreases in effect sizes of the complex psychomotor domain. Additionally, attentional ability predicted effect size differences in executive functioning as well as verbal memory ability. Although the majority of meta-analyzed studies demonstrated significant differences between patients with OUD and controls, the average raw scores for patients with OUD in these studies typically fell within the normal range. CONCLUSION: The pattern of neuropsychological performance among patients with OUD appears to reflect mild generalized cognitive dysfunction, with a large effect in complex psychomotor abilities.

Neuropsychological comparisons of cocaine versus methamphetamine users: A research synthesis and meta-analysis.

BACKGROUND: Previous meta-analytical research examining cocaine and methamphetamine separately suggests potentially different neuropsychological profiles associated with each drug. In addition, neuroimaging studies point to distinct structural changes that might underlie differences in neuropsychological functioning. OBJECTIVES: This meta-analysis compared the effect sizes identified in cocaine versus methamphetamine studies across 15 neuropsychological domains. METHOD: Investigators searched and coded the literature examining the neuropsychological deficits associated with a history of either cocaine or methamphetamine use. A total of 54 cocaine and 41 methamphetamine studies were selected, yielding sample sizes of 1,718 and 1,297, respectively. Moderator analyses were conducted to compare the two drugs across each cognitive domain. RESULTS: Data revealed significant differences between the two drugs. Specifically, studies of cocaine showed significantly larger effect-size estimates (i.e., poorer performance) in verbal working memory when compared to methamphetamine. Further, when compared to cocaine, methamphetamine studies demonstrated significantly larger effect sizes in delayed contextual verbal memory and delayed visual memory. CONCLUSION: Overall, cocaine and methamphetamine users share similar neuropsychological profiles. However, cocaine appears to be more associated with working memory impairments, which are typically frontally mediated, while methamphetamine appears to be more associated with memory impairments that are linked with temporal and parietal lobe dysfunction.

Gray matter abnormalities in opioid-dependent patients: A neuroimaging meta-analysis.

BACKGROUND: Prior research utilizing whole-brain neuroimaging techniques has identified structural differences in gray matter in opioid-dependent individuals. However, the results have been inconsistent. OBJECTIVES: The current study meta-analytically examines the neuroimaging findings of studies published before 2016 comparing opioid-dependent individuals to drug-naïve controls. METHOD: Exhaustive search of five databases yielded 12 studies that met inclusion criteria. Anisotropic Effect-Size Seed-Based d Mapping (AES-SDM) was used to analyze the data extracted by three independent researchers. Voxel-based AES-SDM distinguishes increases and decreases in brain matter significant at the whole-brain level. RESULTS: AES-SDM identified the fronto-temporal region, bilaterally, as being the primary site of gray matter deficits associated with opioid use. Moderator analysis revealed that length of opioid use was negatively associated with gray matter in the left cerebellar vermis and the right Rolandic operculum, including the insula. Meta-regression revealed no remaining significant areas of gray matter reductions, except in the precuneus, following longer abstinence from opioids. CONCLUSIONS: Opioid-dependent individuals had significantly less gray matter in several regions that play a key role in cognitive and affective processing. The findings provide evidence that opioid dependence may result in the breakdown of two distinct yet highly overlapping structural and functional systems. These are the fronto-cerebellar system that might be more responsible for impulsivity, compulsive behaviors, and affective disturbances and the fronto-insular system that might account more for the cognitive and decision-making impairments.

Meta-analyses of clinical neuropsychological tests of executive dysfunction and impulsivity in alcohol use disorder.

BACKGROUND: Promising models for cognitive rehabilitation in alcohol treatment rest on a more nuanced understanding of the associated impairments in the multifaceted domains of executive functioning (EF) and impulsivity. OBJECTIVES: This meta-analysis examined the effects of alcohol on the individual subcomponents of EF and impulsivity in recently detoxified participants, including 1) Inhibition & Self-Regulation, 2) Flexibility & Set Shifting, 3) Planning & Problem Solving, 4) Reasoning & Abstraction, and 5) Verbal Fluency. Impulsivity was further examined through an analysis of motor, cognitive, and decisional subcategories. METHOD: Investigators searched, coded, and calculated effect sizes of impairments demonstrated in a broad range of neuropsychological tests for EF. A total of 77 studies were selected covering 48 years of research with a sample size of 5140. RESULTS: Findings ranged from a Hedges' g effect size of 0.803 for Inhibition to a Hedges' g of 0.359 for Verbal Fluency. Results also varied for the individual subcategories of Inhibition, including a large effect size for decisional impulsivity (g = 0.817) and cognitive impulsivity (0.860), and a moderate effect size for motor impulsivity (g = 0.529). The Hayling Test, Wisconsin Card Sorting Test, and Iowa Gambling Task were the measures most sensitive for alcohol effects. CONCLUSION: Planning, problem solving, and inhibitory abilities are significantly affected by alcohol abuse, with decisional and cognitive forms of impulsivity most impacted. Cognitive remediation targeting these deficits might increase the related functions that mediate the ability to moderate or abstain from alcohol, and so lead to improved treatment results.

What Is the Role of the Bacterium Propionibacterium acnes in Type 1 Modic Changes? A Review of the Literature.

This review presents a summary of the pathology and epidemiology of Modic changes and the possible role of Propionibacterium acnes. This information is followed by a synthesis of the most recent clinical research involved in culturing the discs of patients with degenerative disc disease for the presence of bacteria. We also discuss a randomized controlled trial that investigates the effects of antibiotics on patients with chronic low back pain and type 1 Modic changes. We conclude with a brief discussion of the difficulties involved in this research and the significance of the findings.

White matter abnormalities in long-term heroin users: a preliminary neuroimaging meta-analysis.

BACKGROUND: Diffusion tensor imaging has been used to explore white matter changes in heroin-dependent patients; however, results have been inconsistent. OBJECTIVES: The current study meta-analytically examines the neuroimaging findings of all studies published before 2014 using the novel technique of Effect Size Signed Differential Mapping (ES-SDM). METHODS: Two independent investigators searched three databases for whole-brain voxel-based fractional anisotropy morphometric studies involving heroin use without comorbid polysubstance abuse. Of 59 initial primary studies, four met stringent inclusion criteria. RESULTS: RESULTS from this preliminary analysis indicate that heroin abusers may have significant reductions in fractional anisotropy in the bilateral frontal sub-gyral regions extending from the limbic structures to the prefrontal association cortices, implicating damage to the cingulum and superior longitudinal fasciculus. Exploratory moderator analyses indicate that the potential damage in the left cingulate gyrus may increase with longer use and decrease after long-term abstinence. CONCLUSION: These preliminary findings suggest that heroin abuse is significantly associated with damage to white matter integrity. These results are considered preliminary and analyses should be revisited with more primary studies focusing on either long- or short-term abuse as well as abstinence.

Gray matter abnormalities in cocaine versus methamphetamine-dependent patients: a neuroimaging meta-analysis.

BACKGROUND: Voxel-based morphometry has been used to explore gray matter alterations in cocaine and methamphetamine dependence. However, the results of this research are inconsistent. OBJECTIVES: The current study meta-analytically examined neuroimaging findings of all studies published before 2014 using the Anisotropic Effect-Size Signed Differential Mapping (ES-SDM). METHODS: Independent investigators searched four major databases for relevant neuroimaging studies involving cocaine and methamphetamine dependence. Nine cocaine and four methamphetamine studies met inclusion criteria. RESULTS: Results indicated that cocaine- and methamphetamine-dependent patients share overlapping regional gray matter abnormalities compared to healthy controls. However, subgroup analysis showed some regional differences; with methamphetamine showing more prominent reductions in the left superior temporal gyrus and the right inferior parietal lobe. Reductions in the right insula and the left superior frontal gyrus were more prominent in cocaine dependence. Moderator analyses indicated that with longer use, cocaine is associated with reductions in the right hippocampus, right middle temporal gyrus, and right inferior frontal gyrus, while methamphetamine is associated with reductions in the left precentral gyrus and the right supramarginal gyrus. CONCLUSION: These findings indicate that cocaine and methamphetamine dependence are significantly and differentially associated with gray matter abnormalities. Results also point to possible gray matter recovery after abstinence from methamphetamine. Although the sample size was adequate, these findings should be considered preliminary and analyses should be revisited with additional primary research focusing on long or short-term duration of use, as well as the length of abstinence.

HRV biofeedback for pediatric irritable bowel syndrome and functional abdominal pain: a clinical replication series.

Irritable bowel syndrome (IBS) and Functional Abdominal Pain (FAP) are among the most commonly reported Functional Gastrointestinal Disorders. Both have been associated with varying autonomic dysregulation. Heart Rate Variability Biofeedback (HRVB) has recently begun to show efficacy in the treatment of both IBS and FAP. The purpose of this multiple clinical replication series was to analyze the clinical outcomes of utilizing HRVB in a clinical setting. Archival data of twenty-seven consecutive pediatric outpatients diagnosed with IBS or FAP who received HRVB were analyzed. Clinical outcomes were self-report and categorized as full or remission with patient satisfaction, or no improvement. Qualitative reports of patient experiences were also noted. Full remission was achieved by 69.2 % and partial remission was achieved by 30.8 % of IBS patients. Full remission was achieved by 63.6 % and partial remission was achieved by 36.4 % of FAP patients. No patients in either group did not improve to a level of patient satisfaction or >50 %. Patient's commonly reported feeling validated in their discomfort as a result of psychophysiological education. Results suggest that HRVB is a promising intervention for pediatric outpatients with IBS or FAP. Randomized controlled trials are necessary to accurately determine clinical efficacy of HRVB in the treatment of IBS and FAP.

Cognitive decline in mid-life: Changes in memory and cognition related to hypothyroidism.

This study assessed specific cognitive impairments within a primarily female, hypothyroid population, while controlling for factors that commonly contribute to cognitive decline. Participants (N = 739) included 461 individuals with hypothyroidism. This study involved an online survey assessing several aspects of memory and cognition. Those with hypothyroidism generally scored worse on self-assessments of memory, higher perceived stress, high rates of depression and anxiety, greater fatigue, poorer concentration, and less motivation. A Receiver Operating Characteristic curve indicated that the cognitive questionnaires are successful at classifying hypothyroidism and a mediation analysis showed fatigue is a mediating symptom of these cognitive outcomes.

Contrived Materials and a Data Set for the Evaluation of Liquid Biopsy Tests: A Blood Profiling Atlas in Cancer (BLOODPAC) Community Study.

The Blood Profiling Atlas in Cancer (BLOODPAC) Consortium is a collaborative effort involving stakeholders from the public, industry, academia, and regulatory agencies focused on developing shared best practices on liquid biopsy. This report describes the results from the JFDI (Just Freaking Do It) study, a BLOODPAC initiative to develop standards on the use of contrived materials mimicking cell-free circulating tumor DNA, to comparatively evaluate clinical laboratory testing procedures. Nine independent laboratories tested the concordance, sensitivity, and specificity of commercially available contrived materials with known variant-allele frequencies (VAFs) ranging from 0.1% to 5.0%. Each participating laboratory utilized its own proprietary evaluation procedures. The results demonstrated high levels of concordance and sensitivity at VAFs of >0.1%, but reduced concordance and sensitivity at a VAF of 0.1%; these findings were similar to those from previous studies, suggesting that commercially available contrived materials can support the evaluation of testing procedures across multiple technologies. Such materials may enable more objective comparisons of results on materials formulated in-house at each center in multicenter trials. A unique goal of the collaborative effort was to develop a data resource, the BLOODPAC Data Commons, now available to the liquid-biopsy community for further study. This resource can be used to support independent evaluations of results, data extension through data integration and new studies, and retrospective evaluation of data collection.

Mechanisms of electron-phonon coupling unraveled in momentum and time: The case of soft phonons in TiSe2.

The complex coupling between charge carriers and phonons is responsible for diverse phenomena in condensed matter. We apply ultrafast electron diffuse scattering to unravel electron-phonon coupling phenomena in 1T-TiSe2 in both momentum and time. We are able to distinguish effects due to the real part of the many-body bare electronic susceptibility, [Formula: see text], from those due to the electron-phonon coupling vertex, g q , by following the response of semimetallic (normal-phase) 1T-TiSe2 to the selective photo-doping of carriers into the electron pocket at the Fermi level. Quasi-impulsive and wave vector-specific renormalization of soft zone-boundary phonon frequencies (stiffening) is observed, followed by wave vector-independent electron-phonon equilibration. These results unravel the underlying mechanisms driving the phonon softening that is associated with the charge density wave transition at lower temperatures.

Initial Validation of the Mid-Atlantic Mental Illness Research, Education, and Clinical Center Assessment of Traumatic Brain Injury.

With the increasing prevalence of traumatic brain injury (TBI), the need for reliable and valid methods to evaluate TBI has also increased. The purpose of this study was to establish the validity and reliability of a new comprehensive assessment of TBI, the Mid-Atlantic Mental Illness Research, Education, and Clinical Center (MIRECC) Assessment of TBI (MMA-TBI). The participants in this study were post-deployment, combat exposed veterans. First, MMA-TBI outcomes were compared with those of independently conducted clinical TBI assessments. Next, MMA-TBI outcomes were compared with those of a different validated TBI measure (the Ohio State University TBI Identification method [OSU-TBI-ID]). Next, four TBI subject matter experts independently evaluated 64 potential TBI events based on both clinical judgment and Veterans Administration/Department of Defense (VA/DoD) Clinical Practice Guidelines. Results of the MMA-TBI algorithm (based on VA/DoD clinical guideline) were compared with those of the subject matter experts. Diagnostic correspondence with independently conducted expert clinical evaluation was 96% for lifetime TBI and 92% for deployment-acquired TBI. Consistency between the MMA-TBI and the OSU-TBI-ID was high (κ = 0.90; Kendall Tau = 0.94). Comparison of MMA-TBI algorithm results with those of subject matter experts was high (κ = 0.97-1.00). The MMA-TBI is the first TBI interview to be validated against an independently conducted clinical TBI assessment. Overall, results demonstrate the MMA-TBI is a highly valid and reliable instrument for determining TBI based on VA/DoD clinical guidelines. These results support the need for application of standardized TBI criteria across all diagnostic contexts.

Reliable Gene Expression Profiling from Small and Hematoxylin and Eosin-Stained Clinical Formalin-Fixed, Paraffin-Embedded Specimens Using the HTG EdgeSeq Platform.

Clinical biomarker studies are often hindered by the scarcity or suboptimal quality of biological specimens. EdgeSeq, a transcriptomics analysis platform, combines quantitative nuclease protection assay technology with next-generation sequencing, using small amounts of starting material and delivering reproducible gene expression profiles from challenging material, such as formalin-fixed, paraffin-embedded (FFPE) tissue. To evaluate EdgeSeq for analysis of archives of stained FFPE tissue, EdgeSeq was performed on unstained, hematoxylin and eosin (H&E)-stained, and immunohistochemistry-stained slides from patients with small-cell and non-small-cell lung cancer. Pairwise comparisons of gene expression profiles from stained and unstained slides showed higher Pearson correlation coefficients with H&E staining (0.86 to 0.97) than with immunohistochemistry staining (0.21 to 0.56). A 25-gene interferon-γ signature score from unstained slides showed a Pearson correlation coefficient of 0.92 with H&E-stained slides and a significant Spearman correlation (P = 0.0025) with immune scores. To test gene expression profiling in small samples, FFPE sample equivalents were examined from 5.0 to 0.08 mm2 of a section (5 µm thick); sample equivalents ≥0.31 mm2 showed alignment rates >69% and pairwise Pearson correlation coefficients ≥0.87. EdgeSeq can, thus, be used to profile small and H&E-stained FFPE tumor specimens to obtain biomarker data from limited tissue in oncology clinical trials and enable research into tumor microenvironment and immune cell engagement with tumors at the locoregional level.

An open-source software ecosystem for the interactive exploration of ultrafast electron scattering data.

This paper details a software ecosystem comprising three free and open-source Python packages for processing raw ultrafast electron scattering (UES) data and interactively exploring the processed data. The first package, iris, is graphical user-interface program and library for interactive exploration of UES data. Under the hood, iris makes use of npstreams, an extensions of numpy to streaming array-processing, for high-throughput parallel data reduction. Finally, we present scikit-ued, a library of reusable routines and data structures for analysis of UES data, including specialized image processing algorithms, simulation routines, and crystal structure manipulation operations. In this paper, some of the features or all three packages are highlighted, such as parallel data reduction, image registration, interactive exploration. The packages are fully tested and documented and are released under permissive licenses.

Clinical evaluation of a flexible fecal incontinence management system.

BACKGROUND: Management of fecal incontinence is a priority in acute and critical care to reduce risk of perineal dermatitis and transmission of nosocomial infections. OBJECTIVE: To evaluate the safety of the Flexi-Seal Fecal Management System in hospitalized patients with diarrhea and incontinence. METHODS: A prospective, single-arm clinical study with 42 patients from 7 hospitals in the United States was performed. The fecal management system could be used for up to 29 days. The first 11 patients (all from critical care) underwent endoscopic proctoscopy at baseline; 8 of these had endoscopy again after treatment. The remaining 31 patients (from critical or acute care) did not have endoscopy. RESULTS: Rectal mucosa was healthy after use of the device in all patients who had baseline and follow-up endoscopy. Physicians and nurses reported that the system was easy to insert, remove, and dispose of; its use improved management of fecal incontinence; and it was practical, caregiver- and patient-friendly, time-efficient, and efficacious. Skin condition improved or was maintained in more than 92% of patients. Patients' reports of discomfort, pain, burning, or irritation were uncommon. Adverse events were reported for 11 patients (26%). Death (considered unrelated to study treatment) occurred in 5 patients, 2 patients had generalized skin breakdown, and 1 patient had gastrointestinal bleeding after 4 days of treatment. CONCLUSIONS: The fecal management system can be used safely in hospitalized patients with diarrhea and fecal incontinence. Additional well-designed, controlled clinical trials may help to measure clinical and economic outcomes associated with the device.

Age-related parieto-occipital and other gray matter changes in borderline personality disorder: A meta-analysis of cortical and subcortical structures.

Previous research suggests that core borderline personality disorder (BPD) symptoms vary in severity with advancing age. While structural neuroimaging studies show smaller limbic and prefrontal gray matter volumes (GMV) in primarily adult and adolescent BPD patients, respectively, findings are inconsistent. Using the effect-size signed differential mapping (ES-SDM) meta-analytic method, we investigated the relationship between advancing age and GMV abnormalities in BPD patients. A total of nine voxel-based morphometry (VBM) studies comparing regional GMV of 256 BPD patients and 272 healthy control subjects were included. Meta-analysis identified lower GMV in the right superior/middle temporal gyri and higher GMV in the right supplementary motor area of BPD patients. Meta-regression showed that increasing age was significantly associated with increased GMV in the left superior parieto-occipital gyri, with younger-aged patients starting at lower GMV compared to controls. In contrast, increasing age was associated with decreased GMV in the right amygdala. These findings suggest that while GMV deficits in limbic structures may become pronounced with advancing age in the course of BPD, parieto-occipital rather than frontal GMV deficits could be especially prominent in younger-aged BPD patients.

CtBP is required for proper development of peripheral nervous system in Drosophila.

C-terminal binding protein (CtBP) is an evolutionarily and functionally conserved transcriptional corepressor known to integrate diverse signals to regulate transcription. Drosophila CtBP (dCtBP) regulates tissue specification and segmentation during early embryogenesis. Here, we investigated the roles of dCtBP during development of the peripheral nervous system (PNS). Our study includes a detailed quantitative analysis of how altered dCtBP activity affects the formation of adult mechanosensory bristles. We found that dCtBP loss-of-function resulted in a series of phenotypes with the most prevalent being supernumerary bristles. These dCtBP phenotypes are more complex than those caused by Hairless, a known dCtBP-interacting factor that regulates bristle formation. The emergence of additional bristles correlated with the appearance of extra sensory organ precursor (SOP) cells in earlier stages, suggesting that dCtBP may directly or indirectly inhibit SOP cell fates. We also found that development of a subset of bristles was regulated by dCtBP associated with U-shaped through the PxDLS dCtBP-interacting motif. Furthermore, the double bristle with sockets phenotype induced by dCtBP mutations suggests the involvement of this corepressor in additional molecular pathways independent of both Hairless and U-shaped. We therefore propose that dCtBP is part of a gene circuitry that controls the patterning and differentiation of the fly PNS via multiple mechanisms.