Exploring a general multi-pronged activation strategy for natural product discovery in Actinomycetes.

Natural products possess significant therapeutic potential but remain underutilized despite advances in genomics and bioinformatics. While there are approaches to activate and upregulate natural product biosynthesis in both native and heterologous microbial strains, a comprehensive strategy to elicit production of natural products as well as a generalizable and efficient method to interrogate diverse native strains collection, remains lacking. Here, we explore a flexible and robust integrase-mediated multi-pronged activation approach to reliably perturb and globally trigger antibiotics production in actinobacteria. Across 54 actinobacterial strains, our approach yielded 124 distinct activator-strain combinations which consistently outperform wild type. Our approach expands accessible metabolite space by nearly two-fold and increases selected metabolite yields by up to >200-fold, enabling discovery of Gram-negative bioactivity in tetramic acid analogs. We envision these findings as a gateway towards a more streamlined, accelerated, and scalable strategy to unlock the full potential of Nature's chemical repertoire.

67 million natural product-like compound database generated via molecular language processing.

Natural products are a rich resource of bioactive compounds for valuable applications across multiple fields such as food, agriculture, and medicine. For natural product discovery, high throughput in silico screening offers a cost-effective alternative to traditional resource-heavy assay-guided exploration of structurally novel chemical space. In this data descriptor, we report a characterized database of 67,064,204 natural product-like molecules generated using a recurrent neural network trained on known natural products, demonstrating a significant 165-fold expansion in library size over the approximately 400,000 known natural products. This study highlights the potential of using deep generative models to explore novel natural product chemical space for high throughput in silico discovery.

Cost-effective hybrid long-short read assembly delineates alternative GC-rich Streptomyces hosts for natural product discovery.

With the advent of rapid automated in silico identification of biosynthetic gene clusters (BGCs), genomics presents vast opportunities to accelerate natural product (NP) discovery. However, prolific NP producers, Streptomyces, are exceptionally GC-rich (>80%) and highly repetitive within BGCs. These pose challenges in sequencing and high-quality genome assembly which are currently circumvented via intensive sequencing. Here, we outline a more cost-effective workflow using multiplex Illumina and Oxford Nanopore sequencing with hybrid long-short read assembly algorithms to generate high quality genomes. Our protocol involves subjecting long read-derived assemblies to up to 4 rounds of polishing with short reads to yield accurate BGC predictions. We successfully sequenced and assembled 8 GC-rich Streptomyces genomes whose lengths range from 7.1 to 12.1 Mb with a median N50 of 8.2 Mb. Taxonomic analysis revealed previous misrepresentation among these strains and allowed us to propose a potentially new species, Streptomyces sydneybrenneri. Further comprehensive characterization of their biosynthetic, pan-genomic and antibiotic resistance features especially for molecules derived from type I polyketide synthase (PKS) BGCs reflected their potential as alternative NP hosts. Thus, the genome assemblies and insights presented here are envisioned to serve as gateway for the scientific community to expand their avenues in NP discovery.

Do demographic factors influence detection of invalid neuropsychological test performance using common performance validity tests? A multisite investigation.

OBJECTIVE: This study examined the extent to which demographic variables (i.e., age, education, premorbid IQ, sex, ethnoracial identity, and presence/absence of external incentive) affect performance validity test (PVT) performance. METHOD: This cross-sectional study examined two distinct, diverse outpatient clinical samples at an academic medical center (AMC, N = 268) and a Veterans Affairs (VA) medical center (N = 111). All patients completed a battery including five PVTs. Premorbid IQ was assessed using the Test of Premorbid Functioning (TOPF) in the AMC sample. RESULTS: Multiple correlations between demographic variables and individual PVT performance were statistically significant, but accompanying effect sizes were small, except for the relationship of premorbid IQ and reliable digit span (RDS). Regressions showed demographic variables accounted for 7%-11% of the variance in individual PVT scores in the AMC sample, and 6%-26% in the VA sample, premorbid IQ driving results in the AMC sample and compensation-seeking status in the VA sample. Other demographic variables did not correlate with compensation-seeking status. Additionally, premorbid IQ was found to be significantly higher in validly performing individuals compared to those performing invalidly in the AMC sample. CONCLUSION: Most demographic factors evaluated accounted for relatively little variance in individual PVT performance and did not significantly predict overall validity categorization. Compensation-seeking status correlated with validity classification across both groups, but offers limited diagnostic utility itself compared to objective PVT scores. Premorbid IQ within the AMC group demonstrated influence on particular PVTs (i.e., RDS) reflecting the difficulty of assessing validity within low IQ populations, particularly with PVTs more strongly correlated with IQ. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Multivariable analysis of the relative utility and additive value of eight embedded performance validity tests for classifying invalid neuropsychological test performance.

INTRODUCTION: This study investigated a combination of eight embedded performance validity tests (PVTs) derived from commonly administered neuropsychological tests to optimize sensitivity/specificity for detecting invalid neuropsychological test performance. The goal of this study was to evaluate what combination of these common embedded PVTs that have the most robust predictive power for detecting invalid neuropsychological test performance in a single diverse clinical sample. METHOD: Eight previously validated memory- and nonmemory-based embedded PVTs were examined among 231 patients undergoing neuropsychological evaluation. Patients were classified into valid/invalid groups based on four independent criterion PVTs. Embedded PVT accuracy was assessed using standard and stepwise multiple logistic regression models. RESULTS: Three PVTs, the Brief Visuospatial Memory Test-Revised Recognition Discrimination (BVMT-R-RD), Rey Auditory Verbal Learning Test Forced Choice, and WAIS-IV Digit Span Age Corrected Scaled Score, predicted 45.5% of the variance in validity group membership. BVMT-RD independently accounted for 32% of the variance in prediction of independent, criterion-defined validity group membership. CONCLUSIONS: This study demonstrated the incremental predictive power of multiple embedded PVTs derived from common neuropsychological measures in detecting invalid test performance and those measures accounting for the greatest portion of the variance. These results provide guidance for evaluating the most fruitful embedded PVTs and proof of concept to better guide selection of embedded validity indices. Further, this offers clinicians an efficient, empirically derived approach to assessing performance validity when time restraints potentially limit the use of freestanding PVTs.

Resisted Inspiration: A New Technique to Aid in the Detection of CSF-Venous Fistulas.

We describe a technique termed "resisted inspiration" that could be used during myelography to decrease superior vena cava venous pressure and increase lumbar CSF pressure, potentially aiding in the detection of CSF-venous fistulas.

MRI Findings after Recent Image-Guided Lumbar Puncture: The Rate of Dural Enhancement and Subdural Collections.

BACKGROUND AND PURPOSE: The rate of abnormal intracranial MR imaging findings including subdural collections and dural enhancement after recent lumbar puncture is not known. The purpose of our study was to examine the intracranial MR imaging findings after recent image-guided lumbar puncture. MATERIALS AND METHODS: Patients who underwent contrast-enhanced MR imaging of the brain within 7 days of a CT-guided lumbar puncture between January 2014 and April 2021 were included. Contrast-enhanced MR images were reviewed for diffuse dural enhancement, morphologic findings of brain sag, dural venous sinus distension, and subdural collections. RESULTS: Of the 160 patients who met the inclusion criteria, only 6 patients (3.9%) had new diffuse dural enhancement, though none had dural enhancement when the MR imaging was within 2 days of lumbar puncture. All 6 patients with dural enhancement had small, concurrent subdural collections. Two additional patients had subdural collections, for a total of 5.2% of our population. CONCLUSIONS: Our study is the first to examine intracranial MR imaging after recent lumbar puncture and has 2 key findings: First, 5.2% of patients had small, bilateral subdural collections after recent lumbar puncture, suggesting that asymptomatic subdural collections after recent lumbar puncture are not atypical and do not require further work-up. Additionally, when MR imaging was performed within 2 days of lumbar puncture, none of our patients had diffuse dural enhancement. This argues against the commonly held practice of performing MR imaging before lumbar puncture to avoid findings of dural enhancement, and should not delay diagnostic work-up.

Masking effect of high IQ on the Rey Auditory Verbal Learning Test in an adult sample with attention deficit/hyperactivity disorder.

OBJECTIVE: High intelligence (IQ) adults with attention-deficit/hyperactivity disorder (ADHD) often perform better on neuropsychological tests relative to average IQ adults with ADHD, despite commensurate functional impairment. This study compared adults with ADHD and high versus average IQ on the Rey Auditory Verbal Learning Test (RAVLT) to specifically assess this proposed masking effect of IQ on verbal learning/memory performance among those undergoing neuropsychological evaluation. METHOD: RAVLT performance between patients with ADHD and average versus high Test of Premorbid Function-estimated IQ were compared. Latent growth curve modeling (LGCM) evaluated learning acquisition across trials. RESULTS: RAVLT total learning, immediate, and delayed free recall performances were significantly better in the high IQ relative to the average IQ group. LGCM showed similar quadradic growth trajectories for both IQ groups. Both groups reported equivalent symptom severity and functional complaints in childhood and adulthood. CONCLUSIONS: Adults with ADHD and high IQ performed normally on a verbal learning/memory test compared to adults with average IQ, who scored 0.5-1.0 standard deviations below the mean. These results suggest a masking of performance-based memory deficits in the context of higher IQ in adults with ADHD, supporting growing evidence that higher IQ masks neurocognitive deficits during the assessment of adults with ADHD.

Cross-validation of a forced-choice validity indicator to enhance the clinical utility of the Rey Auditory Verbal Learning Test.

A forced-choice (FC) recognition trial was recently developed as an embedded validity indicator for the Rey Auditory Verbal Learning Test (RAVLT), although it has not been replicated outside of the initial validation study. This study cross-validated the RAVLT FC trial for detecting invalid neuropsychological test performance and assessed the degree to which material-specific verbal memory impairment severity impacts its classification accuracy as a performance validity test (PVT). This cross-sectional study included 172 neuropsychiatric patients who completed the RAVLT and 4 independent criterion PVTs, which were used to classify validity groups (134 valid/38 invalid). Overall results showed the RAVLT FC had excellent classification accuracy for detecting invalid performance at a ≤13 cut-score (66% sensitivity/87% specificity). When patients were subdivided by memory impairment status, FC retained excellent classification accuracy among the normal memory and mild memory impairment groups with 66%-82% sensitivity and ≥89% specificity. Accuracy decreased among those with severe memory impairment, but remained significant with a lower, alternative cut-score of ≤11 (37% sensitivity/88% specificity). Findings were consistent with FC trials developed for other memory measures and support the utility of this novel RAVLT FC index for reliably identifying invalid performance, even in the context of significant verbal memory impairment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Spinal Compliance Curves: Preliminary Experience with a New Tool for Evaluating Suspected CSF Venous Fistulas on CT Myelography in Patients with Spontaneous Intracranial Hypotension.

BACKGROUND AND PURPOSE: Craniospinal space compliance reflects the distensibility of the spinal and intracranial CSF spaces as a system. Craniospinal space compliance has been studied in intracranial pathologies, but data are limited in assessing it in spinal CSF leak. This study describes a method to estimate craniospinal space compliance using saline infusion during CT myelography and explores the use of craniospinal space compliance and pressure-volume curves in patients with suspected cerebrospinal-venous fistula. MATERIALS AND METHODS: Patients with suspected cerebrospinal-venous fistula underwent dynamic CT myelography. During the procedure, 1- to 5-mL boluses of saline were infused, and incremental changes in CSF pressure were recorded. These data were used to plot craniospinal space compliance curves. We calculated 3 quantitative craniospinal space compliance parameters: overall compliance, compliance at opening pressure, and the pressure volume index. These variables were compared between patients with confirmed cerebrospinal-venous fistula and those with no confirmed source of CSF leak. RESULTS: Thirty-four CT myelograms in 22 patients were analyzed. Eight of 22 (36.4%) patients had confirmed cerebrospinal-venous fistulas. Bolus infusion was well-tolerated with no complications and transient headache in 2/34 (5.8%). Patients with confirmed cerebrospinal-venous fistulas had higher compliance at opening pressure and overall compliance (2.6 versus 1.8 mL/cm H20, P < .01). There was no difference in the pressure volume index (77.5 versus 54.3 mL, P = .13) between groups. CONCLUSIONS: A method of deriving craniospinal space compliance curves using saline intrathecal infusion is described. Preliminary analysis of craniospinal space compliance curves provides qualitative and quantitative information about pressure-volume dynamics and may serve as a diagnostic tool in patients with known or suspected cerebrospinal-venous fistulas.

Recent Administration of Iodinated Contrast Renders Core Infarct Estimation Inaccurate Using RAPID Software.

BACKGROUND AND PURPOSE: Automated CTP software is increasingly used for extended window emergent large-vessel occlusion to quantify core infarct. We aimed to assess whether RAPID software underestimates core infarct in patients with an extended window recently receiving IV iodinated contrast. MATERIALS AND METHODS: We reviewed a prospective, single-center data base of 271 consecutive patients who underwent CTA ± CTP for acute ischemic stroke from May 2018 through January 2019. Patients with emergent large-vessel occlusion confirmed by CTA in the extended window (>6 hours since last known well) and CTP with RAPID postprocessing were included. Two blinded raters independently assessed CT ASPECTS on NCCT performed at the time of CTP. RAPID software used relative cerebral blood flow of <30% as a surrogate for irreversible core infarct. Patients were dichotomized on the basis of receiving recent IV iodinated contrast (<8 hours before CTP) for a separate imaging study. RESULTS: The recent IV contrast and contrast-naïve cohorts comprised 23 and 15 patients, respectively. Multivariate linear regression analysis demonstrated that recent IV contrast administration was independently associated with a decrease in the RAPID core infarct estimate (proportional increase = 0.34; 95% CI, 0.12-0.96; P = .04). CONCLUSIONS: Patients who received IV iodinated contrast in proximity (<8 hours) to CTA/CTP as part of a separate imaging study had a much higher likelihood of core infarct underestimation with RAPID compared with contrast-naïve patients. Over-reliance on RAPID postprocessing for treatment disposition of patients with extended window emergent large-vessel occlusion should be avoided, particularly with recent IV contrast administration.

Long-Term Effectiveness of Direct CT-Guided Aspiration and Fenestration of Symptomatic Lumbar Facet Synovial Cysts.

BACKGROUND AND PURPOSE: Lumbar facet synovial cysts are commonly seen in facet degenerative arthropathy and may be symptomatic when narrowing the spinal canal or compressing nerve roots. The purpose of this study was to analyze the safety, effectiveness, and long-term outcomes of direct CT-guided lumbar facet synovial cyst aspiration and fenestration for symptom relief and for obviating an operation. MATERIALS AND METHODS: We retrospectively reviewed the medical records and imaging studies of 64 consecutive patients between 2006 and 2016 who underwent 85 CT-guided lumbar facet synovial cyst fenestration procedures in our department. We recorded patient demographics, lumbar facet synovial cyst imaging characteristics, presenting symptoms, change in symptoms after the procedure, and whether they underwent a subsequent operation. We also assessed long-term outcomes from the medical records and via follow-up telephone surveys with patients. RESULTS: Direct CT-guided lumbar facet synovial cyst puncture was technically successful in 98% of procedures. At first postprocedural follow-up, 86% of patients had a complete or partial symptomatic response. During a mean follow-up of 49 months, 56% of patients had partial or complete long-term relief without the need for an operation; 44% of patients underwent an operation. Patients with calcified, thick-rimmed, or low T2 signal intensity cysts were less likely to respond to the procedure and more likely to need an operation. CONCLUSIONS: CT-guided direct lumbar facet synovial cyst aspiration and fenestration procedures are safe, effective, and minimally invasive for symptomatic treatment of lumbar synovial facet cysts. This procedure obviates an operation in a substantial number of patients, even at long-term follow-up, and should be considered before surgical intervention.

[18F]-Sodium Fluoride PET MR-Based Localization and Quantification of Bone Turnover as a Biomarker for Facet Joint-Induced Disability.

Our aim was to prospectively evaluate the relationship between low back pain-related disability and quantitative measures from [18F]-sodium fluoride ([18F]-NaF) MR imaging. Six patients with facetogenic low back pain underwent dynamic [18F]-NaF PET/MR imaging. PET metrics were correlated with clinical measures and MR imaging grading of lumbar facet arthropathy. A significant positive correlation was observed between maximum facet joint uptake rate and clinical disability (P < .05). These data suggest that dynamic [18F]-NaF PET may serve as a useful biomarker for facetogenic disability.

Entorhinal Cortex: Antemortem Cortical Thickness and Postmortem Neurofibrillary Tangles and Amyloid Pathology.

BACKGROUND AND PURPOSE: The entorhinal cortex, a critical gateway between the neocortex and hippocampus, is one of the earliest regions affected by Alzheimer disease-associated neurofibrillary tangle pathology. Although our prior work has automatically delineated an MR imaging-based measure of the entorhinal cortex, whether antemortem entorhinal cortex thickness is associated with postmortem tangle burden within the entorhinal cortex is still unknown. Our objective was to evaluate the relationship between antemortem MRI measures of entorhinal cortex thickness and postmortem neuropathological measures. MATERIALS AND METHODS: We evaluated 50 participants from the Rush Memory and Aging Project with antemortem structural T1-weighted MR imaging and postmortem neuropathologic assessments. Here, we focused on thickness within the entorhinal cortex as anatomically defined by our previously developed MR imaging parcellation system (Desikan-Killiany Atlas in FreeSurfer). Using linear regression, we evaluated the association between entorhinal cortex thickness and tangles and amyloid-ß load within the entorhinal cortex and medial temporal and neocortical regions. RESULTS: We found a significant relationship between antemortem entorhinal cortex thickness and entorhinal cortex (P = .006) and medial temporal lobe tangles (P = .002); we found no relationship between entorhinal cortex thickness and entorhinal cortex (P = .09) and medial temporal lobe amyloid-ß (P = .09). We also found a significant association between entorhinal cortex thickness and cortical tangles (P = .003) and amyloid-ß (P = .01). We found no relationship between parahippocampal gyrus thickness and entorhinal cortex (P = .31) and medial temporal lobe tangles (P = .051). CONCLUSIONS: Our findings indicate that entorhinal cortex-associated in vivo cortical thinning may represent a marker of postmortem medial temporal and neocortical Alzheimer disease pathology.

Multiple Procedure Payment Reduction: Health Policy Update.

Multiple Procedure Payment Reduction currently applies to multiple diagnostic imaging services administered to the same patient during the same day and entails a 50% decrease in the technical component and a 25% decrease in the professional component reimbursement. This might change with time due to further legislation, so it is important to be up-to-date on these health policy developments.

Pro-angiogenic cellular and genomic expression patterns within glioblastoma influences dynamic susceptibility weighted perfusion MRI.

AIM: To investigate whether quantitative dynamic susceptibility-weighted contrast-enhanced (DSC) perfusion magnetic resonance imaging (MRI) metrics are influenced by cellular and genomic expression patterns of glioblastoma angiogenesis. MATERIALS AND METHODS: Twenty-five stereotactic neurosurgical tissue samples were prospectively obtained from enhancing and non-enhancing tumour regions from 10 patients with treatment-naïve glioblastoma. Using monoclonal antibodies, histopathological features of angiogenesis were examined: total microvascular density, vascular morphology, and hypoxia. Angiogenic expression patterns of tissue samples were investigated using RNA microarrays. DSC perfusion MRI metrics were measured from the tissue sampling sites. MRI and histopathological variables were compared using Pearson's correlations. Microarray analysis was performed using false discovery rate (FDR) statistics. RESULTS: Thirteen enhancing and 12 non-enhancing MR image-guided tissue specimens were prospectively obtained. Enhancing tumour regions demonstrated a significant difference in DSC perfusion and histopathological metrics of angiogenesis when compared to non-enhancing regions. Four angiogenic pathways (vascular endothelial growth factor [VEGF], hypoxia inducible factor [HIF], platelet-derived growth factor [PDGF], fibroblast growth factor [FGF]; 25 individual genes) were significantly up-regulated within enhancing regions when compared to non-enhancing regions (adjusted p<0.05, FDR <0.05). A statistically significant correlation was observed between VEGF-A expression, microvascular density, microvascular morphology, and DSC perfusion MRI metrics (p<0.05). CONCLUSION: Pro-angiogenic genomic and cellular expression patterns of treatment-naïve primary glioblastoma significantly influences morphological and physiological DSC perfusion metrics suggesting that expression levels of therapeutically relevant genetic signatures can be quantified using MRI.

MR myelography for identification of spinal CSF leak in spontaneous intracranial hypotension.

BACKGROUND AND PURPOSE: CT myelography has historically been the test of choice for localization of CSF fistula in patients with spontaneous intracranial hypotension. This study evaluates the additional benefits of intrathecal gadolinium MR myelography in the detection of CSF leak. MATERIALS AND METHODS: We performed a retrospective review of patients with spontaneous intracranial hypotension who underwent CT myelography followed by intrathecal gadolinium MR myelography. All patients received intrathecal iodine and off-label gadolinium-based contrast followed by immediate CT myelography and subsequent intrathecal gadolinium MR myelography with multiplanar T1 fat-suppressed sequences. CT myelography and intrathecal gadolinium MR myelography images were reviewed by an experienced neuroradiologist to determine the presence of CSF leak. Patient records were reviewed for demographic data and adverse events following the procedure. RESULTS: Twenty-four patients met both imaging and clinical criteria for spontaneous intracranial hypotension and underwent CT myelography followed by intrathecal gadolinium MR myelography. In 3/24 patients (13%), a CSF leak was demonstrated on both CT myelography and intrathecal gadolinium MR myelography, and in 9/24 patients (38%), a CSF leak was seen on intrathecal gadolinium MR myelography (P = .011). Four of 6 leaks identified independently by intrathecal gadolinium MR myelography related to meningeal diverticula. CT myelography did not identify any leaks independently. There were no reported adverse events. CONCLUSIONS: Present data demonstrate a higher rate of leak detection with intrathecal gadolinium MR myelography when investigating CSF leaks in our cohort of patients with spontaneous intracranial hypotension. Although intrathecal gadolinium is an FDA off-label use, all patients tolerated the medication without evidence of complications. Our data suggest that intrathecal gadolinium MR myelography is a well-tolerated examination with significant benefit in the evaluation of CSF leak, particularly for patients with leak related to meningeal diverticula.

Changes in the thalamus in atypical parkinsonism detected using shape analysis and diffusion tensor imaging.

BACKGROUND AND PURPOSE: The thalamus is interconnected with the nigrostriatal system and cerebral cortex and has a major role in cognitive function and sensorimotor integration. The purpose of this study was to determine how regional involvement of the thalamus differs among Parkinson disease, progressive supranuclear palsy, and corticobasal syndrome. MATERIALS AND METHODS: Nine patients with Parkinson disease, 5 with progressive supranuclear palsy, and 6 with corticobasal syndrome underwent 3T MR imaging along with 12 matched, asymptomatic volunteers by using a protocol that included volumetric T1 and diffusion tensor imaging. Acquired data were automatically processed to delineate the margins of the motor and nonmotor thalamic nuclear groups, and measurements of ADC were calculated from the DTI data within these regions. Thalamic volume, shape, and ADC were compared across groups. RESULTS: Thalamic volume was smaller in the progressive supranuclear palsy and corticobasal syndrome groups compared with the Parkinson disease and control groups. Shape analysis revealed that this was mainly due to the diminished size of the lateral thalamus. Overall, ADC measurements were higher in the progressive supranuclear palsy group compared with both the Parkinson disease and control groups, and anatomic subgroup analysis demonstrated that these changes were greater within the motor regions of the thalamus in progressive supranuclear palsy and corticobasal degeneration. CONCLUSIONS: Reduced size and increased ADC disproportionately involve the lateral thalamus in progressive supranuclear palsy and corticobasal syndrome, consistent with selective neurodegeneration and atrophy in this region. Because these findings were not observed in Parkinson disease, they may be more specific markers of tau-related neurodegeneration.