Western Diet Triggers NLRP3-Dependent Innate Immune Reprogramming.

Long-term epigenetic reprogramming of innate immune cells in response to microbes, also termed "trained immunity," causes prolonged altered cellular functionality to protect from secondary infections. Here, we investigated whether sterile triggers of inflammation induce trained immunity and thereby influence innate immune responses. Western diet (WD) feeding of Ldlr-/- mice induced systemic inflammation, which was undetectable in serum soon after mice were shifted back to a chow diet (CD). In contrast, myeloid cell responses toward innate stimuli remained broadly augmented. WD-induced transcriptomic and epigenomic reprogramming of myeloid progenitor cells led to increased proliferation and enhanced innate immune responses. Quantitative trait locus (QTL) analysis in human monocytes trained with oxidized low-density lipoprotein (oxLDL) and stimulated with lipopolysaccharide (LPS) suggested inflammasome-mediated trained immunity. Consistently, Nlrp3-/-/Ldlr-/- mice lacked WD-induced systemic inflammation, myeloid progenitor proliferation, and reprogramming. Hence, NLRP3 mediates trained immunity following WD and could thereby mediate the potentially deleterious effects of trained immunity in inflammatory diseases.

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

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

Geographic variability in limited English proficiency: A cross-cultural study of cognitive profiles.

OBJECTIVE: This study was designed to evaluate the effect of limited English proficiency (LEP) on neurocognitive profiles. METHOD: Romanian (LEP-RO; n = 59) and Arabic (LEP-AR; n = 30) native speakers were compared to Canadian native speakers of English (NSE; n = 24) on a strategically selected battery of neuropsychological tests. RESULTS: As predicted, participants with LEP demonstrated significantly lower performance on tests with high verbal mediation relative to US norms and the NSE sample (large effects). In contrast, several tests with low verbal mediation were robust to LEP. However, clinically relevant deviations from this general pattern were observed. The level of English proficiency varied significantly within the LEP-RO and was associated with a predictable performance pattern on tests with high verbal mediation. CONCLUSIONS: The heterogeneity in cognitive profiles among individuals with LEP challenges the notion that LEP status is a unitary construct. The level of verbal mediation is an imperfect predictor of the performance of LEP examinees during neuropsychological testing. Several commonly used measures were identified that are robust to the deleterious effects of LEP. Administering tests in the examinee's native language may not be the optimal solution to contain the confounding effect of LEP in cognitive evaluations.

From "below chance" to "a single error is one too many": Evaluating various thresholds for invalid performance on two forced choice recognition tests.

This study was designed to empirically evaluate the classification accuracy of various definitions of invalid performance in two forced-choice recognition performance validity tests (PVTs; FCRCVLT-II and Test of Memory Malingering [TOMM-2]). The proportion of at and below chance level responding defined by the binomial theory and making any errors was computed across two mixed clinical samples from the United States and Canada (N = 470) and two sets of criterion PVTs. There was virtually no overlap between the binomial and empirical distributions. Over 95% of patients who passed all PVTs obtained a perfect score. At chance level responding was limited to patients who failed ≥2 PVTs (91% of them failed 3 PVTs). No one scored below chance level on FCRCVLT-II or TOMM-2. All 40 patients with dementia scored above chance. Although at or below chance level performance provides very strong evidence of non-credible responding, scores above chance level have no negative predictive value. Even at chance level scores on PVTs provide compelling evidence for non-credible presentation. A single error on the FCRCVLT-II or TOMM-2 is highly specific (0.95) to psychometrically defined invalid performance. Defining non-credible responding as below chance level scores is an unnecessarily restrictive threshold that gives most examinees with invalid profiles a Pass.

Take Their Word for It: The Inventory of Problems Provides Valuable Information on Both Symptom and Performance Validity.

This study was designed to compare the validity of the Inventory of Problems (IOP-29) and its newly developed memory module (IOP-M) in 150 patients clinically referred for neuropsychological assessment. Criterion groups were psychometrically derived based on established performance and symptom validity tests (PVTs and SVTs). The criterion-related validity of the IOP-29 was compared to that of the Negative Impression Management scale of the Personality Assessment Inventory (NIMPAI) and the criterion-related validity of the IOP-M was compared to that of Trial-1 on the Test of Memory Malingering (TOMM-1). The IOP-29 correlated significantly more strongly (z = 2.50, p = .01) with criterion PVTs than the NIMPAI (rIOP-29 = .34; rNIM-PAI = .06), generating similar overall correct classification values (OCCIOP-29: 79-81%; OCCNIM-PAI: 71-79%). Similarly, the IOP-M correlated significantly more strongly (z = 2.26, p = .02) with criterion PVTs than the TOMM-1 (rIOP-M = .79; rTOMM-1 = .59), generating similar overall correct classification values (OCCIOP-M: 89-91%; OCCTOMM-1: 84-86%). Findings converge with the cumulative evidence that the IOP-29 and IOP-M are valuable additions to comprehensive neuropsychological batteries. Results also confirm that symptom and performance validity are distinct clinical constructs, and domain specificity should be considered while calibrating instruments.

New live attenuated tuberculosis vaccine MTBVAC induces trained immunity and confers protection against experimental lethal pneumonia.

Among infectious diseases, tuberculosis is the leading cause of death worldwide, and represents a serious threat, especially in developing countries. The protective effects of Bacillus Calmette-Guerin (BCG), the current vaccine against tuberculosis, have been related not only to specific induction of T-cell immunity, but also with the long-term epigenetic and metabolic reprogramming of the cells from the innate immune system through a process termed trained immunity. Here we show that MTBVAC, a live attenuated strain of Mycobacterium tuberculosis, safe and immunogenic against tuberculosis antigens in adults and newborns, is also able to generate trained immunity through the induction of glycolysis and glutaminolysis and the accumulation of histone methylation marks at the promoters of proinflammatory genes, facilitating an enhanced response after secondary challenge with non-related bacterial stimuli. Importantly, these findings in human primary myeloid cells are complemented by a strong MTBVAC-induced heterologous protection against a lethal challenge with Streptococcus pneumoniae in an experimental murine model of pneumonia.

BNT-15: Revised Performance Validity Cutoffs and Proposed Clinical Classification Ranges.

BACKGROUND: Abbreviated neurocognitive tests offer a practical alternative to full-length versions but often lack clear interpretive guidelines, thereby limiting their clinical utility. OBJECTIVE: To replicate validity cutoffs for the Boston Naming Test-Short Form (BNT-15) and to introduce a clinical classification system for the BNT-15 as a measure of object-naming skills. METHOD: We collected data from 43 university students and 46 clinical patients. Classification accuracy was computed against psychometrically defined criterion groups. Clinical classification ranges were developed using a z -score transformation. RESULTS: Previously suggested validity cutoffs (≤11 and ≤12) produced comparable classification accuracy among the university students. However, a more conservative cutoff (≤10) was needed with the clinical patients to contain the false-positive rate (0.20-0.38 sensitivity at 0.92-0.96 specificity). As a measure of cognitive ability, a perfect BNT-15 score suggests above average performance; ≤11 suggests clinically significant deficits. Demographically adjusted prorated BNT-15 T-scores correlated strongly (0.86) with the newly developed z -scores. CONCLUSION: Given its brevity (<5 minutes), ease of administration and scoring, the BNT-15 can function as a useful and cost-effective screening measure for both object-naming/English proficiency and performance validity. The proposed clinical classification ranges provide useful guidelines for practitioners.

C-Terminal 1-Aminoethyltetrazole-Containing Oligopeptides as Novel Alanine Racemase Inhibitors.

In clinical culture media inoculated with patient samples, selective inhibition of commensal bacteria is essential for accurate diagnosis and effective treatment, as they can mask the presence of pathogenic bacteria. The alanine analogue, 1-aminoethyltetrazole was investigated as a potential alanine racemase inhibitor. For effective uptake and enhanced and selective antibacterial activity, a library of C-terminal 1-aminoethyltetrazole containing di- and oligopeptides were synthesized by solid phase peptide coupling techniques. The investigation of the antimicrobial activity of the synthesised compounds identified several clinically applicable selective inhibitors. These enabled differentiation between the closely related bacteria, Salmonella and Escherichia coli, which can be difficult to discriminate between in a clinical setting. In addition, differentiation between enterococci and other Gram-positive cocci was also seen.

Differentiating epilepsy from psychogenic nonepileptic seizures using neuropsychological test data.

OBJECTIVE: Differentiating epileptic seizures (ES) from psychogenic nonepileptic seizures (PNES) represents a challenging differential diagnosis with important treatment implications. This study was designed to explore the utility of neuropsychological test scores in differentiating ES from PNES. METHOD: Psychometric data from 72 patients with ES and 33 patients with PNES were compared on various tests of cognitive ability and performance validity. Individual measures that best discriminated the diagnoses were then entered as predictors in a logistic regression equation with group membership (ES vs. PNES) as the criterion. RESULTS: On most tests of cognitive ability, the PNES sample outperformed the ES sample (medium-large effect) and was less likely to fail the Reliable Digit Span. However, patients with PNES failed two embedded validity indicators at significantly higher rates (risk ratios (RR): 2.45-4.16). There were no group differences on the Test of Memory Malingering (TOMM). A logistic regression equation based on seven neuropsychological tests correctly classified 85.1% of patients. The cutoff with perfect specificity was associated with 0.47 sensitivity. CONCLUSIONS: Consistent with previous research, the utility of psychometric methods of differential diagnosis is limited by the complex neurocognitive profiles associated with ES and PNES. Although individual measures might help differentiate ES from PNES, multivariate assessment models have superior discriminant power. The strongest psychometric evidence for PNES appears to be a consistent lack of impairment on tests sensitive to diffuse neurocognitive deficits such as processing speed, working memory, and verbal fluency. While video-electroencephalogram (EEG) monitoring is the gold standard of differential diagnosis, psychometric testing has the potential to enhance clinical decision-making, particularly in complex or unclear cases such as patients with nondiagnostic video-EEGs. Adopting a standardized, fixed neuropsychological battery at epilepsy centers would advance research on the differential diagnostic power of psychometric testing.

A single error is one too many: Examining alternative cutoffs on Trial 2 of the TOMM.

OBJECTIVE: This study investigated the potential of alternative, more liberal cutoffs on Trial 2 of the Test of Memory Malingering (TOMM) to improve classification accuracy relative to the standard cutoffs (≤44). METHOD: The sample consisted of 152 patients (49.3% male) with psychiatric conditions (PSY) and traumatic brain injury (TBI) referred for neuropsychological assessment in a medico-legal setting (MAge = 44.4, MEducation = 11.9 years). Classification accuracy for various TOMM Trial 2 cutoffs was computed against three criterion measures. RESULTS: Patients with TBI failed TOMM Trial 2 cutoffs at higher rates than patients with PSY. Trial 2 ≤49 achieved acceptable combinations of sensitivity (0.38-0.67) and specificity (0.89-0.96) in all but one comparison group. Trial 2 ≤48 improved specificity (0.94-0.98) with minimal loss in sensitivity. The standard cutoff (≤44) disproportionally traded sensitivity (0.15-0.50) for specificity (0.96-1.00). CONCLUSIONS: One error on TOMM Trial 2 constitutes sufficient evidence to question the credibility of a response set. However, the confidence in classifying a score as invalid continues to increase with each additional error. Even at the most liberal conceivable cutoff (≤49), the TOMM detected only about half of the patients who failed other criterion measures. Therefore, it should never be used in isolation to determine performance validity.

Dense 3D Face Alignment from 2D Video for Real-Time Use.

To enable real-time, person-independent 3D registration from 2D video, we developed a 3D cascade regression approach in which facial landmarks remain invariant across pose over a range of approximately 60 degrees. From a single 2D image of a person's face, a dense 3D shape is registered in real time for each frame. The algorithm utilizes a fast cascade regression framework trained on high-resolution 3D face-scans of posed and spontaneous emotion expression. The algorithm first estimates the location of a dense set of landmarks and their visibility, then reconstructs face shapes by fitting a part-based 3D model. Because no assumptions are required about illumination or surface properties, the method can be applied to a wide range of imaging conditions that include 2D video and uncalibrated multi-view video. The method has been validated in a battery of experiments that evaluate its precision of 3D reconstruction, extension to multi-view reconstruction, temporal integration for videos and 3D head-pose estimation. Experimental findings strongly support the validity of real-time, 3D registration and reconstruction from 2D video. The software is available online at http://zface.org.

Spontaneous facial expression in unscripted social interactions can be measured automatically.

Methods to assess individual facial actions have potential to shed light on important behavioral phenomena ranging from emotion and social interaction to psychological disorders and health. However, manual coding of such actions is labor intensive and requires extensive training. To date, establishing reliable automated coding of unscripted facial actions has been a daunting challenge impeding development of psychological theories and applications requiring facial expression assessment. It is therefore essential that automated coding systems be developed with enough precision and robustness to ease the burden of manual coding in challenging data involving variation in participant gender, ethnicity, head pose, speech, and occlusion. We report a major advance in automated coding of spontaneous facial actions during an unscripted social interaction involving three strangers. For each participant (n = 80, 47 % women, 15 % Nonwhite), 25 facial action units (AUs) were manually coded from video using the Facial Action Coding System. Twelve AUs occurred more than 3 % of the time and were processed using automated FACS coding. Automated coding showed very strong reliability for the proportion of time that each AU occurred (mean intraclass correlation = 0.89), and the more stringent criterion of frame-by-frame reliability was moderate to strong (mean Matthew's correlation = 0.61). With few exceptions, differences in AU detection related to gender, ethnicity, pose, and average pixel intensity were small. Fewer than 6 % of frames could be coded manually but not automatically. These findings suggest automated FACS coding has progressed sufficiently to be applied to observational research in emotion and related areas of study.

Complexation of ß-cyclodextrin with a gemini surfactant studied by isothermal titration microcalorimetry and surface tensiometry.

We report on the inclusion complex formation of ß-cyclodextrin (ßCD) with a cocogem surfactant (counterion-coupled gemini surfactant; (bis(4-(2-alkyl)benzenesulfonate)-Jeffamine salt, abbreviated as ABSJ), studied by isothermal titration calorimetry (ITC) and surface tension (SFT) measurements. We measured the critical micelle concentration (cmc) of ABSJ in water by the two experimental techniques in the temperature range 283-343 K, and determined the thermodynamic parameters of the complex formation directly by ITC and indirectly by the SFT. The stoichiometry (N), the binding constant (K), and the enthalpy of complexation were determined, and the Gibbs free energy and the entropy term were calculated from the experimental data. A novel method is presented for the determination of N and K by using surface tensiometry.

The classification accuracy of Warrington's recognition memory test (words) as a performance validity Test in a neurorehabilitation setting.

This study was designed to evaluate the classification accuracy of the Warrington's Recognition Memory Test (RMT) in 167 patients (97 or 58.1% men; MAge = 40.4; MEducation= 13.8) medically referred for neuropsychological evaluation against five psychometrically defined criterion groups. At the optimal cutoff (≤42), the RMT produced an acceptable combination of sensitivity (.36-.60) and specificity (.85-.95), correctly classifying 68.4-83.3% of the sample. Making the cutoff more conservative (≤41) improved specificity (.88-.95) at the expense of sensitivity (.30-.60). Lowering the cutoff to ≤40 achieved uniformly high specificity (.91-.95) but diminished sensitivity (.27-.48). RMT scores were unrelated to lateral dominance, education, or gender. The RMT was sensitive to a three-way classification of performance validity (Pass/Borderline/Fail), further demonstrating its discriminant power. Despite a notable decline in research studies focused on its classification accuracy within the last decade, the RMT remains an effective free-standing PVT that is robust to demographic variables. Relatively low sensitivity is its main liability. Further research is needed on its cross-cultural validity (sensitivity to limited English proficiency).

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

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

Dual-Pathway Inhibition with Rivaroxaban and Low-Dose Aspirin Does Not Alter Immune Cell Responsiveness and Distribution in Patients with Coronary Artery Disease.

INTRODUCTION: Cardiovascular diseases (CVD) are the leading cause of death globally. Inflammation is an important driver of CVD where tissue damage may lead to the formation of deadly thrombi. Therefore, antithrombotic drugs, such as platelet inhibitors, are crucial for secondary risk prevention in coronary artery disease (CAD) and peripheral artery disease (PAD). For severe forms of the disease, dual-pathway inhibition (DPI) where low-dose aspirin is combined with rivaroxaban has shown improved efficacy in reducing cardiovascular mortality. METHODS: Given this greater improvement in mortality, and the importance of inflammation in driving atherosclerosis, the potential for off-target inflammation-lowering effects of these drugs was evaluated by looking at the change in immune cell distribution and responsiveness to ex vivo lipopolysaccharide (LPS) stimulation after 3 months of DPI in patients with CAD. RESULTS: We observed no changes in whole blood or peripheral blood mononuclear cell (PBMC) immune cell responsiveness to LPS after 3 months of DPI. Additionally, we did not observe any changes in the distribution of total white blood cells, monocytes, neutrophils, lymphocytes, or platelets during the study course. Signs of systemic inflammation were studied using Olink proteomics in 33 patients with PAD after 3 months of DPI. No changes were observed in any of the inflammatory proteins measured after the treatment period, suggesting that the state of chronic inflammation was not altered in these subjects. CONCLUSION: Three months of DPI does not result in any meaningful change in immune cell responsiveness and distribution in patients with CAD or PAD. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT05210725.

A chromatin-regulated biphasic circuit coordinates IL-1ß-mediated inflammation.

Inflammation is characterized by a biphasic cycle consisting initially of a proinflammatory phase that is subsequently resolved by anti-inflammatory processes. Interleukin-1ß (IL-1ß) is a master regulator of proinflammation and is encoded within the same topologically associating domain (TAD) as IL-37, which is an anti-inflammatory cytokine that opposes the function of IL-1ß. Within this TAD, we identified a long noncoding RNA called AMANZI, which negatively regulates IL-1ß expression and trained immunity through the induction of IL37 transcription. We found that the activation of IL37 occurs through the formation of a dynamic long-range chromatin contact that leads to the temporal delay of anti-inflammatory responses. The common variant rs16944 present in AMANZI augments this regulatory circuit, predisposing individuals to enhanced proinflammation or immunosuppression. Our work illuminates a chromatin-mediated biphasic circuit coordinating expression of IL-1ß and IL-37, thereby regulating two functionally opposed states of inflammation from within a single TAD.

Multivariate Models of Performance Validity: The Erdodi Index Captures the Dual Nature of Non-Credible Responding (Continuous and Categorical).

This study was designed to examine the classification accuracy of the Erdodi Index (EI-5), a novel method for aggregating validity indicators that takes into account both the number and extent of performance validity test (PVT) failures. Archival data were collected from a mixed clinical/forensic sample of 452 adults referred for neuropsychological assessment. The classification accuracy of the EI-5 was evaluated against established free-standing PVTs. The EI-5 achieved a good combination of sensitivity (.65) and specificity (.97), correctly classifying 92% of the sample. Its classification accuracy was comparable with that of another free-standing PVT. An indeterminate range between Pass and Fail emerged as a legitimate third outcome of performance validity assessment, indicating that the underlying construct is an inherently continuous variable. Results support the use of the EI model as a practical and psychometrically sound method of aggregating multiple embedded PVTs into a single-number summary of performance validity. Combining free-standing PVTs with the EI-5 resulted in a better separation between credible and non-credible profiles, demonstrating incremental validity. Findings are consistent with recent endorsements of a three-way outcome for PVTs (Pass, Borderline, and Fail).

Limited English proficiency inhibits auditory verbal learning in cognitively healthy young adults - exploring culturally responsive diagnostic and educational safeguards.

This study was designed to examine the effect of limited English proficiency (LEP) on the Hopkins Verbal Learning Test-Revised (HVLT-R). The HVLT-R was administered to 28 undergraduate student volunteers. Half were native speakers of English (NSE), half had LEP. The LEP sample performed significantly below NSE on individual acquisition trials and delayed free recall (large effects). In addition, participants with LEP scored 1.5-2 SDs below the normative mean. There was no difference in performance during recognition testing. LEP status was associated with a clinically significant deficit on the HVLT-R in a sample of cognitively healthy university students. Results suggest that low scores on auditory verbal learning tests in individuals with LEP should not be automatically interpreted as evidence of memory impairment or learning disability. LEP should be considered as grounds for academic accommodations. The generalizability of the findings is constrained by the small sample size.

Video-Based Elevated Skin Temperature Detection.

In this work, we propose a non-contact video-based approach that detects when an individual's skin temperature is elevated beyond the normal range. The detection of elevated skin temperature is critical as a diagnostic tool to infer the presence of an infection or an abnormal health condition. Detection of elevated skin temperature is typically achieved using contact thermometers or non-contact infrared-based sensors. The ubiquity of video data acquisition devices such as mobile phones and computers motivates the development of a binary classification approach, the Video-based TEMPerature (V-TEMP) to classify subjects with non-elevated/elevated skin temperature. We leverage the correlation between the skin temperature and the angular reflectance distribution of light, to empirically differentiate between skin at non-elevated temperature and skin at elevated temperature. We demonstrate the uniqueness of this correlation by 1) revealing the existence of a difference in the angular reflectance distribution of light from skin-like and non-skin like material and 2) exploring the consistency of the angular reflectance distribution of light in materials exhibiting optical properties similar to human skin. Finally, we demonstrate the robustness of V-TEMP by evaluating the efficacy of elevated skin temperature detection on subject videos recorded in 1) laboratory controlled environments and 2) outside-the-lab environments. V-TEMP is beneficial in two ways; 1) it is non-contact-based, reducing the possibility of infection due to contact and 2) it is scalable, given the ubiquity of video-recording devices.