Virus specificity and nucleoporin requirements for MX2 activity are affected by GTPase function and capsid-CypA interactions.

Human myxovirus resistance 2 (MX2/MXB) is an interferon-induced GTPase that inhibits human immunodeficiency virus-1 (HIV-1) infection by preventing nuclear import of the viral preintegration complex. The HIV-1 capsid (CA) is the major viral determinant for sensitivity to MX2, and complex interactions between MX2, CA, nucleoporins (Nups), cyclophilin A (CypA), and other cellular proteins influence the outcome of viral infection. To explore the interactions between MX2, the viral CA, and CypA, we utilized a CRISPR-Cas9/AAV approach to generate CypA knock-out cell lines as well as cells that express CypA from its endogenous locus, but with specific point mutations that would abrogate CA binding but should not affect enzymatic activity or cellular function. We found that infection of CypA knock-out and point mutant cell lines with wild-type HIV-1 and CA mutants recapitulated the phenotypes observed upon cyclosporine A (CsA) addition, indicating that effects of CsA treatment are the direct result of blocking CA-CypA interactions and are therefore independent from potential interactions between CypA and MX2 or other cellular proteins. Notably, abrogation of GTP hydrolysis by MX2 conferred enhanced antiviral activity when CA-CypA interactions were abolished, and this effect was not mediated by the CA-binding residues in the GTPase domain, or by phosphorylation of MX2 at position T151. We additionally found that elimination of GTPase activity also altered the Nup requirements for MX2 activity. Our data demonstrate that the antiviral activity of MX2 is affected by CypA-CA interactions in a virus-specific and GTPase activity-dependent manner. These findings further highlight the importance of the GTPase domain of MX2 in regulation of substrate specificity and interaction with nucleocytoplasmic trafficking pathways.

DeepPL: A deep-learning-based tool for the prediction of bacteriophage lifecycle.

Bacteriophages (phages) are viruses that infect bacteria and can be classified into two different lifecycles. Virulent phages (or lytic phages) have a lytic cycle that can lyse the bacteria host after their infection. Temperate phages (or lysogenic phages) can integrate their phage genomes into bacterial chromosomes and replicate with bacterial hosts via the lysogenic cycle. Identifying phage lifecycles is a crucial step in developing suitable applications for phages. Compared to the complicated traditional biological experiments, several tools have been designed for predicting phage lifecycle using different algorithms, such as random forest (RF), linear support-vector classifier (SVC), and convolutional neural network (CNN). In this study, we developed a natural language processing (NLP)-based tool-DeepPL-for predicting phage lifecycles via nucleotide sequences. The test results showed that our DeepPL had an accuracy of 94.65% with a sensitivity of 92.24% and a specificity of 95.91%. Moreover, DeepPL had 100% accuracy in lifecycle prediction on the phages we isolated and biologically verified previously in the lab. Additionally, a mock phage community metagenomic dataset was used to test the potential usage of DeepPL in viral metagenomic research. DeepPL displayed a 100% accuracy for individual phage complete genomes and high accuracies ranging from 71.14% to 100% on phage contigs produced by various next-generation sequencing technologies. Overall, our study indicates that DeepPL has a reliable performance on phage lifecycle prediction using the most fundamental nucleotide sequences and can be applied to future phage and metagenomic research.

Group A Streptococcus induces lysosomal dysfunction in THP-1 macrophages.

The human-specific bacterial pathogen group A Streptococcus (GAS) is a significant cause of morbidity and mortality. Macrophages are important to control GAS infection, but previous data indicate that GAS can persist in macrophages. In this study, we detail the molecular mechanisms by which GAS survives in THP-1 macrophages. Our fluorescence microscopy studies demonstrate that GAS is readily phagocytosed by macrophages, but persists within phagolysosomes. These phagolysosomes are not acidified, which is in agreement with our findings that GAS cannot survive in low pH environments. We find that the secreted pore-forming toxin Streptolysin O (SLO) perforates the phagolysosomal membrane, allowing leakage of not only protons but also large proteins including the lysosomal protease cathepsin B. Additionally, GAS recruits CD63/LAMP-3, which may contribute to lysosomal permeabilization, especially in the absence of SLO. Thus, although GAS does not inhibit fusion of the lysosome with the phagosome, it has multiple mechanisms to prevent proper phagolysosome function, allowing for persistence of the bacteria within the macrophage. This has important implications for not only the initial response but also the overall functionality of the macrophages, which may lead to the resulting pathologies in GAS infection. Our data suggest that therapies aimed at improving macrophage function may positively impact patient outcomes in GAS infection.

Efficacy and safety of catheter-based thrombectomy versus catheter-directed thrombolysis in acute pulmonary embolism.

Data comparing catheter-based thrombectomy (CBT) and catheter-directed thrombolysis (CDT) in acute pulmonary embolism are lacking. To address this, we performed a meta-analysis of prospective and retrospective studies of CBT and compared it to performance goal rates of mortality and major bleeding from a recently published network meta-analysis. When compared with performance goal for CDT based on historical studies, CBT was noninferior for all-cause mortality (6.0% vs 6.87%; P-valueNI < .001), non-inferior and superior for major bleeding (4.9% vs 11%; P-valueNI < .001 and P < .001 for superiority).

Low left ventricular outflow tract velocity time integral predicts normotensive shock in patients with acute pulmonary embolism.

In this study, we found that a low LVOT VTI (<15 cm), a simple bedside point-of-care measurement, predicts normotensive shock in patients with acute intermediate-risk PE.

Quality and rapidity of anticoagulation in patients with acute pulmonary embolism undergoing mechanical thrombectomy.

The primary objective of our study was to determine the proportion of intermediate-risk PE patients undergoing mechanical thrombectomy (MT) who achieved therapeutic anticoagulation (AC) at the time of the procedure. The salient findings of our study showed that only a minority of patients (14.3%) were in the therapeutic range by ACT at the time of MT (primary outcome). Furthermore, in this higher-risk PE cohort selected for MT, 18.2% of patients were subtherapeutic after initially reaching therapeutic AC, 43% experienced supratherapeutic AC at some point before MT, and less than half (43%) attained therapeutic AC at 6 hours, highlighting the necessity for optimizing anticoagulation practices in acute PE.

Genetic Differences between 129S Substrains Affect Antiretroviral Immune Responses.

Inbred mouse lines vary in their ability to mount protective antiretroviral immune responses, and even closely related strains can exhibit opposing phenotypes upon retroviral infection. Here, we found that 129S mice inherit a previously unknown mechanism for the production of anti-murine leukemia virus (MLV) antibodies and control of infection. The resistant phenotype in 129S1 mice is controlled by two dominant loci that are independent from known MLV resistance genes. We also show that production of anti-MLV antibodies in 129S7 mice, but not 129S1 mice, is independent of interferon gamma signaling. Thus, our data indicate that 129S mice inherit an unknown mechanism for control of MLV infection and demonstrate that there is genetic variability in 129S substrains that affects their ability to mount antiviral immune responses. IMPORTANCE Understanding the genetic basis for production of protective antiviral immune responses is crucial for the development of novel vaccines and adjuvants. Additionally, characterizing the genetic and phenotypic variability in inbred mice has implications for the selection of strains for targeted mutagenesis, choice of controls, and for broader understanding of the requirements for protective immunity.

Percutaneous mechanical thrombectomy in acute pulmonary embolism: Outcomes from a safety-net hospital.

BACKGROUND: Our study aims to present clinical outcomes of mechanical thrombectomy (MT) in a safety-net hospital. METHODS: This is a retrospective study of intermediate or high-risk pulmonary embolism (PE) patients who underwent MT between October 2020 and May 2023. The primary outcome was 30-day mortality. RESULTS: Among 61 patients (mean age 57.6 years, 47% women, 57% Black) analyzed, 12 (19.7%) were classified as high-risk PE, and 49 (80.3%) were intermediate-risk PE. Of these patients, 62.3% had Medicaid or were uninsured, 50.8% lived in a high poverty zip code. The prevalence of normotensive shock in intermediate-risk PE patients was 62%. Immediate hemodynamic improvements included 7.4 mmHg mean drop in mean pulmonary artery pressure (-21.7%, p < 0.001) and 93% had normalization of their cardiac index postprocedure. Thirty-day mortality for the entire cohort was 5% (3 patients) and 0% when restricted to the intermediate-risk group. All 3 patients who died at 30 days presented with cardiac arrest. There were no differences in short-term mortality based on race, insurance type, citizenship status, or socioeconomic status. All-cause mortality at most recent follow up was 13.1% (mean follow up time of 13.4 ± 8.5 months). CONCLUSION: We extend the findings from prior studies that MT demonstrates a favorable safety profile with immediate improvement in hemodynamics and a low 30-day mortality in patients with acute PE, holding true even with relatively higher risk and more vulnerable population within a safety-net hospital.

Colchicine for the Prevention of Cardiovascular Disease: Potential Global Implementation.

PURPOSE OF REVIEW: Targeting traditional cardiovascular risk factors is effective in reducing recurrent cardiovascular events, yet the presence of residual cardiovascular risk due to underlying systemic inflammation is a largely unaddressed opportunity. This review aims to comprehensively assess the evolving role of colchicine as a therapeutic approach targeting residual inflammatory risk in the context of those with coronary artery disease (CAD). RECENT FINDINGS: Inflammation plays a significant role in promoting atherosclerosis, and targeting anti-inflammatory pathways has the potential to decrease cardiovascular events. Low-dose colchicine (0.5 mg/day orally), when added to guideline-directed medical care for CAD, safely decreases major adverse cardiovascular events (MACE) by 31% in stable atherosclerosis patients and 23% in those after recent myocardial infarctions. Meta-analyses of recent randomized control trials further support both the efficacy and safety of colchicine, particularly when added to other standard cardiovascular therapies, including statin therapy. The European Society of Cardiology and other national guidelines endorse the use of low-dose colchicine in patients across the spectrum of CAD. Recently, colchicine was FDA-approved in the United States as the first anti-inflammatory therapy for the reduction of cardiovascular events. In a period of a rising incidence of CAD across the globe, colchicine represents a unique opportunity to decrease MACE due to its large magnitude of benefits and general affordability. However, challenges with drug interactions must be addressed, especially in those regions where HIV, hepatitis, and tuberculosis are prevalent. Colchicine is safe and effective at reducing cardiovascular events across a broad spectrum of coronary syndromes. The ability to simultaneously target traditional risk factors and mitigate residual inflammatory risk marks a substantial advancement in cardiovascular prevention strategies, heralding a new era in the global battle against CAD.

Echocardiography in the Recognition and Management of Mechanical Complications of Acute Myocardial Infarction.

PURPOSE OF REVIEW: Although rare, the development of mechanical complications following an acute myocardial infarction is associated with a high morbidity and mortality. Here, we review the clinical features, diagnostic strategy, and treatment options for each of the mechanical complications, with a focus on the role of echocardiography. RECENT FINDINGS: The growth of percutaneous structural interventions worldwide has given rise to new non-surgical options for management of mechanical complications. As such, select patients may benefit from a novel use of these established treatment methods. A thorough understanding of the two-dimensional, three-dimensional, color Doppler, and spectral Doppler findings for each mechanical complication is essential in recognizing major causes of hemodynamic decompensation after an acute myocardial infarction. Thereafter, echocardiography can aid in the selection and maintenance of mechanical circulatory support and potentially facilitate the use of a percutaneous intervention.

Study While You Sleep: Using Targeted Memory Reactivation as an Independent Research Project for Undergraduates.

Newly acquired information is stabilized into long-term memory through the process of consolidation. Memories are not static; rather, they are constantly updated via reactivation, and this reactivation occurs preferentially during Slow-Wave Sleep (SWS, also referred to as N3 in humans). Here we present a scalable neuroscience research investigation of memory reactivation using low-cost electroencephalogram (EEG) recording hardware and open-source software, for students and educators across the K-12 and higher education spectrum. The investigation uses a method called targeted memory reactivation (TMR), whereby auditory cues that were previously associated with learning are re-presented during sleep, triggering the recall of stored memories and (through this) strengthening these memories. We demonstrated the efficacy of this technique on seven healthy human subjects (ages 19-35). The subjects learned to play a spatial memory game on an app where they associated pictures (e.g., a clock) with locations on a grid while they listened to picture-appropriate sounds (e.g., "tic-toc"); next, they took a nap while undergoing EEG recordings. During SWS, half of the sounds from the game were replayed by the app, while half were substituted with non-learned sounds. Subjects then played the memory game again after waking. Results showed that spatial recall was improved more for cued than uncued memories, demonstrating the benefits of memory replay during sleep and suggesting that one may intervene in this process to boost recall of specific memories. This research investigation takes advantage of the importance of sleep for memory consolidation and demonstrates improved memory performance by cueing sounds during SWS.

Short-term professional bereavement reactions and their links with the meaning of patient death: Evidence from network analyses.

OBJECTIVES: Taking a dimensional view, this study aims to understand, among professional caregivers after patient deaths, the symptom distribution and development of the short-term bereavement reaction (SBR) network and the node-level links between the meaning of patient death (MPD) and the SBR network. METHODS: A cross-sectional secondary analysis was conducted with existing data from 220 Chinese urban hospital nurses and physicians who experienced the most recent patient death within a month. MPD was measured by the 10 formative items of the meaning of patient death model, and SBR was measured by the Short-term Bereavement Reactions Subscale of the Professional Bereavement Scale. Both Gaussian graphical network analysis and Bayesian network analysis were applied to the SBR network, and Gaussian graphical network analysis was used to estimate the MPD-SBR network. RESULTS: Frustrated and guilty are central nodes in the regularized partial correlation SBR network. Meanwhile, a traumatic event and failure at work are important bridge nodes between the MPD network and the SBR network. In the Bayesian SBR network, moved by the family's understanding, moved by the family's gratitude and sad mainly drive other nodes. CONCLUSION: After a patient death, nurses' and physicians' SBR networks feature professional-dimension symptoms at their core, while they follow 'personal to professional' and 'concrete to abstract' symptom development patterns. The personal meaning of a traumatic event and the professional meaning of a failure at work play key roles in bridging the MPD and SBR networks, and meanings of both the personal and the professional dimensions can link to professional-dimension reactions. REPORTING METHOD: The manuscript followed the STROBE checklist for reporting cross-sectional studies. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Interdependency or submission to authority? The impacts of horizontal and vertical collectivist orientation on vaccine attitudes in mainland China.

Culture has a profound impact on preventive measures during the COVID-19 pandemic. Previous research has revealed that collectivism is associated with more effective responses to COVID-19 on the national or regional level. However, the impact of different components of collectivist orientation on vaccine attitudes remains insufficiently explored on the individual level. Two survey studies conducted in August 2021 in mainland China consistently found that individual-level horizontal collectivist orientation, rather than vertical collectivist orientation, was linked with more favourable vaccine attitudes. Specifically, Study 1 (N = 731) indicated that horizontal collectivist orientation was positive associated with vaccination intention indirectly via risk perception, and horizontal collectivist orientation was also positively associated with vaccination persuasion both directly and indirectly via risk perception. Study 2 (N = 1481), employing multilevel modelling, demonstrated that the link between horizontal collectivist orientation and confidence in vaccines remained robust regardless of provincial-level variations in socioeconomic development and cultural tightness. These findings convergently suggest that the positive vaccine attitudes among mainland Chinese are primarily driven by an amplified risk perception due to concern for others, rather than submission to authority.

Implicit intertemporal trajectories in cognitive representations of the self and nation.

Individual selves and the collectives to which people belong can be mentally represented as following intertemporal trajectories-progress, decline, or stasis. These studies examined the relation between intertemporal trajectories for the self and nation in American and British samples collected at the beginning and end of major COVID-19 restrictions. Implicit temporal trajectories can be inferred from asymmetries in the cognitive availability of positive and negative events across different mentally represented temporal periods (e.g., memory for the past and the imagined future). At the beginning of COVID-19 restrictions, both personal and collective temporal thought demonstrated implicit temporal trajectories of decline, in which future thought was less positive than memory. The usually reliable positivity biases in personal temporal thought may be reversable by major public events. This implicit trajectory of decline attenuated in personal temporal thought after the lifting of COVID-19 restrictions. However, collective temporal thought demonstrated a pervasive negativity bias across temporal domains at both data collection points, with the collective future more strongly negative than collective memory. Explicit beliefs concerning collective progress, decline, and hope for the national future corresponded to asymmetries in the cognitive availability of positive and negative events within collective temporal thought.

Classifying social determinants of health from unstructured electronic health records using deep learning-based natural language processing.

OBJECTIVE: Social determinants of health (SDOH) are non-medical factors that can profoundly impact patient health outcomes. However, SDOH are rarely available in structured electronic health record (EHR) data such as diagnosis codes, and more commonly found in unstructured narrative clinical notes. Hence, identifying social context from unstructured EHR data has become increasingly important. Yet, previous work on using natural language processing to automate extraction of SDOH from text (a) usually focuses on an ad hoc selection of SDOH, and (b) does not use the latest advances in deep learning. Our objective was to advance automatic extraction of SDOH from clinical text by (a) systematically creating a set of SDOH based on standard biomedical and psychiatric ontologies, and (b) training state-of-the-art deep neural networks to extract mentions of these SDOH from clinical notes. DESIGN: A retrospective cohort study. SETTING AND PARTICIPANTS: Data were extracted from the Medical Information Mart for Intensive Care (MIMIC-III) database. The corpus comprised 3,504 social related sentences from 2,670 clinical notes. METHODS: We developed a framework for automated classification of multiple SDOH categories. Our dataset comprised narrative clinical notes under the "Social Work" category in the MIMIC-III Clinical Database. Using standard terminologies, SNOMED-CT and DSM-IV, we systematically curated a set of 13 SDOH categories and created annotation guidelines for these. After manually annotating the 3,504 sentences, we developed and tested three deep neural network (DNN) architectures - convolutional neural network (CNN), long short-term memory (LSTM) network, and the Bidirectional Encoder Representations from Transformers (BERT) - for automated detection of eight SDOH categories. We also compared these DNNs to three baselines models: (1) cTAKES, as well as (2) L2-regularized logistic regression and (3) random forests on bags-of-words. Model evaluation metrics included micro- and macro- F1, and area under the receiver operating characteristic curve (AUC). RESULTS: All three DNN models accurately classified all SDOH categories (minimum micro-F1 = 0.632, minimum macro-AUC = 0.854). Compared to the CNN and LSTM, BERT performed best in most key metrics (micro-F1 = 0.690, macro-AUC = 0.907). The BERT model most effectively identified the "occupational" category (F1 = 0.774, AUC = 0.965) and least effectively identified the "non-SDOH" category (F = 0.491, AUC = 0.788). BERT outperformed cTAKES in distinguishing social vs non-social sentences (BERT F1 = 0.87 vs. cTAKES F1 = 0.06), and outperformed logistic regression (micro-F1 = 0.649, macro-AUC = 0.696) and random forest (micro-F1 = 0.502, macro-AUC = 0.523) trained on bag-of-words. CONCLUSIONS: Our study framework with DNN models demonstrated improved performance for efficiently identifying a systematic range of SDOH categories from clinical notes in the EHR. Improved identification of patient SDOH may further improve healthcare outcomes.

Physics approaches to the spatial distribution of immune cells in tumors.

The goal of immunotherapy is to mobilize the immune system to kill cancer cells. Immunotherapy is more effective and, in general, the prognosis is better, when more immune cells infiltrate the tumor. We explore the question of whether the spatial distribution rather than just the density of immune cells in the tumor is important in forecasting whether cancer recurs. After reviewing previous work on this issue, we introduce a novel application of maximum entropy to quantify the spatial distribution of discrete point-like objects. We apply our approach to B and T cells in images of tumor tissue taken from triple negative breast cancer patients. We find that the immune cells are more spatially dispersed in good clinical outcome (no recurrence of cancer within at least 5 years of diagnosis) compared to poor clinical outcome (recurrence within 3 years of diagnosis). Our results highlight the importance of spatial distribution of immune cells within tumors with regard to clinical outcome, and raise new questions on their role in cancer recurrence.

The prevalence and prognostic implications of pre-procedural hyperbilirubinemia in patients undergoing transcatheter aortic valve replacement.

Preoperative hyperbilirubinemia is associated with increased mortality and morbidity after cardiac surgery. However, this clinical significance is unclear with transcatheter aortic valve replacement (TAVR) procedures. The aims of this study were to determine the prevalence and prognostic implications of preoperative elevations of serum total bilirubin on TAVR outcomes. In 611 consecutive patients who underwent an elective TAVR procedure, 576 patients had recorded serum total bilirubin levels. Hyperbilirubinemia was defined as any value of serum total bilirubin ≥ 1.2 mg/dL obtained within 30-days prior to the TAVR procedure. The primary composite endpoint was post-TAVR all-cause in-hospital mortality or stroke. The overall prevalence of hyperbilirubinemia was 10% (n = 58). There were no patients with a prespecified diagnosis of liver cirrhosis. Pre-TAVR hyperbilirubinemia compared to normal bilirubin level was more common in younger (78 ± 10 vs. 82 ± 8 years old, p < 0.001) males (15 vs. 6%, p < 0.001), with history of pacemaker or ICD (33 vs. 18%, p = 0.005), congestive heart failure New York Heart Association class IV within 2 weeks from TAVR (35 vs. 14%, p < 0.001), severe tricuspid regurgitation (14 vs. 4%, p < 0.001), and atrial fibrillation or flutter (60 vs. 40%, p = 0.004, respectively). Pre-TAVR hyperbilirubinemia was independently associated with an increased post-TAVR in-hospital mortality (7 vs. 2% in normal bilirubin, p = 0.03), stroke (5 vs. 1%, p = 0.019, respectively), and a composite endpoint of death or stroke (12 vs. 3%, p < 0.001). Preoperative hyperbilirubinemia in patients undergoing TAVR is more prevalent than previously considered with multifactorial causes. Hyperbilirubinemia is independently associated with an increased post-TAVR in-hospital mortality and stroke.

Absence of electrocardiographic left ventricular hypertrophy in patients undergoing Transcatheter aortic valve replacement is associated with increased mortality.

BACKGROUND: We examined the association between the absence ECG LVH and all-cause mortality in patients with severe AS undergoing TAVR. METHODS: We conducted a retrospective single center study on 399 TAVR patients from 2012 to 2016. ECGs were reviewed for LVH diagnosed by Sokolow-Lyon's voltage criteria. All patients met echocardiographic criteria for LVH. Logistic regression was used to examine the association between ECG LVH and covariates. Survival analysis was performed using Cox regression analysis and Kaplan Meier curves. RESULTS: Patients without ECG LVH were younger (81.0 ± 8.4 vs. 84.0 ± 7.7 years, p = 0.001) with a higher BMI (29.3 ± 7.0 vs. 27.1 ± 5.6 kg/m2, p = 0.006) and lower FEV1 (65.6 ± 22.8 vs. 74.1 ± 21.6%, p = 0.002). In multivariable analysis, increased BMI and decreased FEV1 remained predictive of the absence of ECG LVH. Over a mean follow-up time of 32 (± 17.0) months, the 5-year cumulative survival was 79% in the ECG LVH group and 58% in the group without ECG LVH (p = 0.039). Absence of ECG LVH remained predictive of all-cause mortality (HR 1.56, 95% CI 1.01-2.59, p = 0.045) in multivariable Cox regression analysis. When patients were grouped by comorbidities, patients with the highest mortality were those with increased BMI or decreased FEV1. CONCLUSIONS: Absence of LVH by ECG criteria in patients with severe AS undergoing TAVR was associated with increased all-cause mortality. Routinely performed, noninvasive and inexpensive ECG may aid in identification of high-risk patients that may not benefit from TAVR and warrant further evaluation of underlying comorbidities.

The Assessment of Cough in a Sarcoidosis Clinic Using a Validated instrument and a Visual Analog Scale.

PURPOSE: Cough is a common symptom of pulmonary sarcoidosis. We analyzed the severity of cough and factors associated with cough in a university sarcoidosis clinic cohort. METHODS: Consecutive patients completed the Leicester Cough Questionnaire (LCQ) and a cough visual analog scale (VAS). Clinical and demographic data were collected. Means of the LCQ were analyzed in patients who had multiple visits in terms of constant variables (e.g., race, sex). RESULTS: 355 patients completed the LCQ and VAS at 874 visits. Cough was significantly worse in blacks than whites as determined by the LCQ-mean (16.5 ± 2.6 vs. 17.8 ± 3.0, p < 0.001) and VAS-mean (3.8 ± 3.0 vs. 2.0 ± 2.6, p < 0.0001). Cough was worse in women than men as measured by the VAS-mean (2.7 ± 2.9 vs. 2.2 ± 2.7, p = 0.002), one of the LCQ-mean domains (LCQ-Social-mean 5.4 ± 0.9 vs. 5.2 ± 1.0, p = 0.03), but not the total LCQ-mean score. Cough was not significantly different by either measure in terms of smoking status, age, or spirometric parameter (FVC % predicted, FEV1 % predicted, FEV1/FVC). In a multivariable linear regression analysis, cough was significantly worse in blacks than whites and in pulmonary sarcoidosis than non-pulmonary sarcoidosis with both cough measures, in women than men for the VAS only, and not for spirometric parameters, Scadding stage, or age. The LCQ and VAS were strongly correlated. CONCLUSIONS: In a large university outpatient sarcoidosis cohort, cough was worse in blacks than whites. Cough was not statistically significantly different in terms of age, spirometric measures, Scadding stage, or smoking status. The LCQ correlated strongly with a visual analog scale for cough.

Assessing the Limitations of Relief-Based Algorithms in Detecting Higher-Order Interactions.

Background: The investigation of epistasis becomes increasingly complex as more loci are considered due to the exponential expansion of possible interactions. Consequently, selecting key features that influence epistatic interactions is crucial for effective downstream analyses. Recognizing this challenge, this study investigates the efficiency of Relief-Based Algorithms (RBAs) in detecting higher-order epistatic interactions, which may be critical for understanding the genetic architecture of complex traits. RBAs are uniquely non-exhaustive, eliminating the need to construct features for every possible interaction and thus improving computational tractability. Motivated by previous research indicating that some RBAs rank predictive features involved in higher-order epistasis as highly negative, we explore the utility of absolute value ranking of RBA feature weights as an alternative method to capture complex interactions. We evaluate ReliefF, MultiSURF, and MultiSURFstar on simulated genetic datasets that model various patterns of genotype-phenotype associations, including 2-way to 5-way genetic interactions, and compare their performance to two control methods: a random shuffle and mutual information. Results: Our findings indicate that while RBAs effectively identify lower-order (2 to 3-way) interactions, their capability to detect higher-order interactions is significantly limited, primarily by large feature count but also by signal noise. Specifically, we observe that RBAs are successful in detecting fully penetrant 4-way XOR interactions using an absolute value ranking approach, but this is restricted to datasets with a minimal number of total features. Conclusions: These results highlight the inherent limitations of current RBAs and underscore the need for enhanced detection capabilities for the investigation of epistasis, particularly in datasets with large feature counts and complex higher-order interactions.