Palmitoylation at a conserved cysteine residue facilitates gasdermin D-mediated pyroptosis and cytokine release.

Gasdermin D (GSDMD)-mediated pyroptotic cell death drives inflammatory cytokine release and downstream immune responses upon inflammasome activation, which play important roles in host defense and inflammatory disorders. Upon activation by proteases, the GSDMD N-terminal domain (NTD) undergoes oligomerization and membrane translocation in the presence of lipids to assemble pores. Despite intensive studies, the molecular events underlying the transition of GSDMD from an autoinhibited soluble form to an oligomeric pore form inserted into the membrane remain incompletely understood. Previous work characterized S-palmitoylation for gasdermins from bacteria, fungi, invertebrates, as well as mammalian gasdermin E (GSDME). Here, we report that a conserved residue Cys191 in human GSDMD was S-palmitoylated, which promoted GSDMD-mediated pyroptosis and cytokine release. Mutation of Cys191 or treatment with palmitoyltransferase inhibitors cyano-myracrylamide (CMA) or 2-bromopalmitate (2BP) suppressed GSDMD palmitoylation, its localization to the membrane and dampened pyroptosis or IL-1ß secretion. Furthermore, Gsdmd-dependent inflammatory responses were alleviated by inhibition of palmitoylation in vivo. By contrast, coexpression of GSDMD with palmitoyltransferases enhanced pyroptotic cell death, while introduction of exogenous palmitoylation sequences fully restored pyroptotic activities to the C191A mutant, suggesting that palmitoylation-mediated membrane localization may be distinct from other molecular events such as GSDMD conformational change during pore assembly. Collectively, our study suggests that S-palmitoylation may be a shared regulatory mechanism for GSDMD and other gasdermins, which points to potential avenues for therapeutically targeting S-palmitoylation of gasdermins in inflammatory disorders.

Long-distance swimming by African lions in Uganda.

Earth's most imperiled and iconic wildlife are facing tough decisions under increasing human pressure and limited resources. Swimming across rivers and water bodies filled with high densities of predators may be one such example. In African lions Panthera leo, previous water crossings (recorded in the peer-reviewed and gray literature, on film, and found using Google Search, and YouTube) have recorded distances ranging from <10 to 100 m, with some resulting in mortality by Nile Crocodiles Crocodylis niloticus. However, we observed a coalition of male lions swimming >1 km across Uganda's Kazinga channel located in the Queen Elizabeth National Park six times, and recorded this behavior on film on February 1st 2024. We speculate that three factors could be driving these lions to take long-distance swims with a high density of crocodiles and hippos Hippopotamus amphibius, namely (1) the lack of lionesses in this ecosystem, (2) intraspecific fights over territory with other male coalitions, and (3) the only other land connection giving lions access to the peninsula is a small road bridge with a strong human presence.

Characterizing a learning curve for robotic-assisted bronchoscopy: Analysis of skills acquisition in a high-volume academic center.

OBJECTIVE: Shape-sensing robotic-assisted bronchoscopy (ssRAB) is an emerging technology for the sampling of pulmonary lesions. We seek to characterize the ssRAB learning curve at an academic center. METHODS: SsRAB procedures performed by 9 proceduralists at a single institution were analyzed. Cumulative sum analyses were performed to examine diagnostic sampling and procedure time over each operator's first 50 cases, with the acceptable yield threshold set to 73%. RESULTS: During the study period, 442 patients underwent sampling of 551 lesions. Each operator sampled 61 (IQR, 60-63) lesions. Lesion size was 1.90 cm (IQR, 1.33-2.80). The median procedure time for single-target cases decreased from 62 minutes during the first 10 cases to 39 minutes after case 40 (P<0.001). The overall diagnostic yield was 72% (range, 58-83%). Six of 9 operators achieved proficiency over the study period. An aggregated cumulative sum analysis of those who achieved competency demonstrated a steep improvement between lesions 1 and 21 and crossing of the competency threshold by lesion 25. Temporal analysis of yield-related lesion characteristics demonstrated that at approximately lesion 20, more challenging lesions were increasingly targeted, as evidenced by smaller target size, higher rates of unfavorable radial endobronchial ultrasound views and a negative bronchus sign. CONCLUSIONS: Skills acquisition in ssRAB is variable. Approximately half of proceduralists become facile with the technology within 25 lesions. After the initial learning phase, operators increasingly target lesions with more challenging features. Overall, these findings can inform certification and competency standards and provide new users with expectations related to performance over time.

Investigation of cardiopulmonary bypass parameters on embolus transport in a patient-specific aorta.

Neurological complexities resulting from surgery requiring cardiopulmonary bypass (CPB) remain a major concern, encompassing a spectrum of complications including thromboembolic stroke and various cognitive impairments. Surgical manipulation during CPB is considered the primary cause of these neurological complications. This study addresses the overall lack of knowledge concerning CPB hemodynamics within the aorta, employing a combined experimental-computational modeling approach, featuring computational fluid dynamics simulations validated with an in vitro CPB flow loop under steady conditions. Parametric studies were systematically performed, varying parameters associated with CPB techniques (pump flow rate and hemodiluted blood viscosity) and properties related to formed emboli (size and density). This represents the first comprehensive investigation into the individual and combined effects of these factors. Our findings reveal critical insights into the operating conditions of CPB, indicating a positive correlation between pump flow rate and emboli transport into the aortic branches, potentially increasing the risk of stroke. It was also found that larger emboli were more often transported into the aortic branches at higher pump flow rates, while smaller emboli preferred lower flow rates. Further, as blood is commonly diluted during CPB to decrease its viscosity, more emboli were found to enter the aortic branches with greater hemodilution. The combined effects of these parameters are captured using the non-dimensional Stokes number, which was found to positively correlate with emboli transport into the aortic branches. These findings contribute to our understanding of embolic stroke risk factors during CPB and shed light on the complex interplay between CPB parameters.

Intramuscular diacylglycerol accumulates with acute hyperinsulinemia in insulin-resistant phenotypes.

Elevated skeletal muscle diacylglycerols (DAG) and ceramides can impair insulin signaling, and acylcarnitines (acylCN) reflect impaired fatty acid oxidation, thus the intramuscular lipid profile is indicative of insulin resistance. Acute (i.e., postprandial) hyperinsulinemia has been shown to elevate lipids in healthy muscle and is an independent risk factor for type 2 diabetes (T2D). It is unclear how the relationship between acute hyperinsulinemia and the muscle lipidome interacts, thus contributing to or exacerbating insulin resistance. We investigated the impact of acute hyperinsulinemia on the muscle lipidome in order to help characterize the physiological basis in which hyperinsulinemia elevates T2D risk. Endurance athletes (n=12), sedentary lean adults (n=12), and individuals with obesity (n=13) and T2D (n=7) underwent a hyperinsulinemic-euglycemic clamp with muscle biopsies. While there were no significant differences in total 1,2-DAG fluctuations, there was a 2% decrease in athletes versus a 53% increase in T2D. C18 1,2-DAGs increased during the clamp with T2D only, which negatively correlated with insulin sensitivity. Basal muscle C18:0 ceramides were elevated with T2D, but not altered by clamp. Acylcarnitines were universally lowered during hyperinsulinemia, with more robust reductions of 80% in athletes compared to only 46% with T2D. Similar fluctuations with acute hyperinsulinemia increasing 1,2 DAGs in insulin-resistant phenotypes and universally lowering acylcarnitines were observed in male mice. In conclusion, acute hyperinsulinemia elevates muscle 1,2-DAG levels with insulin-resistant phenotypes. This suggests a possible dysregulation of intramuscular lipid metabolism in the fed state in individuals with low insulin sensitivity, which may exacerbate insulin resistance.

Smoking-informed methylation and expression QTLs in human brain and colocalization with smoking-associated genetic loci.

Smoking is a leading cause of preventable morbidity and mortality. Smoking is heritable, and genome-wide association studies (GWASs) of smoking behaviors have identified hundreds of significant loci. Most GWAS-identified variants are noncoding with unknown neurobiological effects. We used genome-wide genotype, DNA methylation, and RNA sequencing data in postmortem human nucleus accumbens (NAc) to identify cis-methylation/expression quantitative trait loci (meQTLs/eQTLs), investigate variant-by-cigarette smoking interactions across the genome, and overlay QTL evidence at smoking GWAS-identified loci to evaluate their regulatory potential. Active smokers (N = 52) and nonsmokers (N = 171) were defined based on cotinine biomarker levels and next-of-kin reporting. We simultaneously tested variant and variant-by-smoking interaction effects on methylation and expression, separately, adjusting for biological and technical covariates and correcting for multiple testing using a two-stage procedure. We found >2 million significant meQTL variants (padj < 0.05) corresponding to 41,695 unique CpGs. Results were largely driven by main effects, and five meQTLs, mapping to NUDT12, FAM53B, RNF39, and ADRA1B, showed a significant interaction with smoking. We found 57,683 significant eQTL variants for 958 unique eGenes (padj < 0.05) and no smoking interactions. Colocalization analyses identified loci with smoking-associated GWAS variants that overlapped meQTLs/eQTLs, suggesting that these heritable factors may influence smoking behaviors through functional effects on methylation/expression. One locus containing MUSTN1 and ITIH4 colocalized across all data types (GWAS, meQTL, and eQTL). In this first genome-wide meQTL map in the human NAc, the enriched overlap with smoking GWAS-identified genetic loci provides evidence that gene regulation in the brain helps explain the neurobiology of smoking behaviors.

Development of Luminescent Biosensors for Calprotectin.

Calprotectin, a metal ion-binding protein complex, plays a crucial role in the innate immune system and has gained prominence as a biomarker for various intestinal and systemic inflammatory and infectious diseases, including inflammatory bowel disease (IBD) and tuberculosis (TB). Current clinical testing methods rely on enzyme-linked immunosorbent assays (ELISAs), limiting accessibility and convenience. In this study, we introduce the Fab-Enabled Split-luciferase Calprotectin Assay (FESCA), a novel quantitative method for calprotectin measurement. FESCA utilizes two new fragment antigen binding proteins (Fabs), CP16 and CP17, that bind to different epitopes of the calprotectin complex. These Fabs are fused with split NanoLuc luciferase fragments, enabling the reconstitution of active luciferase upon binding to calprotectin either in solution or in varied immobilized assay formats. FESCA's output luminescence can be measured with standard laboratory equipment as well as consumer-grade cell phone cameras. FESCA can detect physiologically relevant calprotectin levels across various sample types, including serum, plasma, and whole blood. Notably, FESCA can detect abnormally elevated native calprotectin from TB patients. In summary, FESCA presents a convenient, low-cost, and quantitative method for assessing calprotectin levels in various biological samples, with the potential to improve the diagnosis and monitoring of inflammatory diseases, especially in at-home or point-of-care settings.

Artificial intelligence enables unified analysis of historical and landscape influences on genetic diversity.

While genetic variation in any species is potentially shaped by a range of processes, phylogeography and landscape genetics are largely concerned with inferring how environmental conditions and landscape features impact neutral intraspecific diversity. However, even as both disciplines have come to utilize SNP data over the last decades, analytical approaches have remained for the most part focused on either broad-scale inferences of historical processes (phylogeography) or on more localized inferences about environmental and/or landscape features (landscape genetics). Here we demonstrate that an artificial intelligence model-based analytical framework can consider both deeper historical factors and landscape-level processes in an integrated analysis. We implement this framework using data collected from two Brazilian anurans, the Brazilian sibilator frog (Leptodactylus troglodytes) and granular toad (Rhinella granulosa). Our results indicate that historical demographic processes shape most the genetic variation in the sibulator frog, while landscape processes primarily influence variation in the granular toad. The machine learning framework used here allows both historical and landscape processes to be considered equally, rather than requiring researchers to make an a priori decision about which factors are important.

Knee Extensor Torque Steadiness and Quadriceps Activation Variability in Collegiate Athletes 4, 6, and 12 Months After ACL Reconstruction.

Background: Quadriceps performance after anterior cruciate ligament reconstruction (ACLR) is typically characterized by peak force/torque, but the ability to generate consistent knee extensor torque may be clinically meaningful. Purpose/Hypothesis: The purpose of this study was to evaluate knee extensor torque steadiness and quadriceps activation variability in collegiate athletes 4 to 12 months after ACLR. It was hypothesized that between-limb asymmetries in torque steadiness and activation variability would be observed and that steadiness would be associated with activation variability and peak knee extensor torque symmetry. Study Design: Case-control study; Level of evidence, 3. Methods: A total of 30 National Collegiate Athletic Association Division I athletes completed maximal voluntary isometric contractions 4, 6, and 12 months after ACLR. Torque and surface electromyography of the superficial quadriceps were recorded. Torque steadiness was calculated as the mean difference between initial and low-pass filtered torque signals and was expressed as a percentage of peak torque. Quadriceps activation variability was calculated similarly and was expressed as a percentage of peak electromyography. Linear mixed models were used to assess change in torque steadiness and activation variability over time. Associations between torque steadiness of the operated limb, activation variability, and quadriceps strength symmetry were evaluated using the Spearman correlation coefficient. Results: Limb-by-time interactions were detected for torque steadiness and activation variability (P < .001), with reductions (improvements) in limb steadiness and activation variability observed with increasing time since surgery. Between-limb differences in torque steadiness and activation variability were observed at 4 and 6 months postoperatively (P < .05). Significant associations between operated limb torque steadiness and quadriceps activation variability were observed at 4 months (P < .001) and 6 months (P < .01). Torque steadiness of the operated limb was associated with peak knee extensor torque symmetry at 4 months (r S = -0.49; P < .01) and 6 months (r S = -0.49; P < .01). Conclusion: In collegiate athletes, impaired knee extensor torque steadiness of the operated limb and associated abnormal quadriceps activation patterns were observed 4 to 12 months after ACLR, and the consistency of knee extensor torque production was associated with greater quadriceps strength asymmetries, particularly 4 to 6 months after surgery. Operated limb torque steadiness and activation variability improved from 4 to 12 months after ACLR. Clinical assessment of knee extensor torque steadiness after ACLR may improve prognosis and specificity of rehabilitation efforts.

An angiotensin system inhibitor (losartan) potentiates antitumor efficacy of cisplatin in a murine model of non-small cell lung cancer.

Objective: Previous studies have demonstrated synergistic antitumor effects of angiotensin system inhibition (ASI) combined with cisplatin therapy in pancreatic cancer. This study examines whether or not synergistic antitumor effects occur with combination ASI and cisplatin treatment in lung cancer, and whether or not ASI-induced changes in epithelial-mesenchymal transition play a role in the mechanism of this antitumor phenomenon. Methods: A set of lung cancer cell lines representing a spectrum of epithelial to mesenchymal phenotypes were identified and characterized. Response of epithelial-mesenchymal transition markers to losartan was characterized. Cell culture models of lung cancer were next treated with losartan, cisplatin, or combination of both. Markers of epithelial-mesenchymal transition or surrogates of other signaling pathways (AKT, Stat3, and programmed death-ligand), and cell viability were quantified. Findings were confirmed in both allogenic and syngeneic in vivo murine flank tumor models. Results: Losartan treatment significantly increased E-cadherin and reduced vimentin in human lung cancer cell lines. Combination treatment with losartan and cisplatin enhanced epithelial markers, reduced mesenchymal markers, inhibited promesenchymal signaling mediators, and reduced cell viability. Findings were confirmed in vivo in a murine flank tumor model with transition from mesenchymal to epithelial phenotype and reduced tumor size following combination losartan and cisplatin treatment. Conclusions: Combination losartan and cisplatin treatment attenuates the epithelial-mesenchymal transition pathway and enhances the cytotoxic effect of chemotherapy with in vitro and in vivo models of non-small cell lung cancer. This study suggests an important role for ASI therapy in the treatment of lung cancer.

Does It Matter? Isometric or Isokinetic Assessment of Quadriceps Strength Symmetry 9 Months After ACLR in Collegiate Athletes.

BACKGROUND: Greater quadriceps strength symmetry is associated with better outcomes after anterior cruciate ligament reconstruction (ACLR). Isometric and isokinetic assessments of quadriceps strength inform therapeutic exercise prescription and return-to-sport decisions. It is unclear whether isometric and isokinetic measures provide similar information post-ACLR. HYPOTHESIS: Quadriceps strength symmetry is similar between isometric and isokinetic assessments. Isokinetic and isometric strength symmetries have similar associations to functional knee kinetics and self-reported knee function. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 3. METHODS: NCAA Division I athletes (N = 35), 8.9 ± 2.5 months post-ACLR completed isometric and isokinetic quadriceps strength assessments, countermovement jumps (CMJs), and treadmill running. Self-reported knee function was assessed using the International Knee Documentation Committee Subjective Knee Form (IKDC). Agreement between isometric and isokinetic strength symmetry was assessed using Bland-Altman analysis, with associations to functional knee kinetics and IKDC assessed using Pearson correlations and linear regressions. RESULTS: Mean difference in quadriceps strength symmetry between isokinetic and isometric assessments was 1.0% (95% limits of agreement of -25.1% to 23.0%). Functional knee kinetics during running and CMJ were moderately to strongly associated with isometric strength symmetry (r = 0.64-0.80, P < 0.01) and moderately associated with isokinetic strength symmetry (r = 0.41-0.58, P < 0.01). IKDC scores were weakly to moderately associated with isometric (r = 0.39, P = 0.02) and isokinetic (r = 0.49, P < 0.01) strength symmetry. CONCLUSION: Isokinetic and isometric assessments of quadriceps strength symmetry in collegiate athletes 9 months post-ACLR demonstrated strong agreement. Quadriceps strength symmetry is associated with functional knee kinetic symmetry post-ACLR. CLINICAL RELEVANCE: Considerable individual variation suggests mode of contraction should be consistent throughout postoperative assessment. Isometric strength symmetry may be a better indicator of functional knee kinetic symmetry, while isokinetic strength symmetry may be associated more closely with patient-reported outcomes.

Determinants of radiation exposure during mobile cone-beam CT-guided robotic-assisted bronchoscopy.

BACKGROUND AND OBJECTIVE: Robotic-assisted bronchoscopy (RAB) is an emerging modality to sample pulmonary lesions. Cone-beam computed tomography (CBCT) can be incorporated into RAB. We investigated the magnitude and predictors of patient and staff radiation exposure during mobile CBCT-guided shape-sensing RAB. METHODS: Patient radiation dose was estimated by cumulative dose area product (cDAP) and cumulative reference air kerma (cRAK). Staff equivalent dose was calculated based on isokerma maps and a phantom simulation. Patient, lesion and procedure-related factors associated with higher radiation doses were identified by logistic regression models. RESULTS: A total of 198 RAB cases were included in the analysis. The median patient cDAP and cRAK were 10.86 Gy cm2 (IQR: 4.62-20.84) and 76.20 mGy (IQR: 38.96-148.38), respectively. Among staff members, the bronchoscopist was exposed to the highest median equivalent dose of 1.48 µSv (IQR: 0.85-2.69). Both patient and staff radiation doses increased with the number of CBCT spins and targeted lesions (p < 0.001 for all comparisons). Patient obesity, negative bronchus sign, lesion size <2.0 cm and inadequate sampling by on-site evaluation were associated with a higher patient dose, while patient obesity and inadequate sampling by on-site evaluation were associated with a higher bronchoscopist equivalent dose. CONCLUSION: The magnitude of patient and staff radiation exposure during CBCT-RAB is aligned with safety thresholds recommended by regulatory authorities. Factors associated with a higher radiation exposure during CBCT-RAB can be identified pre-operatively and solicit procedural optimization by reinforcing radiation protective measures. Future studies are needed to confirm these findings across multiple institutions and practices.

Neutron Instruments for Research in Coordination Chemistry.

Neutron diffraction and spectroscopy offer unique insight into structures and properties of solids and molecular materials. All neutron instruments located at the various neutron sources are distinct, even if their designs are based on similar principles, and thus, they are usually less familiar to the community than commercial X-ray diffractometers and optical spectrometers. Major neutron instruments in the USA, which are open to scientists around the world, and examples of their use in coordination chemistry research are presented here, along with a list of similar instruments at main neutron facilities in other countries. The reader may easily and quickly find from this minireview an appropriate neutron instrument for research. The instruments include single-crystal and powder diffractometers to determine structures, inelastic neutron scattering (INS) spectrometers to probe magnetic and vibrational excitations, and quasielastic neutron scattering (QENS) spectrometers to study molecular dynamics such as methyl rotation on ligands. Key and unique features of the diffraction and neutron spectroscopy that are relevant to inorganic chemistry are reviewed.

Expanding RNA editing toolkit using an IDR-based strategy.

RNA base editors should ideally be free of immunogenicity, compact, efficient, and specific, which has not been achieved for C > U editing. Here we first describe a compact C > U editor entirely of human origin, created by fusing the human C > U editing enzyme RESCUE-S to Cas inspired RNA targeting system (CIRTS), a tiny, human-originated programmable RNA-binding domain. This editor, CIRTS-RESCUEv1 (V1), was inefficient. Remarkably, a short histidine-rich domain (HRD), which is derived from the internal disordered region (IDR) in the human CYCT1, a protein capable of liquid-liquid phase separation (LLPS), enhanced V1 editing at on-targets as well as off-targets, the latter effect being minor. The V1-HRD fusion protein formed puncta characteristic of LLPS, and various other IDRs (but not an LLPS-impaired mutant) could replace HRD to effectively induce puncta and potentiate V1, suggesting that the diverse domains acted via a common, LLPS-based mechanism. Importantly, the HRD fusion strategy was applicable to various other types of C > U RNA editors. Our study expands the RNA editing toolbox and showcases a general method for stimulating C > U RNA base editors.

Suicidal thoughts and behaviors among gender and sexual minorities: Adults ages 18-24 show highest rates of past month suicidal thoughts.

INTRODUCTION: Sexual and gender minority (SGM) people are at increased risk for suicidal thoughts and behaviors relative to their cisgender heterosexual peers. However, most research in this area has focused on youth, limiting our understanding of suicide risk among SGM adults. METHODS: To address this gap in the literature, the present study examined suicidal thoughts and behaviors among SGM adults across different age groups using a sample of 10,620 US adults. RESULTS: Consistent with the literature on youth, SGM adults showed higher rates of suicidal thoughts and behaviors than cisgender heterosexual adults. When examining prevalence rates across various age groups, young adults (18-24) showed greater lifetime and past month suicidal thoughts and behaviors relative to adults ages 45+. Adults ages 18-24 also showed greater past month suicidal ideation than adults ages 25-44; however, there were no group differences in lifetime suicidal thoughts and behaviors and past month suicidal behavior between adults ages 18-24 and 25-44. CONCLUSIONS: Although suicidal thoughts and behaviors are most common among young SGM adults, other age groups do still show concerning rates of suicidal thoughts and behaviors, suggesting that this risk might extend to later years of life. Additional resources for SGM adults that are not only tailored toward youth and young adults are warranted.

Sexual dimorphism and the multi-omic response to exercise training in rat subcutaneous white adipose tissue.

Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training (ExT) and sex on its molecular landscape is not fully established. Utilizing an integrative multi-omics approach, and leveraging data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we show profound sexual dimorphism in the scWAT of sedentary rats and in the dynamic response of this tissue to ExT. Specifically, the scWAT of sedentary females displays -omic signatures related to insulin signaling and adipogenesis, whereas the scWAT of sedentary males is enriched in terms related to aerobic metabolism. These sex-specific -omic signatures are preserved or amplified with ExT. Integration of multi-omic analyses with phenotypic measures identifies molecular hubs predicted to drive sexually distinct responses to training. Overall, this study underscores the powerful impact of sex on adipose tissue biology and provides a rich resource to investigate the scWAT response to ExT.

Racial Disparities in Evidence-Based Management of Metabolic Dysfunction-Associated Steatotic Liver Disease in Patients With Type 2 Diabetes.

OBJECTIVE: To assess frequency of evidence-based management (EBM) of metabolic dysfunction-associated steatotic liver disease (MASLD) in patients with type 2 diabetes (T2D), and to examine for racial/ethnic disparities in the receipt of EBM. METHODS: We conducted a cross-sectional analysis of patients with T2D and presumptive MASLD in an academic health care system between 2019 and 2021. Presumptive MASLD was defined as at least 1 alanine aminotransferase value ≥30 U/L with exclusions for alcohol overuse, viral hepatitis, liver transplantation, chemotherapy use, and liver disease other than MASLD. We calculated the proportion of patients receiving EBM, defined as a composite of liver ultrasound, transient elastography, or hepatology evaluation. We also examined the association between race/ethnicity and EBM via a logistic regression model. RESULTS: Our sample included 6532 patients; mean age was 58.0 (SD 13.1), 41.7% were female and 3.9%, 26.6%, 58.7%, and 5.8% were of Latino/a/x ethnicity, non-Latino (NL) Black race, NL White race, and NL Asian race, respectively. Rates of EBM were low overall (11.5%), with lower odds of EBM in NL Black versus NL White patients (adjusted odds ratio 0.75; 95% confidence interval 0.59, 0.96). Odds of hepatology evaluation and placement of MASLD diagnosis codes were also lower in NL Black versus NL White patients. CONCLUSION: Racial disparities exist in the receipt of EBM among patients with T2D and presumptive MASLD. These findings highlight the need for research to identify drivers of disparities, and to support development of clinical interventions that equitably facilitate EBM of MASLD in patients with T2D.

Utilizing median and maximum QTc values improves prediction of breakthrough cardiac events in pediatric long QT syndrome.

INTRODUCTION: Although prior studies indicate that a QTc > 500 ms on a single baseline 12-lead electrocardiogram (ECG) is associated with significantly increased risk of arrhythmic events in long QT syndrome (LQTS), less is known about the risk of persistent QT prolongation. We sought to determine QTc persistence and its prognostic effect on breakthrough cardiac events (BCEs) among pediatric patients treated for LQTS. METHODS: We performed a retrospective analysis of 433 patients with LQTS evaluated, risk-stratified, and undergoing active guideline-based LQTS treatment between 1999 and 2019. BCEs were defined as arrhythmogenic syncope/seizure, sudden cardiac arrest (SCA), appropriate VF-terminating ICD shock, and sudden cardiac death (SCD). RESULTS: During the median follow-up of 5.5 years (interquartile range [IQR] = 3-9), 32 (7%) patients experienced a total of 129 BCEs. A maximum QTc threshold of 520 ms and median QTc threshold of 490 ms were determined to be strong predictors for BCEs. A landmark analysis controlling for age, sex, genotype, and symptomatic status demonstrated models utilizing both the median QTc and maximum QTc demonstrated the highest discriminatory value (c-statistic = 0.93-0.95). Patients in the high-risk group (median QTc > 490 ms and maximum QTc > 520 ms) had a significantly lower BCE free survival (70%-81%) when compared to patients in both medium-risk (93%-97%) and low-risk (98%-99%) groups. CONCLUSIONS: The risk of BCE among patients treated for LQTS increases not only based upon their maximum QTc, but also their median QTc (persistence of QTc prolongation). Patients with a maximum QTc > 520 ms and median QTc > 490 ms over serial 12-lead ECGs are at the highest risk of BCE while on guideline-directed medical therapy.