Effect of artificial aging and different surface finishing protocols on the flexural strength and surface hardness of a photopolymer for manufacturing monolithic polychromatic complete dentures using PolyJet 3D printing.

PURPOSE: This study evaluated the effect of thermocycling and three different surface finishing protocols on the flexural strength and surface hardness of a novel photopolymer intended for manufacturing monolithic polychromatic dental prostheses using PolyJet 3D printing. MATERIALS AND METHODS: A total of 90 specimens were manufactured using a photopolymer for 3D printing monolithic polychromatic dental prostheses using PolyJet technology (TrueDent; Stratasys USA). The specimens were divided into three groups (n = 30) according to the surface finishing protocol used: The control group Pumice+Moldent (Pumice), Pumice+Optiglaze (Optiglaze), and Polycril+Moldent (Polycril). Half of the specimens of each group (n = 15) were subjected to 5000 thermocycles (Thermocycling Unit OMC350TSX; Odeme Dental Research, Santa Catarina, Brazil), The other half was stored in distilled water at room temperature for 7 days before testing. The flexural strength of the specimens was assessed in a universal testing machine (MTS Sintech ReNew; MTS Systems Corp, Aiden Prairie, MN), and the Vicker's surface hardness was evaluated with a microhardness tester (Micro indentation Hardness Tester LM247AT; Leco Instruments Ltd, Ontario, Canada). The resulting data was analyzed using two-way ANOVA tests, and Fisher's protected least significant differences (α = 0.05) in a professional statistical analysis computer program (SAS v9.4, SAS Institute, Cary, NC) RESULTS: The two-way ANOVA tests suggested a statistically significant effect of thermocycling and the surface finishing protocol on the flexural strength (p = 0.01) but without significant interaction between both independent variables (p = 0.18). The post hoc analysis revealed no significant differences in the flexural strength between groups without thermocycling (p > 0.05). Thermocycling decreased the flexural strength of all groups (p < 0.05), and the Optiglaze group exhibited significantly higher flexural strength than the Polycril and Pumice groups after thermocycling (p < 0.01). Regarding the surface hardness, the two-way ANOVA indicated a significant 2-way interaction between thermocycling and the surface of the finishing protocol (p = 0.01). The post hoc analysis showed that the Optiglaze group had significantly higher hardness than the other groups, both before and after thermocycling (p < 0.01) After thermocycling, a significant decrease in surface hardness was observed in the Polycril and Pumice groups (p < 0.01). CONCLUSIONS: Surface finishing protocols and artificial aging can affect the surface hardness and flexural strength of the dental prostheses manufactured using the photopolymer studied. Careful polishing and surface finishing are required to ensure favorable clinical performance. Coating with a photopolymerizable glaze material seems to be a favorable surface treatment for monolithic polychromatic complete dentures fabricated using PolyJet 3D printing.

Chronic Right Ventricular Pacing Post-Transcatheter Aortic Valve Replacement Attenuates the Benefit on Left Ventricular Function.

Background: Conduction abnormality post-transcatheter aortic valve implantation (TAVI) remains clinically significant and usually requires chronic pacing. The effect of right ventricular (RV) pacing post-TAVI on clinical outcomes warrants further studies. Methods: We identified 147 consecutive patients who required chronic RV pacing after a successful TAVI procedure and propensity-matched these patients according to the Society of Thoracic Surgeons (STS) risk score to a control group of patients that did not require RV pacing post-TAVI. We evaluated routine echocardiographic measurements and performed offline speckle-tracking strain analysis for the purpose of this study on transthoracic echocardiographic (TTE) images performed at 9 to 18 months post-TAVI. Results: The final study population comprised 294 patients (pacing group n = 147 and non-pacing group n = 147), with a mean age of 81 ± 7 years, 59% male; median follow-up was 354 days. There were more baseline conduction abnormalities in the pacing group compared to the non-pacing group (56.5% vs. 41.5%. p = 0.01). Eighty-eight patients (61.6%) in the pacing group required RV pacing due to atrioventricular (AV) conduction block post-TAVI. The mean RV pacing burden was 44% in the pacing group. Left ventricular ejection fraction (LVEF) was similar at follow-up in the pacing vs. non-pacing groups (57 ± 13.0%, 59 ± 11% p = 0.31); however, LV global longitudinal strain (-12.7 ± 3.5% vs. -18.8 ± 2.7%, p < 0.0001), LV apical strain (-12.9 ± 5.5% vs. 23.2 ± 9.2%, p < 0.0001), and mid-LV strain (-12.7 ± 4.6% vs. -18.7 ± 3.4%, p < 0.0001) were significantly worse in the pacing vs. non-pacing groups. Conclusions: Chronic RV pacing after the TAVI procedure is associated with subclinical LV systolic dysfunction within 1.5 years of follow-up.

Impact of transcatheter edge to edge repair in functional mitral regurgitation and cardiac resynchronization-therapy nonresponders.

BACKGROUND: Despite optimal medical therapy and cardiac resynchronization therapy (CRT), significant functional mitral regurgitation (MR) persisted in 30% of the patients and labeled as CRT nonresponders. AIMS: We sought to study the impact of transcatheter edge-to-edge repair (TEER) in patients with symptomatic grade III and IV functional MR despite CRT. METHODS: A retrospective analysis was conducted of all patients who had prior CRT for at least 6 months and underwent TEER for significant residual functional MR (grade ≥3) and symptomatic heart failure (HF) at our institution. The primary outcomes were the change in New York Heart Association classification (NYHA), MR grade, echo parameters, and NT-ProBNP from baseline to 1-year post-procedure. RESULTS: A total of 28 patients were identified, mean age of 73 ± 6.7 years and 89% males. Procedure success was achieved in all patients. At 1-year follow-up, patients had lower MR grade (median 2, IQR 1 [1,2] vs. 4, IQR 1 [3,4]; p < 0.001), NYHA class (median 2, IQR 1 [2,3] vs. 3, IQR 1 [3,4]; p < 0.001), and NT-ProBNP (7658 ± 11322 vs. 3760 ± 4431; p = 0.035) compared to before the TEER procedure. The left ventricular end-diastolic volume (255 ± 59 vs. 244 ± 66 mm; p = 0.016) and the right ventricular systolic pressure (52 ± 14 mmHg vs. 37 ± 13 mmHg, <0.001) decreased. CONCLUSION: Patients who remain symptomatic after CRT with severe functional MR had improved functional status and MR grade at 1-year following TEER. There was a signal toward reverse remodeling.

Advancing toward precision migraine treatment: Predicting responses to preventive medications with machine learning models based on patient and migraine features.

OBJECTIVE: To develop machine learning models using patient and migraine features that can predict treatment responses to commonly used migraine preventive medications. BACKGROUND: Currently, there is no accurate way to predict response to migraine preventive medications, and the standard trial-and-error approach is inefficient. METHODS: In this cohort study, we analyzed data from the Mayo Clinic Headache database prospectively collected from 2001 to December 2023. Adult patients with migraine completed questionnaires during their initial headache consultation to record detailed clinical features and then at each follow-up to track preventive medication changes and monthly headache days. We included patients treated with at least one of the following migraine preventive medications: topiramate, beta-blockers (propranolol, metoprolol, atenolol, nadolol, timolol), tricyclic antidepressants (amitriptyline, nortriptyline), verapamil, gabapentin, onabotulinumtoxinA, and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) (erenumab, fremanezumab, galcanezumab, eptinezumab). We pre-trained a deep neural network, "TabNet," using 145 variables, then employed TabNet-embedded data to construct prediction models for each medication to predict binary outcomes (responder vs. non-responder). A treatment responder was defined as having at least a 30% reduction in monthly headache days from baseline. All model performances were evaluated, and metrics were reported in the held-out test set (train 85%, test 15%). SHapley Additive exPlanations (SHAP) were conducted to determine variable importance. RESULTS: Our final analysis included 4260 patients. The responder rate for each medication ranged from 28.7% to 34.9%, and the mean time to treatment outcome for each medication ranged from 151.3 to 209.5 days. The CGRP mAb prediction model achieved a high area under the receiver operating characteristics curve (AUC) of 0.825 (95% confidence interval [CI] 0.726, 0.920) and an accuracy of 0.80 (95% CI 0.70, 0.88). The AUCs of prediction models for beta-blockers, tricyclic antidepressants, topiramate, verapamil, gabapentin, and onabotulinumtoxinA were: 0.664 (95% CI 0.579, 0.745), 0.611 (95% CI 0.562, 0.682), 0.605 (95% CI 0.520, 0.688), 0.673 (95% CI 0.569, 0.724), 0.628 (0.533, 0.661), and 0.581 (95% CI 0.550, 0.632), respectively. Baseline monthly headache days, age, body mass index (BMI), duration of migraine attacks, responses to previous medication trials, cranial autonomic symptoms, family history of headache, and migraine attack triggers were among the most important variables across all models. A variable could have different contributions; for example, lower BMI predicts responsiveness to CGRP mAbs and beta-blockers, while higher BMI predicts responsiveness to onabotulinumtoxinA, topiramate, and gabapentin. CONCLUSION: We developed an accurate prediction model for CGRP mAbs treatment response, leveraging detailed migraine features gathered from a headache questionnaire before starting treatment. Employing the same methods, the model performances for other medications were less impressive, though similar to the machine learning models reported in the literature for other diseases. This may be due to CGRP mAbs being migraine-specific. Incorporating medical comorbidities, genomic, and imaging factors might enhance the model performance. We demonstrated that migraine characteristics are important in predicting treatment responses and identified the most crucial predictors for each of the seven types of preventive medications. Our results suggest that precision migraine treatment is feasible.

Coenzyme A protects against ferroptosis via CoAlation of thioredoxin reductase 2.

The Cystine-xCT transporter-Glutathione (GSH)-GPX4 axis is the canonical pathway to protect against ferroptosis. While not required for ferroptosis-inducing compounds (FINs) targeting GPX4, FINs targeting the xCT transporter require mitochondria and its lipid peroxidation to trigger ferroptosis. However, the mechanism underlying the difference between these FINs is still unknown. Given that cysteine is also required for coenzyme A (CoA) biosynthesis, here we show that CoA supplementation specifically prevents ferroptosis induced by xCT inhibitors but not GPX4 inhibitors. We find that, auranofin, a thioredoxin reductase inhibitor, abolishes the protective effect of CoA. We also find that CoA availability determines the enzymatic activity of thioredoxin reductase, but not thioredoxin. Importantly, the mitochondrial thioredoxin system, but not the cytosolic thioredoxin system, determines CoA-mediated ferroptosis inhibition. Our data show that the CoA regulates the in vitro enzymatic activity of mitochondrial thioredoxin reductase (TXNRD2) by covalently modifying the thiol group of cysteine (CoAlation) on Cys-483. Replacing Cys-483 with alanine on TXNRD2 abolishes its in vitro enzymatic activity and ability to protect cells from ferroptosis. Targeting xCT to limit cysteine import and, therefore, CoA biosynthesis reduced CoAlation on TXNRD2, an effect that was rescued by CoA supplementation. Furthermore, the fibroblasts from patients with disrupted CoA metabolism demonstrate increased mitochondrial lipid peroxidation. In organotypic brain slice cultures, inhibition of CoA biosynthesis leads to an oxidized thioredoxin system, mitochondrial lipid peroxidation, and loss in cell viability, which were all rescued by ferrostatin-1. These findings identify CoA-mediated post-translation modification to regulate the thioredoxin system as an alternative ferroptosis protection pathway with potential clinical relevance for patients with disrupted CoA metabolism.

3D-printed shell complete dentures as a diagnostic aid for implant planning and fabricating interim restorations for complete arch rehabilitations: A case series.

3D-printed shell complete dentures generated from a scan of the patient's existing prostheses can simplify and expedite the surgical planning and interim restoration design for complete arch rehabilitations. Three patients were rehabilitated with endosteal implants, and interim restorations were generated from the contours of the 3D-printed shell complete dentures used as diagnostic aids. This case series report presents the recommended protocol and its clinical progression, in addition to clinical and radiographic images of the treatment outcomes.

Association between echocardiographic velocity time integral ratio of mitral valve and left ventricular outflow tract and clinical outcomes post transcatheter edge-to-edge mitral valve repair.

Background: Residual mitral regurgitation (MR) is frequent after transcatheter edge-to-edge repair (TEER). There is controversy regarding the clinical impact of residual MR and its quantitative assessment by transthoracic echocardiography (TTE), which is often challenging with multiple eccentric jets and artifact from the clip. The utility of the velocity time integral (VTI) ratio between the mitral valve (MV) and left ventricular outflow tract (LVOT), (VTIMV/LVOT), a simple Doppler measurement that increases with MR, has not been assessed post TEER. Methods: Baseline characteristics, clinical outcomes, and TTE data from patients who underwent TEER between 2014 and 2021 across three academic centers were retrospectively analyzed. Post-procedure TTEs were evaluated for VTIMV/LVOT in the first three months after TEER. One-year outcomes including all-cause and cardiac mortality, major adverse cardiac events, and MV reintervention were compared between patients with high VTIMV/LVOT (≥2.5) and low (<2.5). Results: In total, 372 patients were included (mean age 78.7 ± 8.8 years, 68 % male, mean pre-TEER ejection fraction of 50.5 ± 14.7 %). Follow up TTEs were performed at a median of 37.5 (IQR 30-48) days post-procedure. Patients with high VTIMV/LVOT had significantly higher all-cause mortality (HR 2.10, p = 0.003), cardiac mortality (HR 3.03, p = 0.004) and heart failure admissions (HR 2.28, p < 0.001) at one-year post-procedure. There was no association between raised VTIMV/LVOT and subsequent MV reintervention. Conclusion: High VTIMV/LVOT has clinically significant prognostic value at one year post TEER. This tool could be used to select patients for consideration of repeat intervention.

Color stability of precolored and extrinsically colored monolithic multilayered polychromatic zirconia: Effects of surface finishing and aging.

PURPOSE: To explore the impact of zirconia types, coloring methods, and surface finishing on the color stability of monolithic multilayered polychromatic zirconia after artificial aging, including thermocycling and simulated toothbrushing. MATERIALS AND METHODS: Eighty square-shaped zirconia samples were divided into 2 types (M3Y-TZP and M6Y-PSZ), further categorized based on coloring methods (precolored and extrinsically colored) and surface finishing techniques (mechanical polishing or glazing). The color stability was assessed using the CIEDE2000 formula. Artificial aging was simulated via thermocycling and toothbrushing. All samples were analyzed with a spectrophotometer to determine the post-aging color changes (ΔE00). The ΔE00 were interpreted and classified using the 50:50% perceptibility threshold (PT) and the 50:50% acceptability threshold (AT). Comparisons between groups for ΔE00 differences were performed using three-way ANOVA, with pairwise comparisons facilitated by Fisher's protected least significant difference test, α = 0.05. RESULTS: The study results indicated significant impacts of zirconia type, coloring method, and surface finishing on color stability. The M6Y groups experienced significantly greater color changes (6.61 ± 1.63) compared to the M3Y groups (3.40 ± 2.24), p < 0.0001. For both types of zirconia, extrinsically colored samples exhibited significantly higher ΔE00 when mechanically polished (p = 0.004). However, surface finishing had no significant effect on ΔE00 in precolored samples of either zirconia material (p = 1.000). The evaluation and categorization of ΔE00 variations indicated that nearly all color changes in the M6Y groups, regardless of being precolored, extrinsically colored, polished, or glazed, were deemed extremely unacceptable (Grade 1). In contrast, the M3Y groups showed more acceptable results, with the majority of color changes classified as moderately unacceptable (Grade 3). CONCLUSIONS: The color stability of multilayered polychromatic zirconia is influenced by the type of material, extrinsic coloring, and the chosen surface treatment post-artificial aging. The translucent 6Y-PSZ exhibited lower color stability, especially with only mechanical polishing. For the fabrication of M3Y-TZP and 6Y-PSZ monolithic multilayered polychromatic zirconia restorations, extrinsic coloring should be paired with glazing to maintain color stability. Conversely, in the absence of extrinsic coloring, both glazing and mechanical polishing are effective in preserving color stability.

Lipoprotein(a) and Long-term In-stent Restenosis after Percutaneous Coronary Intervention.

AIM: Lipoprotein(a) [Lp(a)] has demonstrated its association with atherosclerosis and myocardial infarction. However, its role in the development of in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) is not clearly established. The aim of this study is to investigate the association between Lp(a) and ISR. METHODS: A retrospective study of adult patients who underwent successful PCI between January 2006 and December 2017 at the three Mayo Clinic sites and had a preprocedural Lp(a) measurement was conducted. Patients were divided into two groups according to the serum Lp(a) concentration (high Lp(a) ≥50 mg/dl and low Lp(a) <50 mg/dl). Univariable and multivariable analyses were performed to compare risk of ISR between patients with high Lp(a) versus those with low Lp(a). RESULTS: A total of 1209 patients were included, with mean age 65.9 ±11.7 years and 71.8% were male. Median follow-up after baseline PCI was 8.8 (IQR 7.4) years. Restenosis was observed in 162 (13.4%) patients. Median serum levels of Lp(a) were significantly higher in patients affected by ISR versus non-affected cases: 27 (IQR 73.8) vs. 20 (IQR 57.5) mg/dL, p=0.008. The rate of ISR was significantly higher among patients with high Lp(a) versus patients with low Lp(a) values (17.0% vs 11.6%, p=0.010). High Lp(a) values were independently associated with ISR events (HR 1.67, 95%CI 1.18 to 2.37, p=0.004), and this association was more prominent after the first year following the PCI. CONCLUSION: Lipoprotein(a) is an independent predictor for long-term in-stent restenosis and should be considered in the evaluation of patients undergoing PCI.

The role of Lp(a) in the development of in-stent restenosis is not clearly established. In this study including 1209 patients who underwent successful percutaneous coronary intervention and had a preprocedural Lp(a) measurement between 2006 and 2017, the rates of restenosis were significantly higher among patients with high Lp(a) versus patients with low Lp(a) values and high Lp(a) concentrations were independently associated with restenosis events. Lp(a) should be considered as a risk factor for long term in-stent restenosis in the evaluation of patients undergoing percutaneous coronary intervention and assessed as a potential therapeutic target for reducing residual cardiovascular risk in this population.

The prognostic value of artificial intelligence to predict cardiac amyloidosis in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement.

Aims: Cardiac amyloidosis (CA) is common in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Cardiac amyloidosis has poor outcomes, and its assessment in all TAVR patients is costly and challenging. Electrocardiogram (ECG) artificial intelligence (AI) algorithms that screen for CA may be useful to identify at-risk patients. Methods and results: In this retrospective analysis of our institutional National Cardiovascular Disease Registry (NCDR)-TAVR database, patients undergoing TAVR between January 2012 and December 2018 were included. Pre-TAVR CA probability was analysed by an ECG AI predictive model, with >50% risk defined as high probability for CA. Univariable and propensity score covariate adjustment analyses using Cox regression were performed to compare clinical outcomes between patients with high CA probability vs. those with low probability at 1-year follow-up after TAVR. Of 1426 patients who underwent TAVR (mean age 81.0 ± 8.5 years, 57.6% male), 349 (24.4%) had high CA probability on pre-procedure ECG. Only 17 (1.2%) had a clinical diagnosis of CA. After multivariable adjustment, high probability of CA by ECG AI algorithm was significantly associated with increased all-cause mortality [hazard ratio (HR) 1.40, 95% confidence interval (CI) 1.01-1.96, P = 0.046] and higher rates of major adverse cardiovascular events (transient ischaemic attack (TIA)/stroke, myocardial infarction, and heart failure hospitalizations] (HR 1.36, 95% CI 1.01-1.82, P = 0.041), driven primarily by heart failure hospitalizations (HR 1.58, 95% CI 1.13-2.20, P = 0.008) at 1-year follow-up. There were no significant differences in TIA/stroke or myocardial infarction. Conclusion: Artificial intelligence applied to pre-TAVR ECGs identifies a subgroup at higher risk of clinical events. These targeted patients may benefit from further diagnostic evaluation for CA.

Color stability of CAD-CAM hybrid ceramic materials following immersion in artificial saliva and wine.

PURPOSE: To examine the color stability of 3D-printed and milled, interim, and definitive, restorative materials after immersion in artificial saliva and wine for 1, 3, and 6 months. MATERIAL AND METHODS: The study used a 2 × 5 factorial design with 10 subgroups, including 2 immersion liquids (artificial saliva and wine) and 5 manufacturing technology and restorative material combinations (n = 10). Color measurements were taken using a contact-type digital spectrophotometer (CM-2600d Spectrophotometer; Konica Minolta Healthcare Americas Inc) before immersion and at 1 month (T1), 3 months (T3), and 6 months (T6) after immersion. The CIE2000 system was used to calculate quantitative measurements of color differences in ΔE00, and comparisons were made to the acceptability threshold (AT) and perceptibility threshold (PT). Repeated measures of ANOVA (α = 0.05) were used to compare differences in color changes between manufacturing technology/restorative material-immersion liquid combinations at T1, T3, and T6. RESULTS: To compare the effect of immersion liquid and time on the manufacturing technology/restorative material groups, the ΔE00 values were compared to the PT of 0.8 and the AT of 1.8. Wine caused significant color changes in ΔE00 values beyond the PT and AT values in all groups at all time intervals, except for the AT value of milled definitive crowns (hybrid nano-ceramic material). Wine immersion caused significant ΔE00 for all manufacturing technology/restorative material groups at all time intervals (1 month, 3 months, and 6 months) when compared to artificial saliva immersion (all p < 0.001). CONCLUSION: Upon exposure to artificial saliva, 80%-100% of samples from all groups remained within the acceptable and perceptible color change thresholds. The wine had significant chromogenic effects on all tested restorative materials, however, the milled definitive crowns (hybrid nano-ceramic material) showed the greatest color stability. For patients with heavy wine consumption, 3D-printed definitive crowns (hybrid ceramic-filled material) may show discoloration exceeding acceptable and perceptible color change limits.

The 3D-printed shell complete denture technique: Simplifying prosthodontic diagnosis prior to implant planning.

Traditionally, artificial teeth arrangements or the definitive complete dentures are used to establish important prosthodontic parameters such as the occlusal plane orientation, vertical dimension, and the incisal edge position. The relationship of these elements with the underlying bony structures is commonly evaluated using advanced planning protocols such as the dual scan technique. This technique article presents an uncomplicated alternative approach to establish these parameters intraorally using a 3D-printed shell complete denture generated from a 3D scan of the patient's existing complete denture.

Disproportionately high aortic valve calcium scores in atrial fibrillation: implications for transcatheter aortic valve replacement.

AIMS: Doppler mean gradient (MG) can underestimate aortic stenosis (AS) severity in patients with atrial fibrillation (AF) compared with patients with sinus rhythm (SR), potentially delaying intervention in AF. This study compared outcomes in patients with AF and SR following transcatheter aortic valve replacement (TAVR) and investigated delay in TAVR based on computed tomography aortic valve calcium score (AVCS). METHODS AND RESULTS: Patients who underwent TAVR from 2013 to 2017 for native valve severe AS were identified from an institutional database. Baseline characteristics and overall survival were compared between those with SR and AF. There were 820 patients (mean age 81 years; 41.6% females) included in this study. AF was present in 356 patients. Patients with AF were older (82.2 vs. 80.5, P = 0.003) and had a lower MG compared with patients with SR (42.0 vs. 44.9, P = 0.002) with similar indexed aortic valve area (0.4 vs. 0.4, P = 0.17). Median AVCS was higher in AF (males: AF 2850.0 vs. SR 2561.0, P = 0.044; females: AF 1942.0 vs. SR 1610.5, P = 0.025). Projected AVCS, assuming the same age of diagnosis, was similar between AF and SR. Median survival post-TAVR was worse in AF compared with SR (3.2 vs. 5.4 years, log rank P < 0.001). AF, lower MG, higher right ventricular systolic pressure, dialysis, diabetes, and significant tricuspid regurgitation were associated with higher mortality (P < 0.05 for all). CONCLUSION: Older age and higher AVCS in patients with AF compared with those with SR suggest that AS was both underestimated and more advanced at TAVR referral.

Role of Genetics in Diagnosis and Management of Hypertrophic Cardiomyopathy: A Glimpse into the Future.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. It follows an autosomal dominant inheritance pattern in most cases, with incomplete penetrance and heterogeneity. It is familial in 60% of cases and most of these are caused by pathogenic variants in the core sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1). Genetic testing using targeted disease-specific panels that utilize next-generation sequencing (NGS) and include sarcomeric genes with the strongest evidence of association and syndrome-associated genes is highly recommended for every HCM patient to confirm the diagnosis, identify the molecular etiology, and guide screening and management. The yield of genetic testing for a disease-causing variant is 30% in sporadic cases and up to 60% in familial cases and in younger patients with typical asymmetrical septal hypertrophy. Genetic testing remains challenging in the interpretation of results and classification of variants. Therefore, in 2015 the American College of Medical Genetics and Genomics (ACMG) established guidelines to classify and interpret the variants with an emphasis on the necessity of periodic reassessment of variant classification as genetic knowledge rapidly expands. The current guidelines recommend focused cascade genetic testing regardless of age in phenotype-negative first-degree relatives if a variant with decisive evidence of pathogenicity has been identified in the proband. Genetic test results in family members guide longitudinal clinical surveillance. At present, there is emerging evidence for genetic test application in risk stratification and management but its implementation into clinical practice needs further study. Promising fields such as gene therapy and implementation of artificial intelligence in the diagnosis of HCM are emerging and paving the way for more effective screening and management, but many challenges and obstacles need to be overcome before establishing the practical implications of these new methods.

A large language model-based generative natural language processing framework fine-tuned on clinical notes accurately extracts headache frequency from electronic health records.

OBJECTIVE: To develop a natural language processing (NLP) algorithm that can accurately extract headache frequency from free-text clinical notes. BACKGROUND: Headache frequency, defined as the number of days with any headache in a month (or 4 weeks), remains a key parameter in the evaluation of treatment response to migraine preventive medications. However, due to the variations and inconsistencies in documentation by clinicians, significant challenges exist to accurately extract headache frequency from the electronic health record (EHR) by traditional NLP algorithms. METHODS: This was a retrospective cross-sectional study with patients identified from two tertiary headache referral centers, Mayo Clinic Arizona and Mayo Clinic Rochester. All neurology consultation notes written by 15 specialized clinicians (11 headache specialists and 4 nurse practitioners) between 2012 and 2022 were extracted and 1915 notes were used for model fine-tuning (90%) and testing (10%). We employed four different NLP frameworks: (1) ClinicalBERT (Bidirectional Encoder Representations from Transformers) regression model, (2) Generative Pre-Trained Transformer-2 (GPT-2) Question Answering (QA) model zero-shot, (3) GPT-2 QA model few-shot training fine-tuned on clinical notes, and (4) GPT-2 generative model few-shot training fine-tuned on clinical notes to generate the answer by considering the context of included text. RESULTS: The mean (standard deviation) headache frequency of our training and testing datasets were 13.4 (10.9) and 14.4 (11.2), respectively. The GPT-2 generative model was the best-performing model with an accuracy of 0.92 (0.91, 0.93, 95% confidence interval [CI]) and R2 score of 0.89 (0.87, 0.90, 95% CI), and all GPT-2-based models outperformed the ClinicalBERT model in terms of exact matching accuracy. Although the ClinicalBERT regression model had the lowest accuracy of 0.27 (0.26, 0.28), it demonstrated a high R2 score of 0.88 (0.85, 0.89), suggesting the ClinicalBERT model can reasonably predict the headache frequency within a range of ≤ ± 3 days, and the R2 score was higher than the GPT-2 QA zero-shot model or GPT-2 QA model few-shot training fine-tuned model. CONCLUSION: We developed a robust information extraction model based on a state-of-the-art large language model, a GPT-2 generative model that can extract headache frequency from EHR free-text clinical notes with high accuracy and R2 score. It overcame several challenges related to different ways clinicians document headache frequency that were not easily achieved by traditional NLP models. We also showed that GPT-2-based frameworks outperformed ClinicalBERT in terms of accuracy in extracting headache frequency from clinical notes. To facilitate research in the field, we released the GPT-2 generative model and inference code with open-source license of community use in GitHub. Additional fine-tuning of the algorithm might be required when applied to different health-care systems for various clinical use cases.

Efficacy of Sacubitril-Valsartan on Survival and Cardiac Remodeling in Hypotensive Heart Failure With Reduced Ejection Fraction: A Multicenter Study.

OBJECTIVE: To investigate whether hypotensive patients diagnosed with heart failure and reduced ejection fraction (HFrEF) might benefit from angiotensin receptor-neprilysin inhibitors (ARNis) in real-world practice because patients with baseline systolic blood pressure (SBP) of less than 100 mm Hg have been excluded from landmark trials. PATIENTS AND METHODS: In this multicenter study conducted between January 1, 2013, and December 31, 2021, a total of 7562 symptomatic patients with HFrEF were enrolled and grouped by SBP (hypotension was defined as an SBP of less than 100 mm Hg) and ARNi use as follows: group 1, hypotensive/non-ARNi users (n=484); group 2, hypotensive/ARNi users (n=308); group 3, nonhypotensive/non-ARNi users (n=4560); and group 4, nonhypotensive/ARNi users (n=2210). Inverse probability of treatment weighting was used to balance baseline characteristics for survival analysis. RESULTS: Diverse baseline characteristics and lower rates of medication use were found among non-ARNi users compared with ARNi users. Hypotensive/ARNi users had lower ARNi initiation doses than nonhypotensive/ARNi users. We observed significantly lower mortality, composite heart failure hospitalization, and CV death for hypotensive/ARNi and the other 2 nonhypotensive groups (groups 3 and 4) during a median follow-up of 3.43 years (all P<.05), with a similar effect on reverse remodeling for the hypotensive/ARNi group compared with the hypotensive/non-ARNi group. The event-free survival benefits of ARNi vs renin-angiotensin system inhibitors were consistent with the lower boundary of SBP for clinical benefits found until 88 mm Hg (spline curves) after inverse probability of treatment weighting. CONCLUSION: Patients with HFrEF and hypotension may still benefit from ARNi treatment. Patients with hypotensive HFrEF should not be routinely excluded from ARNi use in a real-world setting.

Cardiac Allograft Vasculopathy: Challenges and Advances in Invasive and Non-Invasive Diagnostic Modalities.

Cardiac allograft vasculopathy (CAV) is a distinct form of coronary artery disease that represents a major cause of death beyond the first year after heart transplantation. The pathophysiology of CAV is still not completely elucidated; it involves progressive circumferential wall thickening of both the epicardial and intramyocardial coronary arteries. Coronary angiography is still considered the gold-standard test for the diagnosis of CAV, and intravascular ultrasound (IVUS) can detect early intimal thickening with improved sensitivity. However, these tests are invasive and are unable to visualize and evaluate coronary microcirculation. Increasing evidence for non-invasive surveillance techniques assessing both epicardial and microvascular components of CAV may help improve early detection. These include computed tomography coronary angiography (CTCA), single-photon emission computed tomography (SPECT), positron emission tomography (PET), and vasodilator stress myocardial contrast echocardiography perfusion imaging. This review summarizes the current state of diagnostic modalities and their utility and prognostic value for CAV and also evaluates emerging tools that may improve the early detection of this complex disease.

NINJ1 regulates ferroptosis via xCT antiporter interaction and CoA modulation.

Ninjurin-1 (NINJ1), initially identified as a stress-induced protein in neurons, recently emerged as a key mediator of plasma membrane rupture during apoptosis, necrosis, and pyroptosis. However, its involvement in ferroptosis remains unknown. Here, we demonstrate that NINJ1 also plays a crucial role in ferroptosis, but through a distinct mechanism. NINJ1 knockdown significantly protected cancer cells against ferroptosis induced by xCT inhibitors but no other classes of ferroptosis-inducing compounds (FINs). Glycine, known to inhibit canonical NINJ1-mediated membrane rupture in other cell deaths, had no impact on ferroptosis. A compound screen revealed that NINJ1-mediated ferroptosis protection can be abolished by pantothenate kinase inhibitor (PANKi), buthionine sulfoximine (BSO), and diethylmaleate (DEM). These results suggest that this ferroptosis protection is mediated via Coenzyme A (CoA) and glutathione (GSH), both of which were found to be elevated upon NINJ1 knockdown. Furthermore, we discovered that NINJ1 interacts with the xCT antiporter, which is responsible for cystine uptake for the biosynthesis of CoA and GSH. The removal of NINJ1 increased xCT levels and stability, enhanced cystine uptake, and contributed to elevated CoA and GSH levels, collectively contributing to ferroptosis protection. These findings reveal that NINJ1 regulates ferroptosis via a non-canonical mechanism, distinct from other regulated cell deaths.

Influence of exposure protocol, voxel size, and artifact removal algorithm on the trueness of segmentation utilizing an artificial-intelligence-based system.

PURPOSE: To evaluate the effects of exposure protocol, voxel sizes, and artifact removal algorithms on the trueness of segmentation in various mandible regions using an artificial intelligence (AI)-based system. MATERIALS AND METHODS: Eleven dry human mandibles were scanned using a cone beam computed tomography (CBCT) scanner under differing exposure protocols (standard and ultra-low), voxel sizes (0.15 mm, 0.3 mm, and 0.45 mm), and with or without artifact removal algorithm. The resulting datasets were segmented using an AI-based system, exported as 3D models, and compared to reference files derived from a white-light laboratory scanner. Deviation measurement was performed using a computer-aided design (CAD) program and recorded as root mean square (RMS). The RMS values were used as a representation of the trueness of the AI-segmented 3D models. A 4-way ANOVA was used to assess the impact of voxel size, exposure protocol, artifact removal algorithm, and location on RMS values (α = 0.05). RESULTS: Significant effects were found with voxel size (p < 0.001) and location (p < 0.001), but not with exposure protocol (p = 0.259) or artifact removal algorithm (p = 0.752). Standard exposure groups had significantly lower RMS values than the ultra-low exposure groups in the mandible body with 0.3 mm (p = 0.014) or 0.45 mm (p < 0.001) voxel sizes, the symphysis with a 0.45 mm voxel size (p = 0.011), and the whole mandible with a 0.45 mm voxel size (p = 0.001). Exposure protocol did not affect RMS values at teeth and alveolar bone (p = 0.544), mandible angles (p = 0.380), condyles (p = 0.114), and coronoids (p = 0.806) locations. CONCLUSION: This study informs optimal exposure protocol and voxel size choices in CBCT imaging for true AI-based automatic segmentation with minimal radiation. The artifact removal algorithm did not influence the trueness of AI segmentation. When using an ultra-low exposure protocol to minimize patient radiation exposure in AI segmentations, a voxel size of 0.15 mm is recommended, while a voxel size of 0.45 mm should be avoided.