Lethal Events Research Articles

Long-term effectiveness and safety of deucravacitinib in psoriasis: A 52-week real-world study of genital, scalp, and nail lesions.

The long-term (around 1-year) effectiveness and safety of deucravacitinib for the treatment of psoriasis have not been extensively studied in real-world settings, particularly in difficult-to-treat areas, such as the genital, scalp, and nail regions. To evaluate the 52-week real-world effectiveness and safety of deucravacitinib in patients with moderate-to-severe psoriasis of the genital, scalp, and nail regions. This prospective study analyzed 104 patients with moderate-to-severe plaque psoriasis treated with deucravacitinib. Clinical scores, psoriasis area and severity index (PASI), static or regional physician's global assessment (PGA), dermatology life quality index (DLQI), and laboratory inflammatory indices were assessed during a 52-week period. Deucravacitinib decreased clinical severity scores, and the decrease was sustained for 52 weeks. At week 52, 86.0%, 62.8%, and 25.6% of patients achieved PASI 75, 90, and 100, respectively. Deucravacitinib reduced the PGA scores for the genital, scalp, and nail regions, as well as the DLQI. The 52-week treatment had no impact on laboratory inflammatory indices, and no severe or lethal adverse events were reported. Deucravacitinib may be a promising long-term treatment option for psoriasis, demonstrating sustained effectiveness and safety, including in difficult-to-treat areas, such as the genital, scalp, and nail regions, in real-world clinical practice.

Impact of prolonged QTc interval on mortality risk with hypertrophic cardiomyopathy.

The association between corrected QT (QTc) interval and life-threatening cardiac events in patients with hypertrophic cardiomyopathy (HCM) remains unclear. This study sought to investigate whether the prolonged QTc was associated with HCM-related death in patients with HCM. We included 445 patients with HCM (mean age 51 ± 16 years, 67% men). The QTc interval was measured at the time of the initial evaluation and the patients were classified into those with and without QTc prolongation, which was defined as a QTc interval >450 ms. HCM-related death was defined as a combined endpoint of sudden death or potentially lethal arrhythmic events, heart failure-related death, and stroke-related death. Prolonged QTc interval was found in 120 patients (26.4%) at the time of enrollment. Over a median (IQR) follow-up period of 8.1 (4.6-11.9) years, a total of 67 patients (15.1%) experienced HCM-related deaths including 57 (12.8%) with the endpoint of sudden death or potentially lethal arrhythmic events. In a multivariable analysis that included prolonged QTc interval and the risk factors for life-threatening events, prolonged QTc interval was independently associated with an HCM-related death (adjusted hazard ratio [HR]: 1.91; 95% confidence interval [CI]: 1.16-3.16; p = .011) and this trend also persisted for the combined endpoint of sudden death or potentially lethal arrhythmic events (adjusted HR: 2.01: 95% CI: 1.17-3.46; p = .012). In this cohort of patients with HCM, QTc prolongation may be associated with HCM-related death, including the endpoint of sudden death or potentially lethal arrhythmic events.

Optimisation of gene expression noise for cellular persistence against lethal events

Bacterial cell persistence, crucial for survival under adverse conditions like antibiotic exposure, is intrinsically linked to stochastic fluctuations in gene expression. Certain genes, while inhibiting growth under normal circumstances, confer tolerance to antibiotics at elevated expression levels. The occurrence of antibiotic events lead to instantaneous cellular responses with varied survival probabilities correlated with gene expression levels. Notably, cells with lower protein concentrations face higher mortality rates. This study aims to elucidate an optimal strategy for protein expression conducive to cellular survival. Through comprehensive mathematical analysis, we determine the optimal burst size and frequency that maximise cell proliferation. Furthermore, we explore how the optimal expression distribution changes as the cost of protein expression to growth escalates. Our model reveals a hysteresis phenomenon, characterised by discontinuous transitions between deterministic and stochastic optima. Intriguingly, stochastic optima possess a noise floor, representing the minimal level of fluctuations essential for optimal cellular resilience.

Results of treatment of patients 75 years or older with non-metastatic prostate cancer in real clinical practice

Aim. To evaluate the results of radical surgical treatment and radiotherapy in patients with non-metastatic prostate cancer at age ≥75 years.Materials and methods. The retrospective study included data from 151 patients ≥75 years with verified non-metastatic prostate cancer who underwent radical prostatectomy (RP) or external beam radiotherapy (EBRT). Median age was 81.0 (75.0–97.0) years. Median Charlson comorbidity index was 7 (4–12). Median baseline prostate specific antigen (PSA) level was 11.0 (1.8–172.0) ng/mL. Prostatic adenocarcinoma was verified (ISUP grade 4–5 – 30 (19.9 %)) in all patients. сТ category was сТ3–4 in 37 (24.5 %), cN1 category was diagnosed in 10 (6.6 %) patients. The groups of unfavorable intermediate, high and very high risk included 93 (61.6 %) patients. Radical treatmentwas performed in all cases: RP in 38 (25.2 %), EBRT in 113 (74.8 %) patients (109 (72.2 %) men completed EBRT). Adjuvant treatment was administered in 8 (21.1 %) patients who underwent surgery. In the EBRT group neoadjuvant androgen-deprivation therapy (ADT) was administered in 74 (65.5 %), adjuvant ADT in 79 (70.0 %) cases. Treatment groups were matched by the main characteristics (р >0.05 for all) excluding lower baseline PSA in the RP group (р = 0.013). Median follow-up was 46.2 (1.5–234.2) months for all patients.Results. RP complications were registered in 3 (7.8 %), EBRT complications – in 7 (6.2 %) patients. No serious or lethal adverse event was observed. Recurrences were diagnosed in 9 (23.7 %) patients after surgery and in 26 (23.9 %) of 109 patients who completed EBRT. In the total study population, 4-year recurrence-free, cancer-specific, overall, and cardiac-specific survival rates were 74.5; 96.3; 91.2 and 90.8 %, respectively. The only factor significantly decreasing overall survival was Charlson comorbidity index ³8 (р = 0.05). Significant decrease of recurrence-free survival was observed in the surgery group compared to the EBRT group (р = 0.032). It did not translate into decreased cancerspecific and overall survival (р >0.05 for all). There was no significant difference in cardiac-specific survival between the groups (р = 0.626). Significant unfavorable prognostic factors of recurrence-free survival in the EBRT group included сN1 category (р = 0.045), very high risk (р = 0.049), and EBRT dose.Conclusion. RP and EBRT in elderly patients with non-metastatic prostate cancer receiving treatment in real clinical practice have acceptable safety profile and provide effectiveness comparable to the historical data on patients not sampled by age. The optimal candidates for radical treatment are men with Charlson comorbidity index <8.

Abstract 4132838: Coronary Collaterals Provide Cardioprotection in Hemorrhagic ST-elevation MI (STEMI)

Introduction: Development of intramyocardial hemorrhage (IMH) in acute STEMI following reperfusion is estimated to affect 35-50% of patients. IMH is a lethal event as it contributes to larger MI size, compromised myocardial salvage, adverse left ventricular (LV) remodeling, lower LVEF, and consequential major adverse CV events post-MI. Whether coronary collateral circulation reduces the deleterious effects of IMH has not been investigated. Hypothesis: We hypothesized that coronary collaterals could reduce the extent of post-reperfusion IMH volume and offer cardioprotection to hemorrhagic MI patients. Methods: MIRON-CL (NCT05898425) recruited and studied STEMI patients (n=294) reperfused via PCI. Pre-PCI coronary angiography allowed for assessment of collateral vessels using the Rentrop grading system, from Grade 0 (no collaterals) to Grade III (complete collateral filling). Post-PCI cardiac MRI, performed 3 days later, was used to determine area affected (extent of myocardial edema) from T2 maps, extent of IMH from T2* maps and MI size from LGE as %LV. Statistical analyses were used to examine relationships between collateral grades, MI size, IMH, and area affected. Results: 124 patients were hemorrhagic and 170 were non-hemorrhagic. Patients with no collaterals (Grade 0; CL-) exhibited significantly higher IMH volumes (7.41 ± 5.33% LV) compared to those with collaterals (Grade I: 5.23 ± 3.21% LV, Grade II: 3.11 ± 2.78% LV, Grade III: 2.05 ± 1.89% LV; p<0.001). Total area affected post-PCI was larger in CL- (37.62 ± 15.32% LV) compared to CL+ (21.48 ± 13.21% LV, p<0.001). Presence of collateral circulation (Grade>0 combined; CL+) was correlated with smaller MI sizes (CL-: 38.66 ± 14.63% LV vs. CL+: 19.84 ± 13.72% LV, p<0.001) and reduced MVO volumes (CL-: 8.07 ± 6.60% LV vs. CL+: 2.17 ± 2.35% LV, p<0.001). Patients with no collaterals had a significantly higher adj. risk of IMH (OR: 5.71, 95% CI: 3.16-10.33, p<0.0001). Conclusion: Coronary collaterals reduce post-reperfusion IMH volume in STEMI patients and provide significant cardioprotection: reductions in area affected, MVO and MI size. Insight into collateral grade offers opportunities to improve risk stratification and management of revascularized STEMI patients.

Abstract 4145821: Serial Vascular Responses of Balloon-expandable Stent with Biodegradable Film-type Graft in a Rabbit Iliac Artery Dissection Model (BioGard Study)

Introduction and Background: Arterial dissection during endovascular therapy rarely occurs but can be lethal. A significant blood volume extravasation during coronary artery interventions is related to the very high mortality (20-30%). In this hyperacute emergent clinical situation, covered stents have been considered as a primary measure to prevent further serious arterial events. A fabric-based covered graft stents yield poor clinical outcomes. To overcome these challenges, the balloon-expandable stent with biodegradable film-type graft for treating arterial dissection was invented. Research Questions and Objectives: A novel balloon-expandable stent with biodegradable film graft for overcoming these issues would be valid for efficacy and safety in a rabbit iliac artery dissection model. Method and Approach: Eighteen iliac artery dissections were induced by balloon over-inflation on angiography (Ellis type 2 or 3) and treated using the test device (3.0 x 24 mm). Subsequently, twelve animals underwent histologic examinations and micro-computed tomography (CT) at 0, 2, 4, and 8 weeks and 3, 6, 9, and 12 months and angiography at one-year. Results and Data: There were no adverse cardiovascular events during the one-year. Early-stage histologic examination revealed complete sealing of disrupted vessels by the device, exhibiting mural hematoma, peri-stent red thrombi, and dense infiltration of inflammatory cells. Mid- and long-term histologic examination showed patent stents with neointimal hyperplasia over the stents (% area stenosis: 11.8 at 2weeks, 26.1 at 1month, 29.7 at 3months, 49.2 at 9months, and 51.0 at 1year), along with mild peri-strut inflammatory response (Grade: 1-2 at mid-term and 0-1 at long-term). The graft film became scarcely visible after six months. Both CT and angiography revealed no instances of thrombotic occlusion or in-stent restenosis (% diameter stenosis: 5.7 at 2weeks, 12.3 at 1month, 14.2 at 3months, 25.1 at 9months, and 26.6 at 1 year). Conclusion: The novel balloon-expandable stent with a biodegradable film graft demonstrates feasibility in managing severe artery dissection and preventing lethal vascular events in animal model. Future human studies are warranted to validate these findings and elucidate the clinical outcomes of the study.

Evaluation of tolvaptan-associated hepatic disorder using different national pharmacovigilance databases

Tolvaptan-associated hepatic disorder is a rare, but lethal adverse event; however, the precise risk and time of onset remain unclear. This study aimed to characterize the severity, time‑to‑onset, and outcomes of hepatic disorder based on patient age and sex. Patient data were acquired from the Japanese Adverse Drug Event Report database (JADER) and the JAPIC AERS database, which consists of the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) processed by the Japan Pharmaceutical Information Center. Hepatic disorder was classified as severe or nonsevere. Tolvaptan use was associated with hepatic disorder in analyses using the FAERS [Severe hepatic disorder: reporting odds ratio (ROR) 4.93, 95% confidence interval (CI) 4.33‒5.61; information component (IC) 2.11, 95% CI 1.92‒2.29; nonsevere hepatic disorder: ROR 6.78, 95% CI 6.01‒7.65; IC 2.51, 95% CI 2.33‒2.68] and the JADER (severe hepatic disorder: ROR 4.21, 95% CI 3.57‒4.97; IC 1.86, 95% CI 1.63‒2.10; nonsevere hepatic disorder: ROR 4.27, 95% CI 3.68‒4.95; IC 1.83, 95% CI 1.62‒2.04). A time‑to‑onset analysis revealed that the median onset time was significantly longer in patients aged < 60 years compared with patients aged ≥ 60, regardless of the severity (FAERS: severe hepatic disorder 7 vs. 58 days, p < 0.0001; nonsevere hepatic disorder 8 vs. 52.5 days, p < 0.0001; JADER: severe hepatic disorder 9.5 vs. 32 days, p = 0.0017; nonsevere hepatic disorder 9 vs. 89 days, p < 0.0001). Severe outcomes were observed, regardless of the severity of hepatic disorder. Patients should be monitored for liver function based on age to prevent fatal outcomes.

Novel electric predictors of lethal arrhythmic event in patients with hypertrophic cardiomyopathy

Abstract Background Little is known regarding the association between electrical markers and lethal arrhythmic events (LAE) in patients with hypertrophic cardiomyopathy (HCM). This study aimed to identify the electrical predictors of LAE in adult patients with HCM. Methods This study was a retrospective analysis of patients with HCM at a single center from 1998 to 2021. LAE was defined as a composite outcome of (1) sustained ventricular arrhythmia, (2) aborted sudden cardiac death (SCD), (3) implantable cardioverter defibrillator (ICD) implantation, and (4) appropriate ICD shock. A 12-lead electrocardiography was performed at the time of diagnosis. Results A total of 611 patients with HCM were analyzed, and 48 (7.8%) experienced LAE. Patients who experienced LAE were diagnosed at a younger age and more frequently had history of ventricular arrhythmia, new-onset atrial fibrillation (AF) or non-sustained ventricular tachycardia. New-onset AF, an increase in the QTc interval, and the absence of massive LVH were associated with LAE risk. In addition to conventional markers of HCM Risk-SCD, consideration of the QTc interval and massive LVH on electrocardiography improved the prediction of LAE (area under curve 0.682 to 0.740). Further inclusion of new-onset AF, history of ventricular arrhythmia, HCM type, and left ventricular mass index improved the predictability to 0.867. Conclusion An increase in the QTc interval, the absence of a massive LVH pattern on electrocardiography (ECG), and new-onset AF were independently associated with an increased risk of LAE. Comprehensive stratification using electrical markers improves the prediction of LAE when combined with conventional markers.

Evaluating corticosteroid treatment strategies for cardiac sarcoidosis: analysis of the nationwide claims-based JROAD-DPC dataset

Abstract Background Corticosteroid-based immunosuppressive therapy is the cornerstone of treatment for cardiac sarcoidosis (CS), aimed at preventing severe adverse events including death, heart failure and lethal arrhythmic events. Nevertheless, data on the optimal initial dosing, appropriate tapering schedules, suitable maintenance dosages, and the recurrence rates among patients are insufficient. Purpose This study sought to scrutinize real-world data on corticosteroid therapy regimen for CS and to reassess optimal treatment protocols. Methods From the Japanese Diagnosis Procedure Combination database, 6,282 patients with hospitalized CS were identified between 2012 and 2022. Among them, 3,067 CS patients who were initiated on corticosteroid therapy during hospitalization were analyzed. We examined the baseline patient characteristics and treatment strategies for corticosteroid therapy, including starting dose, tapering period, maintenance dose, and their correlation with the onset of adverse events. Results The cohort had a mean age was 63±11 years, and 1,256 patients (41.0 %) were female. The starting dose of corticosteroids was 30.3±6.9 mg, with 88.6% of patients receiving a dose of ≧30 mg/day. The doses of corticosteroids at 30, 60, 90, 120, 150 and 180 days post-discharge were 21.4±9.8, 15.7±6.9, 12.2±5.7, 10.4±5.0, 9.3±4.5 and 9.0±4.6 mg, respectively. By day 180, 83.7% of the patients were maintained on ≦10 mg/day. However, 17.1 % of patients required an increase in corticosteroid dosage during the tapering course, primarily due to exacerbation of sarcoidosis. When analyzing only the group without corticosteroid escalation up to 180 days post-discharge, the average corticosteroid dose was 8.7±3.8 mg, with 95.3% of patients on ≦10 mg/day. We observed 965 re-hospitalization (31.5 %) during follow-up, with 58.8% of these patients having corticosteroid escalation to ≧30 mg, and 12.8% of patients received second-line immunosuppressive therapy, such as methotrexate. Conclusion The majority of CS patients were initiated on a corticosteroid regimen of 30 mg/day, which was subsequently tapered to below 10 mg/day by day 180. However, non-negligible number of patients experienced clinical events or relapse, underscoring the necessity for vigilant follow-up during corticosteroid therapy.Figure

Risk factors for fatal ventricular arrhythmias in heart failure with preserved ejection fraction: a report from the CHART-2 Study

Abstract Background Fatal ventricular arrhythmia events (FAE), such as sustained ventricular tachycardia (VT) and ventricular fibrillation (VF), along with sudden cardiac death (SCD), represent serious complications in patients with heart failure (HF). While individuals with severely reduced left ventricular ejection fraction (LVEF), particularly below 35%, are deemed at high risk for lethal arrhythmic events and are considered for implantable cardioverter-defibrillator (ICD) therapy, recent studies have highlighted the occurrence of FAE or SCD in heart failure with preserved ejection fraction (HFpEF) as well. However, the specific risk factors for FAE or SCD in patients with HFpEF remain inadequately elucidated. Purpose This study aimed to investigate the incidence of FAE or SCD and identify their associated risk factors in patients with HFpEF. Methods We retrospectively analyzed the data from our multicenter observational study, the CHART-2 Study, where a total of 10,219 patients were enrolled between 2006 and 2010. Among them, we included patients with HF and LVEF≥50% (n=2,423) with available LVEF data at one year (Figure 1A). They were categorized into two groups based on LVEF status; 198 with decreased LVEF (35-50%; D-group) and 2,225 with preserved LVEF (≥50%; P-group). The primary endpoint was the composite event of FAE or SCD, and all statistical analyses were adjusted for competing risks due to all-cause mortality. Results Among the 2,423 patients with HFpEF (mean age: 69±12 years, 35% female), 120 patients (5.0%) experienced the composite event of FAE or SCD during a median follow-up of 9.1 years (interquartile range: 4.5-11.2 years), with a cumulative incidence of 5.1% at 10 years. Gray’s test revealed a significantly higher incidence of the primary endpoint in the D-group compared with the P-group (10.6% vs. 4.5% at 10 years, p&amp;lt;0.001, Figure 2A). Multivariable analysis identified mild decline of LVEF (Hazard Ratio [HR] 2.20, 95% confidence interval [CI] 1.34-1.60; p=0.002) and non-sustained VT (HR 2.33, 95% CI 1.37-3.97; p=0.002) as independent risk factors for composite event. Landmark analysis demonstrated a consistent trend in the composite event of FAE or SCD in both groups (Figure 2B). Conclusion In patients with HFpEF, even a mild decline in LVEF, which typically does not prompt ICD consideration, was significantly associated with a heightened risk of FAE or SCD. Therefore, a chronological clinical assessment, encompassing changes in LVEF, is essential for patients with HFpEF.

Endothelium-targeted NF-κB siRNA nanogel for magnetic resonance imaging and visualized-anti-inflammation treatment of atherosclerosis

Atherosclerosis-induced lethal cardiovascular disease remains a severe healthcare threat due to the limited drug efficiency and untimely prediction of high-risk events caused by inadequate target specificity of medications, incapable recognition of insensitive patients, and variable morphology of vulnerable plaques. Therefore, it is necessary to develop efficient strategies to improve the diagnosis accuracy and achieve visualized treatment of atherosclerosis. Herein, we establish an inflamed endothelium-targeted three-in-one nucleic acid nanogel system that can reverse the inflammatory state of endothelial cells (ECs) in plaques and simultaneously achieve real-time monitoring of the therapy process for efficient atherosclerosis diagnosis and treatment. For this purpose, contrast agent (Gd-DOTA) and VCAM-1-targeted peptide (VP) are first covalently conjugated onto DNA strands by click reaction respectively, which could self-assemble into Y-shaped structures (Gd-Y1 and VP-Y2 motifs) with magnetic resonance (MR) imaging and endothelium targeting capacities. Thereafter, NF-κB subunit p65-targeting siRNA (siNF-κB) is crosslinked with Gd-Y1 and VP-Y2 motifs to construct the endothelium-targeting nanogel platform. With contrast agents inside, the nanogel enables MR-based diagnosis and visualized therapy of atherosclerosis, providing accurate prognostic analysis and indications for treatment results, which ensures timely disclosure of insensitive individuals and avoids acute lethal events. By delivering siNF-κB to inflammatory endothelium, the nanogel significantly regresses plaques in both the aorta and carotid artery with reduced inflammation cytokines, collagens, macrophages, and apoptotic cells, providing a potential anti-inflammation strategy to treat atherosclerosis and avoid acute cardiovascular disease.

Safety and efficacy of oxycodone for refractory dyspnea in end-stage heart failure patients with chronic kidney disease: a case series of eight patients

BackgroundMorphine is effective in palliative care for patients with end-stage heart failure; however, its use is avoided in patients with impaired renal function because it tends to induce adverse effects. Although oxycodone has been reported to be a useful alternative, the evidence is insufficient. Therefore, we investigated the safety and efficacy of oxycodone in eight patients with end-stage heart failure complicated by chronic kidney disease. MethodsThis single-center retrospective study reviewed patients with end-stage heart failure who were referred to the heart failure multidisciplinary team at our institution and administered oxycodone for refractory dyspnea during hospitalization between January 2011 and December 2018. We examined the details of oxycodone usage, vital signs, and the Modified Borg Scale (MBS), which quantifies the symptoms of dyspnea and adverse events.ResultsOxycodone was administered for refractory dyspnea in eight patients with end-stage heart failure [mean age: 81 years, men: 4, New York Heart Association functional class IV: 8, median left ventricular ejection fraction: < 40% (n = 6) and ≥ 50% (n = 2)]. Renal function was reduced in all patients; the estimated glomerular filtration rate (eGFR) in seven patients was < 30 mL/min/1.73 m2. The median initial intravenous dose of oxycodone was 7.05 mg/day (range: 5–10 mg/day), and the average duration of administration was 15.8 days. Significant decreases in MBS (before: median 9, range 7–10 vs. after: median 2.5, range 1–8; p < 0.01) were observed at a median of 2.0 days (range: 2 h to 7 days) after beginning oxycodone administration. Systolic blood pressure, heart rate, and respiratory rate were not significantly altered after treatment. Adverse events, including constipation, nausea, and tremors, were observed in three patients. However, no lethal adverse events related to oxycodone treatment occurred during treatment.ConclusionsThis study revealed the clinical practice of oxycodone treatment and suggested that it is an alternative therapy as a viable palliative for refractory dyspnea in patients with end-stage heart failure who should avoid the use of morphine.

Survival of a young male patient with catastrophic acute left main coronary artery occlusion and cardiogenic shock

ABSTRACT Total occlusion of the left main coronary artery (LMCA) is a rare but highly lethal event in acute coronary syndrome. It can lead to extensive myocardial infarction and hemodynamic instability. Despite advancements in percutaneous coronary intervention (PCI), mortality remains high. A 35-year-old male presented with chest pain, dyspnea, and hemodynamic instability. Diagnostic workup revealed LMCA thrombotic occlusion with extensive myocardial involvement and cardiogenic shock (CS). Prompt intervention, including thrombus aspiration, angioplasty, and hemodynamic support with intra-aortic balloon pump and venoarterial extracorporeal membrane oxygenation, was initiated. The patient’s condition gradually improved with comprehensive management, including pharmacotherapy and intensive care support. LMCA occlusion presents challenges due to its extensive myocardial distribution and high mortality rates, particularly when complicated by CS. PCI combined with circulatory support is crucial for restoring perfusion and improving outcomes. Achieving optimal flow and providing postprocedural care significantly impact patient prognosis. Rapid diagnosis and intervention are critical in LMCA occlusion with CS. A multidisciplinary approach incorporating advanced circulatory support and timely revascularization are the keys in improving patient outcomes. Comprehensive postprocedural care is essential for ensuring successful recovery and survival.

Impairment of Cognitive Function Increases Mortality Risk in Relation to Cardiac Sympathetic Denervation and Renal Dysfunction in Patients With Systolic Heart Failure.

In contrast to the well-known prognostic values of the cardiorenal linkage, it remains unclear whether impaired cognitive function affects cardiac prognosis in relation to cardiac sympathetic innervation and renal function in patients with heart failure (HF). A total of 433 consecutive HF patients with left ventricular ejection fraction (LVEF) <50% underwent the Mini-Mental State Examination (MMSE) and a neuropsychological test for screening of cognition impairment or subclinical dementia. Following metaiodobenzylguanidine (MIBG) scintigraphy, patient outcomes with a primary endpoint of lethal cardiac events (CEs) were evaluated for a mean period of 14.8 months. CEs were documented in 84 HF patients during follow-up. MMSE score, estimated glomerular filtration rate (eGFR) and standardized heart-to-mediastinum ratio of MIBG activity (sHMR) were significantly reduced in patients with CEs compared with patients without CEs. Furthermore, overall multivariate analysis revealed that these parameters were significant independent determinants of CEs. The cutoff values of MMSE score (<26), sHMR (<1.80) and eGFR (<47.0 mL/min/1.73 m2) determined by receiver operating characteristic (ROC) analysis successfully differentiated HF patients at more increased risk for CEs from other HF patients. Impairment of cognitive function is not only independently related to but also synergistically increases cardiac mortality risk in association with cardiac sympathetic function and renal function in patients with HF.

Single Construct Suppression and Replacement Gene Therapy for the Treatment of All CALM1-, CALM2-, and CALM3-Mediated Arrhythmia Disorders.

CaM (calmodulin)-mediated long-QT syndrome is a genetic arrhythmia disorder (calmodulinopathies) characterized by a high prevalence of life-threatening ventricular arrhythmias occurring early in life. Three distinct genes (CALM1, CALM2, and CALM3) encode for the identical CaM protein. Conventional pharmacotherapies fail to adequately protect against potentially lethal cardiac events in patients with calmodulinopathy. Five custom-designed CALM1-, CALM2-, and CALM3-targeting short hairpin RNAs (shRNAs) were tested for knockdown (KD) efficiency using TSA201 cells and reverse transcription-quantitative polymerase chain reaction. A dual-component suppression and replacement (SupRep) CALM gene therapy (CALM-SupRep) was created by cloning into a single construct CALM1-, CALM2-, and CALM3-specific shRNAs that produce KD (suppression) of each respective gene and a shRNA-immune CALM1 cDNA (replacement). CALM1-F142L, CALM2-D130G, and CALM3-D130G induced pluripotent stem cell-derived CMs were generated from patients with CaM-mediated long-QT syndrome. A voltage-sensing dye was used to measure action potential duration at 90% repolarization (APD90). Following shRNA KD efficiency testing, a candidate shRNA was identified for CALM1 (86% KD), CALM2 (71% KD), and CALM3 (94% KD). The APD90 was significantly prolonged in CALM2-D130G (647±9 ms) compared with CALM2-WT (359±12 ms; P<0.0001). Transfection with CALM-SupRep shortened the average APD90 of CALM2-D130G to 457±19 ms (66% attenuation; P<0.0001). Additionally, transfection with CALM-SupRep shortened the APD90 of CALM1-F142L (665±9 to 410±15 ms; P<0.0001) and CALM3-D130G (978±81 to 446±6 ms; P<0.001). We provide the first proof-of-principle suppression-replacement gene therapy for CaM-mediated long-QT syndrome. The CALM-SupRep gene therapy shortened the pathologically prolonged APD90 in CALM1-, CALM2-, and CALM3-variant CaM-mediated long-QT syndrome induced pluripotent stem cell-derived CM lines. The single CALM-SupRep construct may be able to treat all calmodulinopathies, regardless of which of the 3 CaM-encoding genes are affected.

Cardiac sympathetic activity and lethal arrhythmic events: insight into bell-shaped relationship between 123I-meta-iodobenzylguanidine activity and event rates

Background123I-meta-iodobenzylguanidine (mIBG) has been applied to patients with chronic heart failure (CHF). However, the relationship between 123I-mIBG activity and lethal arrhythmic events (ArE) is not well defined. This study aimed to determine this relationship in Japanese and European cohorts.ResultsWe calculated heart-to-mediastinum (H/M) count ratios and washout rates (WRs) of 827 patients using planar 123I-mIBG imaging. We defined ArEs as sudden cardiac death, arrhythmic death, and potentially lethal events such as sustained ventricular tachycardia, cardiac arrest with resuscitation, and appropriate implantable cardioverter defibrillator (ICD) discharge, either from a single ICD or as part of a cardiac resynchronization therapy device (CRTD). We analyzed the incidence of ArE with respect to H/M ratios, WRs and New York Heart Association (NYHA) functional classes among Japanese (J; n = 581) and European (E; n = 246) cohorts. We also simulated ArE rates versus H/M ratios under specific conditions using a machine-learning model incorporating 13 clinical variables. Consecutive patients with CHF were selected in group J, whereas group E comprised candidates for cardiac electronic devices. Groups J and E mostly comprised patients with NYHA functional classes I/II (95%) and II/III (91%), respectively, and 21% and 72% were respectively implanted with ICD/CRTD devices. The ArE rate increased with lower H/M ratios in group J, but the relationship was bell-shaped, with a high ArE rate within the intermediate H/M range, in group E. This bell-shaped curve was also evident in patients with NYHA classes II/III in the combined J and E groups, particularly in those with a high (> 15%) mIBG WR and with ischemic, but not in those with non-ischemic etiologies. Machine learning-based prediction of ArE risk aligned with these findings, indicating a bell-shaped curve in NYHA class II/III but not in class I.ConclusionsThe relationship between cardiac 123I-mIBG activity and lethal arrhythmic events is influenced by the background of patients. The bell-shaped relationship in NYHA classes II/III, high WR, and ischemic etiology likely aids in identifying patients at high risk for ArEs.

Heat stress in plants: sensing, signalling and ferroptosis.

In the current context of global warming, high temperature events are becoming more frequent and intense in many places around the world. In this context, understanding how plants sense and respond to heat is essential to develop new tools to prevent plant damage and address global food security, as high temperature events are threatening agricultural sustainability. This review summarizes and integrates our current understanding underlying the cellular, physiological, biochemical and molecular regulatory pathways triggered in plants under moderately high and extremely high temperature conditions. Given that extremely high temperatures can also trigger ferroptosis, the study of this cell death mechanism constitutes a strategic approach to understand how plants might overcome otherwise lethal temperature events.

An optimal promoter regulating cytokine transgene expression is crucial for safe and effective oncolytic virus immunotherapy

In general, ensuring safety is the top priority of a new modality. Although oncolytic virus armed with an immune stimulatory transgene (OVI) showed some promise, the strategic concept of simultaneously achieving maximum effectiveness and minimizing side effects has not been fully explored. We generated a variety of survivin-responsive “conditionally replicating adenoviruses that can target and treat cancer cells with multiple factors (m-CRAs)” (Surv.m-CRAs) armed with the granulocyte-macrophage colony-stimulating factor (GM-CSF) transgene downstream of various promoters using our m-CRA platform technology. We carefully analyzed both therapeutic and adverse effects of them in the in vivo syngeneic Syrian hamster cancer models. Surprisingly, an intratumor injection of a conventional OVI, which expresses the GM-CSF gene under the constitutively and strongly active “cytomegalovirus enhancer and β-actin promoter”, provoked systemic and lethal GM-CSF circulation and shortened overall survival (OS). In contrast, a new conceptual type of OVI, which expressed GM-CSF under the cancer-predominant and mildly active E2F promoter or the moderately active “Rous sarcoma virus long terminal repeat”, not only abolished lethal adverse events but also prolonged OS and systemic anti-cancer immunity. Our study revealed a novel concept that optimal expression levels of an immune stimulatory transgene regulated by a suitable upstream promoter is crucial for achieving high safety and maximal therapeutic effects simultaneously in OVI therapy. These results pave the way for successful development of the next-generation OVI and alert researchers about possible problems with ongoing clinical trials.

Prospective cardiovascular events in patients with advanced thoracic cancer treated with immune checkpoint inhibitor

IntroductionMyocarditis is the most lethal cardiovascular immune related adverse events with a low incidence, depending on the studies. We prospectively studied the potential interest of a systematic screening to early detect immune related myocarditis and confirm the incidence of immune-induced myocarditis in advanced lung cancer and the impact of troponin systematic screening in early detection of other major cardiovascular events (MACE). Material and methodsThis prospective bicentric study includes adults who received at least one dose of immune checkpoint inhibitor (ICI) for advanced lung cancer. Cardiac biomarkers dosage, ECG and transthoracic echography (TTE) were done at baseline. Diagnosis of myocarditis was based on European Society of Cardiology recommendations. MACEs were reported during the observation period. ResultsAmong 298 patients, 5 (1.68 %) immune-induced myocarditis occurred, all being asymptomatic with at first troponin elevation, treated by corticosteroids and ICI’s discontinuation. No attributable death occurred, and no specific clinical characteristics were identified with myocarditis onset. Three patients were rechallenged with ICI after troponin normalization in the absence of other therapeutic options. Recurrence occurred in 2 patients, with a re-increase of troponin and a de novo modification of the ECG. Systematic cardiovascular screening also led to 14 cardiovascular diseases detection and 11 MACEs during ICI. ConclusionSystematic cardiovascular screening has uncovered slightly more immuno-induced myocarditis cases than reported previously, but without altering treatment strategies due to their subclinical nature. Additionally, it helps detecting other cardiovascular diseases in this comorbid population.

Computed tomography-based prediction of pancreatitis following biliary metal stent placement with the convolutional neural network.

Background and study aims Pancreatitis is a potentially lethal adverse event of endoscopic transpapillary placement of a self-expandable metal stent (SEMS) for malignant biliary obstruction (MBO). Deep learning-based image recognition has not been investigated in predicting pancreatitis in this setting. Patients and methods We included 70 patients who underwent endoscopic placement of a SEMS for nonresectable distal MBO. We constructed a convolutional neural network (CNN) model for pancreatitis prediction using a series of pre-procedure computed tomography images covering the whole pancreas (≥ 120,960 augmented images in total). We examined the additional effects of the CNN-based probabilities on the following machine learning models based on clinical parameters: logistic regression, support vector machine with a linear or RBF kernel, random forest classifier, and gradient boosting classifier. Model performance was assessed based on the area under the curve (AUC) in the receiver operating characteristic analysis, positive predictive value (PPV), accuracy, and specificity. Results The CNN model was associated with moderate levels of performance metrics: AUC, 0.67; PPV, 0.45; accuracy, 0.66; and specificity, 0.63. When added to the machine learning models, the CNN-based probabilities increased the performance metrics. The logistic regression model with the CNN-based probabilities had an AUC of 0.74, PPV of 0.85, accuracy of 0.83, and specificity of 0.96, compared with 0.72, 0.78, 0.77, and 0.96, respectively, without the probabilities. Conclusions The CNN-based model may increase predictability for pancreatitis following endoscopic placement of a biliary SEMS. Our findings support the potential of deep learning technology to improve prognostic models in pancreatobiliary therapeutic endoscopy.