The Administration of Lemborexant at Admission is Not Associated with Inpatient Falls: A Multicenter Retrospective Observational Study.

Purpose: There has been no large-scale investigation into the association between the use of lemborexant, suvorexant, and ramelteon and falls in a large population. This study, serving as a pilot investigation, was aimed at examining the relationship between inpatient falls and various prescribed hypnotic medications at admission. Patients and Methods: This study was a sub-analysis of a multicenter retrospective observational study conducted over a period of 3 years. The target population comprised patients aged 20 years or above admitted to eight hospitals, including chronic care, acute care, and tertiary hospitals. We extracted data on the types of hypnotic medications prescribed at admission, including lemborexant, suvorexant, ramelteon, benzodiazepines, Z-drugs, and other hypnotics; the occurrence of inpatient falls during the hospital stay; and patients' background information. To determine the outcome of inpatient falls, items with low collinearity were selected and included as covariates in a forced-entry binary logistic regression analysis. Results: Overall, 150,278 patients were included in the analysis, among whom 3,458 experienced falls. The median age of the entire cohort was 70 years, with men constituting 53.1%. Binary logistic regression analysis revealed that the prescription of lemborexant, suvorexant, and ramelteon at admission was not significantly associated with inpatient falls. Conclusion: The administration of lemborexant, suvorexant, and ramelteon at admission may not be associated with inpatient falls.

Validation and Improvement of the Saga Fall Risk Model: A Multicenter Retrospective Observational Study.

Purpose: We conducted a pilot study in an acute care hospital and developed the Saga Fall Risk Model 2 (SFRM2), a fall prediction model comprising eight items: Bedriddenness rank, age, sex, emergency admission, admission to the neurosurgery department, history of falls, independence of eating, and use of hypnotics. The external validation results from the two hospitals showed that the area under the curve (AUC) of SFRM2 may be lower in other facilities. This study aimed to validate the accuracy of SFRM2 using data from eight hospitals, including chronic care hospitals, and adjust the coefficients to improve the accuracy of SFRM2 and validate it. Patients and Methods: This study included all patients aged ≥20 years admitted to eight hospitals, including chronic care, acute care, and tertiary hospitals, from April 1, 2018, to March 31, 2021. In-hospital falls were used as the outcome, and the AUC and shrinkage coefficient of SFRM2 were calculated. Additionally, SFRM2.1, which was modified from the coefficients of SFRM2 using logistic regression with the eight items comprising SFRM2, was developed using two-thirds of the data randomly selected from the entire population, and its accuracy was validated using the remaining one-third portion of the data. Results: Of the 124,521 inpatients analyzed, 2,986 (2.4%) experienced falls during hospitalization. The median age of all inpatients was 71 years, and 53.2% were men. The AUC of SFRM2 was 0.687 (95% confidence interval [CI]:0.678-0.697), and the shrinkage coefficient was 0.996. SFRM2.1 was created using 81,790 patients, and its accuracy was validated using the remaining 42,731 patients. The AUC of SFRM2.1 was 0.745 (95% CI: 0.731-0.758). Conclusion: SFRM2 showed good accuracy in predicting falls even on validating in diverse populations with significantly different backgrounds. Furthermore, the accuracy can be improved by adjusting the coefficients while keeping the model's parameters fixed.

Increased Left Ventricular End-Diastolic Volume Index Is Associated With Increased Adverse Events After MitraClip Implantation.

This study investigated the association between the left ventricular end-diastolic volume index (LVEDVI) and the incidence of adverse clinical events in patients after MitraClip implantation. In this retrospective, observational study, 123 patients who underwent the MitraClip procedure were enrolled. Participants were divided into 2 groups according to the LVEDVI cut-off level, calculated using receiver operating characteristic curve analysis, to predict the primary end point and the occurrence of cardiovascular events was compared between the groups. The primary end point was all-cause mortality and hospitalization because of heart failure. The receiver operating characteristic curve analysis for the composite primary end point revealed an LVEDVI cut-off point of 118 ml/m2. Based on this threshold, 61 patients (49.6%) were categorized into the LVEDVI <118 ml/m2 group, whereas 62 (50.4%) fell into the LVEDVI ≥118 ml/m2 group. Over a median follow-up period of 336 days (interquartile range 80 to 667), the primary end points occurred in 15 and 26 patients in the LVEDVI <118 and LVEDVI ≥118 ml/m2 groups, corresponding to incidence rates of 24.6% and 41.9%, respectively. Patients in the LVEDVI ≥118 ml/m2 group demonstrated a significantly higher risk of adverse clinical events than those in the LVEDVI <118 ml/m2 group (hazard ratio 2.24, 95% confidence interval 1.17 to 4.28, p = 0.01). This trend persisted even after adjusting for several confounders (p = 0.02). In conclusion, increased LVEDVI values were associated with increased adverse clinical events after MitraClip implantation in patients with severe mitral valve regurgitation.

Liposome Deformation Induced by Membrane-Binding Peptides.

This paper presents an investigation of liposome deformation and shape distortion using four membrane-binding peptides: TAT and C105Y as cell-penetrating peptides (CPPs), and melittin and ovispirin as antimicrobial peptides (AMPs). Liposome deformation was monitored utilizing fluorescent microscopy, while the binding of peptides to the DOPC membrane was estimated through capacitance measurements. The degree of liposome deformation and shape distortion was found to be higher for the CPPs compared to the AMPs. Additionally, it was observed that C105Y did not induce liposome rupture, unlike the other three peptides. We propose that these variations in liposome distortion may be attributed to differences in secondary structure, specifically the presence of an α-helix or random coil. Our studies offer insight into the use of peptides to elicit control of liposome architecture and may offer a promising approach for regulating the bodies of liposomal molecular robots.

Minimum-incision trans-subclavian transcatheter aortic valve replacement with regional anesthesia.

BACKGROUND: Minimum-incision trans-subclavian transcatheter aortic valve replacement (MITS-TAVR) is usually performed in patients who are contraindicated for transfemoral TAVR, under regional anesthesia (RA). This study aimed to evaluate the safety and efficacy of MITS-TAVR under RA compared to MITS-TAVR under general anesthesia (GA). METHODS: This single-center observational study included 44 consecutive patients who underwent MITS-TAVR under RA (RA group, n = 19) and GA (GA group, n = 25). RA was achieved using an ultrasound-guided nerve block. RESULTS: The rates of respiratory disease (RA vs. GA, 36.8 % vs. 4.0 %; p < 0.01) and dialysis (79.0 % vs. 0 %; p < 0.01) were significantly higher in the RA group. STS score was significantly higher in the RA group (RA vs. GA, 10.8 ±â€¯1.06 % vs. 7.87 ±â€¯0.93 %; p < 0.01). Both groups had a 100 % procedural success rate. The two groups showed comparable operation room stay times (RA vs. GA, 160 ±â€¯6.96 min vs. 148 ±â€¯5.90 min; p = 0.058). The mean rate of change in blood pressure, used as an index of hemodynamic stability, was significantly lower in the RA group (RA vs. GA, 19.0 ±â€¯3.4 % vs. 35.5 ±â€¯3.0 %; p < 0.01). No in-hospital deaths occurred in either group. One case of minor dissection occurred in the GA group (RA vs.GA, 0 % vs. 4.0 %, p = 0.378). The intensive care unit stay (RA vs. GA, 0.21 ±â€¯0.11 days vs. 1.24 ±â€¯0.10 days; p < 0.01) and hospital stay (RA vs. GA, 7.00 ±â€¯1.73 days vs. 12.2 ±â€¯1.44 days; p < 0.01) were significantly shorter in the RA group. CONCLUSIONS: MITS-TAVR under RA is safe and effective and might be a promising alternative approach. It could ensure intraoperative hemodynamic stability and shorten intensive care unit and hospital stays.

Effect of hydrophobic moment on membrane interaction and cell penetration of apolipoprotein E-derived arginine-rich amphipathic α-helical peptides.

We previously developed an amphipathic arginine-rich peptide, A2-17, which has high ability to directly penetrate across cell membranes. To understand the mechanism of the efficient cell-penetrating ability of the A2-17 peptide, we designed three structural isomers of A2-17 having different values of the hydrophobic moment and compared their membrane interaction and direct cell penetration. Confocal fluorescence microscopy revealed that cell penetration efficiency of peptides tends to increase with their hydrophobic moment, in which A2-17 L14R/R15L, an A2-17 isomer with the highest hydrophobic moment, predominantly remains on plasma cell membranes. Consistently, Trp fluorescence analysis indicated the deepest insertion of A2-17 L14R/R15L into lipid membranes among all A2-17 isomers. Electrophysiological analysis showed that the duration and charge flux of peptide-induced pores in lipid membranes were prominent for A2-17 L14R/R15L, indicating the formation of stable membrane pores. Indeed, the A2-17 L14R/R15L peptide exhibited the strongest membrane damage to CHO-K1 cells. Atomic force microscopy quantitatively defined the peptide-induced membrane perturbation as the decrease in the stiffness of lipid vesicles, which was correlated with the hydrophobic moment of all A2-17 isomers. These results indicate that optimal membrane perturbation by amphipathic A2-17 peptide is critical for its efficient penetration into cells without inducing stabilized membrane pores.

Utility of dobutamine stress echocardiography in aortic valve regurgitation and reduced left ventricular function.

OBJECTIVE: Predictors for post-operative reverse remodeling in patients with severe aortic regurgitation (AR) and reduced left ventricular ejection fraction (LVEF) are unknown. We performed low-dose dobutamine stress echocardiography (DSE) in patients with severe AR and reduced LVEF to evaluate the relationship between contractile reserve (CR) and reverse remodeling after surgery. METHODS: In 31 patients with chronic severe AR and reduced LVEF (LVEF < 50%), we performed pre-operative DSE, assessed CR, and examined whether changes in preoperative DSE were associated with improvement of post-operative LVEF after aortic valve surgery. RESULTS: The pre-operative echocardiographic findings were as follows: left ventricular (LV) end-diastolic dimension: 67 ± 10 mm, LV end-systolic dimension: 52 ± 13 mm, and LVEF: 42 ± 8%. All patients underwent aortic valve surgery. Patients with pre-operative LVEF of ≥45% exhibited a significant increase in LVEF; however, patients with pre-operative LVEF of <45% showed no significant change. When we examined the results of DSE performed in patients with pre-operative LVEF of <45%, ΔLVEF of ≥6% (with CR) during DSE was related to an improvement in post-operative LVEF; ΔLVEF of ≥6% during DSE predicted an improvement in post-operative LVEF, with sensitivity 100%; specificity 78%; and area under curve (AUC) .92. CONCLUSIONS: DSE might be a helpful tool for predicting post-operative reverse remodeling in patients with severe AR and moderately reduced LVEF.

Left ventricular systolic function affects right atrial pressure as prognosticator in patients with heart failure.

The effect of the left ventricular ejection fraction (LVEF) on the prognostic impact of the right atrial pressure (RAP) in patients with heart failure (HF) requires clarification. We aimed to investigate whether LVEF affects the prognostic impact of RAP estimated from inferior vena cava (IVC) measurements in patients hospitalized with HF. Initially, this observational study included 1349 consecutive patients urgently hospitalized with HF. After patient exclusions, 506 and 484 patients with reduced (< 40%) and with non-reduced (≥ 40%) LVEF, respectively, were assigned according to maximum IVC diameter and its collapsibility, to the Normal-RAP (diameter ≤ 2.1 cm; collapsibility ≥ 50%), High-RAP (diameter > 2.1 cm; collapsibility < 50%), and Intermediate-RAP (others) groups. The endpoint comprised cardiovascular death after discharge and hospitalization for HF recurrence. During the observation period, 247 (49%) patients with LVEF < 40% and 178 (37%) patients with LVEF ≥ 40% experienced the endpoint. The patient subgroups with LVEF < 40% had comparable event rates (ptrend = 0.10). The High-RAP subgroup with LVEF ≥40% had a higher event rate than the other subgroups (p < 0.001). The RAP independently predicted the endpoint in patients with LVEF ≥ 40% (hazard ratio: 1.26; 95% confidence interval: 1.01-1.59). The interaction between the RAP groups and LVEF regarding the primary endpoint was significant (pinteraction = 0.007). Stratifying patients with HF according to IVC measurements may predict the post-discharge cardiovascular prognoses of patients with non-reduced LVEF, but not that of patients with reduced LVEF.

Increased left atrial volume index is associated with more cardiovascular events in patients with acute coronary syndrome: HIJ-PROPER study findings.

AIM: To investigate the association between the left atrial volume index (LAVI) and the incidence of cardiovascular events in patients with acute coronary syndrome (ACS) who did not have atrial fibrillation (AF). METHODS: In this sub-analysis of the HIJ-PROPER study, 226 ACS patients who did not have a history of AF were enrolled. Participants were divided into two groups according to the LAVI cut-off level calculated by receiver operating characteristic (ROC) curve analysis to predict the primary endpoint, and cardiovascular events were compared between groups. The primary endpoint was the first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for heart failure. RESULTS: ROC curve analysis for the occurrence of composite of cardiovascular events indicated a LAVI cut-off point of 34 mL/m2 . Based on this, 131 patients (58.0%) were in the LAVI < 34 mL/m2 group and 95 (42.0%) were in the LAVI ≥ 34 mL/m2 group. Over a median follow-up period of 4.0 years [interquartile range: 3.2, 5.1], cardiovascular events were noted in 7 and 15 patients in the LAVI < 34 mL/m2 and LAVI ≥ 34 mL/m2 groups, corresponding to an incidence rate of 5.3% and 15.8%, respectively. Patients with a LAVI value ≥ 34 mL/m2 had a significantly higher risk of cardiovascular events than those with a LAVI value < 34 mL/m2 (hazard ratio: 2.93; 95% confidence interval: 1.19-7.22; P = .014). The tendency was similar after adjusting for several confounders (P = .025). CONCLUSION: In ACS patients without AF, elevated LAVI was associated with increased cardiovascular events. CLINICAL TRIAL REGISTRATION: International standard randomized controlled trial (URL: https://www.umin.ac.jp; UMIN000002742).

Prognostic Relevance of a Score for Identifying Diastolic Dysfunction according to the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging Recommendations in Patients with Hypertrophic Cardiomyopathy.

BACKGROUND: In hypertrophic cardiomyopathy (HCM), one of the main pathophysiological features is diastolic dysfunction. According to the 2016 American Society of Echocardiography (ASE)/European Association of Cardiovascular Imaging (EACVI) recommendations, diastolic function is assessed with echocardiographic variables. However, the association between the ASE/EACVI recommendations and the outcome in patients with HCM remains unclear. We evaluated the prognostic implications of the ASE/EACVI recommendations in patients with HCM. METHODS: This study included 290 patients with HCM. We evaluated four variables for identifying diastolic dysfunction using the following abnormal cutoff values: septal e' < 7 cm/sec, septal E/e' ratio > 15, left atrial volume index > 34 mL/m2, and peak tricuspid regurgitation velocity > 2.8 m/sec. A score was developed in which one point was designated for each abnormal echo parameter of diastolic function. We divided patients into two groups with an ASE/EACVI score of 3 as the cutoff value. The primary endpoint was the combination of HCM-related adverse outcomes (combination of sudden death or potentially lethal arrhythmic events, heart failure-related death, and heart failure hospitalization). RESULTS: The prevalence of an ASE/EACVI score ≥3 was 37.2%. Over a median follow-up of 9.7 (6.9-12.9) years, 26 (24.1%) patients with an ASE/EACVI score ≥3 and 25 (13.7%) patients with an ASE/EACVI score <3 experienced a combination of HCM-related adverse outcomes. Patients with an ASE/EACVI score ≥3 had a significantly higher incidence of the combined endpoint than those with an ASE/EACVI score <3 (log-rank, P = .010). An ASE/EACVI score ≥3 was an independent determinant of the combined endpoint in multivariate analysis (adjusted hazard ratio = 1.92; 95% CI, 1.05-3.49; P = .033). CONCLUSIONS: The score for identifying diastolic dysfunction by following ASE/EACVI recommendations may be associated with an adverse outcome in patients with HCM.

Prognostic impact of right ventricular function affected by pulmonary hypertension in hospitalized heart failure patients.

BACKGROUND: Pulmonary hypertension (PH) may affect right ventricular (RV) function; however, the prognostic implications of RV function in patients with heart failure and PH remain unclear. We aimed to investigate the impact of RV function on the prognosis of hospitalized heart failure patients with and without PH. METHODS: This observational study initially included 1,349 consecutive hospitalized heart failure patients. After excluding patients who died in hospital, whose left ventricular (LV) function was preserved, and whose echocardiography data were incomplete, 573 patients with heart failure and reduced LV ejection fractions (HFrEF) were analyzed. The patients were grouped according to RV dysfunction that was defined as an RV-tissue Doppler imaging systolic velocity (RV-TDI s') of ≤9.5 cm/s. The primary endpoint was a composite of cardiovascular death and rehospitalization as a consequence of heart failure. RESULTS: Overall, the patients with reduced RV function had significantly higher event rates than those with preserved RV function (log-rank test p = 0.01). This prognostic impact was observed in the patients with PH (p = 0.001) and was not evident among the patients without PH (p = 0.39). In the patients with PH, reduced RV function independently predicted the prognosis after adjusting for the covariates (adjusted hazard ratio: 3.12; 95% confidence interval: 1.44 to 6.73). CONCLUSION: RV dysfunction that was estimated during hospitalization using the RV-TDI s', which is a simply determined index, may predict clinical outcomes in hospitalized patients with HFrEF and PH after discharge, but not in those without PH.

Association between elevated left ventricular mass index and increased cardiovascular events in patients with acute coronary syndrome: A sub-analysis of the HIJ-PROPER study.

AIM: This study aimed to assess the association between left ventricular mass index (LVMI) and cardiovascular events in patients with acute coronary syndrome (ACS) under standard ACS management. METHODS AND RESULTS: This study is the sub-analysis of the HIJ-PROPER study. A total of 299 patients who had echocardiographic LVMI data were included in the current analysis. The participants were divided into four groups according to the LVMI quartile [quartile 1 (Q1), 77 (25.8%); quartile 2 (Q2), 73 (24.4%); quartile 3 (Q3), 74 (24.7%); and quartile 4 (Q4), 75 (25.1%)]. The incidence of cardiovascular events was compared among the four groups. The primary endpoint was defined as the composite endpoint of all-cause death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for heart failure. Mean LVMI in the four groups was 68.1±8.6, 86.2±3.8, 101.1±4.9, and 126.0±18.5 g/m2 , respectively. The primary endpoint was noted in 4, 4, 7, and 14 patients in Q1, Q2, Q3, and Q4, corresponding to an incidence of 5.2%, 5.5%, 9.5%, and 18.7%, respectively (p = 0.03 for difference among four groups). The cumulative incidence of the primary endpoint was significantly higher in patients in Q4 than in those in Q1 and Q2 [hazard ratio (HR) 3.75; 95% confidence interval (CI), 1.23-11.4; p = 0.02 for Q4 vs Q1; HR 3.43; 95% CI, 1.13-10.4; p = 0.03 for Q4 vs Q2]. This tendency was noted even after adjusting for patient characteristics and echocardiography parameters (p = 0.039 for Q4 vs Q1). CONCLUSION: Elevated LVMI was associated with increased cardiovascular events in patients with ACS under standard management. Adequately powered studies are warranted to validate these findings.

Development of enzyme immunoassay for chromogranin A (CgA) and profiling of plasma CgA concentrations in the cow.

The objectives of this study were to establish and characterize a homologous immunoassay for bovine chromogranin A (bCgA) and to profile plasma bCgA concentrations during early pregnancies. We synthesized oligopeptide corresponding to the amino acid sequence 341-355 of bCgA for immunizing rabbits and peptide corresponding to the amino acid sequence 336-365 of bCgA for both a biotinylated tracer and reference standards. Recombinant bCgA protein was also generated in Escherichia coli lysate. Dose-dependent displacement curves were obtained from 1 to 1,000 nM of the reference standards. The displacement curves showed a good relationship between the reference standards of the synthetic peptide and the serially diluted plasma sample or recombinant bCgA protein generated in the present study. The assay sensitivity defined as the value of two standard deviations below the zero standard was calculated as 0.46 nM. The intraassay and interassay coefficients of variation were 6.48% and 13.4%, respectively. Changes in the plasma bCgA concentrations in early pregnancies undulated in nonpregnant animals. The results of the present study suggest that assaying plasma bCgA concentrations could be utilized as measures to evaluate the physiological status of cattle.

Utility of the minimum-incision transsubclavian approach for transcatheter aortic valve replacement on clinical outcomes in patients with small vessel anatomy.

BACKGROUND: The optimal approach for patients undergoing transcatheter aortic valve replacement (TAVR), who are contraindicated for a transfemoral (TF) approach, is still controversial. The present study aimed to evaluate the utility of the TAVR via a subclavian artery with a small diameter, by minimal incision and a double Z suture hemostasis technique using 18 Fr DrySeal Flex sheath, namely minimum-incision transsubclavian TAVR (MITS-TAVR), in patients contraindicated for the TF approach. METHODS: We included consecutive patients who underwent the MITS-TAVR (MITS group; n = 21) and TF-TAVR (TF group; n = 81) using the CoreValve Evolut R/PRO valves and examined the incidence of in-hospital adverse events and post-discharge mortality between the two groups. RESULTS: The mean body surface area was significantly smaller in the MITS group (1.33 ± 0.04 vs. 1.43 ± 0.02 m2; p = 0.045). The minimal lumen diameter of the femoral artery was significantly smaller in the MITS group (5.01 vs. 6.43 mm; p < 0.01). The lumen diameter of the left subclavian artery (LSA) in the MITS group was 4.97 ± 0.14 mm. The duration of the TAVR procedure to discharge was not significantly different (9.7 ± 2.0 days vs. 13.2 ± 1.0 days; p = 0.239). We did not experience in-hospital death in both groups, and no significant differences were observed in the incidence of major adverse cardiac and cerebrovascular events between the two groups. The post-discharge survival rate was not significantly different between the groups (at 2-year; MITS group vs. TF group = 91.0% vs. 89.0%; p = 0.725). CONCLUSIONS: The MITS-TAVR using 18 Fr Dryseal Flex sheath was safe and effective and might be a promising alternative approach even in patients with a small body and small LSA diameter, who are contraindicated to the TF approach.

Development of Antimicrobial Stapled Peptides Based on Magainin 2 Sequence.

Magainin 2 (Mag2), which was isolated from the skin of the African clawed frog, is a representative antimicrobial peptide (AMP) that exerts antimicrobial activity via microbial membrane disruption. It has been reported that the helicity and amphipathicity of Mag2 play important roles in its antimicrobial activity. We investigated and recently reported that 17 amino acid residues of Mag2 are required for its antimicrobial activity, and accordingly developed antimicrobial foldamers containing α,α-disubstituted amino acid residues. In this study, we further designed and synthesized a set of Mag2 derivatives bearing the hydrocarbon stapling side chain for helix stabilization. The preferred secondary structures, antimicrobial activities, and cell-membrane disruption activities of the synthesized peptides were evaluated. Our analyses revealed that hydrocarbon stapling strongly stabilized the helical structure of the peptides and enhanced their antimicrobial activity. Moreover, peptide 2 stapling between the first and fifth position from the N-terminus showed higher antimicrobial activity than that of Mag2 against both gram-positive and gram-negative bacteria without exerting significant hemolytic activity. To investigate the modes of action of tested peptides 2 and 8 in antimicrobial and hemolytic activity, electrophysiological measurements were performed.

Effect of Renal Dysfunction on Risk of Sudden Cardiac Death in Patients With Hypertrophic Cardiomyopathy.

Renal dysfunction is a known risk of sudden cardiac death in patients with ischemic heart disease. However, the association between renal dysfunction and sudden death in hypertrophic cardiomyopathy (HC) patients remains unknown. This study investigated the significance of an impaired renal function for the sudden death risk in a cohort of patients with HC. We included 450 patients with HC (mean age 52.9 years, 65.1% men). The estimated glomerular filtration rate (eGFR) was evaluated at the time of the initial evaluation. Renal dysfunction was defined as an eGFR <60 ml/min/1.73 m2. Renal dysfunction was found in 171 patients (38.0%) at the time of enrollment. Over a median (IQR) follow-up period of 8.8 (5.0 to 12.5) years, 56 patients (12.4%) experienced the combined end point of sudden death or potentially lethal arrhythmic events, including 20 with sudden death (4.4%), 11 resuscitated after a cardiac arrest, and 25 with appropriate implantable defibrillator shocks. Patients with renal dysfunction were at a significantly higher risk of sudden death (Log-rank p = 0.034) and the combined end point (Log-rank p <0.001) than patients without renal dysfunction. After adjusting for the highly imbalanced baseline variables, the eGFR remained as an independent correlate of the combined end point (adjusted hazard ratio: 1.24 per 10 ml/min decline in the eGFR; 95% confidence interval 1.04 to 1.47; p = 0.013). In conclusion, an impaired renal function may be associated with an incremental risk of sudden death or potentially lethal arrhythmic events in patients with HC.

Rational Design of Helix-Stabilized Antimicrobial Peptide Foldamers Containing α,α-Disubstituted Amino Acids or Side-Chain Stapling.

Antimicrobial peptides (AMPs) are expected to be good candidate molecules for novel antimicrobial therapies. Most AMPs exert their antimicrobial activity through disruption of microbial membranes due to their amphipathic properties. Recently, the helical peptide 'Stripe' was reported by our group, a rationally designed amphipathic AMP focused on distribution of natural cationic and hydrophobic amino acid residues. In this study, a set of Stripe-based AMP foldamers was designed, synthesized and investigated that contain α,α-disubstituted amino acids or side-chain stapling to stabilize their helical structures. Our results showed that a peptide containing 2-aminoisobutyric acid (Aib) residues exhibited potent antimicrobial activity against both Gram-positive S.aureus (MIC value: 3.125 µM) and Gram-negative bacteria (including a multidrug-resistant strain, MDRP, MIC value: 1.56 µM), without significant hemolytic activity (>100 µM). Electrophysiological measurements revealed that this peptide formed stable pores in a 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)/1,2-dioleoyl-sn-glycero-3-phosphoglycerol (DOPG) bilayer but not in a dioleoylphosphocholine (DOPC) bilayer. The introduction of Aib residues into Stripe could be a promising way to increase the antimicrobial activity of AMP foldamers, and the peptide could represent a promising novel therapeutic candidate to treat multidrug-resistant bacterial infection.

Prognostic Significance of the Mitral L-Wave in Patients With Hypertrophic Cardiomyopathy.

A mitral L-wave indicates advanced diastolic dysfunction with elevated left ventricular filling pressure. Previous studies have reported that the presence of a mitral L-wave is associated with a poor prognosis in patients with heart failure. However, whether the L-wave can predict adverse events in patients with hypertrophic cardiomyopathy (HC) is still unclear. Therefore, we aimed to investigate the prevalence of a mitral L-wave in patients with HC, and the prognosis of patients with or without an L-wave. We analyzed 445 patients with HC. The end points of this study were HC-related death, such as sudden death or potentially lethal arrhythmic events, heart failure-related death, and stroke-related death. A mitral L-wave was defined as a distinct mid-diastolic flow velocity after the E wave with a peak velocity >20 cm/s. The prevalence of an L-wave was 32.4% in patients with HC. Patients with an L-wave were significantly younger, more likely to be women, had higher New York Heart Association functional class, and had a higher prevalence of atrial fibrillation than did patients without an L-wave. Patients with an L-wave had a significantly higher incidence of HC-related death compared with those without an L-wave (log-rank, p < 0.001). The L-wave was an independent determinant of HC-related death in multivariate analysis adjusted for imbalanced baseline variables (adjusted hazard ratio 2.38; 95% confidence interval 1.42 to 4.01; p = 0.001). In conclusion, the presence of a mitral L-wave may be associated with adverse outcome in patients with HC.