Sex-Specific Left Ventricular and Aorta Size Cut-Off Values for Hemodynamically Significant Chronic Aortic Regurgitation　- Implications for Treatment in Asian Populations.

BACKGROUND: There are no sex-specific guidelines for chronic aortic regurgitation (AR). This retrospective study examined sex-specific differences and propose treatment criteria from an Asian AR cohort.Methods and Results: Consecutive 1,305 patients with moderate-severe AR or greater at 3 tertiary centers in Taiwan and Japan (2008-2022) were identified. Study endpoints were aortic valve surgery (AVS), all-cause death (ACD), and cardiovascular death (CVD). The median follow up was 3.9 years (interquartile range 1.3-7.1 years). Compared with men (n=968), women (n=337) were older, had more advanced symptoms, more comorbidities, larger indexed aorta size (iAortamax) and indexed left ventricular (LV) end-systolic dimension (LVESDi; P<0.001 for all). Symptomatic status was poorly correlated with the degree of LV remodeling in women (P≥0.18). Women received fewer AVS (P≤0.001) and men had better overall 10-year survival (P<0.01). Ten-year post-AVS survival (P=0.9) and the progression of LV remodeling were similar between sexes (P≥0.16). Multivariable determinants of ACD and CVD were age, advanced symptoms, iAortamax, LV ejection fraction (LVEF), LVESDi, LV end-systolic volume index (LVESVi), and Taiwanese ethnicity (all P<0.05), but not female sex (P≥0.05). AVS was associated with better survival (P<0.01). Adjusted LVEF, LVESDi, LVESVi, and iAortamaxcut-off values for ACD were 53%, 24.8 mm/m2, 44 mL/m2, and 25.5 mm/m2, respectively, in women and 52%, 23.4 mm/m2, 52 mL/m2, and 23.2 mm/m2, respectively, in men. CONCLUSIONS: Early detection and intervention using sex-specific cut-off values may improve survival in women with AR.

Lyophilization as an effective tool to develop AAV8 gene therapy products for refrigerated storage.

Recombinant adeno-associated virus (rAAV) has emerged as the leading gene delivery platform for treatment of monogenic disorders. Currently, for clinical and commercial products, rAAVs are typically formulated and stored below -65 °C as frozen liquid. Their long-term storage is often far from ideal because it may result in shorter drug product (DP) shelf-life compared to recombinant protein-based biologics, and also presents challenges for supply chain and inventory management. Consequently, there is great interest in developing robust lyophilized AAV DPs that are stable at 2 to 8 °C. In this study, we evaluated formulation excipients required for stable lyophilized AAV8 products including buffers, salts, cryoprotectants/lyoprotectants, surfactants, and bulking agents, and optimized the concentrations and ratios between the excipients. This led to the identification of the lead formulation that demonstrated short-term in-solution stability at 25 °C and, upon lyophilization, sufficient long-term stability at 2 to 8 °C. Our study demonstrated that, in the presence of 110 mM salts, mannitol can serve as an effective bulking agent with the appropriate formulation and lyophilization process design, and the sucrose to mannitol ratio is critical to maintain the stability and cake appearance of the lyophilized AAV8 DP. Thorough characterization of the effect of formulation components on the properties and quality of the lyophilized DP led to an optimized AAV8 lyophilized DP. This approach could be applied to streamline the future development of lyophilized AAV gene therapy products with various target transgenes and capsid serotypes.

Clinical and Metabolic Characteristics of Hyperuricemia with Risk of Liver Fibrosis: A Cross-Sectional Study.

The role of serum uric acid (SUA) in the role of advanced fibrosis is not fully explored. The study assesses the risk of advanced fibrosis according to SUA in an Asian population with a total of 3612 subjects enrolled in one health management center between 2006 and 2008. The fibrosis-4 score was used for the prediction of the high risk of advanced fibrosis. SUA scores higher than 7.6 mg/dL in men and 6.6 mg/dL in women were defined as hyperuricemia. A proportional odds model was used to assess cumulative risks of advanced fibrosis. The prevalence of high risk of advanced fibrosis was 2.5% in the hyperuricemia group and 0.6% in the normal SUA group (p < 0.001). After adjustment for confounding factors, the odds ratios (OR) for more severe advanced fibrosis were 1.37 (95% confidence interval [CI]: 1.07−1.78) in the hyperuricemia group. Hyperuricemia only increased the risk of advanced fibrosis in the non-T2DM group (OR, 1.29; 95% CI, 1.04 to 1.74) instead of T2DM group (OR, 1.85; 95% CI, 0.97 to 3.53). SUA is a risk factor for a higher risk of advanced fibrosis, with the disease likely progressing from a steatotic to a fibrotic picture. The focus should be more emphasized in non-T2DM groups.

Are the measurement structures of the Traditional Chinese Dispositional Flow Scale-2 equivalent between schizophrenic patients and healthy subjects?

BACKGROUND: The Dispositional Flow Scale-2 (DFS-2) is an instrument for measuring the flow experiences of the general population while participating in daily activities. This study aimed to examine the equivalence in the measurement structure of Traditional Chinese DFS-2 (TCDFS-2) between the schizophrenic patients and healthy subjects. METHODS: We recruited 100 adults with schizophrenia or schizoaffective disorder from the psychiatric clinics or the centers for daycare or rehabilitation and 104 healthy adults. Each participant finished the TCDFS-2 by recalling the most important and meaningful daily activity. RESULTS: We conducted two two-group confirmatory factor analyses (CFA) with the healthy subjects and schizophrenic patients as the reference group respectively in LISREL. When the healthy subjects as the reference standard, 43 items of the TCDFS-2 were added to this constrained two-group CFA model for the schizophrenic patients, but the cross-group equivalence was still unsatisfactory. By contrast, when the schizophrenic patients as the reference standard, only 6 items were added for the healthy subjects, and the cross-group equivalence was barely acceptable. CONCLUSION: Thus, the measurement structures of the TCDFS-2 were quite different between the schizophrenic patients and healthy subjects. The flow states experienced by the schizophrenic patients might not entirely be the same as those of the healthy subjects.

LanCLs add glutathione to dehydroamino acids generated at phosphorylated sites in the proteome.

Enzyme-mediated damage repair or mitigation, while common for nucleic acids, is rare for proteins. Examples of protein damage are elimination of phosphorylated Ser/Thr to dehydroalanine/dehydrobutyrine (Dha/Dhb) in pathogenesis and aging. Bacterial LanC enzymes use Dha/Dhb to form carbon-sulfur linkages in antimicrobial peptides, but the functions of eukaryotic LanC-like (LanCL) counterparts are unknown. We show that LanCLs catalyze the addition of glutathione to Dha/Dhb in proteins, driving irreversible C-glutathionylation. Chemo-enzymatic methods were developed to site-selectively incorporate Dha/Dhb at phospho-regulated sites in kinases. In human MAPK-MEK1, such "elimination damage" generated aberrantly activated kinases, which were deactivated by LanCL-mediated C-glutathionylation. Surveys of endogenous proteins bearing damage from elimination (the eliminylome) also suggest it is a source of electrophilic reactivity. LanCLs thus remove these reactive electrophiles and their potentially dysregulatory effects from the proteome. As knockout of LanCL in mice can result in premature death, repair of this kind of protein damage appears important physiologically.

Test-Retest Reliability and Minimal Detectable Change of the Comprehensive Occupational Therapy Evaluation Scale (COTES) in People With Schizophrenia.

IMPORTANCE: A reliable observational measure is necessary to measure clients' behaviors as they participate in activities. The Comprehensive Occupational Therapy Evaluation Scale (COTES) is designed to measure strengths and difficulties in various behaviors that support occupational performance. OBJECTIVE: To examine the test-retest reliability of the COTES (overall score and scores on the General Behavior, Social Behavior, and Work Behavior subscales) and calculate the minimal detectable change (MDC) for people with schizophrenia. DESIGN: Prospective, observational study. SETTING: A psychiatric center. PARTICIPANTS: COTES data for 118 people with schizophrenia were collected from occupational therapy records. Data from the initial and second COTES measurements were chosen for analysis. OUTCOMES AND MEASURES: Test-retest reliability of the overall scale and three subscales was evaluated using the intraclass correlation coefficient (ICC). The MDC was calculated on the basis of the standard error of measurement. RESULTS: ICCs for the overall scale and three subscales ranged from .91 to .97. The MDC values (MDC%) were 6.5 (10.5%) for the overall scale, 3.4 (13.5%) for the General Behavior subscale, 2.3 (15.2%) for the Social Behavior subscale, and 2.4 (11.0%) for the Work Behavior subscale. CONCLUSION AND RELEVANCE: The COTES has good test-retest reliability. Clinicians and researchers can use the MDC values provided in this study to explain the implications of change scores for behaviors that affect occupational performance for people with schizophrenia. WHAT THIS ARTICLE ADDS: The COTES has sound reliability and support for its use in determining whether people with schizophrenia make real improvements in behavior that affects occupational performance over time.

Body mass index and albumin levels are prognostic factors for long-term survival in elders with limited performance status.

Elderly long-term care facility residents typically have musculoskeletal conditions that may lead to long-term disability and increased mortality. Our main objective was to explore the relationship between body mass index (BMI), albumin levels, and mortality in elderly individuals with limited performance status. Among 182 participants (mean age, 78.8 years; 57% women), 11%, 64%, and 25% had serum albumin levels of <2.8, 2.8-3.5, and >3.5 g/dL, respectively. After multivariate adjustments, diastolic blood pressure >90 mmHg was associated with all-cause mortality [hazard ratio (HR) = 2.08, 95% confidence interval (CI) = 1.13-3.82; P = 0.018]. In addition, BMI <18.5 kg/m2 and albumin level <2.8 g/dL associated with higher mortality than BMI = 18.5-24 kg/m2 and albumin level > 3.5 g/dL (HR = 1.80, 95% CI = 1.11-2.94 and HR = 2.54, 95% CI 1.22-5.30, respectively; P = 0.018 and 0.013, respectively). Highest mortality was noted in participants with albumin levels <2.8 g/dL and BMIs <18.5 kg/m2 (HR = 6.12, 95% CI = 1.85-20.21, P = 0.003). Combined hypoalbuminemia (albumin level < 2.8 g/dL) and low BMI (<18.5 kg/m2) may be a useful prognostic indicator of high mortality risk in elderly individuals with limited performance status.

Traditional-Chinese Dispositional Flow Scale-2 and Flow State Scale-2 in Taiwanese subjects with schizophrenia or schizoaffective disorder.

INTRODUCTION: The 36-item Dispositional Flow Scale-2 (DFS-2) and Flow State Scale-2 (FSS-2) were developed to assess flow experience in daily and specific activities. Although their validity and reliability had been examined in general populations and different cultures, little is known for schizophrenic subjects. Thus, this study aimed to validate Traditional-Chinese DFS-2 (TCDFS-2) and FSS-2 (TCFSS-2) in Taiwanese subjects with schizophrenia or schizoaffective disorder. METHODS: We recruited 229 adult participants from outpatient clinics, day care centers, and psychiatric rehabilitation centers in Taipei. They filled out 36-item TCDFS-2 and TCFSS-2 under guidance. The LISREL 9.30 software was used to conduct exploratory factor analysis for exploring measurement structures, and then confirmatory factor analysis for identifying factor models. RESULTS: The six first-order factor and one second-order factor measurement models were obtained for both 36-item TCDFS-2 (Chi-square statistic = 999.1, df = 545, p < 0.0001, Root Mean Square Error of Approximation [RMSEA] = 0.0603, and Comparative Fit Index [CFI] = 0.9213) and TCFSS-2 (Chi-square statistic = 987.9, df = 539, p < 0.0001, RMSEA = 0.0603, and CFI = 0.9213). CONCLUSION: Our factor models differed remarkably from those of 36-item DFS-2 and FSS-2. Yet, they were barely acceptable to be used to measure flow experiences in schizophrenic subjects in clinical applications. Since the factor scores, measurement structures, or even definitions of flow experiences could differ substantially between healthy people and patients with mental illness, disease-specific instruments of flow experiences should be considered in the future.

Construct Validity and Reliability of the Comprehensive Occupational Therapy Evaluation Scale (COTES) in People With Schizophrenia.

OBJECTIVE: We evaluated the construct validity (i.e., unidimensionality and convergent validity) and Rasch reliability of the 20-item Comprehensive Occupational Therapy Evaluation Scale (COTES) in people with schizophrenia. METHOD: Retrospective chart review was used to collect COTES data from 505 inpatients with schizophrenia. For construct validity, we first examined unidimensionality of each of the three COTES subscales using Rasch analysis. After unidimensionality was supported, we examined convergent validity using Pearson's r and Rasch reliability of the individual subscales. RESULTS: After deleting two misfitting items, the remaining items (i.e., the COTES-18) showed unidimensionality. Infit and outfit mean squares were 0.73-1.25. Moderate correlations were found among the three COTES-18 subscales (rs = .57-.71). The Rasch reliabilities of the three subscales were .83-.92. CONCLUSION: The COTES-18 has sufficient construct validity and reliability to assess three specific dimensions of behavior affecting occupational performance in people with schizophrenia.

Lanthionine synthetase C-like protein 2 (LanCL2) is important for adipogenic differentiation.

Adipogenic differentiation is a highly regulated process that is necessary for metabolic homeostasis and nutrient sensing. The expression of PPARγ and the subsequent activation of adipogenic genes is critical for the process. In this study, we identified lanthionine synthetase C-like protein 2 (LanCL2) as a positive regulator of adipogenesis in 3T3-L1 cells. Knockdown of LanCL2, but not LanCL1, inhibited adipogenic differentiation, and this effect was not mediated through cAMP or Akt signaling pathways. The expression of early adipogenic markers CCAAT enhancer binding protein ß (C/EBPß) and C/EBPδ remained intact in LanCL2 knockdown cells, but levels of late adipogenic markers PPARγ and C/EBPα were suppressed. The addition of the naturally occurring PPARγ activator 15-deoxy-Δ12,14-prostaglandin J2 or conditioned medium from differentiating cells did not restore differentiation, implying that LanCL2 may not be involved in the production of a secreted endogenous PPARγ ligand. Pulldown assays demonstrated a direct physical interaction between LanCL2 and PPARγ. Consistent with a regulatory role of LanCL2, luciferase reporter assays revealed that full transcriptional activation by PPARγ was dependent on LanCL2. Taken together, our study reveals a novel role of LanCL2 in adipogenesis, specifically involved in PPARγ-mediated transactivation of downstream adipogenic genes.

A placental growth factor is silenced in mouse embryos by the zinc finger protein ZFP568.

Insulin-like growth factor 2 (IGF2) is the major fetal growth hormone in mammals. We identify zinc finger protein 568 (ZFP568), a member of the rapidly evolving Kruppel-associated box-zinc finger protein (KRAB-ZFP) family linked primarily to silencing of endogenous retroelements, as a direct repressor of a placental-specific Igf2 transcript (designated Igf2-P0) in mice. Loss of Zfp568, which causes gastrulation failure, or mutation of the ZFP568-binding site at the Igf2-P0 promoter causes inappropriate Igf2-P0 activation. Deletion of Igf2 can completely rescue Zfp568 gastrulation phenotypes through late gestation. Our data highlight the exquisite selectivity with which members of the KRAB-ZFP family repress their targets and identify an additional layer of transcriptional control of a key growth factor regulating fetal and placental development.

Synthesis of Novel µ-Star Copolymers with Poly(N-Octyl Benzamide) and Poly(ε-Caprolactone) Miktoarms through Chain-Growth Condensation Polymerization, Styrenics-Assisted Atom Transfer Radical Coupling, and Ring-Opening Polymerization.

Star copolymers are known to phase separate on the nanoscale, providing useful self-assembled morphologies. In this study, the authors investigate synthesis and assembly behavior of miktoarm star (µ-star) copolymers. The authors employ a new strategy for the synthesis of unprecedented µ-star copolymers presenting poly(N-octyl benzamide) (PBA) and poly(ε-caprolactone) (PCL) arms: a combination of chain-growth condensation polymerization, styrenics-assisted atom transfer radical coupling, and ring-opening polymerization. Gel permeation chromatography, mass-analyzed laser desorption/ionization mass spectrometry, and 1 H NMR spectroscopy reveal the successful synthesis of a well-defined (PBA11 )2 -(PCL15 )4 µ-star copolymer (Mn,NMR ≈ 12 620; D = 1.22). Preliminary examination of the PBA2 PCL4 µ-star copolymer reveals assembled nanofibers having a uniform diameter of ≈20 nm.

Construct Validity of the Chinese Version of the Activities of Daily Living Rating Scale III in Patients with Schizophrenia.

BACKGROUND: The Chinese version of the Activities of Daily Living Rating Scale III (ADLRS-III), which has 10 domains, is commonly used for assessing activities of daily living (ADL) in patients with schizophrenia. However, construct validity (i.e., unidimensionality) for each domain of the ADLRS-III is unknown, limiting the explanations of the test results. PURPOSE: This main purpose of this study was to examine unidimensionality of each domain in the ADLRS-III. We also examined internal consistency and ceiling/floor effects in patients with schizophrenia. METHODS: From occupational therapy records, we obtained 304 self-report data of the ADLRS-III. Confirmatory factor analysis (CFA) was conducted to examine the 10 one-factor structures. If a domain showed an insufficient model fit, exploratory factor analysis (EFA) was performed to investigate the factor structure and choose one factor representing the original construct. Internal consistency was examined using Cronbach's alpha (α). Ceiling and floor effects were determined by the percentage of patients with the maximum and minimum scores in each domain, respectively. RESULTS: CFA analyses showed that 4 domains (i.e., leisure, picture recognition, literacy ability, communication tools use) had sufficient model fits. These 4 domains had acceptable internal consistency (α = 0.79-0.87) and no ceiling/floor effects, except the leisure domain which had a ceiling effect. The other 6 domains showed insufficient model fits. The EFA results showed that these 6 domains were two-factor structures. CONCLUSION: The results supported unidimensional constructs of the leisure, picture recognition, literacy ability, and communication tool uses domains. The sum scores of these 4 domains can be used to represent their respective domain-specific functions. Regarding the 6 domains with insufficient model fits, we have explained the two factors of each domain and chosen one factor to represent its original construct. Future users may use the items from the chosen factors to assess domain-specific functions in patients with schizophrenia.

In vitro scleral lutein distribution by cyclodextrin containing nanoemulsions.

Lutein is a macular pigment that contributes to maintaining eye health. The development of lutein-laden nanocarriers for ocular delivery would have the advantages of user friendliness and cost-effectiveness. Nano-scaled vehicles such as cyclodextrin (CD) and nanoemulsion could overcome the barriers caused by the scleral structure. This study focused on the development of hybrid nanocarriers containing nanoemulsion and CD for scleral lutein accumulation. In the presence of the nanoemulsion, CD forms such as ßCD and hydroxyethyl (HE) ßCD increased the partition of lutein into the porcine sclera. A combination of nanoemulsion and 2% HEßCD enhanced lutein accumulation to 119±6 µg g(-1) h(-1), which was 9.2-fold higher than that with lutein suspension alone. We explored the dose effect of CD in nanoemulsion on scleral lutein and found that the scleral accumulation of lutein was enhanced by increasing the CD content. The novel nanoemulsion had 95% drug-loading efficiency and low cytotoxicity in retinal cells. The CD-modified nanoemulsion not only improved the stability and entrapment efficacy of lutein in the aqueous system but also enhanced scleral lutein accumulation. An increase in the partition coefficient of lutein in porcine sclera when using the CD-modified nanoemulsion was also confirmed.

Targeted disruption in mice of a neural stem cell-maintaining, KRAB-Zn finger-encoding gene that has rapidly evolved in the human lineage.

Understanding the genetic basis of the physical and behavioral traits that separate humans from other primates is a challenging but intriguing topic. The adaptive functions of the expansion and/or reduction in human brain size have long been explored. From a brain transcriptome project we have identified a KRAB-Zn finger protein-encoding gene (M003-A06) that has rapidly evolved since the human-chimpanzee separation. Quantitative RT-PCR analysis of different human tissues indicates that M003-A06 expression is enriched in the human fetal brain in addition to the fetal heart. Furthermore, analysis with use of immunofluorescence staining, neurosphere culturing and Western blotting indicates that the mouse ortholog of M003-A06, Zfp568, is expressed mainly in the embryonic stem (ES) cells and fetal as well as adult neural stem cells (NSCs). Conditional gene knockout experiments in mice demonstrates that Zfp568 is both an NSC maintaining- and a brain size-regulating gene. Significantly, molecular genetic analyses show that human M003-A06 consists of 2 equilibrated allelic types, H and C, one of which (H) is human-specific. Combined contemporary genotyping and database mining have revealed interesting genetic associations between the different genotypes of M003-A06 and the human head sizes. We propose that M003-A06 is likely one of the genes contributing to the uniqueness of the human brain in comparison to other higher primates.