Rational quinidine dosage regimen for atrial fibrillation in Thoroughbred racehorses based on population pharmacokinetics.

Introduction: Quinidine (QND) sulfate is an effective treatment for atrial fibrillation (AF) in horses, and several dosage regimens have been proposed to address its wide variability in response and potential adverse effects. The purpose of this study was to analyze the variability in plasma quinidine concentrations using population pharmacokinetics to determine an effective and safe dosage regimen for Thoroughbred horses. Methods: Six healthy Thoroughbred horses were treated with 20 mg/kg quinidine sulfate dihydrate (16.58 mg/kg QND base) administered PO or 5 mg/kg quinidine hydrochloride monohydrate (4.28 mg/kg QND base) administered IV (single administration), and blood samples were taken regularly. Four healthy horses were treated with 20 mg/kg quinidine sulfate dihydrate administered twice (every 6 h) via PO route. For the other 19 Thoroughbred racehorses that developed AF, blood samples were taken during quinidine therapy. Quinidine concentrations were measured in all plasma samples using liquid chromatography with tandem mass spectrometry, and the data from 29 horses were modeled using a nonlinear mixed-effects model, followed by Monte Carlo simulations (MCS). Results: The median quinidine concentration for successful sinus rhythm conversion was 2.0 µg/mL (range: 0.5-2.7 µg/mL) in AF horses, while a median concentration of 3.8 µg/mL (range: 1.6-5.1 µg/mL) showed adverse effects. MCS predicted that plasma quinidine concentrations for quinidine sulfate dihydrate PO administration (loading dose: 30 mg/kg, maintenance dose: 6.5 mg/kg q 2 h) reached 1.4, 2.0 and 2.7 µg/mL in 90, 50 and 10% of the horse populations, respectively. Increasing the loading dose to 45 mg/kg and the maintenance dose to 9 mg/kg q 2 h, the plasma concentrations achieved were 1.9, 2.8, and 3.8 µg/mL in 90, 50, and 10% of horse populations, respectively. Discussion: Using simulations, different empirical dosing regimens were proposed to achieve plasma quinidine concentrations immediately or progressively, representing a tradeoff between optimizing therapeutic effects and minimizing adverse effects. A combination of these dosing regimens is recommended to gradually increase the therapeutic concentration levels of quinidine for safe and effective treatment of AF in racehorses.

Survey on Awareness and Implementation Rate of Ultrasound Elastography and Attenuation Imaging.

Aim Recent developments in ultrasound elastography (UE) and ultrasound attenuation imaging (UA) have enabled the detection of advanced liver fibrosis and steatosis in patients with steatotic liver disease (SLD), which is prevalent worldwide. In patients with SLD, the presence of advanced liver fibrosis determines the risk of hepatocarcinogenesis, and UE and UA are expected to play important roles in liver cancer surveillance. We conducted a questionnaire survey among medical facilities in Saga Prefecture regarding the actual status of awareness and implementation of UE and UA. Methods A 16-item questionnaire was sent to 275 facilities that employed members of the Liver Cancer Control Medical Association in Saga Prefecture. The response rate was 56% (153 facilities), and data from 142 facilities were analyzed after excluding 11 facilities. Results The most common facilities were outpatient clinics (60%) followed by hospitals with ≥100 beds (14%). In 48% of the facilities, an average of 10-49 abdominal ultrasound examinations were performed monthly. The rates of recognition that UE and UA are useful for fibrosis and steatosis were 65% (92/142) and 41% (58/142), respectively. The actual availability of UE and UA in facilities with ultrasound machines was 21% (30/142) and 12% (17/142), respectively; UE and UA were used in 90% (27/30) and 88% (15/17) of these facilities, respectively. Conclusion Even among medical facilities in Saga Prefecture that are active in liver cancer surveillance, awareness of UE and UA is not high. The availability of UE and UA may be inadequate, considering the high prevalence of SLD.

FIB-4 Index and Liver Stiffness Measurement are Potential Predictors of Atherosclerosis in Metabolic Dysfunction-Associated Steatotic Liver Disease.

AIMS: Cardiovascular disease (CVD) is a common cause of death in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Therefore, CVD surveillance is important, but it is not well established. We evaluated the association between liver fibrosis, carotid artery atherosclerosis, and coronary artery stenosis in patients with MASLD. METHODS: Overall, 153 patients with MASLD who underwent carotid artery ultrasound were enrolled. Maximum intima-media thickness including plaques (Max-IMT) was measured by ultrasound. To predict liver fibrosis, liver stiffness was measured by vibration-controlled transient elastography and the fibrosis 4 (FIB-4) index was calculated. Coronary computed tomography angiography was performed to detect coronary artery stenosis based on a Max-IMT of ≥ 1.1 mm. RESULTS: The median Max-IMT was 1.3 mm, and 63 patients (41.2%) had a Max-IMT of ≥ 1.5 mm. FIB-4 index and liver stiffness was significantly correlated with Max-IMT, respectively (ρ=0.356, p＜0.001, ρ=0.25, p=0.002). Liver stiffness was significantly associated with a Max-IMT of ≥1.5 mm, independent of age. Individuals with higher FIB-4 index had moderate or severe coronary artery stenosis more frequently. Individuals with higher LSM level also had moderate or severe coronary artery stenosis more frequently, especially severe stenosis. CONCLUSIONS: Liver fibrosis parameters were associated with carotid artery atherosclerosis and coronary artery stenosis. Evaluation of liver fibrosis may be useful to identify significant atherosclerosis and coronary artery stenosis in patients with MASLD.

Evaluation of the associations of interlukin-7 genetic variants with toxicity and efficacy of immune checkpoint inhibitors: A replication study of a Japanese population, based on the findings of a European genome-wide association study.

AIM: Recent genome-wide association studies of European populations have identified rs16906115, a single-nucleotide polymorphism in the interleukin-7 gene, as a predictor of immune-related adverse events (irAEs) and the therapeutic efficacy of immune checkpoint inhibitors. We evaluated this single-nucleotide polymorphism in a Japanese population. METHODS: From January 2021, we stored host DNA from individuals who received various types of immune checkpoint inhibitors. From this population, we categorized 510 participants into cases (grade ≥2 irAEs) and controls (received ≥3 immune checkpoint inhibitor doses, follow-up ≥12 weeks, no irAEs), and divided 339 hepatocellular carcinoma patients treated with atezolizumab/bevacizumab into responders and non-responders, evaluated using the modified response evaluation criteria in solid tumors. We compared the minor allele frequencies of rs16906115 between cases and controls, and responders and non-responders. RESULTS: In the irAE prediction analysis of 234 cases and 276 controls, the minor allele frequency was 0.244 in the case group and 0.265 in the control group. This difference is not significant. In the analysis predicting the therapeutic efficacy for hepatocellular carcinoma patients, the responders had a significantly lower minor allele frequency of 0.220, compared with 0.300 for the non-responders (p = 0.022). Univariate and multivariate analyses identified the minor allele homozygosity as a significant predictor of treatment response, with odds ratios of 0.292 (p = 0.015) in the univariate analysis and 0.315 (p = 0.023) in the multivariate analysis. CONCLUSIONS: In our Japanese cohort, no association was found between the rs16906115 minor allele and irAEs or treatment efficacy. The minor allele homozygosity may be associated with a negative therapeutic outcome. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry with the number UMIN000043798.

Sex and ethnic disparities in hepatitis B evaluation and treatment across the world.

BACKGROUND & AIMS: Oral antiviral therapy with nucleos(t)ide analogues (NAs) for chronic hepatitis B (CHB) is well-tolerated and lifesaving, but real-world data on utilization are limited. We examined rates of evaluation and treatment in patients from the REAL-B consortium. METHODS: This was a cross-sectional study nested within our retrospective multinational clinical consortium (2000-2021). We determined the proportions of patients receiving adequate evaluation, meeting AASLD treatment criteria, and initiating treatment at any time during the study period. We also identified factors associated with receiving adequate evaluation and treatment using multivariable logistic regression analyses. RESULTS: We analyzed 12,566 adult treatment-naïve patients with CHB from 25 centers in 9 countries (mean age 47.1 years, 41.7% female, 96.1% Asian, 49.6% Western region, 8.7% cirrhosis). Overall, 73.3% (9,206 patients) received adequate evaluation. Among the adequately evaluated, 32.6% (3,001 patients) were treatment eligible by AASLD criteria, 83.3% (2,500 patients) of whom were initiated on NAs, with consistent findings in analyses using EASL criteria. On multivariable logistic regression adjusting for age, sex, cirrhosis, and ethnicity plus region, female sex was associated with adequate evaluation (adjusted odds ratio [aOR] 1.13, p = 0.004), but female treatment-eligible patients were about 50% less likely to initiate NAs (aOR 0.54, p <0.001). Additionally, the lowest evaluation and treatment rates were among Asian patients from the West, but no difference was observed between non-Asian patients and Asian patients from the East. Asian patients from the West (vs. East) were about 40-50% less likely to undergo adequate evaluation (aOR 0.60) and initiate NAs (aOR 0.54) (both p <0.001). CONCLUSIONS: Evaluation and treatment rates were suboptimal for patients with CHB in both the East and West, with significant sex and ethnic disparities. Improved linkage to care with linguistically competent and culturally sensitive approaches is needed. IMPACT AND IMPLICATIONS: Significant sex and ethnic disparities exist in hepatitis B evaluation and treatment, with female treatment-eligible patients about 50% less likely to receive antiviral treatment and Asian patients from Western regions also about 50% less likely to receive adequate evaluation or treatment compared to Asians from the East (there was no significant difference between Asian patients from the East and non-Asian patients). Improved linkage to care with linguistically competent and culturally sensitive approaches is needed.

Mortality in patients with chronic hepatitis B treated with tenofovir or entecavir: A multinational study.

BACKGROUND AND AIM: The benefits of entecavir (ETV) versus tenofovir disoproxil fumarate (TDF) in reducing the development of chronic hepatitis B (CHB)-related hepatocellular carcinoma remain controversial. Whether mortality rates differ between patients with CHB treated with ETV and those treated with TDF is unclear. METHODS: A total of 2542 patients with CHB treated with either ETV or TDF were recruited from a multinational cohort. A 1:1 propensity score matching was performed to balance the differences in baseline characteristics between the two patient groups. We aimed to compare the all-cause, liver-related, and non-liver-related mortality between patients receiving ETV and those receiving TDF. RESULTS: The annual incidence of all-cause mortality in the entire cohort was 1.0/100 person-years (follow-up, 15 757.5 person-years). Patients who received TDF were younger and had a higher body mass index, platelet count, hepatitis B virus deoxyribonucleic acid levels, and proportion of hepatitis B e-antigen seropositivity than those who received ETV. The factors associated with all-cause mortality were fibrosis-4 index > 6.5 (hazard ratio [HR]/confidence interval [CI]: 3.13/2.15-4.54, P < 0.001), age per year increase (HR/CI: 1.05/1.04-1.07, P < 0.001), alanine aminotransferase level per U/L increase (HR/CI: 0.997/0.996-0.999, P = 0.003), and γ-glutamyl transferase level per U/L increase (HR/CI: 1.002/1.001-1.003, P < 0.001). No significant difference in all-cause mortality was observed between the ETV and TDF groups (log-rank test, P = 0.69). After propensity score matching, no significant differences in all-cause, liver-related, or non-liver-related mortality were observed between the two groups. CONCLUSIONS: Long-term outcomes of all-cause mortality and liver-related and non-liver-related mortality did not differ between patients treated with ETV and those receiving TDF.

Racial and ethnic disparities in untreated patients with hepatitis C virus-related hepatocellular carcinoma but not in those with sustained virologic response.

BACKGROUND: Racial and ethnic disparities exist for hepatitis C virus (HCV) treatment and hepatocellular carcinoma (HCC) survival. AIM: To evaluate the impact of HCV treatment on such disparities. METHODS: In a retrospective cohort study, we analysed 6069 patients with HCV-related HCC (54.2% Asian, 30.1% White, 8.5% Black, and 7.3% Hispanic) from centres in the United States and Asia. RESULTS: The mean age was 61, 60, 59 and 68, respectively, for White, Black, Hispanic and Asian patients. Black patients were most likely to have Barcelona Clinic Liver Cancer stage D, vascular invasion and distant metastasis (23% vs. 5%-15%, 20% vs. 10%-17% and 10% vs. 5%-7%, respectively; all p < 0.0001). Treatment rate with direct-acting antiviral agents (DAA) was 35.9% for Asian, 34.9% for White, 30.3% for Hispanic (30.3%), and 18.7% for Black patients (p < 0.0001). Among those untreated or without sustained virologic response (SVR), 10-year survival rates were 35.4, 27.5, 19.3 and 14.0, respectively, for Asian, Hispanic, White and Black patients (p < 0.0001). There were no statistically significant differences among those with SVR (p = 0.44). On multivariable analysis adjusted for relevant confounders, there was no statistically significant association between survival and being Hispanic (aHR: 0.68, p = 0.26) or Black (aHR: 1.18, p = 0.60) versus White. There was a significant association between being Asian American and survival (aHR: 0.24, p = 0.001; non-U.S. Asian: aHR: 0.66, p = 0.05), and for SVR (aHR: 0.30, p < 0.0001). CONCLUSION: DAA treatment rates were suboptimal. Racial and ethnic disparities resolved with HCV cure. Early diagnosis and improved access to HCV treatment is needed for all patients with HCV infection.

Sex Differences in Treatment Response to Nucleos(t)ide Therapy in Chronic Hepatitis B: A Multicenter Longitudinal Study.

BACKGROUND & AIMS: It is unclear if there may be sex differences in response to nucleos(t)ide analogs including virologic response (VR), biochemical response (BR), complete response (CR), and hepatocellular carcinoma (HCC) incidence among hepatitis B patients. We compared nucleos(t)ide analog treatment outcomes by sex. METHODS: We performed a retrospective cohort study of 3388 treatment-naïve adult hepatitis B patients (1250 female, 2138 male) from the Real-World Evidence from the Global Alliance for the Study of Hepatitis B Virus consortium who initiated therapy with either entecavir or tenofovir from 22 sites (Argentina, Korea, Japan, Taiwan, and the United States). We used propensity-score matching to balance background characteristics of the male and female groups and competing-risks analysis to estimate the incidence and subdistribution hazard ratios (SHRs) of VR, BR, CR, and HCC. RESULTS: Females (vs males) were older (52.0 vs 48.6 y); less likely to be overweight/obese (49.3% vs 65.7%), diabetic (9.9% vs 13.1%), or cirrhotic (27.9% vs 33.0%); and had a lower HBV DNA level (5.9 vs 6.0 log10 IU/mL) and alanine aminotransferase level (91 vs 102 IU/L) (all P < .01). However, after propensity-score matching, relevant background characteristics were balanced between the 2 groups. Females (vs males) had similar 5-year cumulative VR (91.3% vs 90.3%; P = .40) and HCC incidence rates (5.1% vs 4.4%; P = .64), but lower BR (84.0% vs 90.9%; P < .001) and CR (78.8% vs 83.4%; P = .016). Males were more likely to achieve BR (SHR, 1.31; 95% CI, 1.17-1.46; P < .001) and CR (SHR, 1.16; 95% CI, 1.03-1.31; P = .016), but VR and HCC risks were similar. CONCLUSIONS: Sex differences exist for treatment outcomes among hepatitis B patients. Male sex was associated with a 16% higher likelihood of clinical remission and a 31% higher likelihood of biochemical response than females, while virologic response and HCC incidence were similar between the 2 groups.

Increased spine bone density in patients with chronic hepatitis B switched to tenofovir alafenamide: A prospective, multinational study.

BACKGROUND: Data on patients switched to tenofovir alafenamide (TAF) from nucleos(t)ide analogues (NUCs) other than tenofovir disoproxil fumarate are limited. AIMS: To assess the treatment and renal/bone safety outcomes following the switch to TAF. METHODS: We prospectively enrolled adult patients with chronic hepatitis B (CHB) who switched from any NUC to TAF at 14 centres in Japan, Korea, Taiwan and the U.S. Study outcomes were viral suppression (VR; HBV DNA < 20 IU/mL), biochemical response (BR; alanine aminotransferase normalisation), and changes in estimated glomerular filtration rate (eGFR) and T-scores (L-spine) by bone absorptiometry by 24 months after switch to TAF. RESULTS: We enrolled 270 eligible patients. Mean age was 58.1; 58.2% were male; 12.2% had cirrhosis and 73.3% previously received entecavir monotherapy. VR rate increased significantly from 95.2% to 98.8% by 24 months after the switch to TAF (p = 0.014). Between the switch and 24 months later, the mean spine T-score improved significantly from -1.43 ± 1.36 to -1.17 ± 1.38 (p < 0.0001), while there was no significant change in mean eGFR (88.4 ± 16.9-89.5 ± 16.3 mL/min/1.73 m2 , p = 0.13). On multivariable analysis adjusted for age, sex, baseline spine T-score and prior TDF or adefovir dipivoxil use, male sex was significantly associated with lower risk of worsening spine T-score (odds ratio: 0.29, p = 0.020), while age was significantly associated with a higher risk of worsening chronic kidney disease stage (OR: 1.07, p = 0.019). CONCLUSIONS: At 24 months after the switch to TAF, VR rates and spine bone density improved significantly while renal function remained stable.

Pretreatment gamma-glutamyl transferase predicts mortality in patients with chronic hepatitis B treated with nucleotide/nucleoside analogs.

Elevated serum gamma-glutamyl transferase (GGT) levels are associated with chronic hepatitis B (CHB)-related hepatocellular carcinoma. However, their role in predicting mortality in patients with CHB treated with nucleotide/nucleoside analogs (NAs) remains elusive. Altogether, 2843 patients with CHB treated with NAs were recruited from a multinational cohort. Serum GGT levels before and 6 months (Month-6) after initiating NAs were measured to explore their association with all-cause, liver-related, and non-liver-related mortality. The annual incidence of all-cause mortality was 0.9/100 person-years over a follow-up period of 17,436.3 person-years. Compared with patients who survived, those who died had a significantly higher pretreatment (89.3 vs. 67.4 U/L, p = 0.002) and Month-6-GGT levels (62.1 vs. 38.4 U/L, p < 0.001). The factors associated with all-cause mortality included cirrhosis (hazard ratio [HR]/95% confidence interval [CI]: 2.66/1.92-3.70, p < 0.001), pretreatment GGT levels (HR/CI: 1.004/1.003-1.006, p < 0.001), alanine aminotransferase level (HR/CI: 0.996/0.994-0.998, p = 0.001), and age (HR/CI: 1.06/1.04-1.07, p < 0.001). Regarding liver-related mortality, the independent factors included cirrhosis (HR/CI: 4.36/2.79-6.89, p < 0.001), pretreatment GGT levels (HR/CI: 1.006/1.004-1.008, p < 0.001), alanine aminotransferase level (HR/CI: 0.993/0.990-0.997, p = 0.001), age (HR/CI: 1.03/1.01-1.05, p < 0.001), and fatty liver disease (HR/CI: 0.30/0.15-0.59, p = 0.001). Pretreatment GGT levels were also independently predictive of non-liver-related mortality (HR/CI: 1.003/1.000-1.005, p = 0.03). The results remained consistent after excluding the patients with a history of alcohol use. A dose-dependent manner of <25, 25-75, and >75 percentile of pretreatment GGT levels was observed with respect to the all-cause mortality (trend p < 0.001). Pretreatment serum GGT levels predicted all-cause, liver-related, and non-liver-related mortality in patients with CHB treated with NAs.

Antiviral therapy substantially reduces HCC risk in patients with chronic hepatitis B infection in the indeterminate phase.

BACKGROUND AND AIMS: HCC risk in chronic hepatitis B (CHB) is higher in the indeterminate phase compared with the inactive phase. However, it is unclear if antiviral therapy reduces HCC risk in this population. We aimed to evaluate the association between antiviral therapy and HCC risk in the indeterminate phase. APPROACH AND RESULTS: We analyzed 855 adult (59% male), treatment-naïve patients with CHB infection without advanced fibrosis in the indeterminate phase at 14 centers (USA, Europe, and Asia). Inverse probability of treatment weighting (IPTW) was used to balance the treated (n = 405) and untreated (n = 450) groups. The primary outcome was HCC development. The mean age was 46±13 years, the median alanine transaminase was 38 (interquartile range, 24-52) U/L, the mean HBV DNA was 4.5±2.1 log 10 IU/mL, and 20% were HBeAg positive. The 2 groups were similar after IPTW. After IPTW (n = 819), the 5-, 10-, and 15-year cumulative HCC incidence was 3%, 4%, and 9% among treated patients (n = 394) versus 3%, 15%, and 19%, among untreated patients (n = 425), respectively ( p = 0.02), with consistent findings in subgroup analyses for age >35 years, males, HBeAg positive, HBV DNA>1000 IU/mL, and alanine transaminase

Syntactic Impairment Associated with Hypoperfusion in the Left Middle and Inferior Frontal Gyri after Right Cerebellar Hemorrhage.

Cerebellar injuries can cause syntax impairments. Cortical dysfunction due to cerebello-cerebral diaschisis is assumed to play a role in this phenomenon. Functional magnetic resonance imaging studies have repeatedly shown the activation of Broca's area in response to syntactic tasks. However, there have been no reports of selective syntax impairment and hypoperfusion restricted to this area after cerebellar injury. We herein report a patient with right cerebellar hemorrhage that led to marked syntax impairment along with severe hypoperfusion confined to the Brodmann area (BA) 45 (anterior part of Broca's area) and BA46.

Dystonia-like Movement Disorders Ameliorated by Shear Force and Pressure Stimulation after Small Infarction in the Left Posterolateral Thalamus.

Focal dystonia (FD) can develop after thalamic lesions. Abnormal somatic sensations were argued to be responsible for FD. Our patient experienced FD-like movement disorders, agraphesthesia, and a reduced sense of shear force on the skin and pressure to deep tissues of the right upper limb following a small infarction in the left posterolateral thalamus. FD-like symptoms improved while the skin was being pulled or the deep tissue was being pushed in a manner proportional to the strength of muscle contractions. Therefore, the lack of these sensations was suggested to be related to FD-like symptoms.

On-treatment gamma-glutamyl transferase predicts the development of hepatocellular carcinoma in chronic hepatitis B patients.

BACKGROUND & AIMS: Gamma-glutamyl transferase (GGT) has been predictive of chronic hepatitis C-related hepatocellular carcinoma (HCC) development. Its role in the risk of HCC in chronic hepatitis B (CHB) patients treated with nucleotide/nucleoside analogues (NAs) is elusive. METHODS: A total of 2172 CHB patients from East Asia were randomized into development and validation groups in a 1:2 ratio. Serum GGT levels before and 6 months (M6) after initiating NAs and the potential risk factors were measured. The primary endpoint was HCC development 12 months after NA initiation. RESULTS: The annual incidence of HCC was 1.4/100 person-years in a follow-up period of 11 370.7 person-years. The strongest factor associated with HCC development was high M6-GGT levels (>25 U/L; hazard ratio [HR]/95% confidence interval [CI]: 3.31/2.02-5.42, P < .001), followed by cirrhosis (HR/CI: 2.06/1.39-3.06, P < .001), male sex (HR/CI: 2.01/1.29-3.13, P = .002) and age (HR/CI: 1.05/1.03-1.17, P < .001). Among cirrhotic patients, the incidence of HCC did not differ between those with high or low M6-GGT levels (P = .09). In contrast, among non-cirrhotic patients, the incidence of HCC was significantly higher for those with M6-GGT level >25 U/L than for their counterparts (P < .001). Cox regression analysis revealed that the strongest factor associated with HCC development in non-cirrhotic patients was high M6-GGT levels (HR/CI: 5.05/2.52-10.16, P < .001), followed by age (HR/CI: 1.07/1.04-1.09, P < .001). Non-cirrhotic elderly patients with high M6-GGT levels had a similarly high HCC risk as cirrhotic patients did (P = .29). CONCLUSIONS: On-treatment serum GGT levels strongly predicted HCC development in CHB patients, particularly non-cirrhotic patients, treated with NAs.

Effect of skin-capsular distance on controlled attenuation parameter for diagnosing liver steatosis in patients with nonalcoholic fatty liver disease.

The effect of the skin-capsular distance (SCD) on the controlled attenuation parameter (CAP) for diagnosis of liver steatosis in patients with nonalcoholic fatty liver disease (NAFLD) remains unclear. The SCD was measured using B-mode ultrasound, and the CAP was measured using the M probe of FibroScan®. According to the indications of the M probe, 113 patients with an SCD of ≤ 25 mm were included in the present study. The association between the SCD and CAP was investigated, and the diagnostic performance of the SCD-adjusted CAP was tested. The SCD showed the most significant positive correlation with the CAP (ρ = 0.329, p < 0.001). In the multiple regression analysis, the SCD and serum albumin concentration were associated with the CAP, independent of pathological liver steatosis. According to the multivariate analysis, two different formulas were developed to obtain the adjusted CAP using the SCD and serum albumin concentration as follows: adjusted CAP (dB/m) = CAP - (5.26 × SCD) and adjusted CAP (dB/m) = CAP - (5.35 × SCD) - (25.77 × serum albumin concentration). The area under the receiver operating characteristic curve for diagnosis of a steatosis score ≥ 2 of adjusted CAP was 0.678 and 0.684 respectively, which were significantly greater than the original CAP (0.621: p = 0.030 and p = 0.024). The SCD is associated with the CAP independent of liver steatosis. Adjustment of the CAP using the SCD improves the diagnostic performance of the CAP in NAFLD.

Analysis of Vertical Micro Acceleration While Standing Reveals Age-Related Changes.

In this study, we investigated the fluctuation characteristics of micro vertical acceleration of center of mass (vCOMacc) in standing and examined the usefulness of vCOMacc as an aging marker for standing control abilities. Sixteen young and 18 older adults participated in this experiment. Data for vCOMacc were calculated as the vertical ground reaction force value divided by each participant's body mass using a force plate. The COMacc frequency structure was determined using the continuous wavelet transform to analyze the relative frequency characteristics. For time domain analysis, we determined the root mean square (RMS) and maximum amplitude (MA) of the integrated power spectral density. We also analyzed the correlation between vCOMacc and lower limb muscle activity. The relative frequency band of vCOMacc was higher in older than young adults, and the time domain indicators were sufficient to distinguish the effects of aging. Regarding the relationship between vCOMacc during standing and muscle activity, a correlation was found with the soleus muscle in young adults, while it was moderately correlated with the gastrocnemius muscle in older adults. The cause of vCOM may be related to differences in muscle activity, and vCOMacc may be utilized to more easily assess the effects of aging in standing control.

ZG16p, an Animal Homologue of Plant ß-Prism Fold Lectins: Purification Methods of Natural and Recombinant ZG16p and Inhibition Assay of Cancer Cell Growth Using ZG16p.

ZG16p is a soluble 16-kDa protein abundantly expressed in the pancreas and gut, and has a ß-prism fold structure similar to that of mannose-binding Jacalin-related lectins (mJRLs) such as BanLec, Heltuba, and Artocarpin. ZG16p binds to mannose via the well-conserved GXXXD loop among mJRLs and sulfated glycosaminoglycans (e.g., heparin and heparan sulfate) via the basic patch of molecular surface. In addition to the above binding activities, ZG16p has inhibitory activity against proliferation of colon cancer cells. This manuscript describes purification of rat pancreatic ZG16p and recombinant ZG16p expressed in Escherichia coli expression system, and cell growth inhibition assay using ZG16p as an inhibitor.

Epidemiological Aspects of Escherichia albertii Outbreaks in Japan and Genetic Characteristics of the Causative Pathogen.

Zoonotic pathogen Escherichia albertii has been identified as the cause of several human disease outbreaks; however, factors such as the general symptoms and incubation period of E. albertii infection have yet to be defined. Therefore, we aimed to determine the unique aspects of E. albertii outbreaks in Japan and to examine the genetic characteristics of the causative pathogen. We studied all known E. albertii outbreaks that occurred in Japan up until 2015, which consisted of five confirmed outbreaks and one putative outbreak (Outbreaks 1-6). Outbreaks were re-examined based on personal communications between researchers in prefectural and municipal public health institutes, and through examination of any published study conducted at the time. Draft genome sequences of outbreak-associated E. albertii isolates were also generated. The most common symptom displayed by patients across the six episodes was watery diarrhea (>80%), followed by abdominal pain (50-84%) and fever (37.0-39.5°C) (26-44%). The estimated average incubation period of E. albertii infection was 12-24 h. We assumed that most of the outbreaks were foodborne or waterborne, with restaurant foods, restaurant water, and boxed lunches being the suspected transmission vehicles. Three of the six outbreak-associated E. albertii isolates possessed intact ETT2 regions, while the remaining isolates contained disrupted ETT2-encoding genes. Virulence gene screening revealed that more than half (44/70) of the tested genes were present in all 5 strains examined, and that each of the strains contained more than 1 gene from 14 out of the 21 groups of virulence genes examined in this study. The five E. albertii strains were classified into four of the five known phylogroups. Therefore, we determined that multiple E. albertii genotypes in Japan have the potential to cause outbreaks of diarrhea, abdominal pain, and/or fever following infection of a human host.

Optimal cutoff values of fasting plasma glucose (FPG) variability for detecting retinopathy and the threshold of FPG levels for predicting the risk of retinopathy in type 2 diabetes: A longitudinal study over 27 years.

AIMS: To determine the cutoff values of fasting plasma glucose (FPG) variability for detecting retinopathy and examine the threshold of FPG levels for predicting retinopathy incidence in type 2 diabetes. METHODS: Subjects comprised 170 patients with type 2 diabetes who had no retinopathy at their first visit, and continuously visited thereafter for 27 years. Retinopathy was evaluated by ophthalmologists at least annually. RESULTS: 114 patients developed retinopathy. 46 of them had advanced retinopathy. The optimal cutoff values of intrapersonal mean and standard deviation (SD) of FPG over 27 years and intrapersonal mean HbA1c from the initial measurement to the last visit for detecting retinopathy were 7.4 mmol/L, 1.4 mmol/L, and 7.2% (56 mmol/mol), respectively. Similarly, for advanced retinopathy, 7.7 mmol/L, 1.9 mmol/L, and 7.5% (59 mmol/mol), respectively. Hazard ratios of deciles of intrapersonal mean FPG (mmol/L) during the initial 2 years for retinopathy incidence significantly increased from eighth-decile (6.9-7.4), and were sharply elevated from ninth-decile (7.4-8.7). CONCLUSIONS: Our study provides new cutoff values for FPG variability. Cutoff values of FPG and HbA1c were slightly higher than recommended targets of the current guideline. The threshold of FPG levels (6.9 mmol/L) is proposed to predict retinopathy incidence during the subsequent 25 years.

Effect of Dialkyl Ammonium Cationic Surfactants on the Microfluidity of Membranes Containing Raft Domains.

It has been reported that a lot of receptors localize in lipid raft domains and that the microfluidity of these domains regulates the activation of these receptors. In this study, we focused on the lipid raft and in order to evaluate the physicochemical effects of surfactants on microfluidity of lipid membranes, we used liposomes comprising of egg-yolk L-α-phosphatidylcholine, egg-yolk sphingomyelin, and cholesterol as a model of cell membranes containing raft domains. The microfluidity of the domains was characterized by fluorescence spectrometry using 1,6-diphenyl-1,3,5-hexatriene and 2-dimethylamino-6-lauroylnaphthalene. Among several surfactants, dialkylammonium-type cationic surfactants most efficiently increased the microfluidity. It is therefore concluded that (1) the electrostatic interaction between the cationic surfactant and eggPC/eggSM/cholesterol liposome could be important, (2) surfactants with alkyl chains more effectively inserted into membranes than those with acyl chains, and (3) cationic surfactants with lower Tm values have a greater ability to increase the fluidity.