Inserting Single-Atom Zn by Tannic Acid Confinement To Regulate the Selectivity of Pd Nanocatalysts for Hydrogenation Reactions.

Precisely controlling the selectivity of nanocatalysts has always been a hot topic in heterogeneous catalysis but remains difficult owing to their complex and inhomogeneous catalytic sites. Herein, an effective strategy to regulate the chemoselectivity of Pd nanocatalysts for selective hydrogenation reactions by inserting single-atom Zn into Pd nanoparticles is reported. Taking advantage of the tannic acid coating-confinement strategy, small-sized Pd nanoparticles with inserted single-atom Zn are obtained on the O-doped carbon-coated alumina. Compared with the pure Pd nanocatalyst, the Pd nanocatalyst with single-atom Zn insertion exhibits prominent selectivity for the hydrogenation of p-iodonitrobenzene to afford the hydrodeiodination product instead of nitro hydrogenation ones. Further computational studies reveal that the single-atom Zn on Pd nanoparticles strengthens the adsorption of the nitro group to avoid its reduction and increases the d-band center of Pd atoms to facilitate the reduction of the iodo group, which leads to enhanced selectivity. This work provides new guidelines to tune the selectivity of nanocatalysts with guest single-atom sites.

Comparison of azithromycin plus chloroquine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in children in Africa: a randomized, open-label study.

BACKGROUND: This randomized, open-label study was conducted to establish the non-inferiority of a combination of azithromycin (AZ) and chloroquine (CQ) to artemether-lumefantrine (AL) for treatment of uncomplicated malaria in children from six sites in sub-Saharan Africa. METHODS: Children with uncomplicated Plasmodium falciparum malaria between six and 59 months of age were randomized 1:1 to either AZCQ (30 mg/kg AZ + 10 mg/kg CQ base) or AL per prescribing information for three days (Days 0, 1, 2). Each site could enrol in the study population once the treatment of uncomplicated malaria in five children five to 12 years of age was deemed to be effective and well tolerated. The primary efficacy evaluation was the proportion of subjects in both the modified intent-to-treat (MITT) and per-protocol (PP) populations with an adequate clinical and parasitological response (PCR corrected) at Day 28. Non-inferiority was concluded if the lower bound of the 95% confidence interval comparing the two groups was 10 percentage points or greater. RESULTS: A total of 255 children were enrolled in the efficacy analysis (AZCQ, n = 124; AL, n = 131). The PCR corrected clearance rates were 89% (AZCQ) versus 98% (AL) for MITT, a difference of -9.10 (95% confidence interval; -16.02, -2.18) and 93% (AZCQ) versus 99% (AL) for PP, a difference of -6.08 (-12.10, -0.05). Early and late treatment failures were more common in subjects receiving AZCQ. Adverse events were more common in subjects treated with AZCQ. Drug concentrations obtained at specified time points following AZCQ administration had a large coefficient of variation partially due to sparse sampling with sample collection time window. CONCLUSIONS: In this study, non-inferiority of AZCQ to AL was not demonstrated. TRIAL REGISTRATION: ClinicalTrials.gov NCT00677833 .

Population pharmacokinetics of azithromycin and chloroquine in healthy adults and paediatric malaria subjects following oral administration of fixed-dose azithromycin and chloroquine combination tablets.

BACKGROUND: Population pharmacokinetics (PK) of azithromycin (AZ) and chloroquine (CQ) following administration of fixed-dose combination tablet formulations of AZ and CQ (AZCQ) was evaluated using data from two studies: 1) in children with symptomatic uncomplicated falciparum malaria in sub-Saharan Africa; and 2) in healthy adults in the United States. METHODS: Study 1 included paediatric subjects randomized to either AZCQ or artemether-lumefantrine treatment in Cohort 1 (age 5-12 years) and Cohort 2 (age 6-59 months). Dosing of AZCQ was approximately 30 mg/kg AZ and 10 mg/kg CQ once daily for 3 days (for ≥20 kg weight: AZ/CQ 300/100 mg per tablet; 5 to <20 kg weight: AZ/CQ 150/50 mg per tablet). Study 2 included adults randomized to receive either two AZCQ tablets (AZ/CQ 250/155 mg per tablet) or individual commercial tablets of AZ 500 mg and CQ 300 mg. Serum AZ and plasma CQ concentrations from both studies were pooled. Population PK models were constructed using standard approaches to evaluate the concentration-time data for AZ and CQ and to identify any covariates predictive of PK behaviour. RESULTS: A three-compartment PK model with linear clearance and absorption adequately described AZ data, while a two-compartment model with linear clearance and absorption and an absorption lag adequately described CQ data. No overall bias or substantial model misspecification was evident using diagnostic plots and visual predictive checks. Body weight as an allometric function was the only covariate in the final AZ and CQ PK models. There were significantly lower AZ (0.488 vs 0.745 [mg•h/L]/[mg/kg], p < 0.00001) and CQ (0.836 vs 1.27 [mg•h/L]/[mg/kg], p < 0.00001) exposures (AUCinf) normalized by dose (mg/kg) in children compared with the adults. CONCLUSIONS: The PK of AZ and CQ following administration of AZCQ was well described using a three- and two-compartment model, respectively. AZ and CQ exhibited linear absorption and clearance; the model for CQ included an absorption lag. Weight was predictive of exposure for both AZ and CQ. Assuming equivalent dosing (mg/kg), AZ and CQ exposure in children would be expected to be lower than that in adults, suggesting that children may require a higher dose (mg/kg) than adults to achieve the same AZ and CQ exposure.

PANoptosis-related long non-coding RNA signature to predict the prognosis and immune landscapes of pancreatic adenocarcinoma.

Background: Cancer growth is significantly influenced by processes such as pyroptosis, apoptosis, and necroptosis that underlie PANoptosis, a proinflammatory programmed cell death. Several studies have examined the long non-coding RNAs (lncRNAs) associated with pancreatic adenocarcinoma (PAAD). However, the predictive value of lncRNAs related to PANoptosis for PAAD has not been established. Methods: The Clinical Genome Atlas database was used to obtain the transcriptome 、clinical data and the corresponding mutation data of the patients with PAAD in this study. The least absolute shrinkage and selection operator regression analysis was employed to obtain prognosis-related lncRNAs for constructing a risk signature. According to the median risk score of the signature, patients with PAAD were grouped into low- and high-risk groups to further compare the survival prognosis of different risk groups. Time-dependent receiver operating characteristic curves, c-index analysis, nomograms, principal component analysis and univariate Cox and multivariate Cox regression were performed for the internal validation of the signature. In addition, enrichment analysis of different genes was performed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Lastly, differences in tumor mutation burden (TMB), immune function, tumor immune dysfunction and rejection (TIDE), and drug response were determined for the two risk groups. Results: The signature was constructed with six PANoptosis-related lncRNAs (AC067817.2、LINC02004、AC243829.1、AC092171.5、AP005233.2、AC004687.1) that predicted the prognosis of the patients with PAAD. Survival curves showed that patients in the two risk groups had statistically significant differences in prognosis (P < 0.05), and multi-cox regression analysis identified risk score as an independent risk factor for PAAD prognosis, and internal validation of nomograms showed high confidence in the signature. GO and KEGG enrichment analysis showed functional and pathway differences between the high- and low-risk groups. TMB evaluation demonstrated that patients in the high-risk group had a higher frequency of mutations. The TIDE score indicated that the high-risk group had a lower risk of immunotherapy escape and better immunotherapy outcomes. Additionally, the two risk groups revealed significantly different responses to 11 anticancer drugs. Conclusion: We identified a novel risk signature for PANoptosis-related lncRNAs, which is a standalone prognostic indicator for PAAD. The PANoptosis-related lncRNA risk signature may be relevant for immunotherapy and a therapeutic target for PAAD.

Safety and pharmacokinetics of PF-04360365 following a single-dose intravenous infusion in Japanese subjects with mild-to-moderate Alzheimer's disease: a multicenter, randomized, double-blind, placebo-controlled, dose-escalation study.

OBJECTIVE: PF-04360365 is a humanized IgG(2)Δa anti-amyloid ß (Aß) antibody designed to improve outcome in Alzheimer's disease (AD). Single doses of 0.1 - 10 mg/kg were safe and well tolerated in Western (mostly Caucasian) subjects with mild-to-moderate AD. This Phase 1, multicenter, randomized, double-blind, dose-escalation study was the first to evaluate the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of PF-04360365 in Japanese subjects. MATERIALS AND METHODS: 30 subjects with mild-to-moderate AD were enrolled. In each cohort, 3 subjects received PF-04360365 (0.1, 0.5, 1, 5, or 10 mg/kg) and 1 subject received placebo as a single 2-hour intravenous infusion. Subjects were monitored as inpatients for 24 hours and then as outpatients for 1 year. RESULTS: All subjects completed the study. There were no serious or National Cancer Institute Common Terminology Criteria for Adverse Events grade ≥ 3 adverse events, hypersensitivity reactions, or antidrug antibodies. No clinical or MRI evidence of brain microhemorrhage, cerebral edema, or encephalitis was observed. PF-04360365 plasma concentrations increased with dose, and pharmacokinetics were consistent with a small steady-state volume of distribution, slow clearance, and long elimination half-life. Cerebrospinal fluid (CSF):plasma ratios were < 0.5%. Plasma Aß species showed dose-dependent increases in C(max) and AUC(∞), but CSF biomarkers did not differ clearly between treatment arms. CONCLUSIONS: PF-04360365 was safe and well tolerated in Japanese subjects. Pharmacokinetics and plasma pharmacodynamic responses in Japanese subjects were comparable to those in Western subjects. *No longer affiliated with Pfizer.

The link between self-uncertainty and conspicuous consumption: Tolerance of uncertainty as a moderator.

This study, based on self-affirmation theory, aims to investigate the impact of self-uncertainty on individual consumption behavior. Self-uncertainty was categorized into moral, cognitive, and interpersonal self-uncertainty, and different types of self-uncertainty were manipulated through four experiments, including a moral dilemma, a recall paradigm, and a picture quiz task written by E-Prime software to examine the effects of different types of self-uncertainty on conspicuous consumption and their possible boundary conditions. Our results show that moral, cognitive, and interpersonal self-uncertainty contribute to a stronger tendency to engage in conspicuous consumption. Our results also suggest that tolerance of uncertainty moderates the effect of self-uncertainty on conspicuous consumption, meaning that subjects with a high tolerance of uncertainty are less inclined to engage in conspicuous consumption than those with a low tolerance of uncertainty, even if they have high self-uncertainty. This study may provide an explanation for conspicuous consumption behavior, further validating the theory of compensatory consumption. Additionally, the results from this study also provide a reference for understanding people's decision-making behavior in an uncertain social context and can provide new guidance to control irrational consumption behavior.

Being Negatively Cued, are People Less Cooperative? The Influence of Watching Eyes on Cooperative Behavior.

In the course of human evolution, watching eyes have had an important influence on individual cooperative behavior. However, researchers have not explored how the valence of watching eyes affects cooperative behavior. Therefore, this study includes three studies to investigate the effect of watching eyes with different valences on cooperative behavior. The results showed that positive watching eyes (vs. negative watching eyes) induced positive emotions (PA) in the participants and thus increased their tendency to cooperate (Studies 1-2). The role of the decision maker (making decisions for oneself vs. making decisions on behalf of others) moderates the effect of watching eyes on cooperative behavior through emotion (Study 3). In conclusion, the valence of watching eyes significantly affects cooperation. This study not only further enriches research on environmental stimulation and cooperation but also provides inspiration and a reference for solving problems of cooperation in social dilemmas.

Clinical Characteristics of Patients With HNF1-alpha MODY: A Literature Review and Retrospective Chart Review.

The clinical manifestation of hepatocyte nuclear factor-1-alpha (HNF1-alpha) maturity-onset diabetes of the young (MODY) is highly variable. This study aims to investigate the clinical characteristics of patients with HNF1-alpha MODY in general, by geographical regions (Asian or non-Asian), HNF1-alpha mutations, and islet autoantibody status. A literature review and a chart review of patients with HNF1-alpha MODY were performed. The means and proportions from studies were pooled using the inverse variance method for pooling, and subgroup analyses were performed. A total of 109 studies involving 1,325 patients [41.5%, 95% confidence interval (CI): 35.2, 48.1; male] were identified. The mean age of diagnosis was 20.3 years (95% CI: 18.3-22.2), and the mean glycated hemoglobin was 7.3% (95% CI: 7.2-7.5). In comparison, Asian patients exhibited significantly higher HbA1c (p = 0.007) and 2-h post-load C-peptide (p = 0.012) levels and lower levels of triglyceride (TG) (p < 0.001), total cholesterol (TC) (p < 0.001), and high-density lipoprotein cholesterol (HDL-c) (p < 0.001) and less often had macrovascular complications (p = 0.014). The age of diagnosis was oldest in patients with mutations in the transactivation domain (p < 0.001). The levels of 2-h post-load C-peptide (p < 0.001), TG (p = 0.007), TC (p = 0.017), and HDL-c (p = 0.001) were highest and the prevalence of diabetic neuropathy was lowest (p = 0.024) in patients with DNA-binding domain mutations. The fasting (p = 0.004) and 2-h post-load glucose (p = 0.003) levels and the prevalence of diabetic neuropathy (p = 0.010) were higher among patients with positive islet autoantibodies. The study demonstrated that the clinical manifestations of HNF1-alpha MODY differed by geographical regions, HNF1-alpha mutations, and islet autoantibody status.

Construction of a cancer-associated fibroblasts-related long non-coding RNA signature to predict prognosis and immune landscape in pancreatic adenocarcinoma.

Background: Cancer-associated fibroblasts (CAFs) are an essential cell population in the pancreatic cancer tumor microenvironment and are extensively involved in drug resistance and immune evasion mechanisms. Long non-coding RNAs (lncRNAs) are involved in pancreatic cancer evolution and regulate the biological behavior mediated by CAFs. However, there is a lack of understanding of the prognostic signatures of CAFs-associated lncRNAs in pancreatic cancer patients. Methods: Transcriptomic and clinical data for pancreatic adenocarcinoma (PAAD) and the corresponding mutation data were obtained from The Cancer Genome Atlas database. lncRNAs associated with CAFs were obtained using co-expression analysis. lncRNAs were screened by Cox regression analysis using least absolute shrinkage and selection operator (LASSO) algorithm for constructing predictive signature. According to the prognostic model, PAAD patients were divided into high-risk and low-risk groups. Kaplan-Meier analysis was used for survival validation of the model in the training and validation groups. Clinicopathological parameter correlation analysis, univariate and multivariate Cox regression, time-dependent receiver operating characteristic (ROC) curves, and nomogram were performed to evaluate the model. The gene set variation analysis (GSVA) and gene ontology (GO) analyses were used to explore differences in the biological behavior of the risk groups. Furthermore, single-sample gene set enrichment analysis (ssGSEA), tumor mutation burden (TMB), ESTIMATE algorithm, and a series of immune correlation analyses were performed to investigate the relationship between predictive signature and the tumor immune microenvironment and screen for potential responders to immune checkpoint inhibitors. Finally, drug sensitivity analyses were used to explore potentially effective drugs in high- and low-risk groups. Results: The signature was constructed with seven CAFs-related lncRNAs (AP005233.2, AC090114.2, DCST1-AS1, AC092171.5, AC002401.4, AC025048.4, and CASC8) that independently predicted the prognosis of PAAD patients. Additionally, the high-risk group of the model had higher TMB levels than the low-risk group. Immune correlation analysis showed that most immune cells, including CD8+ T cells, were negatively correlated with the model risk scores. ssGSEA and ESTIMATE analyses further indicated that the low-risk group had a higher status of immune cell infiltration. Meanwhile, the mRNA of most immune checkpoint genes, including PD1 and CTLA4, were highly expressed in the low-risk group, suggesting that this population may be "hot immune tumors" and have a higher sensitivity to immune checkpoint inhibitors (ICIs). Finally, the predicted half-maximal inhibitory concentrations of some chemical and targeted drugs differ between high- and low-risk groups, providing a basis for treatment selection. Conclusion: Our findings provide promising insights into lncRNAs associated with CAFs in PAAD and provide a personalized tool for predicting patient prognosis and immune microenvironmental landscape.

Disease progression model for cognitive deterioration from Alzheimer's Disease Neuroimaging Initiative database.

BACKGROUND: A mathematical model was developed to describe the longitudinal response in Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) obtained from the Alzheimer's Disease Neuroimaging Initiative. METHODS: The model was fit to the longitudinal ADAS-cog scores from 817 patients. Risk factors (age, apolipoprotein ɛ4 [APOE ɛ4] genotype, gender, family history of AD, years of education) and baseline severity were tested as covariates. RESULTS: Rate of disease progression increased with baseline severity. Age, APOE ɛ4 genotype, and gender were identified as potential covariates influencing disease progression. The rate of disease progression in patients with mild to moderate AD was estimated as approximately 5.5 points/yr. CONCLUSIONS: A disease progression model adequately described the natural decline of ADAS-cog observed in Alzheimer's Disease Neuroimaging Initiative. Baseline severity is an important covariate to predict a curvilinear rate of disease progression in normal elderly, mild cognitive impairment, and AD patients. Age, APOE ɛ4 genotype, and gender also influence the rate of disease progression.

Meta-Analysis of the Relationship between Abdominal Obesity and Diabetic Kidney Disease in Type 2 Diabetic Patients.

BACKGROUND AND OBJECTIVES: The meta-analysis aimed to investigate the association of visceral fat area (VFA), waist circumference (WC), waist-hip ratio (WHR) and waist-height ratio (WHtR) with diabetic kidney disease (DKD) in type 2 diabetic patients. METHODS: Included studies were searched from Pubmed, Embase, and the Cochrane Library before July 2020. We synthesized the pooled results of the above relationships by meta-analysis. RESULTS: Fourteen cross-sectional studies were enrolled. The pooled results indicated there was a significant difference in continuous VFA, WC and WHR/WHtR between patients with DKD and those without DKD (standard mean difference, SMD, 0.24, 95% confidence interval, CI, 0.13-0.36, p = 0.000). For VFA, patients with DKD had higher VFA levels than those without DKD (SMD 0.27, 95% CI 0.03-0.50). In the WC subgroup, patients with DKD had higher WC levels than those without DKD (SMD 0.17, 95% CI 0.10-0.24); similarly, abdominal obesity (dichotomized WC) was significantly associated with an increase in the odds of DKD (expected shortfall, ES, 1.57, 95% CI 1.32-1.86). However, the association of continuous WHR/WHtR with DKD was not statistically significant (SMD 0.43, 95% CI -0.12 to 0.97), while we found this relationship was statistically significant when analyzed categorically (ES 1.58, 95% CI 1.22-2.06). CONCLUSION: In this meta-analysis, we found abdominal obesity parameters (continuous VFA, WC) were associated with increased odds of DKD, and type 2 diabetic patients with DKD were more likely to have abdominal obesity (categorized using WC or WHR/WHtR).

Surgical Resection of Pancreatic Hepatoid Carcinoma Followed by Combined Transarterial Chemoembolization and Immunotherapy: A Case Report.

Pancreatic hepatoid carcinoma (HC) is a heterogeneous tumor with high degree of malignancy and poor prognosis, which display cytological and/or structural features of focal hepatocellular carcinoma (HCC). For the low incidence and atypical clinical symptoms, it is possible to be diagnosed as pancreatic cancer before operation, and mainly depending on the pathological examination. To the best of our knowledge, surgery combined with radiotherapy and chemotherapy is the common treatment of pancreatic HC. However, the curative effect and prognosis is poor. We report a case of 44-year-old woman with pancreatic HC treated with PD-1 receptor inhibitor and transarterial chemoembolization, whose clinical symptoms and laboratory indexes are significantly improved after treatment.

Perirenal Fat Thickness Is Significantly Associated With the Risk for Development of Chronic Kidney Disease in Patients With Diabetes.

Perirenal fat is adjacent to kidneys and active in metabolism and adipokine secretion. We aimed to investigate whether perirenal fat is an independent predictor for chronic kidney disease (CKD) and compared it with total, subcutaneous, or visceral fat in patients with diabetes. Perirenal fat thickness (PRFT) was measured by computed tomography, and total body fat (TBF), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) were assessed by DEXA. In cross-sectional analysis, patients with higher PRFT had a lower estimated glomerular filtration rate (eGFR). Multiple linear regression analysis showed a negative correlation between PRFT and eGFR after confounders adjustment. No association between eGFR and TBF, SAT, or VAT was observed. Longitudinally, 190 patients with type 2 diabetes mellitus (T2DM) without CKD at baseline were followed for 2 years. A total of 29 participants developed CKD. After VAT-based multivariate adjustment, each SD (per-SD) increment in baseline PRFT was associated with a higher incidence of CKD (hazard ratio 1.67, 95% CI 1.04-2.68), while TBF, SAT, and VAT were not. Furthermore, PRFT predicted CKD, with a C-statistic (95% CI) of 0.668 (0.562, 0.774), which was higher than that of TPF [0.535 (0.433, 0.637)], SAT [0.526 (0.434, 0.618)], and VAT [0.602 (0.506, 0.698)]. In conclusion, with perirenal fat there was a higher predictive value for CKD than with total, subcutaneous, or visceral fat in T2DM.

Bioequivalence and Bioavailability of an Orodispersible Tablet of Sildenafil Citrate in Healthy Chinese Male Subjects.

Sildenafil citrate is approved to treat erectile dysfunction. An orally disintegrating tablet (ODT) of sildenafil citrate that does not require swallowing or administration with fluids has been developed. The bioequivalence and bioavailability of sildenafil citrate ODT (50 mg) without and with water were compared with conventional sildenafil citrate tablets (50 mg) in an open-label, randomized crossover study. Healthy Chinese male subjects (n = 36) were allocated to 1 of 6 sildenafil citrate treatment sequences under fasted conditions, and plasma samples for determination of sildenafil concentrations were collected predose through 14 hours postdose. Bioequivalence was demonstrated for sildenafil citrate ODT administered without water relative to the sildenafil citrate tablet administered with water; 90%CIs for the ratios of adjusted geometric means for sildenafil AUClast , Cmax , and AUCinf (ratio, 101.41%; 90%CI, 95.49%-107.70%; ratio, 93.55%; 90%CI, 84.15%-104.00%; and ratio, 101.03%; 90%CI, 94.80%-107.66%; respectively) were wholly contained within the bioequivalence acceptance range of 80% to 125%, indicating bioequivalence criteria were met. Relative bioavailability of sildenafil citrate ODT administered with water to the sildenafil citrate tablet (50 mg) administered with water was 97.10%, 91.43%, and 97.09% with respect to sildenafil AUClast , Cmax , and AUCinf , respectively (90%CI, 91.43%-03.12%, 82.25%-101.65%, and 90.90%-103.71%, respectively). Both sildenafil citrate formulations were generally well tolerated in healthy Chinese men. Sildenafil citrate ODT administered without or with water was bioequivalent to or met bioequivalence criteria compared with conventional sildenafil citrate tablets administered with water under fasted conditions in healthy Chinese men, thus offering a convenient alternative method of oral administration.

Optimal Cut-Offs of Body Mass Index and Waist Circumference to Identify Obesity in Chinese Type 2 Diabetic Patients.

PURPOSE: The prevalence of general obesity (commonly defined by body mass index (BMI) in kg/m2) and abdominal obesity (commonly assessed by waist circumference (WC)) has increased rapidly in China. The aim of this study was to investigate the diagnostic accuracy of traditional cut-offs for BMI or WC to identify general or abdominal obesity in Chinese type 2 diabetic patients and propose optimal cut-offs. PATIENTS AND METHODS: BMI and WC were obtained from 1539 type 2 diabetic patients. Body fat percentage and visceral fat area measured by dual-energy x-ray absorptiometry were set as the gold standard to identify general and abdominal obesity. We assessed the diagnostic power of traditional cut-offs for BMI and WC to define obesity, and analyzed receive operating characteristic (ROC) curves to obtain the optimal cut-offs to identify obesity in Chinese type 2 diabetic patients. RESULTS: In Chinese type 2 diabetic patients, the optimal BMI was 25 kg/m2 with the best trade-off between sensitivity and specificity (men: 74.6% (95% CI: 70.7-78.2%) and 65.1% (95% CI: 59.7-70.3%), AUC 0.78 (95% CI: 0.75-0.81), p<0.05; women: 65.8% (95% CI: 60.3-71.0%) and 80.3% (95% CI: 75.7-84.3%), AUC 0.80 (95% CI: 0.77-0.83), p<0.05) in both genders. The optimal WC was 93 cm in men and 90 cm in women with the best trade-off between sensitivity and specificity (men: 87.2% (95% CI: 84.3-89.8%) and 80.2% (95% CI: 74.9-84.8%), AUC 0.91 (95% CI: 0.88-0.92), p<0.05; women: 81.0% (95% CI: 76.9-84.6%) and 88.7% (95% CI: 83.9-92.4%), AUC 0.92 (95% CI: 0.90-0.94), p<0.05). CONCLUSION: For the Chinese patients with type 2 diabetes, the optimal cut-offs for BMI or WC to identify general or abdominal obesity need to be reconsidered.

Early-onset type 2 diabetes: A high-risk factor for proliferative diabetic retinopathy (PDR) in patients with microalbuminuria.

We aim to explore the relationship between early-onset diabetes and proliferative diabetic retinopathy (PDR) in type 2 diabetes mellitus (T2DM) patients with microalbuminuria.A total of 461 T2DM patients with microalbuminuria were enrolled. Subjects were defined as early-onset or late-onset based on the age at which they were diagnosed with diabetes (<40 and ≥40 years, respectively). Medical history, anthropometry, and laboratory indicators were documented. PDR was defined as the presence of any of the following changes on fundus photography: neovascularization, vitreous hemorrhage, or preretinal hemorrhage.The prevalence of PDR was 6-fold higher in patients with early-onset than late-onset T2DM [(6.1% vs 1.0%), P = .004]. Univariate correlation analysis showed that early-onset diabetes, use of oral hypoglycemic drugs, and insulin therapy were risk factors for PDR. In multivariate logistic analysis, patients with early-onset diabetes exhibited a 7.00-fold [(95% confidence interval 1.40-38.26), P = .019] higher risk of PDR than subjects with late-onset diabetes after adjusting for sex; T2DM duration; systolic blood pressure; total triglyceride; glycated hemoglobin; insulin therapy; and the use of oral hypoglycemic drugs, antihypertensive drugs, and lipid-lowering drugs.In T2DM patients with microalbuminuria, early-onset diabetes is an independent risk factor for the development of PDR.

U.S. Phase I First-in-human Study of Taletrectinib (DS-6051b/AB-106), a ROS1/TRK Inhibitor, in Patients with Advanced Solid Tumors.

PURPOSE: Taletrectinib (DS-6051b/AB-106) is an oral, tyrosine kinase inhibitor of ROS1 and NTRK with potent preclinical activity against ROS1 G2032R solvent-front mutation among others. We report the first-in-human U.S. phase I results of taletrectinib. PATIENTS AND METHODS: Patients ≥18 years old with neuroendocrine tumors, with tumor-induced pain, or tumors harboring ROS1/NTRK rearrangements were eligible. Accelerated titration followed by modified continuous reassessment method and escalation with overdose control was used (50-1,200 mg once daily or 400 mg twice daily). Primary objectives were safety/tolerability, and MTD determination. Secondary objectives were food-effect pharmacokinetics and antitumor activity. RESULTS: A total of 46 patients were enrolled. Steady-state peak concentration (C max) and exposure (AUC0-8) increased dose dependently from 50-mg to 800-mg once-daily doses. The ratio of the geometric mean of AUC0-24 between low-fat-diet-fed/fasted state was 123% (90% confidence interval, 104%-149%). Dose-limiting toxicities (grade 3 transaminases increase) occurred in two patients (1,200-mg once-daily dose). MTD was 800 mg once daily. Most common treatment-related adverse events were nausea (47.8%), diarrhea (43.5%), and vomiting (32.6%). Pain score reductions were observed in the 800-mg once-daily dose cohort. Confirmed objective response rate was 33.3% among the six patients with RECIST-evaluable crizotinib-refractory ROS1+ NSCLC. One patient with TPM3-NTRK1 differentiated thyroid cancer achieving a confirmed partial response of 27 months at data cutoff. We identified a cabozantinib-sensitive ROS1 L2086F as an acquired taletrectinib-resistance mutation. CONCLUSIONS: Taletrectinib has manageable toxicities at the MTD of 800 mg daily. Preliminary efficacy was observed in patients with crizotinib-refractory ROS1+ NSCLC.

Population Pharmacokinetics of Eplerenone in Japanese Patients With Chronic Heart Failure.

To characterize eplerenone pharmacokinetics (PK) in Japanese chronic heart failure (CHF) patients and to estimate the impact of factors that may affect eplerenone PK, population pharmacokinetic (PPK) analysis was conducted. In addition, PK of Japanese CHF and Western CHF patients from a previous clinical pharmacology study were compared in the analysis. Eplerenone PK was characterized by a 1-compartment PPK model with first-order absorption and lag time in Japanese CHF patients. The population mean of apparent oral clearance (CL/F) in Japanese CHF patients was estimated as 5.31 L/h, which was similar to the mean CL/F for Western CHF patients. In the full model approach, creatinine clearance (CLcr) on CL/F and body weight on apparent central volume of distribution (Vc/F) were selected as factors that may affect PK. The effect of CLcr on CL/F predicted that CL/F would be decreased by 25% when CLcr was decreased from 80 mL/min to 50 mL/min. The effect of body weight on Vc/F predicted that Vc/F would be decreased by 18% when body weight was decreased from 80 kg to 60 kg. Distribution of individual CL/F estimates for Japanese CHF patients overlapped CL/F observed values for Western CHF patients, and CL/F values for Western CHF patients were contained within the distribution of CL/F estimates for Japanese CHF patients. No obvious difference between Japanese and Western subjects was detected even in the updated model by adding the data obtained from Western CHF patients and Western healthy adults to the model constructed with data from Japanese CHF patients.

Multiple-dose ponezumab for mild-to-moderate Alzheimer's disease: Safety and efficacy.

INTRODUCTION: Multiple intravenous doses of ponezumab, an anti-amyloid antibody, were evaluated in subjects with mild-to-moderate Alzheimer's disease (AD). METHODS: In part A, 77 subjects were randomized to ponezumab 0.1, 0.5, or 1 mg/kg (75 treated) and 26 to placebo (24 treated). In part B, 63 subjects were randomized and treated with ponezumab 3 or 8.5 mg/kg and 32 with placebo. Subjects received 10 infusions over 18 months and were followed for 6 months thereafter. RESULTS: Ponezumab was generally safe and well tolerated. Most common adverse events were fall (16.7% ponezumab, 21.4% placebo), headache (13.8%, 21.4%), and cerebral microhemorrhage (13.8%, 19.6%). Plasma ponezumab increased dose-dependently with limited accumulation. Cerebrospinal fluid penetration was low. Plasma Aß1-x and Aß1-40 showed robust increases, but cerebrospinal fluid biomarkers showed no dose response. Ponezumab had no effects on cognitive/functional outcomes or brain volume. CONCLUSIONS: Multiple-dose ponezumab was generally safe, but not efficacious, in mild-to-moderate AD.

Rationale for combination therapy with galantamine and memantine in Alzheimer's disease.

A combination of cholinergic and glutamatergic dysfunction appears to underlie the symptomatology of Alzheimer's disease. Therefore, one hypothesis is that treatment strategies should address impairments in both systems. Galantamine is an acetylcholinesterase inhibitor that, unlike other acetylcholinesterase inhibitors, has a postulated dual mode of action as a nicotinic receptor modulator. Galantamine has demonstrated long-term efficacy in improving or maintaining cognition, functionality, and behavior in patients with mild to moderate Alzheimer's disease. Memantine, a noncompetitive N-methyl-D-aspartate-receptor antagonist, reduces deterioration in cognition and function in patients with moderate to severe Alzheimer's disease. Pharmacokinetic and pharmacodynamic as well as ongoing observation studies support the concept of adjunctive therapy with memantine in patients with advanced moderate Alzheimer's disease currently treated with an established galantamine regimen. The potential to modulate both acetylcholine and glutamate pathways in Alzheimer's disease presents a novel treatment strategy for the management of mild to moderately severe Alzheimer's disease.