The cortisol awakening response in a 3 month clinical trial of service dogs for veterans with posttraumatic stress disorder.

Recent literature suggests that service dogs may be a valuable complementary intervention option for posttraumatic stress disorder (PTSD) among military veterans due to the potential influence on stress response dysregulation. The aim of this short-term longitudinal study was to quantify the impact of service dogs in US military veterans with PTSD with particular attention to the cortisol awakening response. A sub aim of the study was to empirically evaluate the physiological effects of PTSD service dogs on veteran partners. We conducted a clinical trial (ID: NCT03245814) that assessed the cortisol awakening response for 245 participants at baseline and 3 months follow-up across an intervention group (service dog: veterans n = 88, partners n = 46) and control group (usual care: n = 73, partners n = 38). A total of N = 161 veterans and N = 84 partners collected whole saliva samples via a passive drool collection immediately upon waking, 30 min after waking, and 45 min after waking on three consecutive weekdays at baseline and again at follow-up. Mixed model repeated measures (MMRM) with a fixed effect of the intervention group (service dog or control) were utilized. Covariates considered for the model included time of awakening, sleep duration, sleep efficiency, prior day experiences (measured via ecological momentary assessment), traumatic brain injury, age, gender, race, ethnicity, socioeconomic status, smoking status, alcohol use, physical health, and body mass index. A total of 3951 salivary samples were collected (veterans: 2613, partners: 1338). MMRM results demonstrated that veterans with a service dog had a statistically significant higher cortisol awakening response, including the area under the curve with respect to both increase (AUCi, ß = 1.46, p = 0.046) and absolute increase (AINC, ß = 0.05, p = 0.035). Results were not statistically significant for partners. Findings suggest that veterans with service dogs have a higher, less blunted CAR in comparison to veterans receiving usual care alone. In veterans with a blunted morning cortisol response, service dog placement could help boost their morning cortisol response.

CITIES: Clinical trials with intercurrent events simulator.

Although clinical trials are often designed with randomization and well-controlled protocols, complications will inevitably arise in the presence of intercurrent events (ICEs) such as treatment discontinuation. These can lead to missing outcome data and possibly confounding causal inference when the missingness is a function of a latent stratification of patients defined by intermediate outcomes. The pharmaceutical industry has been focused on developing new methods that can yield pertinent causal inferences in trials with ICEs. However, it is difficult to compare the properties of different methods developed in this endeavor as real-life clinical trial data cannot be easily shared to provide benchmark data sets. Furthermore, different methods consider distinct assumptions for the underlying data-generating mechanisms, and simulation studies often are customized to specific situations or methods. We develop a novel, general simulation model and corresponding Shiny application in R for clinical trials with ICEs, aptly named the Clinical Trials with Intercurrent Events Simulator (CITIES). It is formulated under the Rubin Causal Model where the considered treatment effects account for ICEs in clinical trials with repeated measures. CITIES facilitates the effective generation of data that resemble real-life clinical trials with respect to their reported summary statistics, without requiring the use of the original trial data. We illustrate the utility of CITIES via two case studies involving real-life clinical trials that demonstrate how CITIES provides a comprehensive tool for practitioners in the pharmaceutical industry to compare methods for the analysis of clinical trials with ICEs on identical, benchmark settings that resemble real-life trials.

Psychiatric service dog placements are associated with better daily psychosocial functioning for military veterans with posttraumatic stress disorder.

OBJECTIVE: Psychiatric service dog placements may benefit psychosocial functioning for veterans with posttraumatic stress disorder (PTSD), however, these effects have never been examined directly in daily life. This nonrandomized longitudinal clinical trial quantified the efficacy of psychiatric service dogs for daily psychosocial functioning among N = 168 veterans with PTSD using ecological momentary assessment (EMA). METHOD: EMA data were collected twice daily for 2 weeks at each assessment period (0 and 3 months), totaling 9,408 survey responses (2 Assessments × 14 Days × 2 Prompts × 168 Participants). RESULTS: At follow-up, regression analysis identified associations between service dog placement and better perceived social interaction quality (ß = 0.42, p < .05), better affect (negative affect: ß = -2.64, p < .001; positive affect: ß = 2.44, p < .001), and lower odds of panic attacks (OR = 0.68, p < .05). Social participation results were mixed: placements were associated with greater activity participation (ß = 3.21, p < .001) but lower odds of being away from home (OR = 0.77, p < .05), indicating possible support for anecdotes that public stigma is an obstacle to community participation. CONCLUSIONS: Results further revealed that the service dog's trained tasks may be particularly important for social functioning outcomes, and the service dog's presence for emotional functioning outcomes. Findings highlight a need for education surrounding service dog etiquette and reveal potential mechanisms underlying psychiatric service dog placements. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Physicians' very brief (30-sec) intervention for smoking cessation on 13 671 smokers in China: a pragmatic randomized controlled trial.

BACKGROUND AND AIMS: Three to 10 minutes of smoking cessation advice by physicians is effective to increase quit rates, but is not routinely practised. We examined the effectiveness of physicians' very brief (approximately 30 sec) smoking cessation intervention on quit rates among Chinese outpatient smokers. DESIGN: A pragmatic, open-label, individually randomized controlled trial. SETTING: Seventy-two medical outpatient departments of hospitals and/or community health centers in Guangdong, China. PARTICIPANTS: Chinese adults who were daily cigarette smokers (n = 13 671, 99% males) were invited by their physician to participate during outpatient consultation. Smokers who were receiving smoking cessation treatment or were judged to need specialist treatment for cessation were excluded. INTERVENTIONS: The intervention group (n = 7015) received a 30-sec intervention including physician's very brief advice, a leaflet with graphic warnings and a card with contact information of available cessation services. The control group (n = 6656) received a very brief intervention on consuming vegetables and fruit. A total of 3466 participants in the intervention group were further randomized to receive a brief booster advice from trained study personnel via telephone 1 month following their doctor visit. MEASUREMENTS: The primary outcome was self-reported 7-day point prevalence abstinence (PPA) in the intervention and control groups at the 12-month follow-up. Secondary outcomes included self-reported 30-day abstinence and biochemically validated abstinence at 12-month follow-up. FINDINGS: By intention-to-treat, the intervention (versus control) group had greater self-reported 7-day abstinence [9.1 versus 7.8%, odds ratio (OR) = 1.14, 95% confidence interval (CI) = 1.03-1.26, P = 0.008] and 30-day abstinence (8.0 versus 6.9%, OR = 1.14, 95% CI = 1.03-1.27, P = 0.01) at 12-month follow-up. The effect size increased when only participants who received the intervention from compliant physicians were included (7-day PPA, OR = 1.42, 95% CI = 1.11-1.74). The group difference in biochemically validated abstinence was small (0.8 versus 0.8%, OR = 1.00, 95% CI = 0.71-1.42, P = 0.99). CONCLUSION: A 30-sec smoking cessation intervention increased self-reported abstinence among mainly male smokers in China at 12-month follow-up (risk difference = 1.3%), and should be feasible to provide in most settings and delivered by all health-care professionals.

Astragaloside IV promotes the proliferation and migration of osteoblast-like cells through the hedgehog signaling pathway.

The present study aimed to investigate the effects of astragaloside IV on osteoblast­like cell proliferation and migration, in addition to the underlying signaling pathway. In order to observe the effect on proliferation, a Cell Counting Kit­8 assay and flow cytometry were used. To detect cell migration ability, cell scratch and Transwell cell migration assays were performed. The RNA and protein expression levels of hedgehog signaling molecules, including Sonic hedgehog (SHH) and GLI family zinc finger 1 (GLI1), were examined by reverse transcription­quantitative polymerase chain reaction and western blot analyses. To inhibit the hedgehog signaling pathway, cyclopamine was used. Astragaloside IV, at a dosage of 1x10­2 µg/ml in MG­63 cells and 1x10­3 µg/ml in U­2OS cells, resulted in the enhanced proliferation and migration of cells, and the gene expression levels of the SHH and GLI1 were significantly increased. The combination of astragaloside IV and cyclopamine reduced MG­63 and U­2OS cell proliferation and migration, and inhibited the gene expression of SHH and GLI1. Astragaloside IV enhanced the proliferation and migration of human osteoblast­like cells through activating the hedgehog signaling pathway. The results of the present study provide a rational for the mechanistic link in astragaloside IV promoting the proliferation and migration of osteoblasts via the hedgehog signaling pathway.

Discovery of AM-6226: A Potent and Orally Bioavailable GPR40 Full Agonist That Displays Efficacy in Nonhuman Primates.

GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets and enteroendocrine L-cells, and, when activated, elicits increased insulin secretion only in the presence of elevated glucose levels. We recently reported the discovery of AM-1638 (2), a full agonist of GPR40. Herein, we present further structure-activity relationships progressing from AM-1638 (2) to AM-6226 (14) that possesses a profile acceptable for dosing cynomolgus monkeys. The GPR40 full agonist AM-6226 (14) is the first molecule to display significant glucose lowering in cynomolgus monkeys providing additional evidence that GPR40 full agonists afford access to a powerful mechanism for maintaining glycemic control.

A good prognostic predictor for liver transplantation recipients with benign end-stage liver cirrhosis.

BACKGROUND: Post-transplant model for predicting mortality (PMPM, calculated as -5.359+1.988Xln (serum creatinine [mg/dL])+1.089Xln (total bilirubin [mg/dL])) score has been proved to be a simple and accurate model for predicting the prognosis after liver transplantation (LT) in a single center study. Here we aim to verify this model in a large cohort of patients. METHODS: A total of 2727 patients undergoing LT with end-stage liver cirrhosis from January 2003 to December 2010 were included in this retrospective study. Data were collected from the China Liver Transplant Registry (CLTR). PMPM score was calculated at 24-h and 7-d following LT. According to the PMPM score at 24-h, all patients were divided into the low-risk group (PMPM score ≤-1.4, n=2509) and the high-risk group (PMPM score >-1.4, n=218). The area under receiver operator characteristic curve (AUROC) was calculated for evaluating the prognostic accuracy. RESULTS: The 1-, 3-, and 5-year patient survival rates in the low-risk group were significantly higher than those in the high-risk group (90.23%, 88.01%, and 86.03% vs 63.16%, 59.62%, and 56.43%, respectively, P<0.001). In the high-risk group, 131 patients had a decreased PMPM score (≤-1.4) at 7-d, and their cumulative survival rate was significantly higher than the other 87 patients with sustained high PMPM score (>-1.4) (P<0.001). For predicting 3-month mortality, PMPM score showed a much higher AUROC than post-transplant MELD score (P<0.05). CONCLUSION: PMPM score is a simple and effective tool to predict short-term mortality after liver transplantation in patients with benign liver diseases, and an indicator for prompt salvaging treatment as well.

Adaptive Estimation of Personalized Maximum Tolerated Dose in Cancer Phase I Clinical Trials Based on All Toxicities and Individual Genomic Profile.

BACKGROUND: Many biomarkers have been shown to be associated with the efficacy of cancer therapy. Estimation of personalized maximum tolerated doses (pMTDs) is a critical step toward personalized medicine, which aims to maximize the therapeutic effect of a treatment for individual patients. In this study, we have established a Bayesian adaptive Phase I design which can estimate pMTDs by utilizing patient biomarkers that can predict susceptibility to specific adverse events and response as covariates. METHODS: Based on a cutting-edge cancer Phase I clinical trial design called escalation with overdose control using normalized equivalent toxicity score (EWOC-NETS), which fully utilizes all toxicities, we propose new models to incorporate patient biomarker information in the estimation of pMTDs for novel cancer therapeutic agents. The methodology is fully elaborated and the design operating characteristics are evaluated with extensive simulations. RESULTS: Simulation studies demonstrate that the utilization of biomarkers in EWOC-NETS can estimate pMTDs while maintaining the original merits of this Phase I trial design, such as ethical constraint of overdose control and full utilization of all toxicity information, to improve the accuracy and efficiency of the pMTD estimation. CONCLUSIONS: Our novel cancer Phase I designs with inclusion of covariate(s) in the EWOC-NETS model are useful to estimate a personalized MTD and have substantial potential to improve the therapeutic effect of drug treatment.

Discovery of the imidazole-derived GPR40 agonist AM-3189.

As a follow-up to the GPR40 agonist AMG 837, which was evaluated in clinical trials for the treatment of type II diabetes, further optimization led to the discovery of AM-3189 (13k). AM-3189 is representative of a new class of compounds with minimal CNS penetration, superior pharmacokinetic properties and in vivo efficacy comparable to AMG 837.

Improving the Pharmacokinetics of GPR40/FFA1 Full Agonists.

We recently reported the discovery of a potent GPR40 full agonist AM-1638 (1). Herein, we describe our efforts in improving the drug-like properties of the full agonists through the systematic introduction of polar groups in the C-, D-, and A-rings. This led to the discovery of new GPR40 full agonists with significantly improved pharmacokinetic propeties. Compound 8 and 20 also showed potent in vivo efficacy in oral glucose tolerance tests in mice in addition to the improvement in properties.

Optimization of GPR40 Agonists for Type 2 Diabetes.

GPR40 (FFA1 and FFAR1) has gained significant interest as a target for the treatment of type 2 diabetes. TAK-875 (1), a GPR40 agonist, lowered hemoglobin A1c (HbA1c) and lowered both postprandial and fasting blood glucose levels in type 2 diabetic patients in phase II clinical trials. We optimized phenylpropanoic acid derivatives as GPR40 agonists and identified AMG 837 (2) as a clinical candidate. Here we report our efforts in searching for structurally distinct back-ups for AMG 837. These efforts led to the identification of more polar GPR40 agonists, such as AM-4668 (10), that have improved potency, excellent pharmacokinetic properties across species, and minimum central nervous system (CNS) penetration.

ZIP4, a novel determinant of tumor invasion in hepatocellular carcinoma, contributes to tumor recurrence after liver transplantation.

BACKGROUND AND PURPOSE: Recently, evidence that Zinc transporter ZRT/IRT-like protein 4 (ZIP4) is involved in invasiveness and apoptosis has emerged in pancreatic cancer and prostate cancer. Our aim was to assess the role of ZIP4 in invasiveness, migration and apoptosis of hepatocellular carcinoma (HCC). The prognostic value of ZIP4 in HCC after liver transplantation was evaluated. METHODS: The role of ZIP4 in HCC was investigated by overexpressing ZIP4 in BEL7402 and HepG2 cells and inhibiting ZIP4 in HuH-7 and HepG2 cells, using overexpression and shRNA plasmids in vitro studies. Immunohistochemical analysis was used to evaluate ZIP4 expression in HCC tissues from 60 patients undergoing liver transplantation, 36 cirrhotic tissue samples, and 6 normal tissue samples. Prognostic significance was assessed using the Kaplan-Meier method and the log-rank test. RESULTS: Specific suppression of ZIP4 reduced cell migration and invasiveness, whereas ZIP4 overexpression caused increases in cell migration and invasiveness. Furthermore, overexpression of ZIP4 resulted in increased expression of pro-metastatic genes (MMP-2, MMP-9) and decreased expression of pro-apoptotic genes (caspase-3, caspase-9, Bax). In contrast, suppression of ZIP4 resulted in an opposite effect. ZIP4 was more highly expressed in tumor tissues than non-tumor tissues (P < 0.0001). ZIP4 expression was significantly associated with tumor recurrence (P = 0.002), tumor node metastasis stage (P = 0.044), Child-Turcotte-Pugh score (P = 0.042), and tumor size (P = 0.022). Univariate analysis showed that ZIP4 expression was significantly associated with overall survival (P = 0.020) and tumor-free survival (P = 0.049). Multivariate analysis revealed that ZIP4 was an independent predictor of overall survival (P = 0.037) after liver transplantation. CONCLUSIONS: ZIP4 could promote migration, invasiveness, and suppress apoptosis in hepatocellular carcinoma, and represent a novel predictor of poor prognosis and therapeutic target for patients with HCC who undergo liver transplantation.

Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles.

GPR40 (FFAR1 or FFA1) is a target of high interest being pursued to treat type II diabetes due to its unique mechanism leading to little risk of hypoglycemia. We recently reported the discovery of AM-1638 (2), a potent full agonist of GPR40. In this report, we present the discovery of GPR40 full agonists containing conformationally constrained tricyclic spirocycles and their structure-activity relationships leading to more potent agonists such as AM-5262 (26) with improved rat PK profile and general selectivity profile. AM-5262 enhanced glucose stimulated insulin secretion (mouse and human islets) and improved glucose homeostasis in vivo (OGTT in HF/STZ mice) when compared to AM-1638.

Potent and Orally Bioavailable GPR142 Agonists as Novel Insulin Secretagogues for the Treatment of Type 2 Diabetes.

GPR142 is a G protein-coupled receptor that is predominantly expressed in pancreatic ß-cells. GPR142 agonists stimulate insulin secretion in the presence of high glucose concentration, so that they could be novel insulin secretagogues with reduced or no risk of hypoglycemia. We report here the optimization of HTS hit compound 1 toward a proof of concept compound 33, which showed potent glucose lowering effects during an oral glucose tolerance test in mice and monkeys.

Aminopyrazole-Phenylalanine Based GPR142 Agonists: Discovery of Tool Compound and in Vivo Efficacy Studies.

Herein, we report the lead optimization of amrinone-phenylalanine based GPR142 agonists. Structure-activity relationship studies led to the discovery of aminopyrazole-phenylalanine carboxylic acid 22, which exhibited good agonistic activity, high target selectivity, desirable pharmacokinetic properties, and no cytochrome P450 or hERG liability. Compound 22, together with its orally bioavailable ethyl ester prodrug 23, were found to be suitable for in vivo proof-of-concept studies. Compound 23 displayed good efficacy in a mouse oral glucose tolerance test (OGTT). Compound 22 showed GPR142 dependent stimulation of insulin secretion in isolated mouse islets and demonstrated a statistically significant glucose lowering effect in a mouse model bearing transplanted human islets.

A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents.

Type 2 diabetes is characterized by impaired glucose homeostasis due to defects in insulin secretion, insulin resistance and the incretin response. GPR40 (FFAR1 or FFA1) is a G-protein-coupled receptor (GPCR), primarily expressed in insulin-producing pancreatic ß-cells and incretin-producing enteroendocrine cells of the small intestine. Several GPR40 agonists, including AMG 837 and TAK-875, have been disclosed, but no GPR40 synthetic agonists have been reported that engage both the insulinogenic and incretinogenic axes. In this report we provide a molecular explanation and describe the discovery of a unique and potent class of GPR40 full agonists that engages the enteroinsular axis to promote dramatic improvement in glucose control in rodents. GPR40 full agonists AM-1638 and AM-6226 stimulate GLP-1 and GIP secretion from intestinal enteroendocrine cells and increase GSIS from pancreatic islets, leading to enhanced glucose control in the high fat fed, streptozotocin treated and NONcNZO10/LtJ mouse models of type 2 diabetes. The improvement in hyperglycemia by AM-1638 was reduced in the presence of the GLP-1 receptor antagonist Ex(9-39)NH(2).

Discovery of AM-1638: A Potent and Orally Bioavailable GPR40/FFA1 Full Agonist.

GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets, the activation of which elicits increased insulin secretion only in the presence of elevated glucose levels. A potent, orally bioavailable small molecule GPR40 agonist is hypothesized to be an effective antidiabetic posing little or no risk of hypoglycemia. We recently reported the discovery of AMG 837 (1), a potent partial agonist of GPR40. Herein, we present the optimization from the GPR40 partial agonist 1 to the structurally and pharmacologically distinct GPR40 full agonist AM-1638 (21). Moreover, we demonstrate the improved in vivo efficacy that GPR40 full agonist 21 exhibits in BDF/DIO mice as compared to partial agonist 1.

AMG 837: a novel GPR40/FFA1 agonist that enhances insulin secretion and lowers glucose levels in rodents.

Agonists of GPR40 (FFA1) have been proposed as a means to treat type 2 diabetes. Through lead optimization of a high throughput screening hit, we have identified a novel GPR40 agonist called AMG 837. The objective of these studies was to understand the preclinical pharmacological properties of AMG 837. The activity of AMG 837 on GPR40 was characterized through GTPγS binding, inositol phosphate accumulation and Ca(2+) flux assays. Activity of AMG 837 on insulin release was assessed on isolated primary mouse islets. To determine the anti-diabetic activity of AMG 837 in vivo, we tested AMG 837 using a glucose tolerance test in normal Sprague-Dawley rats and obese Zucker fatty rats. AMG 837 was a potent partial agonist in the calcium flux assay on the GPR40 receptor and potentiated glucose stimulated insulin secretion in vitro and in vivo. Acute administration of AMG 837 lowered glucose excursions and increased glucose stimulated insulin secretion during glucose tolerance tests in both normal and Zucker fatty rats. The improvement in glucose excursions persisted following daily dosing of AMG 837 for 21-days in Zucker fatty rats. Preclinical studies demonstrated that AMG 837 was a potent GPR40 partial agonist which lowered post-prandial glucose levels. These studies support the potential utility of AMG 837 for the treatment of type 2 diabetes.

[Studies on direct and indirect economic burden of disease and related factor in countryside of Qingdao city in 2001].

OBJECTIVE: To study the condition of economic burden of disease in the countryside and to explore the related factors. METHODS: Human capital method and two-step method were used in the calculation of economic burden of disease. RESULTS: The total economic burden of disease among 3359 persons was 3072 225 Yuan. Noncommunicable conditions were accounted for 62.95%, while communicable disease, maternal and perinatal conditions accounted for 24.25%, and injury accounted for 9.83% respectively. The direct economic burden of disease was 1,559,619 Yuan and the indirect economic burden of disease was 1,472,606 Yuan. The economic burden of disease for each person was 914 Yuan. The equal burden of disease among patients with disability and without disability were 3070 Yuan and 680 Yuan respectively (P < 0.001). There was significant difference among different age groups. The influencing factors were found to include having noncommunicable disease, age, disability and the condition of marriage. CONCLUSION: Corresponding policy to cope with conditions of different age groups needs to be developed to reduce the economic burden of disease in the countryside.

cis-Retinol/androgen dehydrogenase, isozyme 3 (CRAD3): a short-chain dehydrogenase active in a reconstituted path of 9-cis-retinoic acid biosynthesis in intact cells.

9-cis-Retinoic acid activates retinoid X receptors, which serve as heterodimeric partners with other nuclear hormone receptors, yet the enzymology of its physiological generation remains unclear. Here, we report the identification and molecular/enzymatic characterization of a previously unknown member of the short-chain dehydrogenase/reductase family, CRAD3 (cis-retinoid/androgen dehydrogenase, type 3), which catalyzes the first step in 9-cis-retinoic acid biosynthesis, the conversion of 9-cis-retinol into 9-cis-retinal. CRAD3 shares amino acid similarity with other retinoid/steroid short-chain dehydrogenases/reductases: CRAD1, CRAD2, and RDH4. Relative to CRAD1, CRAD3 has greater 9-cis-retinol/all-trans-retinol discrimination and lower efficiency as an androgen dehydrogenase. CRAD3 has apparent efficiency (V/K(m)) for 9-cis-retinol about equivalent to that for CRAD1 and 3 orders of magnitude greater than that for RDH4. (CRAD2 does not recognize 9-cis-retinol as a substrate). CRAD3 contributes to 9-cis-retinoic acid production in intact cells, in conjunction with each of three retinal dehydrogenases that recognize 9-cis-retinal (RALDH1/AHD2, RALDH2, and ALDH12). Liver and kidney, two tissues reportedly with the highest concentrations of 9-cis-retinoids, show the most intense mRNA expression of CRAD3, but expression also occurs in testis, lung, small intestine, heart, and brain. These data are consistent with the participation of CRAD3 in the biogeneration of 9-cis-retinoic acid.