Evaluating a Measure of Social Health Derived from Two Mental Health Recovery Measures: The California Quality of Life (CA-QOL) and Mental Health Statistics Improvement Program Consumer Survey (MHSIP)

Social health is important to measure when assessing outcomes in community mental health. Our objective was to validate social health scales using items from two broader commonly used measures that assess mental health outcomes. Participants were 609 adults receiving psychological treatment services. Items were identified from the California Quality of Life (CA-QOL) and Mental Health Statistics Improvement Program (MHSIP) outcome measures by their conceptual correspondence with social health and compared to the Social Functioning Questionnaire (SFQ) using correlational analyses. Pearson correlations for the identified CA-QOL and MSHIP items with the SFQ ranged from .42 to .62, and the identified scale scores produced Pearson correlation coefficients of .56, .70, and, .70 with the SFQ. Concurrent validity with social health was supported for the identified scales. The current inclusion of these assessment tools allows community mental health programs to include social health in their assessments

Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness

Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually. The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drugs that modulate the activity of a conserved parasite target. However, no such molecular targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases

Evaluating a measure of social health derived from two mental health recovery measures: the California Quality of Life (CA-QOL) and Mental Health Statistics Improvement Program Consumer Survey (MHSIP).

Social health is important to measure when assessing outcomes in community mental health. Our objective was to validate social health scales using items from two broader commonly used measures that assess mental health outcomes. Participants were 609 adults receiving psychological treatment services. Items were identified from the California Quality of Life (CA-QOL) and Mental Health Statistics Improvement Program (MHSIP) outcome measures by their conceptual correspondence with social health and compared to the Social Functioning Questionnaire (SFQ) using correlational analyses. Pearson correlations for the identified CA-QOL and MSHIP items with the SFQ ranged from .42 to .62, and the identified scale scores produced Pearson correlation coefficients of .56, .70, and, .70 with the SFQ. Concurrent validity with social health was supported for the identified scales. The current inclusion of these assessment tools allows community mental health programs to include social health in their assessments

Cost-effectiveness of the LIFE Physical Activity Intervention for Older Adults at Increased Risk for Mobility Disability

BACKGROUND: Losing the ability to walk safely and independently is a major concern for many older adults. The Lifestyle Interventions and Independence for Elders study recently demonstrated that a physical activity (PA) intervention can delay the onset of major mobility disability. Our objective is to examine the resources required to deliver the PA intervention and calculate the incremental cost-effectiveness compared with a health education intervention. METHODS: The Lifestyle Interventions and Independence for Elders study enrolled 1,635 older adults at risk for mobility disability. They were recruited at eight field centers and randomly assigned to either PA or health education. The PA program consisted of 50-minute center-based exercise 2× weekly, augmented with home-based activity to achieve a goal of 150min/wk of PA. Health education consisted of weekly workshops for 26 weeks, and monthly sessions thereafter. Analyses were conducted from a health system perspective, with a 2.6-year time horizon. RESULTS: The average cost per participant over 2.6 years was US$3,302 and US$1,001 for the PA and health education interventions, respectively. PA participants accrued 0.047 per person more Quality-Adjusted Life-Years (QALYs) than health education participants. PA interventions costs were slightly higher than other recent PA interventions. The incremental cost-effectiveness ratios were US$42,376/major mobility disability prevented and US$49,167/QALY. Sensitivity analyses indicated that results were relatively robust to varied assumptions. CONCLUSIONS: The PA intervention costs and QALYs gained are comparable to those found in other studies. The ICERS are less than many commonly recommended medical treatments. Implementing the intervention in non-research settings may reduce costs further

Cost-effectiveness of the LIFE Physical Activity Intervention for Older Adults at Increased Risk for Mobility Disability

BackgroundLosing the ability to walk safely and independently is a major concern for many older adults. The Lifestyle Interventions and Independence for Elders study recently demonstrated that a physical activity (PA) intervention can delay the onset of major mobility disability. Our objective is to examine the resources required to deliver the PA intervention and calculate the incremental cost-effectiveness compared with a health education intervention.MethodsThe Lifestyle Interventions and Independence for Elders study enrolled 1,635 older adults at risk for mobility disability. They were recruited at eight field centers and randomly assigned to either PA or health education. The PA program consisted of 50-minute center-based exercise 2× weekly, augmented with home-based activity to achieve a goal of 150 min/wk of PA. Health education consisted of weekly workshops for 26 weeks, and monthly sessions thereafter. Analyses were conducted from a health system perspective, with a 2.6-year time horizon.ResultsThe average cost per participant over 2.6 years was US$3,302 and US$1,001 for the PA and health education interventions, respectively. PA participants accrued 0.047 per person more Quality-Adjusted Life-Years (QALYs) than health education participants. PA interventions costs were slightly higher than other recent PA interventions. The incremental cost-effectiveness ratios were US$42,376/major mobility disability prevented and US$49,167/QALY. Sensitivity analyses indicated that results were relatively robust to varied assumptions.ConclusionsThe PA intervention costs and QALYs gained are comparable to those found in other studies. The ICERS are less than many commonly recommended medical treatments. Implementing the intervention in non-research settings may reduce costs further

Novel tricyclic pyrazolopyrimidines as potent and selective GPR119 agonists

Systematic SAR optimization of the GPR119 agonist lead 1, derived from an internal HTS campaign, led to compound 29. Compound 29 displays significantly improved in vitro activity and oral exposure, leading to GLP1 elevation in acutely dosed mice and reduced glucose excursion in an OGTT study in rats at doses ≥10 mg/kg

Targeting Mitochondrial DNA with a Platinum-Based Anticancer Agent

An analog of the anticancer drug cisplatin (mtPt) was delivered to mitochondria of human cells using a peptide specifically targeting this organelle. mtPt induces apoptosis without damaging nuclear DNA, indicating that mtDNA damage is sufficient to mediate the activity of a platinum-based chemotherapeutic. This study demonstrates the specific delivery of a platinum drug to mitochondria and investigates the effects of directing this agent outside the nucleus.National Cancer Institute (U.S.) (Grant CA034992)David H. Koch Graduate Fellowshi

Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a Novel, Potent and WT Sparing Covalent Inhibitor of Oncogenic (L858R, ex19del) and Resistant (T790M) EGFR Mutants for the Treatment of EGFR Mutant Non-Small Cell Lung Cancers

Over the last decade, first and second generation EGFR inhibitors have significantly improved outcomes for lung cancer patients with activating mutations in EGFR. However, both resistance through a secondary T790M mutation at the gatekeeper residue and dose-limiting toxicities from wild-type (WT) EGFR inhibition ultimately limit the full potential of these therapies to control mutant EGFR-driven tumors and new therapies are urgently needed. Herein, we describe our approach towards the discovery of 47 (EGF816), a novel, covalent mutant-selective EGFR inhibitor with equipotent activity on both oncogenic and T790M-resistant EGFR mutations. Through molecular docking studies we converted a mutant-selective high-throughput screening hit (7) into a number of targeted covalent EGFR inhibitors with equipotent activity across mutants EGFR and good WT-EGFR selectivity. We used an abbreviated in vivo efficacy study for prioritizing compounds with good tolerability and efficacy that ultimately led to the selection of 47 as the clinical candidate

The legacy of ICTY and its impact upon the Statue and the practice of the ICC

Legacy of ICTY and its Impact on Statute and Case Law of ICC Establishing of International Criminal Court is a significant moment in evolution of international criminal law. It is the first permanent institution of international justice with personal jurisdiction and it was founded for one purpose only - to finally end the era of impunity for war criminals all over the world. But ICC didn't appear from nowhere. There was a long road towards its establishment and who knows if it would ever happen without influence of so called ad hoc tribunals, International Criminal Tribunal for the former Yugoslavia and International Criminal Tribunal for Rwanda. It is a sad truth that international criminal law made its biggest evolution as a reflection of the world's most horrible conflicts. The purpose of this thesis is to analyze a legacy of one of these tribunals, International Criminal Tribunal for the former Yugoslavia, and to explore its influence not only on the Statute of International Criminal Court, but also on its case law. International Criminal Court is not operating for long, but we can still notice many references on ICTY case law in its judgments. The reason for this research is my particular relation towards Balkan region as well as my interest in international justice in general. The thesis is composed..

Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis (NASH)

Farnesoid X receptor (FXR) agonists are emerging as important potential therapeutics for the treatment of nonalcoholic steatohepatitis (NASH) patients as they exert positive effects on multiple aspects of the disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular inflammation, hepatic injury and fibrosis. While there are currently no approved therapies for NASH, the bile acid-derived FXR agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in clinical studies. Previously, we have described the discovery of tropifexor (LJN452), the most potent non-bile acid FXR agonist currently in clinical investigation. Here, we describe the discovery of a novel chemical series of non-bile acid FXR agonists based on a tricyclic dihydrochromenopyrazole core from which emerged nidufexor (LMB763), a compound with partial FXR agonistic activity in vitro and FXR-dependent gene modulation in vivo. Nidufexor has advanced to Phase 2 human clinical trials in patients with NASH and diabetic nephropathy