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Peptide therapeutics have played a notable role in medical practice since the advent of insulin therapy in the 1920s. Over 60 peptide drugs are approved in the United States and other ...major markets, and peptides continue to enter clinical development at a steady pace. Peptide drug discovery has diversified beyond its traditional focus on endogenous human peptides to include a broader range of structures identified from other natural sources or through medicinal chemistry efforts. We maintain a comprehensive dataset on peptides that have entered human clinical studies that includes over 150 peptides in active development today. Here we provide an overview of the peptide therapeutic landscape, including historical perspectives, molecular characteristics, regulatory benchmarks, and a therapeutic area breakdown.
Norms clarification has been identified as an effective component of college student drinking interventions, prompting research on norms clarification as a single-component intervention known as ...Personalized Normative Feedback (PNF). Previous reviews have examined PNF in combination with other components but not as a stand-alone intervention.
To investigate the degree to which computer-delivered stand-alone personalized normative feedback interventions reduce alcohol consumption and alcohol-related harms among college students and to compare gender-neutral and gender-specific PNF.
Electronic databases were searched systematically through November 2014. Reference lists were reviewed manually and forward and backward searches were conducted.
Outcome studies that compared computer-delivered, stand-alone PNF intervention with an assessment only, attention-matched, or active treatment control and reported alcohol use and harms among college students.
Between-group effect sizes were calculated as the standardized mean difference in change scores between treatment and control groups divided by pooled standard deviation. Within-group effect sizes were calculated as the raw mean difference between baseline and follow-up divided by pooled within-groups standard deviation.
Eight studies (13 interventions) with a total of 2,050 participants were included. Compared to control participants, students who received gender-neutral (dbetween = 0.291, 95% CI 0.159, 0.423) and gender-specific PNF (dbetween = 0.284, 95% CI 0.117, 0.451) reported greater reductions in drinking from baseline to follow-up. Students who received gender-neutral PNF reported 3.027 (95% CI 2.171, 3.882) fewer drinks per week at first follow-up and gender-specific PNF reported 3.089 (95% CI 0.992, 5.186) fewer drinks. Intervention effects were small for harms (dbetween = 0.157, 95% CI 0.037, 0.278).
Computer-delivered PNF is an effective stand-alone approach for reducing college student drinking and has a small impact on alcohol-related harms. Effects are small but clinically relevant when considered from a public health perspective. Additional research is needed to examine computer-delivered, stand-alone PNF as a population-level prevention program.
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► Allosteric interactions control substrate channeling in tryptophan synthase. ► Allosteric interactions are mediated by substrate binding and covalent reaction. ► Binding of a ...monovalent cation cofactor also exerts allosteric interactions. ► The allosteric transition switches the enzyme between open and closed states. ► Efficiency is achieved by the synchronization of the α- and β-catalytic cycles.
The tryptophan synthase α2β2 bi-enzyme complex catalyzes the last two steps in the synthesis of l-tryptophan (l-Trp). The α-subunit catalyzes cleavage of 3-indole-d-glycerol 3′-phosphate (IGP) to give indole and d-glyceraldehyde 3′-phosphate (G3P). Indole is then transferred (channeled) via an interconnecting 25Å-long tunnel, from the α-subunit to the β-subunit where it reacts with l-Ser in a pyridoxal 5′-phosphate-dependent reaction to give l-Trp and a water molecule. The efficient utilization of IGP and l-Ser by tryptophan synthase to synthesize l-Trp utilizes a system of allosteric interactions that (1) function to switch the α-site on and off at different stages of the β-subunit catalytic cycle, and (2) prevent the escape of the channeled intermediate, indole, from the confines of the α- and β-catalytic sites and the interconnecting tunnel. This review discusses in detail the chemical origins of the allosteric interactions responsible both for switching the α-site on and off, and for triggering the conformational changes between open and closed states which prevent the escape of indole from the bienzyme complex.
Sofosbuvir and ledipasvir, which have recently been approved for treatment of chronic hepatitis C virus (HCV) infection, are more efficacious and safer than the old standard of care (oSOC) but are ...substantially more expensive. Whether and in which patients their improved efficacy justifies their increased cost is unclear.
To evaluate the cost-effectiveness and budget impact of sofosbuvir and ledipasvir.
Microsimulation model of the natural history of HCV infection.
Published literature.
Treatment-naive and treatment-experienced HCV population defined on the basis of HCV genotype, age, and fibrosis distribution in the United States.
Lifetime.
Third-party payer.
Simulation of sofosbuvir-ledipasvir compared with the oSOC (interferon-based therapies).
Quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), and 5-year spending on antiviral drugs.
Sofosbuvir-based therapies added 0.56 QALY relative to the oSOC at an ICER of $55 400 per additional QALY. The ICERs ranged from $9700 to $284 300 per QALY depending on the patient's status with respect to treatment history, HCV genotype, and presence of cirrhosis. At a willingness-to-pay threshold of $100 000 per QALY, sofosbuvir-based therapies were cost-effective in 83% of treatment-naive and 81% of treatment-experienced patients. Compared with the oSOC, treating eligible HCV-infected persons in the United States with the new drugs would cost an additional $65 billion in the next 5 years, whereas the resulting cost offsets would be $16 billion.
Results were sensitive to drug price, drug efficacy, and quality of life after successful treatment.
Data on real-world effectiveness of new antivirals are lacking.
Treatment of HCV is cost-effective in most patients, but additional resources and value-based patient prioritization are needed to manage patients with HCV.
National Institutes of Health.
Adolescent unintentional pregnancy and sexual transmitted infections (STIs) are at an alarming rating in the United States. The factors that contribute to high rates of unintentional pregnancy and ...STIs among adolescents are lack of contraception use and other risk behaviors. As such, this study sought to assess the relationship between type of contraception used during last sexual intercourse and risk behaviors among high school adolescents. Data for this study were derived from the 2019 Youth Risk Behavior Study (YRBS). A total of 13,677 participants completed the YRBS in 2019. Multiple logistic regression was used to estimate the association between contraceptive type (i.e., condom, oral birth control, withdrawal, no method) and risk behavior. Results found that those students who reported condom use were less likely to engage in certain substance use behaviors and sexual risk taking compared to those who used no contraceptive method, oral birth control, or withdrawal. The results seem to suggest that condom use and risk-taking behaviors are somewhat interconnected in that condom users were found to be more protective in their behaviors.
Rhizobia are bacteria in the α-proteobacterial genera Rhizobium, Sinorhizobium, Mesorhizobium, Azorhizobium and Bradyrhizobium that reduce (fix) atmospheric nitrogen in symbiotic association with a ...compatible host plant. In free-living and/or symbiotically associated rhizobia, amino acids may, in addition to their incorporation into proteins, serve as carbon, nitrogen or sulfur sources, signals of cellular nitrogen status and precursors of important metabolites. Depending on the rhizobia-host plant combination, microsymbiont amino acid metabolism (biosynthesis, transport and/or degradation) is often crucial to the establishment and maintenance of an effective nitrogen-fixing symbiosis and is intimately interconnected with the metabolism of the plant. This review summarizes past findings and current research directions in rhizobial amino acid metabolism and evaluates the genetic, biochemical and genome expression studies from which these are derived. Specific sections deal with the regulation of rhizobial amino acid metabolism, amino acid transport, and finally the symbiotic roles of individual amino acids in different plant-rhizobia combinations.
Sarcopenia is associated with increased wait‐list mortality, but a standard definition is lacking. In this retrospective study, we sought to determine the optimal definition of sarcopenia in ...end‐stage liver disease (ESLD) patients awaiting liver transplantation (LT). Included were 396 patients newly listed for LT in 2012 at 5 North American transplant centers. All computed tomography scans were read by 2 individuals with interobserver correlation of 98%. Using image analysis software, the total cross‐sectional area (cm2) of abdominal skeletal muscle at the third lumbar vertebra was measured. The skeletal muscle index (SMI), which normalizes muscle area to patient height, was then calculated. The primary outcome was wait‐list mortality, defined as death on the waiting list or removal from the waiting list for reasons of clinical deterioration. Sex‐specific potential cutoff values to define sarcopenia were determined with a grid search guided by log‐rank test statistics. Optimal search methods identified potential cutoffs to detect survival differences between groups. The overall median SMI was 47.6 cm2/m2: 50.0 in men and 42.0 in women. At a median of 8.8 months follow‐up, mortality was 25% in men and 36% in women. Patients who died had lower SMI than those who survived (45.6 versus 48.5 cm2/m2; P < 0.001), and SMI was associated with wait‐list mortality (hazard ratio, 0.95; P < 0.001). Optimal search method yielded SMI cutoffs of 50 cm2/m2 for men and 39 cm2/m2 for women; these cutoff values best combined statistical significance with a sufficient number of events to detect survival differences between groups. In conclusion, we recommend that an SMI < 50 cm2/m2 for men and < 39 cm2/m2 for women be used to define sarcopenia in patients with ESLD awaiting LT. Liver Transplantation 23 625–633 2017 AASLD.
Frailty has emerged as a powerful predictor of outcomes in patients with cirrhosis and has inevitably made its way into decision making within liver transplantation. In an effort to harmonize ...integration of the concept of frailty among transplant centers, the AST and ASTS supported the efforts of our working group to develop this statement from experts in the field. Frailty is a multidimensional construct that represents the end‐manifestation of derangements of multiple physiologic systems leading to decreased physiologic reserve and increased vulnerability to health stressors. In hepatology/liver transplantation, investigation of frailty has largely focused on physical frailty, which subsumes the concepts of functional performance, functional capacity, and disability. There was consensus that every liver transplant candidate should be assessed at baseline and longitudinally using a standardized frailty tool, which should guide the intensity and type of nutritional and physical therapy in individual liver transplant candidates. The working group agreed that frailty should not be used as the sole criterion for delisting a patient for liver transplantation, but rather should be considered one of many criteria when evaluating transplant candidacy and suitability. A road map to advance frailty in the clinical and research settings of liver transplantation is presented here.
This summary statement about frailty in liver transplantation addresses how to define and measure frailty, and how to incorporate frailty into the care of patients with end‐stage liver disease, including those awaiting liver transplantation.
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