"I am nothing, but I may be everything," John Adams, the first vice president, wrote of his office. And for most of American history, the "nothing" part of Adams's formulation accurately captured the ...importance of the vice presidency, at least as long as the president had a heartbeat. But a job that once was "not worth a bucket of warm spit," according to John Nance Garner, became, in the hands of the most recent vice presidents, critical to the governing of the country on an ongoing basis. It is this dramatic development of the nation's second office that Joel K. Goldstein traces and explains inThe White House Vice Presidency.The rise of the vice presidency took a sharp upward trajectory with the vice presidency of Walter Mondale. In Goldstein's work we see how Mondale and Jimmy Carter designed and implemented a new model of the office that allowed the vice president to become a close presidential adviser and representative on missions that mattered. Goldstein takes us through the vice presidents from Mondale to Joe Biden, presenting the arrangements each had with his respective president, showing elements of continuity but also variations in the office, and describing the challenges each faced and the work each did. The book also examines the vice-presidential selection process and campaigns since 1976, and shows how those activities affect and/or are affected by the newly developed White House vice presidency.The book presents a comprehensive account of the vice presidency as the office has developed from Mondale to Biden. ButThe White House Vice Presidencyis more than that; it also shows how a constitutional office can evolve through the repetition of accumulated precedents and demonstrates the critical role of political leadership in institutional development. In doing so, the book offers lessons that go far beyond the nation's second office, important as it now has become.
Background
Mast cells (MC) are powerful inflammatory immune sentinel cells that drive numerous allergic, inflammatory, and pruritic disorders when activated. MC‐targeted therapies are approved in ...several disorders, yet many patients have limited benefit suggesting the need for approaches that more broadly inhibit MC activity. MCs require the KIT receptor and its ligand stem cell factor (SCF) for differentiation, maturation, and survival. Here we describe CDX‐0159, an anti‐KIT monoclonal antibody that potently suppresses MCs in human healthy volunteers.
Methods
CDX‐0159‐mediated KIT inhibition was tested in vitro using KIT‐expressing immortalized cells and primary human mast cells. CDX‐0159 safety and pharmacokinetics were evaluated in a 13‐week good laboratory practice (GLP)‐compliant cynomolgus macaque study. A single ascending dose (0.3, 1, 3, and 9 mg/kg), double‐blinded placebo‐controlled phase 1a human healthy volunteer study (n = 32) was conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of CDX‐0159.
Results
CDX‐0159 inhibits SCF‐dependent KIT activation in vitro. Fc modifications in CDX‐0159 led to elimination of effector function and reduced serum clearance. In cynomolgus macaques, multiple high doses were safely administered without a significant impact on hematology, a potential concern for KIT inhibitors. A single dose of CDX‐0159 in healthy human subjects was generally well tolerated and demonstrated long antibody exposure. Importantly, CDX‐0159 led to dose‐dependent, profound suppression of plasma tryptase, a MC‐specific protease associated with tissue MC burden, indicative of systemic MC suppression or ablation.
Conclusion
CDX‐0159 administration leads to systemic mast cell ablation and may represent a safe and novel approach to treat mast cell‐driven disorders.
This study presents the preclinical characterization, safety, pharmacokinetic and pharmacodynamic activity in a placebo‐controlled phase 1a healthy volunteer study of CDX‐0159, a specific and potent anti‐KIT inhibitory monoclonal antibody. CDX‐0159 inhibits SCF‐dependent KIT and mast cell activation. In a dose‐dependent manner, CDX‐0159 induces suppression of plasma tryptase – a marker of mast cell burden – showing a potential as a therapeutic strategy in mast cell‐driven disorders.Abbreviations: CDX‐0159, anti‐KIT inhibitory monoclonal antibody; FcR, Fc receptor; KIT, KIT proto‐oncogene, receptor tyrosine kinase; MRGPRX2, mas‐related G protein‐coupled receptor‐X2; SCF, stem cell factor
Abstract Purpose Although mental health screening is recommended for adolescents, little is known about the predictors of referral to mental health services or engagement in treatment. We examined ...predictors of mental health referral from primary care and service use for commercially insured youth who had been screened using the Pediatric Symptom Checklist or Youth-Pediatric Symptom Checklist. Methods A retrospective chart review was conducted of commercially insured patients 14–17 years of age who were newly identified by the Pediatric Symptom Checklist or Youth-Pediatric Symptom Checklist at a well-child visit. Comparisons were made with propensity-matched negative adolescents meeting the same criteria. Bivariate analyses were conducted to examine differences between positives and negatives and between referred and nonreferred positives. Logistic regression analyses were performed to assess predictors of mental health referral for positive youth. Results Medical records of 117 positive and 110 negative youth were examined. Compared with negative youth, positive youth were significantly more likely to be referred for mental health treatment ( p < .0001) and receive specialty mental health services ( p < .0001). Of the positives, 54% were referred for mental health care and 67% of them accepted. However, only 18% completed a face-to-face mental health visit in the next 180 days. Pediatric Symptom Checklist score (odds ratio, 1.21; confidence interval, 1.03–1.42), parental or personal concern (odds ratio, 10.87; confidence interval, 2.70–43.76), and having depressive symptoms (odds ratio, 9.18; confidence interval, 1.49–56.60) were predictive of referral. Conclusions Despite identification after behavioral health screening, limited treatment engagement by referred patients persists. Primary care physicians and mental health specialists must enhance their efforts to engage and monitor identified patients.
Polysorbate 80 is one of the key components of protein formulations. It primarily inhibits interfacial damage of the protein molecule due to mechanical stress during shipping and handling. However, ...polysorbate 80 also affects the formulation photostability. Exposure to light of polysorbate 80 aqueous solution results in peroxide generation, which in turn may result in oxidation of the susceptible amino acid residues in the protein molecule. The purpose of this study was to determine if the photostability of our proprietary IgG
1
monoclonal antibody formulation containing polysorbate 80 is affected by the quality (grade/vendor) of polysorbate 80. Following four types of polysorbate80 were tested: (1) Polysorbate 80 Super-Refined, Mallinckrodt Baker, (2) Polysorbate 80 NF, Mallinckrodt Baker, (3) Polysorbate 80 NF, EMD Chemicals, and (4) Ultra-pure Polysorbate 80 (HX), NOF Corporation. The samples were exposed to light as per ICH guidelines Q1B. The results of the study show that photostability of the antibody formulation is indeed affected by the quality of polysorbate 80. This study underscores the importance of carefully choosing the quality of polysorbate 80 to ensure the robustness of formulation.
Polysorbate 80 is widely used in protein formulations to protect protein against agitation-induced aggregation. In this study, we address concerns about residual peroxide present in Polysorbate 80 on ...protein stability. Residual peroxide may oxidize active pharmaceutical ingredients leading to reduced stability and may ultimately lead to lower potency and efficacy. The effect of Polysorbate 80 concentration on thermal and photostability of monoclonal antibody of the IgG1 subclass (MAb1) was evaluated at Polysorbate 80 concentrations ranging from 0.00% to 1.00% (
w
/
v
). MAb1 samples at 5 mg/mL with various Polysorbate 80 concentrations were subjected to accelerated thermal stress by incubation at 25°C, 40°C, and 50°C for a period of 4 weeks and light stress per ICH guideline Q1B, option 1. Our results show that Polysorbate 80 concentration of 1.00% (
w
/
v
) adversely affected thermal and photostability of MAb1. This study demonstrates the importance of carefully choosing Polysorbate 80 concentration in protein formulations to prevent destabilizing effect of Polysorbate 80 on thermal and photostability.
Dealing with the vice presidency since 1953, this book recommends Walter Mondale's vice presidency as a model for future occupants of the office. The author considers the selection, campaign roles, ...and electoral impact of vice-presidential candidates.
Originally published in 1982.
ThePrinceton Legacy Libraryuses the latest print-on-demand technology to again make available previously out-of-print books from the distinguished backlist of Princeton University Press. These paperback editions preserve the original texts of these important books while presenting them in durable paperback editions. The goal of the Princeton Legacy Library is to vastly increase access to the rich scholarly heritage found in the thousands of books published by Princeton University Press since its founding in 1905.
This study demonstrates that arginine is a highly effective solvent additive which significantly reduces the light induced aggregation of four IgG1 type monoclonal antibodies (named as IMC-1A, ...IMC-1B, IMC-1C and IMC-1D) as measured by size exclusion chromatography. All experiments were performed in a phosphate buffer system containing either sodium chloride or arginine hydrochloride. The protein samples were exposed to light in a photo chamber according to ICH (International Conference on Harmonization) guidelines. Thermal unfolding transition temperature (T(m)) of IMC-1A as determined by differential scanning calorimetry (DSC) was significantly decreased ( approximately 3.3 degrees C) in the presence of arginine hydrochloride as compared to in sodium chloride. However, a noticeable increase in thermal stability was observed for IMC-1B, IMC-1C and IMC-1D in the presence of arginine hydrochloride. The photostability of all these molecules was significantly enhanced by arginine hydrochloride and both a direct and inverse correlation was observed between conformational stability and photostability. To our knowledge, this paper for the first time, demonstrates that arginine hydrochloride considerably reduces the light induced aggregation of monoclonal antibodies. Arginine hydrochloride is also known to increase protein solubility and its ability to extensively reduce light induced aggregation makes it a potential solvent additive for the formulation development of therapeutic proteins.
Attention-deficit/hyperactivity disorder (ADHD) affects almost 2.4 million US children. Because American Academy of Pediatrics guidelines for ADHD recommend use of standardized diagnostic ...instruments, regular follow-up and the chronic care model, this pilot project sought to implement and assess an electronic registry of patients with ADHD combined with care coordination by a planned care team.
This quality improvement project was structured with 2 intervention and 2 control clinics to facilitate evaluation of the use of a planned care system for management of ADHD. Care teams included a pediatrician, nurse, medical assistant, and care coordinator and tracked patients using an electronic registry with data drawn from the EMR. Clinical work flows were pilot tested to facilitate use of the Vanderbilt scales and their incorporation into the EMR at intervention sites. Outcome measures included 2 recommended clinical follow-ups based on HEDIS measures as well as use of the Vanderbilt rating scales. Initiation phase measure was for follow-up after initiating medication, while the continuation phase measure was for subsequent follow-up during the first year of treatment. Measures were monitored during the project year and then also in the ensuing period of spread of the intervention to other sites.
Although the modified HEDIS initiation phase measure for patients newly on medication remained static at approximately 50% throughout the project period, the continuation phase measure showed improvement from 35% at baseline to 45% at the end of the project assessment year, a 29% increase. Follow-up for patients stable on medications also remained unchanged during the project period, but during subsequent spreading of the intervention to nonproject sites, follow-up of these patients improved to over 90%. In adjusted analyses, patients with ADHD at intervention sites were over 2 times more likely than patients at control sites to have had a Vanderbilt score documented in their records.
The project achieved modest improvements in the diagnostic and treatment process for patients with ADHD. The use of a planned care system and electronic patient registry shows promise for improving the diagnosis and treatment process for patients with ADHD.
PDF
