Cost-effectiveness analysis of five drugs for treating postmenopausal women in the United States with osteoporosis and a very high fracture risk.

PURPOSE: Five strategies were recommended by the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) guidelines for the treatment of postmenopausal osteoporosis (PMO) patients with a very high fracture risk. We aimed to assess their cost-effectiveness in the United States (US). METHODS: A microsimulation Markov model was created to compare the cost-effectiveness of five treatment strategies, including zoledronate, denosumab, abaloparatide, teriparatide, and romosozumab in PMO patients with a recent fracture from the healthcare perspective of the US. The data used in the model were obtained from published studies or online resources. Base-case analysis, one-way deterministic sensitivity analysis (DSA) and probability sensitivity analysis (PSA) were conducted for 65-, 70-, 75-, and 80-year-old patients. RESULTS: In base case, at 65 years, zoledronate was the cheapest strategy. The incremental cost-effectiveness ratios (ICER, which represent incremental costs per QALY gained) of denosumab, teriparatide, abaloparatide, and romosozumab against zoledronate were $13,020/QALY (quality-adjusted years), $477,331 /QALY, $176,287/QALY, and $98,953/QALY, respectively. Under a willing-to-pay (WTP, which means the highest price a consumer will pay for one unit of a good of service) threshold of $150,000/QALY, denosumab and romosozumab were cost-effective against zoledronate. The PSA results showed that denosumab was the most cost-effective option with WTP thresholds of $50,000/QALY, $100,000/QALY and $150,000/QALY. The results were similar in other age groups. The DSA results indicated that the most common parameters that have important influence on the outcome were drug persistence, incidence of adverse events, the efficacy of drugs on hip fractures and the cost of the drug. CONCLUSION AND RELEVANCE: Among PMO patients with a very high fracture risk in the US, zoledronate is the cheapest strategy and denosumab is the most cost-effective choice among these five strategies.

Determination of Hydrogen Density by Swift Heavy Ions.

A novel method to determine the total hydrogen density and, accordingly, a precise plasma temperature in a lowly ionized hydrogen plasma is described. The key to the method is to analyze the energy loss of swift heavy ions interacting with the respective bound and free electrons of the plasma. A slowly developing and lowly ionized hydrogen theta-pinch plasma is prepared. A Boltzmann plot of the hydrogen Balmer series and the Stark broadening of the H_{ß} line preliminarily defines the plasma with a free electron density of (1.9±0.1)×10^{16} cm^{-3} and a free electron temperature of 0.8-1.3 eV. The temperature uncertainty results in a wide hydrogen density, ranging from 2.3×10^{16} to 7.8×10^{18} cm^{-3}. A 108 MHz pulsed beam of ^{48}Ca^{10+} with a velocity of 3.652 MeV/u is used as a probe to measure the total energy loss of the beam ions. Subtracting the calculated energy loss due to free electrons, the energy loss due to bound electrons is obtained, which linearly depends on the bound electron density. The total hydrogen density is thus determined as (1.9±0.7)×10^{17} cm^{-3}, and the free electron temperature can be precisely derived as 1.01±0.04 eV. This method should prove useful in many studies, e.g., inertial confinement fusion or warm dense matter.

[Performance evaluation of two N95 filtering-facepiece respirators on decomposition products of sulfur hexafluoride].

OBJECTIVE: To assess the filtration efficiency of two N95 filtering-facepiece respirators (FFRs) for the decomposition products of sulfur hexafluoride (SF6). METHODS: Two types of N95 FFRs (the particulate and the acid-proof respirators) were selected in this study. The decomposition products of SF6, including particles, hydrogen fluoride (HF) and sulfur dioxide (SO2) , were measured under experimental condition by using TSI PortaCount Plus, fluorine ion-selective electrodes and spectrophotometer separately. The filtration efficiency was then calculated and compared. RESULTS: Both two models of N95 respirators had lowest filtration efficiency larger than 95% for particles under airflow ranged from 10 to 95 L/min. When exposed to different concentrations of HF (low: 0.00~1.99 mg/m(3), middle: 2.00~3.99 mg/m(3), high: >4 mg/m(3)) , the acid-proof N95 respirator was more effective than the particulate respirator (P<0.05) with a filtration efficiency of 98.83%, 99.08%, and 99.03% versus 48.44%, 45.71%, and 47.31%. For four SO2 concentration ranges (0.00~2.49 mg/m(3), 2.50~4.99 mg/m(3), 5.00~9.99 mg/m(3), and >10.00 mg/m(3)) , the acid-proof respirator showed a high filtration efficiency within exposure to 1.5 hours: 95.73%, 98.67%, 98.14%, and 97.78%, respectively, when exposure duration extended to 4 hours, the filtration efficiency of the acid-proof respirator decreased to 91.97%, 82.28%, 70.12%, and 58.56%, respectively. CONCLUSION: Both the particulate and the acid-proof N95 FFRs met national standards on the particulate filtration efficiency. The acid-proof N95 respirator demonstrates to be more effective in filtering HF and SO2 than the particulate respirator. The filtration efficiency could decrease to an unsafe condition under longer exposure duration, timely replacement of respirator is recommended at the workplace.

Induction of classical transplantation tolerance in the adult.

Transplantation tolerance across histoincompatibilities in multiple non-H-2 minors (B10.BR into CBA/Ca) and "minor" plus H-2D (B10.A into CBA/Ca) antigens has been achieved successfully by combined adult bone marrow transplantation and treatment with CD4 and CD8 mAbs. The tolerant state was confirmed by permanent acceptance of donor strain skin grafts, and in vitro unresponsiveness to donor cells. Tolerance was associated with partial donor chimerism to various degrees. Tolerance to minor transplantation antigens induced in this manner was restricted to recipient-type MHC. The possibility was raised that tolerance resulted, at least in part, from clonal anergy rather than deletion.

Effect of hydrogen on semiconductive properties of passive film on ferrite and austenite phases in a duplex stainless steel.

Hydrogen effect on semiconductivity and compositions of passive films formed on ferrite and austenite phases in a duplex stainless steel were investigated by current sensing atomic force microscopy and X-ray photoelectron spectroscopy. It is demonstrated that hydrogen significantly increases the conductivity of passive film due to the increase of OH-/O2- ratio. The passive film on austenite has higher conductivity than that on ferrite after hydrogen charging due to more hydrogen in austenite. The presence of hydrogen causes an inversion of conductivity type of passive film from p-type to n-type, attributed to the chemical composition change.

Expression of the chemokine receptor CXCR3 on neurons and the elevated expression of its ligand IP-10 in reactive astrocytes: in vitro ERK1/2 activation and role in Alzheimer's disease.

Inflammatory mediators have been implicated in the pathophysiology of neurodegenerative diseases. Here we report the presence of the chemokine receptor CXCR3 and its ligand, IP-10, in normal and Alzheimer's disease (AD) brains. CXCR3 was detected constitutively on neurons and neuronal processes in various cortical and subcortical regions; IP-10 was observed in a subpopulation of astrocytes in normal brain, and was markedly elevated in astrocytes in AD brains. Many IP-10(+) astrocytes were associated with senile plaques and had an apparently coordinated upregulation of MIP-1beta. Moreover, we showed that CXCR3 ligands, IP-10 and Mig, were able to activate ERK1/2 pathway in mouse cortical neurons, suggesting a novel mechanism of neuronal-glial interaction.

Reprogramming the immune system for tolerance with monoclonal antibodies.

Monoclonal antibodies to CD4, CD8 and CD11a can be used in vivo either to deplete or functionally block T cells to create a tolerance permissive environment. Short courses of non-depleting CD4 and CD8 antibodies were used to induce tolerance separately in CD4+ and CD8+ T cells either to foreign immunoglobulins, bone marrow, or skin grafts. Tolerance was obtained to minor (non-MHC) transplantation antigens without T cell depletion even in actively sensitized mice, or to MHC plus minor antigens presented directly by skin grafts using combinations of depleting followed by blockading CD4 and CD8 antibodies. In all cases, tolerance was specific to the antigen/tissue given under cover of antibody treatment, and in one example it could be shown that T cells directed to MLS-1a had been forced into an anergic state. This induction of tolerant, anergic T cells in the periphery is able to explain many of the features associated with tolerance, not only in the model systems using foreign antigens, but also in the normal regulation of anti-self responses and its failure in autoimmune diseases. It is our new found ability to use antigen under the cover of antibody treatment to accurately control the pattern of tolerant T cells in vivo that we refer to by using the term 'reprogramming'. We also describe the clinical treatment of one patient with an autoimmune vasculitis based on the ideas developed from the mouse models.

Mechanisms of monoclonal antibody-facilitated tolerance induction: a possible role for the CD4 (L3T4) and CD11a (LFA-1) molecules in self-non-self discrimination.

In vivo therapy with a CD4 (L3T4) monoclonal antibody is able to provide a tolerogenic milieu for a limited number of protein antigens. In this study we have analyzed the mechanisms of such tolerance to human gamma globulin, and show that tolerance is induced in adult T helper cells without a need for cellular depletion, and that it is probably not maintained by suppressor mechanisms nor by regulatory cellular circuits involving CD8+ (Ly-2+) cells. Tolerance induction is not a property peculiar to the CD4 molecule, as similar effects can be elicited with a monoclonal antibody directed to the CD11a (LFA-1) molecule. We suggest that tolerance is maintained by the functional deletion of mature T helper cells and that adhesion molecules, such as CD4, CD8 and CD11a, may play a critical role in T cell discernment of self from nonself.

Induction of tolerance in peripheral T cells with monoclonal antibodies.

Our goal has been to develop ways to tolerize the mature immune system to any defined antigen. In this report we show that peripheral (post-thymic) T cells of mice can become tolerant to a range of antigens (human and rat immunoglobulins, and bone marrow and skin grafts that differ at multiple minor transplantation antigens). In the case of human gamma globulin (HGG), this required that the antigen be given under the cover of a short course of non-depleting anti-CD4 antibody, while for tolerance to skin and marrow grafts anti-CD8 antibody was also required. Tolerance to HGG could be reinforced by repeated injections of HGG, but was lost in the absence of any further exposure to antigen. This reversal of tolerance with time was due to new T cells being exported from the thymus, as it was not observed in tolerized, adult thymectomized mice. In contrast, tolerance to marrow and skin grafts was permanent, presumably because the established grafts acted as a continuous source of antigen to reinforce the tolerant state. Tolerance could not be broken by the infusion of unprimed spleen cells and in one example (tolerance to Mls-1a) there was clear evidence that specific peripheral T cells were anergic. We propose that anergic cells may themselves participate in reinforcing the tolerant state by competing at sites of antigen presentation.

Immunohistochemical study of the beta-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer's disease brains.

Chemokines belong to an expanding family of cytokines the primary function of which is recruitment of leukocytes to inflammatory sites. Recent evidence has shown their presence in the central nervous system. Because inflammatory responses have been implicated in the pathogenesis of Alzheimer's disease (AD), we studied the expression of CCR3, CCR5, and their ligands in normal and AD brains by immunohistochemistry. CCR3 and CCR5 are present on microglia of both control and AD brains, with increased expression on some reactive microglia in AD. Immunohistochemistry for MIP-1beta, MIP-1alpha, RANTES, eotaxin, and MCP-3 (ligands for CCR5 and/or CCR3) revealed the presence of MIP-1beta predominantly in a subpopulation of reactive astrocytes, which were more widespread in AD than control brains, and MIP-1alpha predominantly in neurons and weakly in some microglia in both AD and controls. Many of the CCR3+ or CCR5+ reactive microglia and MIP-1beta+ reactive astrocytes were found associated with amyloid deposits. Immunoreactivity for eotaxin, RANTES, and MCP-3 were not detected. Detection of these beta-chemokine receptors on microglia and some of their ligands in reactive astrocytes and neurons as well as microglia suggests a role for this system in glial-glial and glial-neuronal interactions, potentially influencing the progression of AD.

A comparative study of T-cell receptor V beta usage in non-obese diabetic (NOD) and I-E transgenic NOD mice.

The non-obese diabetic (NOD) mouse is a model for the study of insulin-dependent diabetes mellitus (IDDM). Recently transgenic NOD mice have been derived (NOD-E) that express the major histocompatibility complex (MHC) class II I-E molecule. NOD-E do not become diabetic and show negligible pancreatic insulitis. The possibility pertained that NOD-E mice are protected from disease by a process of T-cell deletion or anergy. This paper describes our attempts to discover whether this was so, by comparing NOD and NOD-E mouse T-cell receptor V beta usage. Splenocytes and lymph node cells were therefore tested for their ability to proliferate in response to monoclonal anti-V beta antibodies. We were unable to show any consistent differences between NOD and NOD-E responses to the panel of antibodies used. Previously proposed V beta were shown to be unlikely candidates for deletion or anergy. T cells present at low frequency (V beta 5+) in both NOD and NOD-E mice were shown to be as capable of expansion in response to antigenic stimulation as were more frequently expressed V beta. Our data therefore do not support deletion or anergy as mechanisms which could account for the observed disease protection in NOD-E mice.