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This study estimates the maximum price at which mesenchymal stem cell (MSC) therapy is deemed cost-effective for septic shock patients and identifies parameters that are most important in making treatment decisions.
We developed a probabilistic Markov model according to the sepsis care trajectory to simulate costs and quality-adjusted life years (QALYs) of septic shock patients receiving either MSC therapy or usual care over their lifetime. We calculated the therapeutic headroom by multiplying the gains attributable to MSCs with willingness-to-pay (WTP) threshold and derived the maximum reimbursable price (MRP) from the expected net monetary benefit and savings attributable to MSCs. We performed scenario analyses to assess the impact of changes to assumptions on the study findings. A value of information analysis is performed to identify parameters with greatest impact on the uncertainty around the cost-effectiveness of MSC therapy.
At a WTP threshold of $50,000 per QALY, the therapeutic headroom and MRP of MSC therapy were $20,941 and $16,748, respectively; these estimates increased with the larger WTP values and the greater impact of MSCs on in-hospital mortality and hospital discharge rates. The parameters with greatest information value were MSC's impact on in-hospital mortality and the baseline septic shock in-hospital mortality.
At a common WTP of $50,000/QALY, MSC therapy is deemed to be economically attractive if its unit cost does not exceed $16,748. This ceiling price can be increased to $101,450 if the therapy significantly reduces both in-hospital mortality and increases hospital discharge rates.
It has generally been accepted that moving type IV bursts are generated as synchrotron radiation from energetic electrons high in the solar corona (Boischot and Denisse 1957). At 80 MHz the peak brightness temperature is usually ~ 108 K and the radiation becomes highly circularly polarized as the burst decays. This has led several authors (Kai 1969; Dulk 1970, 1973; Schmahl 1972; Robinson 1974, 1977; Nelson 1977) to the conclusion that the radiation comes from mildly relativistic (~ 100 keV) electrons and occurs at low harmonics of the gyro-frequency (gyro-synchrotron radiation). We present evidence of moving type IV bursts at 43, 80 and 160 MHz with brightness temperatures of ~ 109 K, and one at 43 MHz as high as 1010 K. The number (~ 1033) of energetic (≥ 1 MeV) electrons which is required in order to explain such high brightness temperatures by incoherent gyro-synchrotron emission is very large and near the upper limit for the number of fast electrons accelerated in the second phase of a solar flare. If amplification takes place a smaller number of electrons with energies ~ 100 keV would be required.
The 1665 and 1667 MHz OH intensity towards Halley’s comet has been monitored during the period October 1985 to April 1986. The flux density variation during the course of the apparition roughly follows the predictions of Schloerb and Gerard (1985), although we find a systematically lower flux than they predicted. The relative intensities of these lines are approximately in the ratio expected for thermodynamic equilibrium.
Normally, blood vessels are quiescent structures that fulfill their crucial function delivering blood to tissues and organs throughout the body with remarkable efficiency over the course of the entire normal lifespan. This is accomplished through interactions among a wide variety of regulatory systems that control the structure and function of the vasculature. The endothelium not only makes up the innermost layer of all blood vessels and provides a nonthrombogenic surface, but it also produces awide variety of vascular and growth regulatory signals and participates in repair, remodeling, and regeneration of the vasculature. The endothelium normally exhibits a very slow turnover, with a half-life of several years; however, in response to arterial injury and forms of pathological stress, widespread damage to the endothelium necessitates efficient mechanisms of repair and regeneration. Understanding the endogenous mechanisms that protect and repair this crucial layer may form the basis for new therapeutic strategies for the treatment of vascular diseases.
LOCAL VERSUS SYSTEMIC MECHANISMS OF VASCULAR REPAIR
Until quite recently, repair of the damaged endothelium was thought to occur largely from the migration and proliferation of nearby undamaged endothelial cells (ECs) (1), and the regeneration of new blood vessels was believed to be mainly through the sprouting of ECs from preexisting blood vessels. However, several observations challenged this concept, beginning as early as 1963, when it was found that Dacron patches that were not contiguous with the vascular endothelium could become efficiently endothelialized (2), presumably by seeding from circulating ECs or endothelial progenitor cells (EPCs). In later studies using a genetic tag, it could be shown that the colonizing cells were of bone marrow (BM) origin (3).
Acetate is normally regarded as an endproduct of anaerobic fermentation, but butyrate-producing bacteria found in the human colon can be net utilisers of acetate. The butyrate formed provides a fuel for epithelial cells of the large intestine and influences colonic health. [1-13C]Acetate was used to investigate the contribution of exogenous acetate to butyrate formation. Faecalibacterium prausnitzii and Roseburia spp. grown in the presence of 60 mm-acetate and 10 mm-glucose derived 85–90 % butyrate-C from external acetate. This was due to rapid interchange between extracellular acetate and intracellular acetyl-CoA, plus net acetate uptake. In contrast, a Coprococcus-related strain that is a net acetate producer derived only 28 % butyrate-C from external acetate. Different carbohydrate-derived energy sources affected butyrate formation by mixed human faecal bacteria growing in continuous or batch cultures. The ranking order of butyrate production rates was amylopectin > oat xylan > shredded wheat > inulin > pectin (continuous cultures), and inulin > amylopectin > oat xylan > shredded wheat > pectin (batch cultures). The contribution of external acetate to butyrate formation in these experiments ranged from 56 (pectin) to 90 % (xylan) in continuous cultures, and from 72 to 91 % in the batch cultures. This is consistent with a major role for bacteria related to F. prausnitzii and Roseburia spp. in butyrate formation from a range of substrates that are fermented in the large intestine. Variations in the dominant metabolic type of butyrate producer between individuals or with variations in diet are not ruled out, however, and could influence butyrate supply in the large intestine.
The human pathogen Escherichia coli O157:H7 is thought to be spread by direct or indirect contact with infected animal or human faeces. The present study investigated the effects of the plant coumarin esculin and its aglycone esculetin on the survival of a strain of E. coli O157 under gut conditions. The addition of these compounds to human faecal slurries and in vitro continuous-flow fermenter models simulating conditions in the human colon and rumen caused marked decreases in the survival of an introduced strain of E. coli O157. When four calves were experimentally infected with E. coli O157 and fed esculin, the pathogen was detected in five of twenty-eight (18 %) of faecal samples examined post-inoculation, compared with thirteen of thirty-five (37 %) of faecal samples examined from five control calves not fed esculin. Coumarin compounds that occur naturally in dietary plants or when supplemented in the diet probably inhibit the survival of E. coli O157 in the gut.
Stewart et al. (1978) have reported moving Type IV solar metre-wave radio outbursts with brightness temperatures between 108 and 1010 K. We now report Culgoora radioheliograph observations of four more Type IV radio sources, some moving, some stationary, but all with brightness temperatures above 109 K, and one with a brightness temperature above 1013 K. We also describe one of the previously reported events (that of 1977 September 20) in more detail. The interest of these events is that their high brightnesses place great strain upon the gyro-synchrotron theory of radio emission.
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