Cost-utility analysis in orthopaedic trauma; what pays? A systematic review.

BACKGROUND: As healthcare systems come under ever-increasing pressure to provide more care with fewer resources, emphasis is being placed on value-based systems that maximise quality and minimize cost. The aim of this study was to determine which interventions in fracture care have been demonstrated to be cost effective. METHODS: A systemic review of cost-utility studies on the management of fractures from 1976 to 2015 was carried out using a search of the Cost-Effectiveness Analysis Registry, National Health Service Economic Evaluation Database (NHS EED) and MEDLINE. RESULTS: 20 studies were included with 15 (75%) studies assessing interventions in lower limb trauma and 8 (25%) studies assessing interventions in upper limb trauma. 50% of studies used a decision tree model and 50% used collected data alongside a randomised clinical trial. Interventions which were shown to be cost effective in lower limb trauma were total hip replacement in displaced femoral neck fractures, the SHS in stable (A1 and A2) fractures and IM nailing for unstable (A3) fractures, salvage treatment for grade IIIB and IIIC open tibial fractures and operative treatment of ankle and calcaneal fractures. For systems-based strategies, there is evidence demonstrating cost effectiveness to treating hip fractures in high volume centres and to having resources in place to facilitate fractures being treated within 48 h of injury. In upper limb trauma there was evidence showing operative treatment of displaced proximal humerus fractures to be neither clinically nor cost effective. There was evidence supporting the operative treatment of non-displaced scaphoid fractures. Overall the quality of the studies was poor with only 50% (10) of studies able to make a treatment recommendation. Reasons for this included poor quality primary source data and poor reporting methodological practices. CONCLUSION: Certain aspects of fracture management have been shown to be cost effective. However, there is a paucity of evidence in this area and further research is required so that value-based interventions are chosen by healthcare providers engaged in orthopaedic trauma care.

Coping strategies in a strongly schooling fish, the common carp Cyprinus carpio.

Individual common carp Cyprinus carpio were screened repeatedly for risk taking (rate of exploration of a novel, potentially dangerous environment) and for competitive ability (success in gaining access to a spatially restricted food source). Marked differences in behaviour were evident, and significant consistency in individual responses across trials was found for both risk taking and competitive ability. In addition, there was a significant positive relationship between individual performance in these two contexts, with fish that explored more quickly in the novel environment tending to be among the first to gain access to restricted food. In two follow-up studies, resting metabolic rate, blood lactate and glucose and the expression of the cortisol receptor gene in the head kidney and brain were compared in fish from the two extremes of the risk-taking spectrum. Mass-specific metabolic rate was significantly higher in risk-taking than in risk-avoiding fish, while plasma lactate and glucose concentrations and expression of the cortisol receptor gene were lower. It was concluded that a behavioural syndrome based on boldness and aggression exists in C. carpio, as it does in many other animals, and that this is associated with differences in metabolic and stress physiology (down to the genomic level) similar to those described in animals with different coping strategies.

Nicotine exposure alters in vivo human responses to endotoxin.

The alpha 7 nicotinic receptor is reportedly a key element in the cholinergic anti-inflammatory pathway. Because a prototypical ligand for this receptor is nicotine, we studied the in vivo human response to bacterial endotoxin or lipopolysaccharide (LPS) in the context of nicotine or placebo pretreatment. Twelve adult male normal subjects were studied prospectively. Six received overnight transcutaneous nicotine administration by application of a standard patch (7 mg). Six hours later, all subjects were given an intravenous dose of endotoxin (2 ng/kg) and were evaluated for an additional 24 h for circulating levels of inflammatory biomarkers, vital signs and symptoms. The nicotine subjects had elevated blood levels of the nicotine metabolite, continine, prior to and throughout the 24-h post-endotoxin exposure phase. Subjects receiving nicotine exhibited a significantly lower temperature response as well as attenuated cardiovascular responses for 2.5-6 h after LPS exposure. In addition, increased circulating interkeukin (IL)-10 and cortisol levels were also noted in nicotine subjects. These data indicate an alteration in LPS-induced systemic inflammatory responses in normal subjects exposed to transcutaneous nicotine. In this model of abbreviated inflammation, nicotine exposure attenuates the febrile response to LPS and promotes a more prominent anti-inflammatory phenotype.

Expression of tumour necrosis factor receptor and Toll-like receptor 2 and 4 on peripheral blood leucocytes of human volunteers after endotoxin challenge: a comparison of flow cytometric light scatter and immunofluorescence gating.

Toll-like receptors (TLRs) are involved in the recognition of bacterial products and thus participate in the induction of the inflammatory cascade. However, much less is known about the evolution of leucocyte TLR expression during human inflammatory stress. We hypothesized that a decrease in leucocyte TLRs could account for the so-called tolerance or hyporesponsiveness state to subsequent stimulation with bacteria-derived products. Because of the profound monocytopenia that ensues after in vivo lipopolysaccharide (LPS) challenge, we also compared monocyte TLR expression using two different techniques of flow cytometric gating. In a first set of experiments, 17 healthy volunteers underwent LPS challenge. Blood was drawn at different time-points and analysed by flow cytometry using light scatter gating and one-colour analysis to assess the expression of the tumour necrosis factor receptor (TNFR) and TLR2 and TLR4 on both monocytes and granulocytes. In a second set of experiments, the assessment of those receptors was made using a more specific gating method that utilized light scatter and CD14 immunofluorescence in a two-colour analysis. This was performed using whole blood drawn from five healthy volunteers and incubated ex vivo for different time periods with or without LPS and in 12 volunteers who underwent LPS challenge in vivo. The pattern of expression for monocyte TNFR was similar for both types of gating. Using only the light scatter gating, an initial drop of TLR 2 and 4 was observed on monocytes. By contrast, when using light scatter x immunofluorescence gating, an up-regulation of these two receptors following both in vivo and in vitro LPS exposure was observed. LPS up-regulates the expression of TLRs on monocytes and granulocytes. Depending upon the methodology utilized, contrasting results were obtained with respect to TLR2 and TLR4 expression. The flow cytometric gating technique used is of importance in determining cellular TLR2 and TLR4 expression, especially in blood samples exhibiting significant monocytopenia.

Optical properties of nanostructured metal films.

Nanostructured metal films of platinum, gold and silver up to 675 nm thick we prepared by electrochemical deposition through templates of 700 nm diameter polystyrene spheres assembled as hexagonal close packed monolayer on an evaporated gold surface followed by removal of the template by dissolution in tetrahydrofuran. The reflection spectra of the films at normal incidence were recorded as a function of film thickness and the spectra correlated with the local visual appearance of the film and the surface structure from SEM. For thin films, below one quarter sphere height, the spectra show a single reflectivity dip at a wavelength just below the sphere diameter consistent with surface-plasmon grating-like behaviour. For the thicker films several reflectivity dips are observed which move towards longer wavelength with increasing film thickness. This behaviour is shown to be consistent with a model in which light reflected from the top of the structure interferes with light reflected from within the spherical segment cavities in the film.

Physiological noise in near-infrared spectroscopy: implications for optical brain computer interfacing.

Near-infrared spectroscopy is a non-invasive optical method used to detect functional activation of the cerebral cortex. Cognitive, visual, auditory and motor tasks are among the functions that have been investigated by this technique in the context of optical brain computer interfacing. In order to determine whether the optical response is due to a stimulus, it is essential to identify and reduce the effects of physiological noise. This paper characterizes noise typically present in optical responses and reports signal processing approaches used to overcome such noise.

Confined plasmons in metallic nanocavities.

We investigate the properties of gold surfaces patterned using a nanoscale "lost wax" technique by electrochemical deposition through a self-assembled latex template. Near-spherical gold nanocavities within the resulting porous films support localized surface plasmons which couple strongly to incident light, appearing as sharp spectral features in reflectivity measurements. The energy of the resonances is easily tunable from ultraviolet to near infrared by controlling the diameter and height of the nanocavities. The energies of these features agree well with the Mie resonances of a perfect spherical void.

Shifts in relative prevalence of laryngeal pathology in a treatment-seeking population.

The prevalence of laryngeal pathology in a treatment-seeking population of southwestern Ohio underwent a 15-year reexamination. Relationships between pathology and demographic variables of age, gender, and occupation were investigated. Data were collected from 1,158 new patients seen by participating otolaryngologists between 1996 and 1998. The most frequent pathologies were reflux laryngitis, functional (including diagnoses of laryngeal myasthenia and hoarseness), vocal fold paralysis, nodules, and laryngitis. Pathologies were found to occur more often in females, with some pathologies more common to one gender. Pathologies occurred more often in the older age categories. The most common occupations found in the sample were retired persons, executives/managers, and homemakers. Comparisons were made to an earlier investigation of laryngeal pathology in the same otolaryngology practices. Differences from the previous study were noted in the prevalence of pathology and the distribution of demographic variables. Relationships between pathology and demographic variables reported by the two studies were examined for consistency.

Olfactory conditioning facilitates diet transition in human infants.

We evaluated whether Pavlovian conditioning methods could be used to increase the ingestion of non-preferred solutions by formula-fed human infants. In baseline measures, 5-7 month old infants sucked less frequently and consumed less water than regular formula. During a 3-day olfactory conditioning period, parents placed a small scented disk, the conditioned stimulus, on the rim of their infants' formula bottle at every feeding. Following this training, infants' responses to water were tested when their water bottles had a disk scented with the training odor, a novel odor, or no odor. Infants tested with the training odor sucked more frequently and consumed significantly more water than they had at baseline. Infants tested with no odor or a novel odor consumed water at or below baseline levels. These data demonstrate that olfactory conditioning can be used to enhance ingestion in infants and suggest that such methods may be useful for infants experiencing difficulty when making transitions from one diet to another.

Cost-threshold analyses of the National AIDS Demonstration Research HIV prevention interventions.

OBJECTIVE: The goal of the multisite National AIDS Demonstration Research (NADR) program was to reduce the sexual and drug injection-related HIV risks of out-of-treatment injection drug users and their sex partners. Previous analyses have established that the NADR interventions were effective at changing participants' risky behaviors. This study was to determine whether the NADR program also was cost-effective. METHODS: Data from eight NADR study sites were included in the analysis. A mathematical model was used to translate reported sexual and injection-related behavior changes into an estimate of the number of infections prevented by the NADR interventions and then to calculate the corresponding savings in averted HIV/AIDS medical care costs and quality-adjusted years of life, assuming United States values for these parameters. Because cost data were not collected in the original NADR evaluation, the savings in averted medical care costs were compared with the cost of implementing a similar intervention program for injection drug users. RESULTS: The eight NADR interventions prevented approximately 129 infections among 6629 participants and their partners. Overall, the NADR program would be cost saving (i.e. provide net economic savings) if it cost less than US$2107 per person and would be cost-effective if it cost less than US$10,264 per person. Both of these estimates are considerably larger than the US$273 per person cost of the comparison intervention. There was substantial cross-site variability. CONCLUSIONS: The results of this analysis strongly suggest that the NADR interventions were cost-saving overall and were, at the very least, cost-effective at all eight sites. In the United States and other developed counties, investments in HIV-prevention interventions such as these have the potential to save substantial economic resources by averting HIV-related medical care expenses among injection drug users.

Altered cell cycle response of drug-resistant lung carcinoma cells to doxorubicin.

The effect of doxorubicin treatment on cell cycle parameters in asynchronous populations of multidrug-resistant human lung carcinoma cell lines was investigated. A sensitive (DLKP-SQ) and three resistant (DLKP-SQ A250 10p#7, DLKP-A2B and DLKP-A5F) variants of a human lung carcinoma cell line DLKP were exposed to equitoxic concentrations of doxorubicin. The latter three were 8-fold, 30-fold and 300-fold resistant to doxorubicin, respectively. Irreversible G2/M arrest in sensitive (DLKP-SQ) cells was observed 24 h after initiation of doxorubicin treatment. In resistant variants, G2/M arrest occurred at 12-16 h with a subsequent bypass of the G2/M arrest to re-emerge and accumulate in G1. This transient G2/M arrest and subsequent progression into G1 indicated an inefficient checkpoint for monitoring DNA damage induced by doxorubicin treatment. Caffeine treatment could bypass the G2/M block in DLKP-SQ cells. Doxorubicin treatment did not alter cyclin B or cdc2 protein levels, the ability of cdc2 to form complexes with cyclin B or the levels of cyclin B bound to cdc2. The G2/M arrest seen in sensitive cells was associated with an increase in inhibitory phosphorylation of Tyr15 on cdc2. In contrast, tyrosine 15 phosphorylation did not change in resistant variants after drug treatment and a general increase in cdc2 kinase activity was seen. Cdc25C levels were not altered following drug treatment.

Nurse executives champion change in integrated health systems.

When facilities join integrated health systems, nurse executives must increase their focus on governance, staff education, financial analysis, mentorship, and planning to maintain strong patient advocacy across a continuum of care.

Neutralization of TNF does not influence endotoxininduced changes in thyroid hormone metabolism in humans.

To determine the role of tumor necrosis factor (TNF) in endotoxin-induced changes in plasma thyroid hormone and thyroid-stimulating hormone (TSH) concentrations, 24 healthy postabsorptive humans were studied on a control study day (n = 6), after infusion of a recombinant TNF receptor IgG fusion protein (TNFR:Fc; 6 mg/m2; n = 6) after intravenous injection of endotoxin (2 ng/kg; n = 6), or after administration of endotoxin with TNFR:Fc (n = 6). Administration of TNFR:Fc alone did not affect thyroid hormone or TSH levels when compared with the control day. Endotoxin induced a transient rise in plasma TNF activity (1.5 h: 219 +/- 42 pg/ml), which was completely prevented by TNFR:Fc (P < 0.05). After endotoxin administration, plasma L-thyroxine (T4), free T4, 3,5, 3'-triiodothyronine (T3), and TSH were lower and 3,3', 5'-triiodothyronine was higher than on the control day (all P < 0. 05). Coinfusion of TNFR:Fc with endotoxin did not influence these endotoxin-induced changes. Our results suggest that endogenous TNF does not play an important role in the alterations in plasma thyroid hormone and TSH concentrations induced by mild endotoxemia in healthy humans.

The influence of human endotoxemia on CD95-induced apoptosis.

BACKGROUND: The responses of monocyte and neutrophil tumor necrosis factor receptor type 1 (TNFR-1) and TNFR-2 during systemic inflammation have been described previously. Several other members of the TNFR superfamily also appear to have regulatory roles in immunocyte function, including apoptosis. However, the response of these other receptor members, such as CD95, to systemic inflammation is unclear. OBJECTIVES: To compare the response of CD95 with that of TNFR during systemic inflammation and to assess the influence of the inflammatory milieu on CD95 function. SETTING: Adult clinical research center of a university hospital. SUBJECTS AND METHODS: Five healthy male subjects were administered intravenous endotoxin (2 ng/kg), and systemic response was measured by cytokine analysis and receptor expression assays during a 48-hour period. CD95 function during systemic inflammation was assessed using a Jurkat cell bioassay for degree of apoptosis. RESULTS: Monocyte and neutrophil CD95 expression exhibited changes parallel to that of TNFR following endotoxin injection. In contrast to soluble TNFR, which was transiently elevated during endotoxemia, soluble CD95 levels remained unchanged from baseline. Jurkat cells incubated in normal and post-endotoxin serum samples equally exhibited less than 10% spontaneous apoptosis. No soluble CD95 ligand was detectable in experimental human endotoxemia. CONCLUSIONS: Cell-associated CD95 exhibited changes parallel to its receptor family member TNFR following endotoxin administration. Soluble CD95 is present in human serum samples, but the levels remained unchanged following endotoxin administration. No soluble CD95 ligand activity was detectable by enzyme-linked immunosorbent assay or by functional assay. The potential protective role of soluble CD95 in human serum samples against CD95 ligand-induced apoptosis remains to be defined.

Multivariate analysis of 9 disease-associated variables for outcome prediction in patients with sepsis.

OBJECTIVE: To assess the ability of 9 clinical or biological variables to predict outcome (survival or nonsurvival) using multiple regression and classification analyses. DESIGN: Prospective, descriptive cohort study with no interventions. SETTING: Surgical intensive care unit of a tertiary care hospital and a medical school research laboratory. PATIENTS: Eighteen patients with a documented source of infection who met currently accepted criteria for sepsis syndrome or septic shock. MAIN OUTCOME MEASURES: Prediction of survival or nonsurvival based on analysis of clinical (Multiple Organ Dysfunction score, Acute Physiology and Chronic Health Evaluation III scores) and biological (plasma levels of cortisol, interleukin 6, interleukin 10, phospholipase A2, soluble tumor necrosis factor receptor p75, and monocyte membrane tumor necrosis factor receptor levels) variables, with comparison of predicted and actual outcomes. RESULTS: Plasma interleukin 6, interleukin 10, and phospholipase A2 concentrations were not significantly (P>.05) different between survivors and nonsurvivors. By standard, forward stepwise, and backward stepwise multiple regression analyses, only monocyte membrane tumor necrosis factor receptor levels measured at the onset of sepsis significantly predicted outcome in all 3 analyses. However, by both standard and backward stepwise analyses, Multiple Organ Dysfunction scores based on evaluation at the onset of sepsis and 24 hours later were also significant predictors of outcome. Classification analysis showed that assignment to outcome group was statistically significant when based on monocyte membrane tumor necrosis factor receptor levels determined at the onset of sepsis or on Multiple Organ Dysfunction scores assessed 24 hours after sepsis was diagnosed. CONCLUSION: Although these findings were based on a relatively small cohort, both multiple regression and classification analyses indicated that only monocyte membrane tumor necrosis factor receptor levels are able to discriminate survivors from nonsurvivors at the onset of sepsis.

Enhancement of chemotherapeutic drug toxicity to human tumour cells in vitro by a subset of non-steroidal anti-inflammatory drugs (NSAIDs).

The effect on cytotoxicity of combining a range of clinically important non-steroidal anti-inflammatory drugs (NSAIDs) with a variety of chemotherapeutic drugs was examined in the human lung cancer cell lines DLKP, A549, COR L23P and COR L23R and in a human leukaemia line HL60/ADR. A specific group of NSAIDs (indomethacin, sulindac, tolmetin, acemetacin, zomepirac and mefenamic acid) all at non-toxic levels, significantly increased the cytotoxicity of the anthracyclines (doxorubicin, daunorubicin and epirubicin), as well as teniposide, VP-16 and vincristine, but not the other vinca alkaloids vinblastine and vinorelbine. A substantial number of other anticancer drugs, including methotrexate, 5-fluorouracil, cytarabine, hydroxyurea, chlorambucil, cyclophosphamide, cisplatin, carboplatin, mitoxantrone, actinomycin D, bleomycin, paclitaxel and camptothecin, were also tested, but displayed no synergy in combination with the NSAIDs. The synergistic effect was concentration dependent. The effect appears to be independent of the cyclo-oxygenase inhibitory ability of the NSAIDs, as (i) the synergistic combination could not be reversed by the addition of prostaglandins D2 or E2; (ii) sulindac sulphone, a metabolite of sulindac that does not inhibit the cyclooxygenase enzyme, was positive in the combination assay: and (iii) many NSAIDs known to be cyclo-oxygenase inhibitors, e.g. meclofenamic acid, diclofenac, naproxen, fenoprofen, phenylbutazone, flufenamic acid, flurbiprofen, ibuprofen and ketoprofen, were inactive in the combination assay. The enhancement of cytotoxicity was observed in a range of drug sensitive tumour cell lines, but did not occur in P-170-overexpressing multidrug resistant cell lines. However, in the HL60/ADR and COR L23R cell lines, in which multidrug resistance is due to overexpression of the multidrug resistance-associated protein MRP, a significant increase in cytotoxicity was observed in the presence of the active NSAIDs. Subsequent Western blot analysis of the drug sensitive parental cell lines, DLKP and A549, revealed that they also expressed MRP and reverse-transcription-polymerase chain reaction studies demonstrated that mRNA for MRP was present in both cell lines. It was found that the positive NSAIDs were among the more potent inhibitors of [3H]-LTC4 transport into inside-out plasma membrane vesicles prepared from MRP-expressing cells, of doxorubicin efflux from preloaded cells and of glutathione-S-transferase activity. The NSAIDs did not enhance cellular sensitivity to radiation. The combination of specific NSAIDs with anticancer drugs reported here may have potential clinical applications, especially in the circumvention of MRP-mediated multidrug resistance.