Business cases promoting the introduction of digital water metering (DWM) have, to date, focused on a limited number of benefits, especially water savings, metering costs, occupational health and ...safety (OHS), and deferral of capital works. An earlier study by the authors catalogued 75 possible benefits and developed a taxonomy based on a literature review, interviews and water industry reports. The objective of the present study was to elicit the opinions of Australian water industry experts on the benefits, then use the opinions to form probability distributions which, in future work, could be used to model the value of DWM benefits. The study findings have implications for researchers and practitioners seeking to accurately and stochastically model the benefits of DWM transformation programmes. Thematic analyses on the open ended responses scaled likelihood and estimated value of benefits into comparable units. We found 82% support for the benefits of DWM with only 6% disagreement and 12% non-commital; the savings value of cost of water benefits were predominately expected to range between 5% and 10% and much higher in some individual situations, while charges/operational costs benefits were predominately expected to range between 45% and 100%; and, moreover, we indicated how a risk-based range of project benefit could potentially be calculated. Opportunities for further investigations were identified.
To evaluate the fracture healing capabilities of a GSK3β inhibitor, 6-bromoindirubin-3'-oxime, coupled with an aspartic acid octapeptide in a micellar delivery system.
The efficacy of the ...intravenously administered micelles to accelerate healing of femoral fracture in mice was evaluated. Micro-computed tomography analysis was employed to obtain bone density, total volume, relative volume, trabecular thickness and trabecular spacing.
Both fracture bone mineral density and volume were significantly higher in the micelle treatment groups when compared with controls. The fracture-targeted micelle demonstrates fracture-specific bone anabolism and biocompatibility in off-target tissues.
Accelerated fracture healing in mice was achieved by targeting the GSK3β inhibitor, 6-bromoindirubin-3'-oxime, to the fracture site.
OBJECTIVES/SPECIFIC AIMS: The primary objective of this study was to evaluate the performance of a bone fracture targeted systemically administrable bone anabolic as a potential therapeutic for bone ...fracture repair. Currently all bone fracture repair therapeutic require local administration during surgery. However, the population that need the most assistance in repair bone fractures are not eligible for surgery. So, it was our goal to design an inject-able therapeutic to assist in bone fracture repair to reduce the invasiveness. The injectable nature of it allows for repair administration of the bone anabolic and for therapeutic effect throughout the entire bone fracture healing process. Targeting it to the bone fracture site reduces the toxicity and increases the efficacy. METHODS/STUDY POPULATION: METHODS To achieve the above objective, a bone mineral-(hydroxyapatite-) targeting oligopeptide was conjugated to the non-signaling end of an engineered parathyroid hormone related protein fragment 1-46 with substitutions at Glu22,25, Leu23,28,31, Aib29, Lys26,30 (ePTHrP). The negatively charged oligopeptide has been shown to target raw hydroxyapatite with remarkable specificity, while the attached PTHrP has been demonstrated to induce sustained and accelerated bone growth under control of endogenous morphogenic regulatory factors. The conjugate’s specificity arises from the fact that raw hydroxyapatite is only exposed whenever a bone is fractured, surgically cut, grafted, or induced to undergo accelerated remodeling. The hydroxyapatite-targeted conjugate can therefore be administered systemically (i.e. without invasive surgery or localized injection) and still accumulate on the exposed hydroxyapatite at the fracture site where it accelerates the healing process Murine in vivo experiments were conducted on female Swiss Webster mice (10 per group). Femoral fractures were induced with a 3-point bending device and stabilized. Mice were dosed with 3 nmol/kg/d of targeted-ePTHrP, non-conjugated (free) ePTHrP, or saline. Following a 4-week study, fracture callus densities were measured using microCT. Canine in vivo experiments were conducted on 1-year-old male beagles. Beagles underwent a 10 mm bilateral ulnar ostectomy. Two dogs in the treatment group and Three dogs in the control group were dosed daily with either targeted-ePTHrP 0.5nmol/kg/d or saline respectively. Dogs were x-rayed weekly for the first 6 weeks and then every other week thereafter. One tailed ANOVA followed by Dunnett’s post-hoc test was used to establish significance. All animal experiments were conducted as described in approved IACUC protocols. P<0.05 was considered significant. RESULTS/ANTICIPATED RESULTS: RESULTS SECTION: In the murine studies we observed a marked increase in fracture callus size and a 2-fold increase in bone deposition was observed in the targeted-ePTHrP group over the saline group (P<0.01). A significant doubling in bone density was also observed. Targeted-ePTHrP group fractured femurs were able to achieve their pre-fracture strength as early as 3 weeks compared to 9 weeks in the saline mice representing a 66% reduction in healing time. In the canine studies, we observe a significantly higher closure of the ostectomy gap than saline controls (P<0.05). In addition, no significant differences in weight are observed in the treatment vs. saline controls. No significant difference between the control group and treatment groups was found in a histological investigation of the organs. DISCUSSION/SIGNIFICANCE OF IMPACT: DISCUSSION: Although attempts have been made in developing a systemically administered fracture therapeutic for fracture repair, i.e. teriparatide, to date, no such anabolics have been approved for this use. In these studies there is evidence that anabolic activity was occurring at the fracture site, but at a level that did not meet FDA required end-points.2 It is plausible that if sufficient drug were to be delivered to a fracture site then improved fracture repair would be possible. In previous studies, we demonstrated fracture specific accumulation bone anabolics can be achieved by modifying the drug with acidic oligopeptides.3 Here, by modifying a safe, clinically proven, parathyroid hormone receptor agonist with an acidic oligopeptide we observe improved bone deposition and strength in mice. Furthermore, when administered to canine critical sized defect ostectomies, a more relevant and difficult model, we observe improved ostectomy closure. CLINICAL RELEVANCE:: The ability to accelerate bone fracture repair is a fundamental need that has not been addressed by conventional methods. By targeting bone anabolic agents to bone fractures, we can deliver sufficient concentrations of anabolic agent to the fracture site to accelerate healing, thus avoiding surgery and any ectopic bone growth associated with locally-applied bone anabolic agents.
Ferric hydroxyapatites (Fe-HAp) and oxyapatites (Fe-OAp) of nominal composition Ca10− x Fe x 3+(PO4)6(OH)2−x O x (0 ≤ x ≤ 0.5) were synthesized from a coprecipitated precursor calcined under flowing ...nitrogen. The solid solubility of iron was temperature-dependent, varying from x = 0.5 after firing at 600 °C to x ∼ 0.2 at 1000 °C, beyond which Fe-OAp was progressively replaced by tricalcium phosphate (Fe-TCP). Crystal size (13−116 nm) was controlled by iron content and calcination temperature. Ferric iron replaces calcium by two altervalent mechanisms in which carbonate and oxygen are incorporated as counterions. At low iron loadings, carbonate predominantly displaces hydroxyl in the apatite channels (Ca2+ + OH− → Fe3+ + CO3 2−), while at higher loadings, “interstitial” oxygen is tenanted in the framework (2Ca2+ + ◻vac → 2Fe3+ + O2+). Although Fe3+ is smaller than Ca2+, the unit cell dilates as iron enters apatite, providing evidence of oxygen injection that converts PO4 tetrahedra to PO5 trigonal bipyramids, leading to the crystal chemical formula Ca10−x Fe x (PO4)6−x/2(PO5) x/2(OH)2−y O2y (x ≤ 0.5). A discontinuity in unit cell expansion at x ∼ 0.2 combined with a substantial reduction of the carbonate FTIR fingerprint shows that oxygen infusion, rather than tunnel hydroxyl displacement, is dominant beyond this loading. This behavior is in contrast to ferrous-fluorapatite where Ca2+ → Fe2+ aliovalent replacement does not require oxygen penetration and the cell volume contracts with iron loading. All of the materials were paramagnetic, but at low iron concentrations, a transition arising from crystallographic modification or a change in spin ordering is observed at 90 K. The excipient behavior of Fe-OAp was superior to that of HAp and may be linked to the crystalline component or mediated by a ubiquitous nondiffracting amorphous phase. Fe-HAp and Fe-OAp are not intrinsically suitable magnetic agents for drug delivery but may be useful in reactive cements that promote osteoblast proliferation.
It is uncertain whether the replication of systematic reviews, particularly those with the same objectives and resources, would employ similar methods and/or arrive at identical findings. We compared ...the results and conclusions of two concurrent systematic reviews undertaken by two independent research teams provided with the same objectives, resources, and individual participant-level data.
Two centers in the USA and UK were each provided with participant-level data on 17 multi-site clinical trials of recombinant human bone morphogenetic protein-2 (rhBMP-2). The teams were blinded to each other's methods and findings until after publication. We conducted a retrospective structured comparison of the results of the two systematic reviews. The main outcome measures included (1) trial inclusion criteria; (2) statistical methods; (3) summary efficacy and risk estimates; and (4) conclusions.
The two research teams' meta-analyses inclusion criteria were broadly similar but differed slightly in trial inclusion and research methodology. They obtained similar results in summary estimates of most clinical outcomes and adverse events. Center A incorporated all trials into summary estimates of efficacy and harms, while Center B concentrated on analyses stratified by surgical approach. Center A found a statistically significant, but small, benefit whereas Center B reported no advantage. In the analysis of harms, neither showed an increased cancer risk at 48 months, although Center B reported a significant increase at 24 months. Conclusions reflected these differences in summary estimates of benefit balanced with small but potentially important risk of harm.
Two independent groups given the same research objectives, data, resources, funding, and time produced broad general agreement but differed in several areas. These differences, the importance of which is debatable, indicate the value of the availability of data to allow for more than a single approach and a single interpretation of the data.
PROSPERO CRD42012002040 and CRD42012001907 .
Summary Background The international standard radiotherapy schedule for early breast cancer delivers 50 Gy in 25 fractions of 2·0 Gy over 5 weeks, but there is a long history of non-standard regimens ...delivering a lower total dose using fewer, larger fractions (hypofractionation). We aimed to test the benefits of radiotherapy schedules using fraction sizes larger than 2·0 Gy in terms of local-regional tumour control, normal tissue responses, quality of life, and economic consequences in women prescribed post-operative radiotherapy. Methods Between 1999 and 2001, 2215 women with early breast cancer (pT1-3a pN0-1 M0) at 23 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2·0 Gy over 5 weeks or 40 Gy in 15 fractions of 2·67 Gy over 3 weeks. Women were eligible for the trial if they were aged over 18 years, did not have an immediate reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. Findings 1105 women were assigned to the 50 Gy group and 1110 to the 40 Gy group. After a median follow up of 6·0 years (IQR 5·0–6·2) the rate of local-regional tumour relapse at 5 years was 2·2% (95% CI 1·3–3·1) in the 40 Gy group and 3·3% (95% CI 2·2 to 4·5) in the 50 Gy group, representing an absolute difference of −0·7% (95% CI −1·7% to 0·9%)—ie, the absolute difference in local-regional relapse could be up to 1·7% better and at most 1% worse after 40 Gy than after 50 Gy. Photographic and patient self-assessments indicated lower rates of late adverse effects after 40 Gy than after 50 Gy. Interpretation A radiation schedule delivering 40 Gy in 15 fractions seems to offer rates of local-regional tumour relapse and late adverse effects at least as favourable as the standard schedule of 50 Gy in 25 fractions.
OBJECTIVE To determine whether the β blocker esmolol reduces coronary artery wall stress more than the short acting dihydropyridine calcium antagonist nicardipine. DESIGN Randomised double blind ...placebo controlled trial. SETTING Tertiary cardiology centre. PATIENTS Patients with coronary artery disease. INTERVENTIONS 20 patients were randomised double blind to an infusion of nicardipine (n = 10) or esmolol (n = 10) titrated to reduce systolic blood pressure by 20 mm Hg. MAIN OUTCOME MEASURES Peak systolic wall circumferential stress. RESULTS Esmolol reduced peak coronary stress by a mean of 0.17 × 106 dyn/cm2(95% confidence interval (CI) 0.14 to 0.21 × 106 dyn/cm2) compared with a reduction of 0.07 × 106 dyn/cm2 (95% CI 0.05 to 0.10 × 106 dyn/cm2) after nicardipine. Peak systolic radius was reduced by 0.04 mm (95% CI 0.03 to 0.06 mm) after esmolol compared with an increase of 0.08 mm (95% CI 0.05 to 0.10 mm) after nicardipine. Heart rate increased by 11.5 beats/min (95% CI 6.9 to 16.2 beats/min) after nicardipine and decreased by 5.3 beats/min (95% CI 1.9 to 8.6 beats/min) after esmolol. CONCLUSIONS Intravenous esmolol is more effective than nicardipine at reducing circumferential coronary artery wall stress.
Objectives. This study sought to compare the clinical features and outcome of a first myocardial infarction with onset of symptoms during or within 30 min of exercise, at rest and in bed.
Background. ...It is not known whether activity at onset influences outcome of acute myocardial infarction.
Methods. Information collected using a standard questionnaire was used to relate activity at the onset of symptoms to in-hospital outcome in 2,468 consecutive patients admitted to a coronary care unit with a first myocardial infarction between 1975 and 1993.
Results. Patients with exercise-related onset were more likely to be younger and male. Those with onset in bed were more likely to be older and have a history of stable or unstable angina. Compared with patients whose symptoms began at rest, those with exercise-related onset had a lower in-hospital mortality rate after adjusting for age, gender and year of admission (odds ratio OR 0.60, 95% confidence interval CI 0.40 to 0.89), and patients with onset in bed had a higher mortality rate (OR 1.38, 95% CI 1.03 to 1.85). The incidence of cardiac failure requiring diuretic therapy was also lower for exercise-related onset (OR 0.83, 95% CI 0.67 to 1.04) and higher when onset was in bed (OR 1.36, 95% CI 1.11 to 1.66).
Conclusions. There is an association between activity at onset and outcome of acute myocardial infarction. Differences in pathophysiology or in the population at risk could explain this observation.
(J Am Coll Cardiol 1997;29:250–3)
A phase i clinical trial of didemnin B Stewart, James A.; Low, Jane B.; Roberts, John D. ...
Cancer,
15 December 1991, Letnik:
68, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Didemnin B is a depsipeptide extracted from the marine tunicate Trididemnin cyanophorum. This agent is a potent inhibitor of L1210 growth in vitro and has activity against murine B16 melanoma, P388 ...leukemia, and M5076 sarcoma in vivo. The results of preclinical toxicologic tests demonstrated abnormalities in clotting parameters thought to be secondary to drug‐induced liver dysfunction. Thirty‐five patients with advanced cancer received didemnin B according to a 5‐day bolus schedule with dose levels ranging from 0.03 to 2.00 mg/m2/d. The dose‐limiting toxicity was nausea and vomiting. Sporadic elevation of the hepatic enzyme level occurred but was not dose limiting. Two patients had anaphylactic symptoms possibly related to the 5% polyoxyethylated castor oil (Cremophor EL, BASF, Ludwigshafen, Germany) vehicle during the drug infusion. Clinical bleeding was not observed and myelosuppression was not significant. No partial or complete tumor responses were seen. The recommended Phase II dose for the 5‐day schedule is 1.6 mg/m2/d. Cancer 68:2550–2554, 1991.
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