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1.  Treatment costs associated with interventional cancer clinical trials conducted at a single UK institution over 2 years (2009–2010) 
British Journal of Cancer  2013;109(8):2051-2057.
The conduct of clinical trials should be an integral part of routine patient care. Treating patients in trials incurs additional costs over and above standard of care (SOC), but the extent of the cost burden is not known. We undertook a retrospective cost attribution analysis to quantitate the treatment costs associated with cancer clinical trial protocols conducted over a 2 year period.
All patients entered into oncology (non-haematology) clinical trials involving investigational medicinal products in 2009 and 2010 in a single UK institution were identified. The trial protocols on which they were treated were analysed to identify the treatment costs for the experimental arm(s) of the trial and the equivalent SOC had the patient not been entered in the trial. The treatment cost difference was calculated by subtracting the experimental treatment cost from SOC cost. For randomised trials, an average treatment cost was estimated by taking into account the number of arms and randomisation ratio. An estimate of the annual treatment costs was calculated.
A total of 357 adult oncology patients were treated on 53 different trial protocols: 40 phase III, 2 randomised II/III and 11 phase II design. A total of 27 trials were academic, non-commercial sponsored trials and 26 were commercial sponsored trials. When compared with SOC, the average treatment cost per patient was an excess of £431 for a non-commercial trial (range £6393 excess to £6005 saving) and a saving of £9294 for a commercial trial (range £0 to £71 480). There was an overall treatment cost saving of £388 719 in 2009 and £496 556 in 2010, largely attributable to pharmaceutical company provision of free drug supplies.
On an average, non-commercial trial protocols were associated with a small per patient excess treatment cost, whereas commercial trials were associated with a substantially higher cost saving. Taking into account the total number of patients recruited annually, treatment of patients on clinical trial protocols was associated with considerable cost savings across both the non-commercial and commercial portfolio.
PMCID: PMC3798949  PMID: 24064969
excess treatment costs; treatment costs; clinical trial costs; research costs; cost attribution; treatment cost savings
2.  Interaction between cytokines and inflammatory cells in islet dysfunction, insulin resistance, and vascular disease 
Diabetes, obesity & metabolism  2013;15(0 3):117-129.
Inflammation is an established pathogenic player in insulin resistance, islet demise, and atherosclerosis. The complex interactions between cytokines, immune cells, and affected tissues result in sustained inflammation in diabetes and atherosclerosis. 12- and 15-lipoxygenase (LO), such as 12/15LO, produces a variety of metabolites through peroxidation of fatty acids and potentially contributes to the complex molecular crosstalk at the site of inflammation. 12- and 15-LO pathways are frequently activated in tissues affected by diabetes and atherosclerosis including adipose tissue, islets, and the vasculature. Moreover, mice with whole body and tissue-specific knockout of 12/15-LO are protected against insulin resistance, hyperglycemia, and atherosclerosis supporting functional contribution of 12- and 15-LO pathways in diabetes and atherosclerosis. Recently it has emerged that there is a temporal regulation of the particular isoforms of 12- and 15-LO in human adipose tissue and islets during the development of type 1 and type 2 diabetes and obesity. Analyses of tissues affected by diabetes and atherosclerosis also implied the roles of interleukin (IL)-12 and NADPH oxidase 1 (NOX1) in islets and IL-17A in atherosclerosis. Future studies should aim to test the efficacy of inhibitions of these mediators for treatment of diabetes and atherosclerosis.
PMCID: PMC3777698  PMID: 24003928
12-lipoxygenase; 15-lipoxygenase; interleukin-12; interleukin-17A; NADPH oxidase-1
3.  Designing ‘Smart’ Particles for the Assembly of Complex Macroscopic Structures** 
Surface functionalization with a branched copolymer surfactant is used to create responsive inorganic particles that can self-assemble in complex structures. The assembly process is triggered by a pH switch that reversibly activates multiple hydrogen bonds between ceramic particles and soft templates.
PMCID: PMC3799970  PMID: 23780923
self-assembly; surface chemistry; cellular ceramics; smart particles; responsive surfactant
4.  Using quantitative disease dynamics as a tool for guiding response to avian influenza in poultry in the United States of America☆ 
Preventive Veterinary Medicine  2014;113(4):376-397.
Wild birds are the primary source of genetic diversity for influenza A viruses that eventually emerge in poultry and humans. Much progress has been made in the descriptive ecology of avian influenza viruses (AIVs), but contributions are less evident from quantitative studies (e.g., those including disease dynamic models). Transmission between host species, individuals and flocks has not been measured with sufficient accuracy to allow robust quantitative evaluation of alternate control protocols. We focused on the United States of America (USA) as a case study for determining the state of our quantitative knowledge of potential AIV emergence processes from wild hosts to poultry. We identified priorities for quantitative research that would build on existing tools for responding to AIV in poultry and concluded that the following knowledge gaps can be addressed with current empirical data: (1) quantification of the spatio-temporal relationships between AIV prevalence in wild hosts and poultry populations, (2) understanding how the structure of different poultry sectors impacts within-flock transmission, (3) determining mechanisms and rates of between-farm spread, and (4) validating current policy-decision tools with data. The modeling studies we recommend will improve our mechanistic understanding of potential AIV transmission patterns in USA poultry, leading to improved measures of accuracy and reduced uncertainty when evaluating alternative control strategies.
PMCID: PMC3945821  PMID: 24462191
Avian influenza; USA; Between-farm spread; Disease-dynamic model; Quantitative data; Poultry
5.  Production and function of IL-12 in islets and beta cells 
Diabetologia  2012;56(1):126-135.
IL-12 is an important cytokine in early inflammatory responses and is implicated in the immunemediated pathogenesis of pancreatic islets in diabetes. However, little is known about the direct effects of IL-12 on islets and beta cells.
In this study, beta cell function, gene expression and protein production were assessed in primary human donor islets and murine beta cell lines in response to stimulation with IL-12 or a pro-inflammatory cytokine cocktail (TNF-α, IL-1β and IFN-γ).
The pro-inflammatory cytokine cocktail induced islet dysfunction and potently increased the expression and production of IL-12 ligand and IL-12 receptor in human islets. In human islets, the receptor for IL-12 co-localised to the cell surface of insulin-producing cells. Both IL-12 ligand and IL-12 receptor are expressed in the homogeneous beta cell line INS-1. IL-12 induced changes in gene expression, including a dose-dependent upregulation of IFNγ (also known as IFNG), in INS-1 cells. A neutralising antibody to IL-12 directly inhibited IFNγ gene expression in human donor islets induced by either IL-12 or pro-inflammatory cytokine stimulation. Functionally, IL-12 impaired glucose-stimulated insulin secretion (GSIS) in INS-1 cells and human donor islets. A neutralising antibody to IL-12 reversed the beta cell dysfunction (uncoupling of GSIS or induction of caspase-3 activity) induced by pro-inflammatory cytokines.
These data identify beta cells as a local source of IL-12 ligand and suggest a direct role of IL-12 in mediating beta cell pathology.
PMCID: PMC3651896  PMID: 23052055
Diabetes; Human; Interleukin-12; Islets; Pro-inflammatory cytokines
6.  Investigation of the Distribution of Salmonella within an Integrated Pig Breeding and Production Organisation in the United Kingdom 
ISRN Veterinary Science  2013;2013:943126.
To examine patterns of Salmonella herd infections in units linked by common sources of pigs, the study examined pooled pen faeces samples from 161 nursery and finishing units in a UK integrated pig enterprise. An epidemiological questionnaire was also completed by investigators for each farm. Salmonella was isolated from 630 (19.5%) of the samples: S. Typhimurium was found in 387 (12%) and S. Derby in 157 (4.9%) samples; 111 units yielded at least one sample containing Salmonella. The proportion of Salmonella-positive samples from positive farms ranged from 5% to 95%. In a univariable risk factor analysis, increasing length of time as a pig farm was positively associated with the detection of Salmonella in a herd. Larger farms (>500 pigs) were significantly more likely to be positive for S. Typhimurium than smaller farms. There was an association between Salmonella serovars isolated in the present study and those subsequently isolated in breeding herds linked to the integration.
PMCID: PMC3878397  PMID: 24455292
7.  Effects of frequency- and direction-dependent elastic materials on linearly elastic MRE image reconstructions 
Physics in medicine and biology  2010;55(22):6801-6815.
The mechanical model commonly used in magnetic resonance elastography (MRE) is linear elasticity. However, soft tissue may exhibit frequency-and direction-dependent (FDD) shear moduli in response to an induced excitation causing a purely linear elastic model to provide an inaccurate image reconstruction of its mechanical properties. The goal of this study was to characterize the effects of reconstructing FDD data using a linear elastic inversion (LEI) algorithm. Linear and FDD phantoms were manufactured and LEI images were obtained from time-harmonic MRE acquisitions with variations in frequency and driving signal amplitude. LEI responses to artificially imposed uniform phase shifts in the displacement data from both purely linear elastic and FDD phantoms were also evaluated. Of the variety of FDD phantoms considered, LEI appeared to tolerate viscoelastic data-model mismatch better than deviations caused by poroelastic and anisotropic mechanical properties in terms of visual image contrast. However, the estimated shear modulus values were substantially incorrect relative to independent mechanical measurements even in the successful viscoelastic cases and the variations in mean values with changes in experimental conditions associated with uniform phase shifts, driving signal frequency and amplitude were unpredictable. Overall, use of LEI to reconstruct data acquired in phantoms with FDD material properties provided biased results under the best conditions and significant artifacts in the worst cases. These findings suggest that the success with which LEI is applied to MRE data in tissue will depend on the underlying mechanical characteristics of the tissues and/or organs systems of clinical interest.
PMCID: PMC3776577  PMID: 21030746
8.  Intracellular electroporation site distributions: Modeling examples for nsPEF and IRE pulse waveforms 
We illustrate expected electroporation (EP) responses to two classes of large electric field pulses by employing systems models, one of a cell in vitro and the other of multiple cells in vivo. The first pulse class involves “nsPEF” (nanosecond pulsed electric fields). The durations are less than a microsecond, but the magnitudes are extremely large, often 10 kV/cm or more, and all of the pores remain small. The second class involves “IRE” (irreversible electroporation). Durations are many microseconds to several milliseconds, but with magnitudes smaller than 10 kV/cm, and a wide range of pore sizes evolves. A key feature of both pulse classes is non-thermal cell killing by multiple pulses without delivering external drugs or genes. For small pulses the models respond passively (no pore creation) providing negative controls. For larger pulses transient aqueous pore populations evolve. These greatly increase local membrane conductance temporarily, causing rapid redistribution of fields near and within cells. This complex electrical behavior is generally not revealed by experiments reporting biological end points resulting from cumulative ionic and molecular transport through cell membranes. The underlying, heterogeneous pore population distributions are also not obtained from typical experiments. Further, traditional EP applications involving molecular delivery are usually assumed to create pores solely in the outer, plasma membrane (PM). In contrast, our examples support the occurrence of intracellular EP by both nsPEF and IRE, but with different intracellular spatial distributions of EP sites.
PMCID: PMC3414423  PMID: 22254414
11.  Time-harmonic magnetic resonance elastography of the normal feline brain 
Journal of biomechanics  2010;43(14):2747-2752.
Imaging of the mechanical properties of in vivo brain tissue could eventually lead to non-invasive diagnosis of hydrocephalus, Alzheimer’s disease and other pathologies known to alter the intracranial environment. The purpose of this work is to (1) use time-harmonic magnetic resonance elastography (MRE) to estimate the mechanical property distribution of cerebral tissue in the normal feline brain and (2) compare the recovered properties of grey and white matter. Various in vivo and ex vivo brain tissue property measurement strategies have led to the highly variable results that have been reported in the literature. MR elastography is an imaging technique that can estimate mechanical properties of tissue non-invasively and in vivo. Data was acquired in 14 felines and elastic parameters were estimated using a globo-regional nonlinear image reconstruction algorithm. Results fell within the range of values reported in the literature and showed a mean shear modulus across the subject group of 7–8 kPa with all but one animal falling within 5–15 kPa. White matter was statistically stiffer (p < 0.01) than grey matter by about 1 kPa on a per subject basis. To the best of our knowledge, the results reported represent the most extensive set of estimates in the in vivo brain which have been based on MRE acquisition of the three-dimensional displacement field coupled to volumetric shear modulus image reconstruction achieved through nonlinear parameter estimation. However, the inter-subject variation in mean shear modulus indicates the need for further study, including the possibility of applying more advanced models to estimate the relevant tissue mechanical properties from the data.
PMCID: PMC2963725  PMID: 20655045
Magnetic resonance elastography; brain; grey matter; white matter; finite element method
12.  Severe hyponatraemia: investigation and management in a district general hospital 
Journal of Clinical Pathology  2002;55(12):893-896.
Aims: To study the incidence, investigation, and management of severe hyponatraemia (serum sodium < 120 mmol/litre) over a period of six months in a district general hospital.
Methods: The laboratory computer was used to identify all inpatients who had a serum sodium concentration of less than 120 mmol/litre over a six month period. The records of these patients were reviewed for the relevant demographic, clinical, and laboratory data, in addition to diagnosis, treatment, and outcome of hospitalisation.
Results: Forty two patients were studied, with a female to male ratio of 2 : 1. Nine patients had central nervous system symptoms, and four of these patients died in hospital. Only 14 patients had their urinary electrolytes and/or osmolality checked. A diagnosis of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was mentioned in eight patients, sometimes without checking their urinary electrolytes or osmolality. Twenty one patients died in hospital. The patients who died did not have lower serum sodium values or a higher rate of correction of hyponatraemia, but they all suffered from advanced medical conditions.
Conclusions: The possible cause of hyponatraemia should always be sought and that will require an accurate drug history, clinical examination, and assessment of fluid volume, plus the measurement of urinary electrolytes and osmolality in a spot urine sample. The diagnosis of SIADH should not be confirmed without the essential criteria being satisfied. The current or recent use of diuretics is a possible pitfall in the diagnosis of SIADH. The rate of serum sodium correction of less than 10 mmol/day is probably the safest option in most cases.
PMCID: PMC1769815  PMID: 12461050
hyponatraemia; syndrome of inappropriate secretion of antidiuretic hormone; mortality; investigations
13.  Acquired ocular toxoplasmosis in pregnancy 
PMCID: PMC1771223  PMID: 12140226
ocular toxoplasmosis; pregnancy
15.  Anesthetic efficacy of a combination of hyaluronidase and lidocaine with epinephrine in inferior alveolar nerve blocks. 
Anesthesia Progress  2001;48(1):9-15.
The purpose of this prospective, randomized, double-blind study was to determine the anesthetic efficacy of a buffered lidocaine with epinephrine solution compared to a combination buffered lidocaine with epinephrine plus hyaluronidase solution in inferior alveolar nerve blocks. Thirty subjects randomly received an inferior alveolar nerve block using 1 of the 2 solutions at 2 separate appointments using a repeated-measures design. Mandibular anterior and posterior teeth were blindly pulp tested at 4-minute cycles for 60 minutes postinjection. No response from the subject to the maximum output (80 reading) of the pulp tester was used as the criterion for pulpal anesthesia. Anesthesia was considered successful when 2 consecutive readings of 80 were obtained. A postoperative survey was used to measure pain and trismus. The results demonstrated 100% of the subjects had profound lip numbness with both solutions for inferior alveolar nerve blocks. The anesthetic success rates for individual teeth ranged from 20 to 80%. There were no significant differences (P > .05) between the 2 solutions. However, the combination lidocaine/hyaluronidase solution resulted in a significant increase in postoperative pain and trismus. It was concluded that adding hyaluronidase to a buffered lidocaine solution with epinephrine did not statistically increase the incidence of pulpal anesthesia in inferior alveolar nerve blocks and, because of its potential tissue damaging effect, it should not be added to local anesthetic solutions for inferior alveolar nerve blocks.
PMCID: PMC2007333  PMID: 11495405
20.  Worldwide advancement of anesthesia in dentistry. 
Anesthesia Progress  2000;47(1):1.
PMCID: PMC2149010  PMID: 11212412
24.  Use of sevoflurane inhalation sedation for outpatient third molar surgery. 
Anesthesia Progress  1999;46(1):21-29.
This study attempted to determine if sevoflurane in oxygen inhaled via a nasal hood as a sole sedative agent would provide an appropriate level of deep sedation for outpatient third molar surgery. Twenty-four patients scheduled for third molar removal were randomly assigned to receive either nasal hood inhalation sevoflurane or an intravenous deep sedation using midazolam and fentanyl followed by a propofol infusion. In addition to measuring patient, surgeon, and dentist anesthesiologist subjective satisfaction with the technique, physiological parameters, amnesia, and psychomotor recovery were also assessed. No statistically significant difference was found between the sevoflurane and midazolam-fentanyl-propofol sedative groups in physiological parameters, degree of amnesia, reported quality of sedation, or patient willingness to again undergo a similar deep sedation. A trend toward earlier recovery in the sevoflurane group was identified. Sevoflurane can be successfully employed as a deep sedative rather than a general anesthetic for extraction of third molars in healthy subjects.
PMCID: PMC2148884  PMID: 10551056

Results 1-25 (89)