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1.  Study protocol for valuing EQ-5D-3L and EORTC-8D health states in a representative population sample in Sri Lanka 
Background
Economic evaluations to inform decisions about allocation of health resources are scarce in Low and Middle Income Countries, including in Sri Lanka. This is in part due to a lack of country-specific utility weights, which are necessary to derive appropriate Quality Adjusted Life Years. The EQ-5D-3L, a generic multi-attribute instrument (MAUI), is most widely used to measure and value health states in high income countries; nevertheless, the sensitivity of generic MAUIs has been criticised in some conditions such as cancer. This article describes a protocol to produce both a generic EQ-5D-3L and cancer specific EORTC-8D utility index in Sri Lanka.
Method
EQ-5D-3L and EORTC-8D health states will be valued using the Time Trade-Off technique, by a representative population sample (n = 780 invited) identified using stratified multi-stage cluster sampling with probability proportionate to size method. Households will be randomly selected within 30 clusters across four districts; one adult (≥18 years) within each household will be selected using the Kish grid method.
Data will be collected via face-to-face interview, with a Time Trade-Off board employed as a visual aid. Of the 243 EQ-5D-3L and 81,290 EORTC-8D health states, 196 and 84 respectively will be directly valued. In EQ-5D-3L, all health states that combine level 3 on mobility with either level 1 on usual activities or self-care were excluded. Each participant will first complete the EQ-5D-3L, rank and value 14 EQ-5D-3L states (plus the worst health state and “immediate death”), and then rank and value seven EORTC-8D states (plus “immediate death”). Participant demographic and health characteristics will be also collected.
Regression models will be fitted to estimate utility indices for EQ-5D-3L and EORTC-8D health states for Sri Lanka. The dependent variable will be the utility value. Different specifications of independent variables will be derived from the ordinal EQ-5D-3L to test for the best-fitting model.
Discussion
In Sri Lanka, a LMIC health state valuation will have to be carried out using face to face interview instead of online methods. The proposed study will provide the first country-specific health state valuations for Sri Lanka, and one of the first valuations to be completed in a South Asian Country.
doi:10.1186/1477-7525-11-149
PMCID: PMC3766133  PMID: 24070162
Low and middle income countries; Utilities; Health state valuation; EQ-5D; EORTC-8D; Time trade-off; QALY
2.  Trends of lip, oral cavity and oropharyngeal cancers in Australia 1982–2008: overall good news but with rising rates in the oropharynx 
BMC Cancer  2013;13:333.
Background
Considerable global variation in the incidence of lip, of oral cavity and of pharyngeal cancers exists. Whilst this reflects regional or population differences in risk, interpretation is uncertain due to heterogeneity of definitions of sites and of sub-sites within this anatomically diverse region. For Australia, limited data on sub-sites have been published. This study examines age-standardised incidence trends and demography from 1982 to 2008, the latest data available.
Methods
Numbers of cases within ICD10:C00-C14 were obtained from the Australian Institute of Health and Welfare, recorded by sex, age, and sub-site. Raw data were re-analysed to calculate crude, age-specific and age-standardised incidence using Segi’s world-standard population. Time-trends were analysed using Joinpoint regression.
Results
Lip, Oral Cavity and Pharyngeal (excluding nasopharynx) cancers, considered together, show a biphasic trend: in men rising 0.9% pa from 1982 to 1992, and declining 1.6% pa between 1992 and 2008. For females: rises of 2.0% pa 1982–1997; declines of 2.8% pa 1997–2008. Lip cancer is declining especially significantly. When the Oropharynx is considered separately, steadily increasing trends of 1.2% pa for men and 0.8% pa for women were observed from 1982 to 2008.
Conclusions
Although overall rates of lip/oral/oropharyngeal cancer are declining in Australia, these are still high. This study revealed steady increases in cancers of the oropharynx, beginning in the late 1990s. Continued efforts to reduce the burden of these cancers are needed, focused on reduction of the traditional risk factors of alcohol and tobacco, and with special emphasis on the possible role of human papillomavirus and sexual hygiene for cancers of the oropharynx.
doi:10.1186/1471-2407-13-333
PMCID: PMC3716721  PMID: 23829309
Lip cancer; Oral cancer; Oropharyngeal cancer; Epidemiology; Trends; Australia
3.  Transforming growth factor-β1 treatment of oral cancer induces epithelial-mesenchymal transition and promotes bone invasion via enhanced activity of osteoclasts 
This study investigates relationships between EMT and bone invasion by OSCC. Three OSCC cell lines, SCC25, HN5, and Tca8113 were artificially induced to display EMT by adding 5 ng/mL of TGF-β1 to culture media for 1–3 days. Cell morphology and phenotypic changes was examined by immunocytochemical staining of CK and VIM. EMT markers, cell-invasion factors, and osteoclast-related molecules were analysed at mRNA, gelatine and protein levels by real-time PCR, gelatine zymography and Western blotting respectively. Mature osteoclasts differentiated from Raw264.7 cells were treated by conditioned medium (CM) of OSCC cells with/without TGF-β1. Immunohistochemistry was performed to validate proteins of CK, VIM, E-cad and Snail1 in OSCC tissue samples with bone invasion. Results showed minimal staining of VIM was found in SCC25 and HN5, while Tca8113 cells stained strongly. EMT markers Twist1 and N-cad were up-regulated; Snail1 and E-cad down-regulated in all cells. Of factors associated with invasion, MMP-2 was unchanged and MMP-9 increased in SCC25 and Tca8113, while MMP-2 was increased and MMP-9 unchanged in HN5. For osteoclast-related molecules, both MT1-MMP and RANKL were up-regulated, while OPG was down-regulated in all cells. CM of OSCC cells pre-treated with TGF-β1 showed to prolong survival of osteoclasts up to 4 days. All target molecules were validated in OSCC samples of bone invasion. These findings suggest that TGF-β1 not only induces EMT to increase the capacity of OSCC for invasion, but also promotes factors which prolong osteoclast survival. TGF-β1 may enhance the ability of MMP2/9 in resorbing bone and favouring invasion of cancer cells.
doi:10.1007/s10585-013-9570-0
PMCID: PMC3663202  PMID: 23378237
Bone invasion; Osteoclast; Oral squamous cell carcinoma; Transforming growth factor-β1; Epithelial-mesenchymal transition
4.  Intra-oral colonization of macaque monkeys by Actinobacillus actinomycetemcomitans 
Actinobacillus actinomycetemcomitans was acquired by captive Macaca fascicularis 3 to 6 months after birth, and all monkeys aged over 6 months harbored detectable levels. This microorganism was most frequently isolated from the gingival plaque of the incisor (and other) teeth compared with other oral sites. Strains were leukotoxic by bioassay and Western blot analysis. Antibodies in macaque serum contained neutralized the leukotoxin of a human A. actinomycetemcomitans strain. High titres of maternal neutralizing anti-leukotoxin antibodies were detected in neonates; the titre then fell rapidly so that by 6 months the antibody titer was zero. Antileukotoxin antibody production was detected after 6 months of age, rapidly reaching a high level within 2 years after birth. The presence of leukotoxic strains of A. actinomycetemcomitans in the gingival region did not appear to be correlated with an increase in susceptibility to periodontal disease.
PMCID: PMC3516870  PMID: 2628866
non-human primates; Actinobacillus actinomycetemcomitans; leukotoxin; colonization; maternal antibody
5.  Detection of human herpesvirus 8 by quantitative polymerase chain reaction: development and standardisation of methods 
BMC Infectious Diseases  2012;12:210.
Background
Human herpesvirus 8 (HHV-8), the aetiological agent of Kaposi’s sarcoma (KS), multicentric Castleman’s disease (MCD), and primary effusion lymphoma (PEL) is rare in Australia, but endemic in Sub-Saharan Africa, parts of South-east Asia and Oceania. While the treatment of external KS lesions can be monitored by clinical observation, the internal lesions of KS, MCD and PEL require extensive and expensive internal imaging, or autopsy. In patients with MCD and PEL, if HHV-8 viraemia is not reduced quickly, ~50% die within 24 months. HHV-8 qPCR is a valuable tool for monitoring HHV-8 viraemia, but is not available in many parts of the world, including those with high prevalence of KS and HHV-8.
Methods
A new molecular facility with stringent three-phase workflow was established, adhering to NPAAC and CLSI guidelines. Three fully validated quantitative assays were developed: two for detection and quantification of HHV-8; one for GAPDH, necessary for normalisation of viral loads in tissue and peripheral blood.
Results
The HHV-8 ORF73 and ORF26 qPCR assays were 100% specific. All qPCR assays, displayed a broad dynamic range (102 to 1010 copies/μL TE Buffer) with a limit of detection of 4.85x103, 5.61x102, and 2.59x102 copies/μL TE Buffer and a limit of quantification of 4.85x103, 3.01x102, and 1.38x102 copies/μL TE Buffer for HHV-8 ORF73, HHV-8 ORF26, and GAPDH respectively.
The assays were tested on a panel of 35 KS biopsies from Queensland. All were HHV-8 qPCR positive with average viral load of 2.96x105 HHV-8 copies/μL DNA extract (range: 4.37x103 to 1.47x106 copies/μL DNA extract): When normalised these equate to an average viral load of 2.44x104 HHV-8 copies/103 cells (range: 2.20x102 to 7.38x105 HHV-8 copies/103 cells).
Conclusions
These are the first fully optimised, validated and MIQE compliant HHV-8 qPCR assays established in Australia. They worked well for qualitative detection of HHV-8 in archival tissue, and are well-suited for quantitative detection in whole blood. They are now available for research, for clinical diagnosis of HHV-8 infection, and for monitoring treatment efficacy.
doi:10.1186/1471-2334-12-210
PMCID: PMC3490733  PMID: 22963082
HHV-8; Kaposi’s sarcoma; Human herpesvirus 8; Molecular diagnostics; Laboratory establishment

Results 1-5 (5)