The cost of prevalent and incident cardiovascular disease in people with type 2 diabetes in Scotland: data from the Scottish Care Information-Diabetes Collaboration.

AIM: To compare costs for three groups of people with type 2 diabetes, those at high risk of future cardiovascular disease, those without cardiovascular disease and those with established cardiovascular disease, and to also compare costs incurred by people with type 2 diabetes with an incident cardiovascular disease event with those who remain incident event-free over a 3-year period. METHODS: Data about people with type 2 diabetes in Scotland were obtained from the Scottish Care Information Diabetes registry. Data linkage was used to retrieve information on healthcare utilization, care home use and deaths. Productivity effects were estimated for those of non-pensionable age. We estimated costs over 12 months (prevalent cardiovascular disease) and 3 years from incident cardiovascular disease event. RESULTS: Mean annual cost per person with established cardiovascular disease was £6900, £3300 for a person at high risk of future cardiovascular disease, and £2500 for a person without cardiovascular disease and not at high risk. In year 1, the cost of an incident cardiovascular disease event was £16 700 compared with £2100 for people without an incident event. Over 2 years, the cumulative costs were £21 500 and £4200, and by year 3, £25 000 and £5900, respectively. CONCLUSIONS: Cardiovascular disease in people with type 2 diabetes places a significant financial burden on healthcare and the wider economy. Our results emphasize the financial consequences of cardiovascular disease prevention strategies.

A comparison of attitudes to laryngeal cancer treatment outcomes: A time trade-off study.

DESIGN: Time trade-off choice experiment. SETTING: Two large head and neck cancer centres. PARTICIPANTS: Patients who have received treatment for head and neck cancer and members of the head and neck cancer multidisciplinary team. MAIN OUTCOME MEASURES: Participants were asked to rank the outcome scenarios, assign utility values using time trade-off and rate the importance of survival on treatment choice. RESULTS: A total of 49 patients with head and neck cancer and 73 staff members were recruited. Chemoradiotherapy (CRT) optimal outcome was the most preferred health state (34 of 49, 69% patients, and 50 of 73, 68% staff), and CRT with complications was least preferred (27 of 49, 55% patients, and 51 of 73, 70% staff). Using time trade-off, mean utility values were calculated for CRT optimal outcome (0.73 for patients, 0.77 for staff), total laryngectomy (TL) optimal outcome (0.67 for patients, 0.69 for staff), TL outcome with complications (0.46 for patients, 0.51 for staff) and CRT with complications (0.36 for patients, 0.49 for staff). The average survival advantage required for a participant to change their preferred choice was 2.6 years. CONCLUSIONS: We have demonstrated that a significant proportion of patients with head and neck cancer and staff members would not choose CRT to manage locally advanced laryngeal cancer. Staff members rated the health states associated with laryngeal cancer treatment higher than patients who have experienced them, and this is particularly evident when considering the poorer outcomes. The head and neck cancer community should develop methods of practice and decision-making which incorporate elicitation and reporting of patient values as a central principle.

Clinical effectiveness and cost-effectiveness of foot orthoses for people with established rheumatoid arthritis: an exploratory clinical trial.

OBJECTIVES: Foot orthoses are commonly prescribed as an intervention for people with rheumatoid arthritis (RA). Data relating to the cost-effectiveness of foot orthoses in people with RA are limited. The aim was to evaluate the clinical and cost-effectiveness of two types of foot orthoses in people with established RA. METHOD: A single-blind randomized controlled trial was undertaken to compare custom-made foot orthoses (CMFOs) and simple insoles (SIs) in 41 people with established RA. The Foot Function Index (FFI) was used to measure foot pain, disability, and functional limitation. Costs were estimated from the perspective of the UK National Health Service (NHS), societal (patient and family) perspective, and secondary care resource use in terms of the intervention and staff time. Effects were assessed in terms of health gain expressed as quality-adjusted life years (QALYs). RESULTS: At baseline, 20 participants received a CMFO and 21 participants received an SI. After 16 weeks foot pain improved in both the CMFOs (p = 0.000) and the SIs (p < 0.01). However, disability scores improved for CMFOs (p < 0.001) but not for SIs (p = 0.40). The cost-effectiveness results demonstrated no difference in cost between the arms (CMFOs: £159.10; SIs: £79.10; p = 0.35), with the CMFOs being less effective in terms of cost per QALY gain (p < 0.001). CONCLUSIONS: In people with established RA, semi-rigid customized foot orthoses can improve pain and disability scores in comparison to simple insoles. From a cost-effectiveness perspective, the customized foot orthoses were far more expensive to manufacture, with no significant cost per QALY gain.

Laryngeal cancer management in a small, rural, multidisciplinary team setting: 15-year review.

BACKGROUND: The Cumberland Infirmary, Carlisle, serves a largely remote, rural population of 330 000. The aim of this study was to report the treatment and survival figures for patients treated for laryngeal cancer at this centre. METHODS: The study included 209 consecutive patients with squamous cell carcinoma of the larynx diagnosed between 1996 and 2010 at the Cumberland Infirmary. RESULTS: Disease-specific survival was 100 per cent for stage one, 76 per cent for stage two, 87 per cent for stage three and 46 per cent for stage four. In total, 76 patients (36 per cent) had a laryngectomy, either as primary treatment or as a salvage procedure. CONCLUSION: Our tumour-specific survival rate was very high, and this success may be due in part to high rates of surgical intervention. Survival data compared favourably with other centres, despite less radical radiotherapy regimes. Laryngeal cancer can be managed effectively in a small, relatively remote, multidisciplinary team setting.

LIFELAX - diet and LIFEstyle versus LAXatives in the management of chronic constipation in older people: randomised controlled trial.

OBJECTIVES: To investigate the clinical effectiveness and cost-effectiveness of laxatives versus dietary and lifestyle advice, and standardised versus personalised dietary and lifestyle advice. DESIGN: A prospective, pragmatic, three-armed cluster randomised trial with an economic evaluation. SETTING: General practices in England and Scotland, UK. PARTICIPANTS: People aged ≥ 55 years with chronic constipation, living in private households. Participants were identified as those who had been prescribed laxatives three or more times in the previous 12 months, or with a recorded diagnosis of chronic functional constipation. INTERVENTIONS: Prescription of laxatives, with class of laxative and dose at the discretion of the GP and patient (standard care control arm); standardised, non-personalised dietary and lifestyle advice; and, personalised dietary and lifestyle advice, with reinforcement. OUTCOME MEASURES: The primary outcome was the constipation-specific Patient Assessment of Constipation-Symptoms (PAC-SYM)/Patient Assessment of Constipation-Quality of Life (PAC-QOL). RESULTS: The trial planned to recruit and retain 1425 patients from 57 practices (19 per arm); however, only 154 patients were recruited from 19 practices. Due to these low recruitment rates it was not possible to report the conventional trial findings. Baseline characteristics of the sample from data gathered from both postal self-completion questionnaires and face-to-face interviews suggest that our sample experienced very few symptoms of constipation (PAC-SYM) and that the condition itself did not have a major impact upon their quality of life (PAC-QOL). The low level of symptoms of constipation is most likely explained by 90% of the sample using a laxative in the previous week. Most participants in our sample were satisfied with the performance of their laxatives, and levels of anxiety and depression were low. Their fibre consumption was classified as 'moderate' but their average water consumption fell below the recommended guidelines. Daily diaries, completed each day for a period of 6 months, were analysed primarily in terms of overall response rate and item response rates, and the participants accepted this method of data collection. For the economic evaluation, all of the trial arms experienced a reduction in utility, as measured by EQ-5D. There was no statistical evidence to suggest that either the personalised intervention arm or the standardised intervention arm was associated with significant changes in utility at 3 months compared with the control arm. Data on related health-care costs show a cost saving of £13.34 for those in the personalised arm, compared with the control arm, and a smaller cost saving for the standardised arm. These savings primarily occurred because of reduced hospital costs. There was no significant change measured in utility, so the personalised arm appeared to be the preferred course, producing the greatest cost savings. CONCLUSIONS: Due to the low number of participants in the trial, no firm conclusions could be drawn about the effectiveness of the interventions. However, a number of factors that contributed to the conduct and progress of the trial are highlighted, which may be relevant to others conducting research on a similar topic or population. TRIAL REGISTRATION: ISRCTN73881345. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 14, No. 52. See the HTA programme website for further project information.

Synthesis and structure-activity relationships of a series of penicillin-derived HIV proteinase inhibitors: heterocyclic ring systems containing P1' and P2' substituents.

As an extension of our earlier work based upon a single penicillin-derived thiazolidine moiety we have found that the decahydroisoquinoline grouping, also present in Ro 31-8959, is an effective replacement for one of the thiazolidine units in C2 symmetric penicillin-derived dimers. Reaction of racemic epoxide 6 with [3S-[3 alpha, 4a alpha, 8a alpha]]-decahydro-N-(1,1-dimethylethyl)-3- isoquinolinecarboxamide gave diasteroisomers 34a and 34b. The stereochemistry of the hydroxyl grouping of 34a was determined to be (S). Reaction of the amines derived from 34a and 34b with thiazolidine 8a gave 50 and 51, respectively. Compound 50 was a potent inhibitor of HIV proteinase (IC50 = 23 nM) with antiviral activity against HIV-1 in vitro (EC50 C8166 cells = 50 nM). However, a poor pharmacokinetic profile in the dog for compound 50 and its analogues, in keeping with earlier studies on penicillin-derived dimers in three species, precluded their development as potential antivirals.

A series of penicillin-derived C2-symmetric inhibitors of HIV-1 proteinase: structural and modeling studies.

The binding modes of a series of penicillin-derived C2 symmetric dimer inhibitors of HIV-1 proteinase were investigated by NMR, protein crystallography, and molecular modeling. The compounds were found to bind in a symmetrical fashion, tracing and S-shaped course through the active site, with good hydrophobic interactions in the S1/S1' and S2/S2' pockets and hydrogen bonding of inhibitor amide groups. Interactions with the catalytic aspartates appeared poor and the protein conformation was very similar to that seen in complexes with peptidomimetics, in spite of the major differences in ligand structure.

Synthesis and structure-activity relationships of a series of penicillin-derived HIV proteinase inhibitors containing a stereochemically unique peptide isostere.

A series of HIV-1 proteinase inhibitors was synthesized based upon a single penicillin derived thiazolidine moiety. Reaction of the C-4 carboxyl group with (R)-phenylalaninol gave amide 10 which was a moderately potent inhibitor of HIV-1 proteinase (IC50 = 0.15 microM). Further modifications based on molecular modeling studies led to compound 48 which contained a stereochemically unique statine-based isostere. This was a potent competitive inhibitor (Ki = 0.25 nM) with antiviral activity against HIV-1 in vitro (5 microM). Neither modification to the benzyl group in an attempt to improve interaction with the S2' pocket, nor introduction of a hydrogen bond donating group to interact with residue Gly48' resulted in improved inhibitory or antiviral activity.