A multicentre randomised controlled trial of a guided self-help cognitive behavioural therapy to MANage the impact of hot flushes and night sweats in patients with prostate CANcer undergoing androgen deprivation therapy (MANCAN2).

BACKGROUND: Androgen deprivation therapy (ADT) is prescribed to almost half of all men diagnosed with prostate cancer. Although ADT is effective treatment, with virtually all men with advanced disease showing initial clinical response, it is associated with troublesome side effects including hot flushes and night sweats (HFNS). HFNS can be both frequent and severe and can have a significant impact on quality of life (QoL). They can occasionally be so debilitating that patients stop ADT altogether, despite the increased risk of disease relapse or death. Previous research has found that guided self-help cognitive behavioural therapy (CBT) can be effective in reducing HFNS due to ADT when delivered by a clinical psychologist. MANCAN2 aims test whether we can train the existing NHS Prostate Cancer Nurse Specialist (CNS) team to deliver guided self-help CBT and whether it is effective in reducing the impact of HFNS in men undergoing ADT. METHODS: MANCAN2 is a phase III multicentre randomised controlled trial and process evaluation. Between 144 and 196 men with prostate cancer who are currently receiving ADT and are experiencing problematic HFNS will be individually randomised in a 1:1 ratio in groups of 6-8 participants to either treatment as usual (TAU) or participation in the guided self-help CBT intervention plus TAU. A process evaluation using the normalisation process theory (NPT) framework will be conducted, to understand the CNS team's experiences of delivering the intervention and to establish the key influencers to its implementation as a routine practice service. Fidelity of implementation of the intervention will be conducted by expert assessment. The cost-effectiveness of the intervention and participant adherence to the trial intervention will also be assessed. DISCUSSION: MANCAN2 will advance the program of work already conducted in development of management strategies for HFNS. This research will determine whether the severity of ADT-induced HFNS in men with prostate cancer can be reduced by a guided self-help CBT intervention, delivered by the existing NHS prostate cancer CNS team, within a multicentre study. The emphasis on this existing team, if successful, should facilitate translation through to implementation in routine practice. TRIAL REGISTRATION: ISRCTN reference 58720120 . Registered 13 December 2022.

A randomised controlled trial of a digital intervention (Renewed) to support symptom management, wellbeing and quality of life in cancer survivors.

BACKGROUND: Many cancer survivors following primary treatment have prolonged poor quality of life. AIM: To determine the effectiveness of a bespoke digital intervention to support cancer survivors. DESIGN: Pragmatic parallel open randomised trial. SETTING: UK general practices. METHODS: People having finished primary treatment (<= 10 years previously) for colo-rectal, breast or prostate cancers, with European-Organization-for-Research-and-Treatment-of-Cancer QLQ-C30 score <85, were randomised by online software to: 1)detailed 'generic' digital NHS support ('LiveWell';n=906), 2) a bespoke complex digital intervention ('Renewed';n=903) addressing symptom management, physical activity, diet, weight loss, distress, or 3) 'Renewed-with-support' (n=903): 'Renewed' with additional brief email and telephone support. RESULTS: Mixed linear regression provided estimates of the differences between each intervention group and generic advice: at 6 months (primary time point: n's respectively 806;749;705) all groups improved, with no significant between-group differences for EORTC QLQ-C30, but global health improved more in both intervention groups. By 12 months there were: small improvements in EORTC QLQ-C30 for Renewed-with-support (versus generic advice: 1.42, 95% CIs 0.33-2.51); both groups improved global health (12 months: renewed: 3.06, 1.39-4.74; renewed-with-support: 2.78, 1.08-4.48), dyspnoea, constipation, and enablement, and lower NHS costs (generic advice £265: in comparison respectively £141 (153-128) and £77 (90-65) lower); and for Renewed-with-support improvement in several other symptom subscales. No harms were identified. CONCLUSION: Cancer survivors quality of life improved with detailed generic online support. Robustly developed bespoke digital support provides limited additional short term benefit, but additional longer term improvement in global health enablement and symptom management, with substantially lower NHS costs.

Synthesis, X-ray Single-Crystal Structural Characterization, and Thermal Analysis of Bis(O-alkylxanthato)Cd(II) and Bis(O-alkylxanthato)Zn(II) Complexes Used as Precursors for Cadmium and Zinc Sulfide Thin Films.

This work investigates tuning of the molecular structure of a series of O-alkylxanthato zinc and cadmium precursor complexes to enhance production of ZnS and CdS materials. The structures of several bis(O-alkylxanthato) cadmium(II) complexes (8-13) and bis(O-alkyl xanthato)zinc(II) complexes (18 and 19) are reported based on single crystal X-ray diffraction data. CdS and ZnS films were produced by the spin-coating of these metal complexes followed by their thermal decomposition to the corresponding metal sulfides. Thin films of CdS were deposited by spin-coating the bis(O-alkylxanthato) cadmium(II) precursors (7-13) on glass substrates, followed by annealing at 300 °C for 60 min. Thin films of ZnS were deposited by spin-coating bis(O-alkylxanthato) zinc(II) (14-20), followed by annealing at 200 °C for 60 min. The molecular complexes and solid state materials are characterized using a range of techniques including single-crystal X-ray diffraction, pXRD, EDS and XPS, DSC and TGA, UV-vis and PL spectroscopies, and electron microscopy. These techniques provided information on the influence of alkyl chain length on the thermal conditions required to fabricate metal sulfide films as well as film properties such as film quality, and morphology. For example, the obtained crystallite size of metal sulfide films formed is correlated to the hydrocarbon chain length of xanthate ligands in the precursor. The behavior of the complexes under thermal stress was therefore studied in detail. DTA and TGA profiles explain the relationship between hydrocarbon chain length, decomposition temperatures, and the energies required for decomposition. A higher decomposition temperature for complexes with longer hydrocarbon chains is observed compared to complexes with shorter hydrocarbon chains. Band-gap energies calculated from the optical absorption spectra alongside steady state and time-resolved photoluminescence studies are reported for CdS films.

Effectiveness of nurse-led group CBT for hot flushes and night sweats in women with breast cancer: Results of the MENOS4 randomised controlled trial.

OBJECTIVE: Troublesome hot flushes and night sweats (HFNS) are experienced by many women after treatment for breast cancer, impacting significantly on sleep and quality of life. Cognitive behavioural therapy (CBT) is known to be effective for the alleviation of HFNS. However, it is not known if it can effectively be delivered by specialist nurses. We investigated whether group CBT, delivered by breast care nurses (BCNs), can reduce the impact of HFNS. METHODS: We recruited women with primary breast cancer following primary treatment with seven or more HFNS/week (including 4/10 or above on the HFNS problem rating scale), from six UK hospitals to an open, randomised, phase 3 effectiveness trial. Participants were randomised to Group CBT or usual care (UC). The primary endpoint was HFNS problem rating at 26 weeks after randomisation. Secondary outcomes included sleep, depression, anxiety and quality of life. RESULTS: Between 2017 and 2018, 130 participants were recruited (CBT:63, control:67). We found a 46% (6.9-3.7) reduction in the mean HFNS problem rating score from randomisation to 26 weeks in the CBT arm and a 15% (6.5-5.5) reduction in the UC arm (adjusted mean difference -1.96, CI -3.68 to -0.23, P = .039). Secondary outcomes, including frequency of HFNS, sleep, anxiety and depression all improved significantly. CONCLUSION: Our results suggest that specialist nurses can be trained to deliver CBT effectively to alleviate troublesome menopausal hot flushes in women following breast cancer in the NHS setting.

Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study.

BACKGROUND: Despite improvements in multidisciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adjuvant therapy. We aimed to determine whether adjuvant capecitabine improved overall survival compared with observation following surgery for biliary tract cancer. METHODS: This randomised, controlled, multicentre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eligible patients were aged 18 years or older and had histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had undergone a macroscopically complete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooperative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for biliary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation commencing within 16 weeks of surgery. Treatment was not masked, and allocation concealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. This study is registered with EudraCT, number 2005-003318-13. FINDINGS: Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. The median follow-up for all patients was 60 months (IQR 37-60). In the intention-to-treat analysis, median overall survival was 51·1 months (95% CI 34·6-59·1) in the capecitabine group compared with 36·4 months (29·7-44·5) in the observation group (adjusted hazard ratio [HR] 0·81, 95% CI 0·63-1·04; p=0·097). In a protocol-specified sensitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HR was 0·71 (95% CI 0·55-0·92; p=0·010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30-44) in the observation group (adjusted HR 0·75, 95% CI 0·58-0·97; p=0·028). In the intention-to-treat analysis, median recurrence-free survival was 24·4 months (95% CI 18·6-35·9) in the capecitabine group and 17·5 months (12·0-23·8) in the observation group. In the per-protocol analysis, median recurrence-free survival was 25·9 months (95% CI 19·8-46·3) in the capecitabine group and 17·4 months (12·0-23·7) in the observation group. Adverse events were measured in the capecitabine group only, and of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most frequent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (<1%) patient had grade 4 cardiac ischaemia or infarction. Serious adverse events were observed in 47 (21%) of 223 patients in the capecitabine group and 22 (10%) of 224 patients in the observation group. No deaths were deemed to be treatment related. INTERPRETATION: Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting. FUNDING: Cancer Research UK and Roche.

MENOS4 trial: a multicentre randomised controlled trial (RCT) of a breast care nurse delivered cognitive behavioural therapy (CBT) intervention to reduce the impact of hot flushes in women with breast cancer: Study Protocol.

BACKGROUND: Women who have been treated for breast cancer may identify vasomotor symptoms, such as hot flushes and night sweats (HFNS), as a serious problem. HFNS are unpleasant to experience and can have a significant impact on daily life, potentially leading to reduced adherence to life saving adjuvant hormonal therapy. It is known that Cognitive Behavioural Therapy (CBT) is effective for the alleviation of hot flushes in both well women and women who have had breast cancer. Most women with breast cancer will see a breast care nurse and there is evidence that nurses can be trained to deliver psychological treatments to a satisfactory level, whilst also maintaining treatment fidelity. The research team will assess whether breast care nurses can effectively deliver a CBT intervention to alleviate hot flushes in women with breast cancer. METHODS: This study is a multi-centre phase III individually randomised controlled trial of group CBT versus usual care to reduce the impact of hot flushes in women with breast cancer. 120-160 women with primary breast cancer experiencing seven or more problematic HFNS a week will be randomised to receive either treatment as usual (TAU) or participation in the group CBT intervention plus TAU (CBT Group). A process evaluation using May's Normalisation Process Theory will be conducted, as well as practical and organisational issues relating to the implementation of the intervention. Fidelity of implementation of the intervention will be conducted by expert assessment. The cost effectiveness of the intervention will also be assessed. DISCUSSION: There is a need for studies that enable effective interventions to be implemented in practice. There is good evidence that CBT is helpful for women with breast cancer who experience HFNS, yet it is not widely available. It is not yet known whether the intervention can be effectively delivered by breast care nurses or implemented in practice. This study will provide information on both whether the intervention can effectively help women with hot flushes and whether and how it can be translated into routine clinical practice. TRIAL REGISTRATION: ISRCTN 12824632 . Registered 25-01-2017.

Incidence and cost of medication harm in older adults following hospital discharge: a multicentre prospective study in the UK.

AIMS: Polypharmacy is increasingly common in older adults, placing them at risk of medication-related harm (MRH). Patients are particularly vulnerable to problems with their medications in the period following hospital discharge due to medication changes and poor information transfer between hospital and primary care. The aim of the present study was to investigate the incidence, severity, preventability and cost of MRH in older adults in England postdischarge. METHODS: An observational, multicentre, prospective cohort study recruited 1280 older adults (median age 82 years) from five teaching hospitals in Southern England, UK. Participants were followed up for 8 weeks by senior pharmacists, using three data sources (hospital readmission review, participant telephone interview and primary care records), to identify MRH and associated health service utilization. RESULTS: Overall, 413 participants (37%) experienced MRH (556 MRH events per 1000 discharges), of which 336 (81%) cases were serious and 214 (52%) potentially preventable. Four participants experienced fatal MRH. The most common MRH events were gastrointestinal (n = 158, 25%) or neurological (n = 111, 18%). The medicine classes associated with the highest risk of MRH were opiates, antibiotics and benzodiazepines. A total of 328 (79%) participants with MRH sought healthcare over the 8-week follow-up. The incidence of MRH-associated hospital readmission was 78 per 1000 discharges. Postdischarge MRH in older adults is estimated to cost the National Health Service £396 million annually, of which £243 million is potentially preventable. CONCLUSIONS: MRH is common in older adults following hospital discharge, and results in substantial use of healthcare resources.

National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme research funding and UK burden of disease.

BACKGROUND: HTA Programme funding is governed by the need for evidence and scientific quality, reflecting funding of the National Institute for Health Research (NIHR) by the NHS. The need criterion incorporates covering the spectrum of diseases, but also taking account of research supported by other funders. This study compared the NIHR HTA Programme portfolio of research with the UK burden of disease as measured by Disability-adjusted Life Years (DALYs). METHODS: A retrospective cross-sectional study using a cohort of all funded primary research and evidence syntheses projects received by the HTA Programme from April 2011 to March 2016 (n = 363); to determine the proportion of spend by disease compared with burden of disease in the UK calculated using 2015 UK DALY data. RESULTS: The programme costing just under £44 million broadly reflected UK DALY burden by disease. Spend was lower than disease burden for cancer, cardiovascular and musculoskeletal diseases, which may reflect the importance of other funders, notably medical charities, which concentrate on these diseases. CONCLUSION: The HTA Programme spend, adjusted for other relevant funders, broadly matches disease burden in the UK; no diseases are being neglected.

The clinical utility and cost impact of cystatin C measurement in the diagnosis and management of chronic kidney disease: A primary care cohort study.

BACKGROUND: To reduce over-diagnosis of chronic kidney disease (CKD) resulting from the inaccuracy of creatinine-based estimates of glomerular filtration rate (GFR), UK and international guidelines recommend that cystatin-C-based estimates of GFR be used to confirm or exclude the diagnosis in people with GFR 45-59 ml/min/1.73 m2 and no albuminuria (CKD G3aA1). Whilst there is good evidence for cystatin C being a marker of GFR and risk in people with CKD, its use to define CKD in this manner has not been evaluated in primary care, the setting in which most people with GFR in this range are managed. METHODS AND FINDINGS: A total of 1,741 people with CKD G3a or G3b defined by 2 estimated GFR (eGFR) values more than 90 days apart were recruited to the Renal Risk in Derby study between June 2008 and March 2010. Using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, we compared GFR estimated from creatinine (eGFRcreat), cystatin C (eGFRcys), and both (eGFRcreat-cys) at baseline and over 5 years of follow-up. We analysed the proportion of participants with CKD G3aA1 reclassified to 'no CKD' or more advanced CKD with the latter two equations. We further assessed the impact of using cystatin-C-based eGFR in risk prediction equations for CKD progression and all-cause mortality and investigated non-GFR determinants of eGFRcys. Finally, we estimated the cost implications of implementing National Institute for Health and Care Excellence (NICE) guidance to use eGFRcys to confirm the diagnosis in people classified as CKD G3aA1 by eGFRcreat. Mean eGFRcys was significantly lower than mean eGFRcreat (45.1 ml/min/1.73 m2, 95% CI 44.4 to 45.9, versus 53.6 ml/min/1.73 m2, 95% CI 53.0 to 54.1, P < 0.001). eGFRcys reclassified 7.7% (50 of 653) of those with CKD G3aA1 by eGFRcreat to eGFR ≥ 60 ml/min/1.73 m2. However, a much greater proportion (59.0%, 385 of 653) were classified to an eGFR category indicating more severe CKD. A similar pattern was seen using eGFRcreat-cys, but lower proportions were reclassified. Change in eGFRcreat and eGFRcys over 5 years were weakly correlated (r = 0.33, P < 0.001), but eGFRcys identified more people as having CKD progression (18.2% versus 10.5%). Multivariable analysis using eGFRcreat as an independent variable identified age, smoking status, body mass index, haemoglobin, serum uric acid, serum albumin, albuminuria, and C reactive protein as non-GFR determinants of eGFRcys. Use of eGFRcys or eGFRcreat-cys did not improve discrimination in risk prediction models for CKD progression and all-cause mortality compared to similar models with eGFRcreat. Application of the NICE guidance, which assumed cost savings, to participants with CKD G3aA1 increased the cost of monitoring by £23 per patient, which if extrapolated to be applied throughout England would increase the cost of testing and monitoring CKD by approximately £31 million per year. Limitations of this study include the lack of a measured GFR and the potential lack of ethnic diversity in the study cohort. CONCLUSIONS: Implementation of current guidelines on eGFRcys testing in our study population of older people in primary care resulted in only a small reduction in diagnosed CKD but classified a greater proportion as having more advanced CKD than eGFRcreat. Use of eGFRcys did not improve risk prediction in this population and was associated with increased cost. Our data therefore do not support implementation of these recommendations in primary care. Further studies are warranted to define the most appropriate clinical application of eGFRcys and eGFRcreat-cys.

Health Economics as Rhetoric: The Limited Impact of Health Economics on Funding Decisions in Four European Countries.

BACKGROUND: A response to the challenge of high-cost treatments in health care has been economic evaluation. Cost-effectiveness analysis presented as cost per quality-adjusted life-years gained has been controversial, raising heated support and opposition. OBJECTIVES: To assess the impact of economic evaluation in decisions on what to fund in four European countries and discuss the implications of our findings. METHODS: We used a protocol to review the key features of the application of economic evaluation in reimbursement decision making in England, Germany, the Netherlands, and Sweden, reporting country-specific highlights. RESULTS: Although the institutions and processes vary by country, health economic evaluation has had limited impact on restricting access of controversial high-cost drugs. Even in those countries that have gone the furthest, ways have been found to avoid refusing to fund high-cost drugs for particular diseases including cancer, multiple sclerosis, and orphan diseases. Economic evaluation may, however, have helped some countries to negotiate price reductions for some drugs. It has also extended to the discussion of clinical effectiveness to include cost. CONCLUSIONS: The differences in approaches but similarities in outcomes suggest that health economic evaluation be viewed largely as rhetoric (in D.N. McCloskey's terms in The Rhetoric of Economics, 1985). This is not to imply that economics had no impact: rather that it usually contributed to the discourse in ways that differed by country. The reasons for this no doubt vary by perspective, from political science to ethics. Economic evaluation may have less to do with rationing or denial of medical treatments than to do with expanding the discourse used to discuss such issues.

Heterocyclic dithiocarbamato-iron(III) complexes: single-source precursors for aerosol-assisted chemical vapour deposition (AACVD) of iron sulfide thin films.

Tris-(piperidinedithiocarbamato)iron(III) (1) and tris-(tetrahydroquinolinedithiocarbamato)iron(iii) (2) complexes have been synthesized and their single-crystal X-ray structures were determined. Thermogravimetric analysis (TGA) of the complexes showed decomposition to iron sulfide. Both complexes were then used as single-source precursors for the deposition of iron sulfide thin films by aerosol-assisted chemical vapour deposition (AACVD). Energy-dispersive X-ray (EDX) spectroscopy confirmed the formation of iron sulfide films. The addition of tert-butyl thiol almost doubled the sulfur content in the deposited films. Scanning electron microscopy (SEM) images of the iron sulfide films from both complexes showed flakes/leaves/sheets, spherical granules and nanofibres. The sizes and shapes of these crystallites depended on the nature of the precursor, temperature, solvent and the amount of tert-butyl thiol used. The observed optical properties are dependent upon the variation of reaction parameters such as temperature and solvent. Powder X-ray diffraction (p-XRD) studies revealed that pyrrhotite, hexagonal (Fe0.975S), marcasite and smythite (Fe3S4) phases were differently deposited.

Using systematic reviews to inform NIHR HTA trial planning and design: a retrospective cohort.

BACKGROUND: Chalmers and Glasziou's paper published in 2014 recommends research funding bodies should mandate that proposals for additional primary research are built on systematic reviews of existing evidence showing what is already known. Jones et al. identified 11 (23%) of 48 trials funded during 2006-8 by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme did not reference a systematic review. This study did not explore the reasons for trials not referencing a systematic review or consider trials using any other evidence in the absence of a systematic review. Referencing a systematic review may not be possible in certain circumstances, for instance if the systematic review does not address the question being proposed in the trial. The current study extended Jones' study by exploring the reasons for why trials did not reference a systematic review and included a more recent cohort of trials funded in 2013 to determine if there were any changes in the referencing or use of systematic reviews. METHODS: Two cohorts of NIHR HTA randomised controlled trials were included. Cohort I included the same trials as Jones et al. (with the exception of one trial which was discontinued). Cohort II included NIHR HTA trials funded in 2013. Data extraction was undertaken independently by two reviewers using full applications and trial protocols. Descriptive statistics was used and no formal statistical analyses were conducted. RESULTS: Five (11%) trials of the 47 funded during 2006-2008 did not reference a systematic review. These 5 trials had warranted reasons for not referencing systematic reviews. All trials from Cohort II referenced a systematic review. A quarter of all those trials with a preceding systematic review used a different primary outcome than those stated in the reviews. CONCLUSIONS: The NIHR requires that proposals for new primary research are justified by existing evidence and the findings of this study confirm the adherence to this requirement with a high rate of applications using systematic reviews.

A randomised controlled trial to assess the clinical effectiveness and cost-effectiveness of alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN).

BACKGROUND: Bevacizumab (Avastin®, Roche), which is used in cancer therapy, is the 'parent' molecule from which ranibizumab (Lucentis®, Novartis) was derived for the treatment of neovascular age-related macular degeneration (nAMD). There were reports in the literature on the effectiveness of bevacizumab in treating nAMD, but no trials. The cost per dose of bevacizumab is about 5-10% that of ranibizumab. This trial was a head-to-head comparison of these two drugs. OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of ranibizumab and bevacizumab, and two treatment regimens, for nAMD. DESIGN: Multicentre, factorial randomised controlled trial with within-trial cost-utility and cost-minimisation analyses from the perspective of the UK NHS. Participants, health professionals and researchers were masked to allocation of drug but not regimen. Computer-generated random allocations to combinations of ranibizumab or bevacizumab, and continuous or discontinuous regimen, were stratified by centre, blocked and concealed. SETTING: Twenty-three ophthalmology departments in NHS hospitals. PARTICIPANTS: Patients ≥ 50 years old with active nAMD in the study eye with best corrected distance visual acuity (BCVA) ≥ 25 letters measured on a Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Previous treatment for nAMD, long-standing disease, lesion diameter > 6000 µm, thick blood at the fovea and any other confounding ocular disease were exclusion criteria. One eye per participant was studied; the fellow eye was treated according to usual care, if required. INTERVENTIONS: Ranibizumab and bevacizumab were procured commercially. Doses were ranibizumab 0.5 mg or bevacizumab 1.25 mg. The repackaged bevacizumab was quality assured. All participants were treated at visits 0, 1 and 2. Participants randomised to the continuous regimen were treated monthly thereafter. Participants randomised to the discontinuous regimen were not retreated after visit 2 unless pre-specified criteria for active disease were met. If retreatment was needed, monthly injections over 3 months were mandated. MAIN OUTCOME MEASURES: The primary outcome was BCVA. The non-inferiority margin was 3.5 letters. Secondary outcomes were contrast sensitivity; near visual acuity; reading index; neovascular lesion morphology; generic and disease-specific patient-reported outcomes, including macular disease-specific quality of life; survival free from treatment failure; resource use; quality-adjusted life-years (QALYs); and development of new geographic atrophy (GA) (outcome added during the trial). Results are reported for the study eye, except for patient-reported outcomes. RESULTS: Between 27 March 2008 and 15 October 2010, 610 participants were allocated and treated (314 ranibizumab, 296 bevacizumab; at 3 months, 305 continuous, 300 discontinuous). After 2 years, bevacizumab was neither non-inferior nor inferior to ranibizumab [-1.37 letters, 95% confidence interval (CI) -3.75 to +1.01 letters] and discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1.63 letters, 95% CI -4.01 to +0.75 letters). Lesion thickness at the fovea was similar by drug [geometric mean ratio (GMR) 0.96, 95% CI 0.90 to 1.03; p = 0.24] but 9% less with continuous treatment (GMR 0.91, 95% CI 0.85 to 0.97; p = 0.004). Odds of developing new GA during the trial were similar by drug [odds ratio (OR) 0.87, 95% CI 0.61 to 1.25; p = 0.46] but significantly higher with continuous treatment (OR 1.47, 95% CI 1.03 to 2.11; p = 0.033). Safety outcomes did not differ by drug but mortality was lower with continuous treatment (OR 0.47, 95% CI 0.22 to 1.03; p = 0.05). Continuous ranibizumab cost £3.5M per QALY compared with continuous bevacizumab; continuous bevacizumab cost £30,220 per QALY compared with discontinuous bevacizumab. These results were robust in sensitivity analyses. CONCLUSIONS: Ranibizumab and bevacizumab have similar efficacy. Discontinuing treatment and restarting when required results in slightly worse efficacy. Safety was worse with discontinuous treatment, although new GA developed more often with continuous treatment. Ranibizumab is not cost-effective, although it remains uncertain whether or not continuous bevacizumab is cost-effective compared with discontinuous bevacizumab at £20,000 per QALY threshold. Future studies should focus on the ocular safety of the two drugs, further optimisation of treatment regimens and criteria for stopping treatment. TRIAL REGISTRATION: Current Controlled Trials ISRCTN92166560. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 78. See the NIHR Journals Library website for further project information.

Health economic evaluation in England.

The 2010 National Health Service Constitution for England specified rights and responsibilities, including health economic evaluation for the National Institute for Health and Care Excellence (NICE) and the Joint Committee on Vaccinations and Immunisations. The National Screening Committee and the Health Protection Agency also provide advice to the Government based on health economic evaluation. Each agency largely follows the methods specified by NICE. To distinguish the methods from neoclassical economics they have been termed "extra-welfarist". Key differences include measurement and valuation of both benefits (QALYs) and costs (healthcare related). Policy on discounting has also changed over time and by agency. The debate over having NICE's methods align more closely with neoclassical economics has been prominent in the ongoing development of "value based pricing". The political unacceptability of some decisions has led to special funding for technologies not recommended by NICE. These include the 2002 Multiple Sclerosis Risk Sharing Scheme and the 2010 Cancer Drugs Fund as well as special arrangements for technologies linked to the end of life and for innovation. Since 2009 Patient Access Schemes have made price reductions possible which sometimes enables drugs to meet NICE's cost-effectiveness thresholds. As a result, the National Health Service in England has denied few technologies on grounds of cost-effectiveness.

Designing foldamer-foldamer interactions in solution: the roles of helix length and terminus functionality in promoting the self-association of aminoisobutyric acid oligomers.

The biological activity of antibiotic peptaibols has been linked to their ability to aggregate, but the structure-activity relationship for aggregation is not well understood. Herein, we report a systematic study of a class of synthetic helical oligomer (foldamer) composed of aminoisobutyric acid (Aib) residues, which mimic the folding behavior of peptaibols. NMR spectroscopic analysis was used to quantify the dimerization constants in solution, which showed hydrogen-bond donors at the N terminus promoted aggregation more effectively than similar modifications at the C terminus. Elongation of the peptide chain also favored aggregation. The geometry of aggregation in solution was investigated by means of titrations with [D6]DMSO and 2D NOE NMR spectroscopy, which allowed the NH protons most involved in intermolecular hydrogen bonds in solution to be identified. X-ray crystallography studies of two oligomers allowed a comparison of the inter- and intramolecular hydrogen-bonding interactions in the solid state and in solution and gave further insight into the geometry of foldamer-foldamer interactions. These solution-based and solid-state studies indicated that the preferred geometry for aggregation is through head-to-tail interactions between the N and C termini of adjacent Aib oligomers.

Cost-effectiveness of ranibizumab and bevacizumab for age-related macular degeneration: 2-year findings from the IVAN randomised trial.

OBJECTIVE: To assess the incremental cost and cost-effectiveness of continuous and discontinuous regimens of bevacizumab (Avastin) and ranibizumab (Lucentis) for neovascular age-related macular degeneration (nAMD) from a UK National Health Service (NHS) perspective. DESIGN: A within-trial cost-utility analysis with a 2-year time horizon, based on a multicentre factorial, non-inferiority randomised controlled trial. SETTING: 23 hospital ophthalmology clinics. PARTICIPANTS: 610 patients aged ≥50 years with untreated nAMD in the study eye. INTERVENTIONS: 0.5 mg ranibizumab or 1.25 mg bevacizumab given continuously (monthly) or discontinuously (as-needed) for 2 years. MAIN OUTCOME MEASURES: Quality-adjusted life-years (QALYs). RESULTS: Total 2-year costs ranged from £3002/patient ($4700; 95% CI £2601 to £3403) for discontinuous bevacizumab to £18 590/patient ($29 106; 95% CI £18 258 to £18 922) for continuous ranibizumab. Ranibizumab was significantly more costly than bevacizumab for both continuous (+£14 989/patient ($23 468); 95% CI £14 522 to £15 456; p<0.001) and discontinuous treatment (+£8498 ($13 305); 95% CI £7700 to £9295; p<0.001), with negligible difference in QALYs. Continuous ranibizumab would only be cost-effective compared with continuous bevacizumab if the NHS were willing to pay £3.5 million ($5.5 million) per additional QALY gained. Patients receiving continuous bevacizumab accrued higher total costs (+£599 ($938); 95% CI £91 to £1107; p=0.021) than those receiving discontinuous bevacizumab, but also accrued non-significantly more QALYs (+0.020; 95% CI -0.032 to 0.071; p=0.452). Continuous bevacizumab therefore cost £30 220 ($47 316) per QALY gained versus discontinuous bevacizumab. However, bootstrapping demonstrated that if the NHS is willing to pay £20 000/QALY gained, there is a 37% chance that continuous bevacizumab is cost-effective versus discontinuous bevacizumab. CONCLUSIONS: Ranibizumab is not cost-effective compared with bevacizumab, being substantially more costly and producing little or no QALY gain. Discontinuous bevacizumab is likely to be the most cost-effective of the four treatment strategies evaluated in this UK trial, although there is a 37% chance that continuous bevacizumab is cost-effective. TRIAL REGISTRATION NUMBER: ISRCTN92166560.

Conformational analysis of helical aminoisobutyric acid (Aib) oligomers bearing C-terminal ester Schellman motifs.

The effect of Schellman motifs on the adoption of stable 310 helical conformations in a series of aminoisobutyric (Aib) oligomers has been studied in the solid state and solution. The destabilising effect of the Schellman motif (a local inversion of helical screw-sense due to a C-terminal ester residue) was quantified in the solid state using X-ray crystallography through analysis of the torsion angles and their deviation from those observed in an ideal 310 helix. Investigation of the intramolecular hydrogen-bonding interactions in the solid state led to the identification of a fully extended C5 conformation in one oligomer, which is a novel folding motif for Aib oligomers. The effect of ester groups with differing steric demands on intermolecular hydrogen-bonding contacts in the solid state was also ascertained. In solution, the adoption of a 310 conformation in Aib oligomers appeared to be more finely tuned, depending on a number of factors, including chain length and the steric demands of the C-terminal destabilising Schellman motif.