Quality-adjusted Life Year Estimates Research Articles

Economic evaluations of psychosocial interventions in cancer: a systematic review.

Although the effectiveness of many psychosocial interventions for people with cancer has been established, one barrier to implementation in routine clinical care is a lack of data on cost-effectiveness. We conducted a systematic review to assess the cost-effectiveness of psychosocial interventions for improving psychological adjustment among people with cancer. A systematic review of the literature, study appraisal and narrative synthesis. Eight studies involving 1668 patients were identified. Four of these reported outcomes in a cost per quality adjusted life year (QALY) framework. Six studies reported psychosocial interventions to be cost-effective for improving health-related quality of life, mood, pain, distress or fear of cancer progression, compared with usual care. Of the six psychosocial interventions identified as cost-effective, three were cognitive-behavioural therapy-based interventions, one was a nurse-delivered telephone follow-up plus educational group programme, one was a group-based exercise and psychosocial intervention and one was a series of 10 face-to-face or telephone-based individual support sessions delivered by a nurse. The quality of studies assessed according to the Consensus Health Economic Criteria-list criteria was good overall; however, some studies were limited by their choice of outcome measure and omission of important categories of costs. Several psychosocial interventions, particularly those based on cognitive-behavioural therapy, have been demonstrated to represent good value for money in cancer care. Future research should include a clear definition of the economic question, inclusion of all relevant costs, and consideration of utility-based quality of life measures for QALY estimation. Copyright © 2016 John Wiley & Sons, Ltd.

PMS97 - How Do we Estimate Quality Adjusted Life Years (Qalys) in Rare Diseases? A Case Study in Hypophosphatasia

PMS97 - How Do we Estimate Quality Adjusted Life Years (Qalys) in Rare Diseases? A Case Study in Hypophosphatasia

Cost-effectiveness of adult pneumococcal conjugate vaccination in the Netherlands.

The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) demonstrated the efficacy of 13-valent pneumococcal conjugate vaccine (PCV13) in preventing vaccine-type community-acquired pneumonia and vaccine-type invasive pneumococcal disease in elderly subjects. We examined the cost-effectiveness of PCV13 vaccination in the Netherlands.Using a Markov-type model, incremental cost-effectiveness ratios (ICER) of PCV13 vaccination in different age- and risk-groups for pneumococcal disease were evaluated using a societal perspective. Estimates of quality-adjusted life-years (QALYs), costs, vaccine efficacy and epidemiological data were based on the CAPiTA study and other prospective studies. The base-case was PCV13 vaccination of adults aged 65–74 years compared to no vaccination, assuming no net indirect effects in base-case due to paediatric 10-valent pneumococcal conjugate vaccine use. Analyses for age- and risk-group specific vaccination strategies and for different levels of hypothetical herd effects from a paediatric PCV programme were also conducted.The ICER for base-case was €8650 per QALY (95% CI 5750–17 100). Vaccination of high-risk individuals aged 65–74 years was cost-saving and extension to medium-risk individuals aged 65–74 years yielded an ICER of €2900. Further extension to include medium- and high-risk individuals aged ≥18 years yielded an ICER of €3100.PCV13 vaccination is highly cost-effective in the Netherlands. The transferability of our results to other countries depends upon vaccination strategies already implemented in those countries.

Establishment of Health Utility Indices for Post-Infectious Functional Gastrointestinal Disorders in Active Duty US Military.

Knowledge of disease burden attributable to functional gastrointestinal disorders (FGD) in travelers is lacking, despite the high incidence of travelers' diarrhea (TD) associated with increased FGD risk. One tool for assessing the impact of disease on health-related quality of life is the health utility index (HUI), which values health states based on preferential health outcomes. Health utilities can be used as preference weights in the estimation of quality-adjusted life-years (QALYs). Six months following travel to Egypt or Turkey, 120 US military personnel completed a survey on TD during deployment, health-related quality of life (SF-36), and the onset of functional bowel disorders (Rome II). Elements from the SF-36 were used to develop SF-6D values, which were combined with health state valuations to enable calculation of HUI scores for each subject. Mean index scores were compared across functional outcomes, specific symptoms, and demographic profiles. The presence of FGD significantly reduced index scores, with irritable bowel syndrome (IBS) and dyspepsia showing the greatest impact (-0.17 and -0.19, respectively) compared with those with no FGD (p < 0.05). Importantly, however, several individuals met multiple FGD outcome definitions. Additionally, a number of symptoms associated with abnormal bowel habits and abdominal pain were associated with reduced index scores regardless of outcome. FGD are associated with significant morbidity as assessed by HUIs. Given the strong link between TD and FGD as well as the large number of travelers from the developed to the developing world, additional study is needed to further understand this association and efforts aimed at primary disease prevention are warranted.

Abstract 372: Health Outcomes Associated With Triple Antiplatelet Therapy for the Secondary Prevention of Atherothrombotic Events

Vorapaxar is a protease-activated receptor-1 (PAR-1) antagonist indicated for the reduction of atherothrombotic cardiovascular (CV) events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD), based on the findings of the TRA 2°P-TIMI 50 trial for patients without a history of stroke or transient ischemic attack. This analysis evaluated the health outcomes of triple antiplatelet therapy with vorapaxar when added to a standard care regimen of clopidogrel plus aspirin (ASA) in comparison with standard care alone, for patients without a history of transient ischemic attack or stroke who survived hospitalization for a qualifying MI. A cohort-level state-transition model was developed in Microsoft Excel to estimate membership in health states over a lifetime time horizon: event-free, post-MI, post-stroke, dead due to bleeding, dead due to CV causes, and dead due to other causes. Predictive equations were developed from patient-level data from TRA 2°P, in order to estimate CV event-related transition probabilities, based on patient characteristics. These improve upon Framingham risk equations as they consider the time since the most recent myocardial infarction, and they are based on a greater number of CV events from a larger and more diverse population. Meta-analyses, national statistics, and other publications were used to estimate case fatality and bleeding rates, the risk of non-CV mortality, as well as utilities for estimation of quality-adjusted life years (QALYs). For validation, the risk equation and model results were compared with the observed event rates in TRA 2°P, risk estimates from Framingham Heart Study publications, as well as QALY and life-year outcomes from other published models. Over a lifetime time horizon, the model predicted 8.3 fewer recurrent MIs, 3.8 fewer strokes, and 18.2 fewer CV deaths in the vorapaxar plus standard care arm in comparison with standard care alone, per 1,000 patients treated, with an increase of 26.4 transfusions, 3.6 intracranial hemorrhage, and 0.9 fatal bleeding events. Discounted life-years and QALYs increased by 0.4 and 0.3 respectively with vorapaxar treatment. In validation, modeled CV event counts were within 0.1% of the observed rates in TRA 2°P. The model’s prediction of 8.94 QALYs in the standard care arm is comparable to the prediction of 9.55 to 9.78 QALYs in a recent UK model of antiplatelet monotherapy after MI. Based on model results, triple antiplatelet therapy with vorapaxar provides additional clinical benefit versus standard care after MI, for a patient population that is at high risk for recurrent and potentially fatal events. In validation, the model yielded projections of CV morbidity and mortality comparable to the observed outcomes from the TRA 2°P clinical trial, Framingham equations, and other models.

Relationship of meeting physical activity guidelines with quality-adjusted life-years

ObjectiveThe quality-adjusted life-year (QALY) is a standard outcome measure used in cost-effectiveness analyses. This study investigates whether attainment of federal physical activity guidelines is associated with higher QALY estimates among adults with or at an increased risk for knee osteoarthritis. MethodsThis is a prospective study of 1794 Osteoarthritis Initiative participants. Physical activity was measured using accelerometers at baseline. Participants were classified as (1) Meeting Guidelines [≥150min of moderate-to-vigorous (MV) activity per week acquired in sessions ≥10min], (2) Insufficiently Active (≥1 MV session[s]/week but below the guideline), or (3) Inactive (zero MV sessions/week). A health-related utility score was derived from participant responses to the 12-item Short-Form Health Survey at baseline and 2 years later. The QALY was calculated as the area under utility curve over 2 years. The relationship of physical activity level to median QALY adjusted for socioeconomic and health factors was estimated using quantile regression. ResultsRelative to the Inactive group, median QALYs over 2 years were significantly higher for the Meeting Guidelines (0.112, 95% CI: 0.067–0.157) and Insufficiently Active (0.058, 95% CI: 0.028–0.088) groups, controlling for socioeconomic and health factors. ConclusionWe found a significant graded relationship between greater physical activity level and higher QALYs. Using the more conservative estimate of 0.058, if an intervention could move someone out of the Inactive group and costs <$2900 over 2 years, it would be considered cost effective. Our analysis supports interventions to promote physical activity even if recommended levels are not fully attained.

A Comparative Analysis of Two Contrasting European Approaches for Rewarding the Value Added by Drugs for Cancer: England Versus France

Within Europe, contrasting approaches have emerged for rewarding the value added by new drugs. In Ireland, The Netherlands, Sweden and the UK, the price of, and access to, a new drug has to be justified by the health gain it delivers compared with current therapy, typically expressed in quality-adjusted life-years (QALYs) gained. By contrast, in France and Germany, the assessment of added benefit is expressed on an ordinal scale, based on an assessment of the clinical outcomes as compared with existing care. This assessment then influences price negotiations. The objective of this paper is to assess the pros and cons of each approach, both in terms of the assessments they produce and the efficiency and practical feasibility of the process. We reviewed the technology appraisals performed by the National Institute for Health and Care Excellence (NICE) relating to 49 anticancer drug decisions in the UK from September 2003 to January 2012. Estimates of the QALYs gained and incremental cost per QALY gained were then compared with the assessments of the Amélioration du Service Médical Rendu (ASMR) made by the Haute Autorité de Santé (HAS) in France for the same drugs in the same clinical indications. We also undertook a qualitative assessment of the two approaches, considering the resources required, timeliness, transparency, stakeholder engagement, and political acceptability. In the UK, the estimates of QALYs gained ranged from 0.003 to 1.46 and estimates of incremental cost per QALY from £3,320 to £458,000. The estimate of cost per QALY gained was a good predictor of the level of restriction imposed on the use of the drug concerned. Patient access schemes, which normally imply price reductions, were proposed in 45 % of cases. In France, the distribution of ASMRs was I, 12 %; II, 18 %; III, 24 %; IV, 18 %; V, 22 %; and uncategorized/non-reimbursed, 4 %. Since ASMRs of IV and above signify minor or no improvement over existing therapy, these ratings imply that, in around 40 % of cases, the drugs concerned would face price controls. Overall, the assessments of value added in the two jurisdictions were very similar. A superior ASMR rating was associated with higher QALYs gained. However, a superior ASMR was not associated with a lower incremental cost per QALY. There are substantial differences in respect of the other attributes considered, but these mainly reflect the result of institutional choices in the jurisdictions concerned and it is not possible to conclude that one approach is universally superior to the other. The two approaches produce very similar assessments of added value, but have different attributes in terms of cost, timeliness, transparency and political acceptability. How these considerations impact market access and prices is difficult to assess, because of the lack of transparency concerning prices in both countries and the fact that market access also depends on a broader range of factors. There is some evidence of convergence in the approaches, with the movement in France towards producing cost-effectiveness estimates and the movement in the UK towards negotiated prices.

Estimating QALY Gains in Applied Studies: A Review of Cost-Utility Analyses Published in 2010

Reimbursement agencies in several countries now require health outcomes to be measured in terms of quality-adjusted life-years (QALYs), leading to an immense increase in publications reporting QALY gains. However, there is a growing concern that the various ‘multi-attribute utility’ (MAU) instruments designed to measure the Q in the QALY yield disparate values, implying that results from different instruments are incommensurable. By reviewing cost-utility analyses published in 2010, we aim to contribute to improved knowledge on how QALYs are currently calculated in applied analyses; how transparently QALY measurement is presented; and how large the expected incremental QALY gains are. We searched Embase, MEDLINE and NHS EED for all cost-utility analyses published in 2010. All analyses that had estimated QALYs gained from health interventions were included. Of the 370 studies included in this review, 48 % were pharmacoeconomic evaluations. Active comparators were used in 71 % of studies. The median incremental QALY gain was 0.06, which translates to 3 weeks in best imaginable health. The EQ-5D-3L is the dominant instrument used. However, reporting of how QALY gains are estimated is generally inadequate. In 55 % of the studies there was no reference to which MAU instrument or direct valuation method QALY data came from. The methods used for estimating expected QALY gains are not transparently reported in published papers. Given the wide variation in utility scores that different methodologies may assign to an identical health state, it is important for journal editors to require a more transparent way of reporting the estimation of incremental QALY gains.

The Value of a QALY: Individual Willingness to Pay for Health Gains Under Risk

There is an increased interest in the monetary value of a quality-adjusted life-year (QALY). Past studies commonly derived willingness to pay (WTP) for certain future QALY gains. However, obtaining valid WTP per QALY estimates proved to be difficult. We conducted a contingent valuation study and estimated the individual WTP per QALY under risk. We demonstrate the impact of probability weighting on WTP per QALY estimates in the Netherlands. Our estimates of the value of a QALY are in the range of €80,000-110,000 when the weighting correction was applied, and €250,500 without correction. The validity of these estimates, applying probability weighting, appears to be good. Given the reasonable support for their validity and practical meaningfulness, the estimates derived while correcting for probability weighting may provide valuable input for the debate on the consumption value of health. While decision makers should not apply these estimates without further consideration, since strictly individual valuations may not carry all relevant information and values for societal decision-making, the current estimates may provide a good and informed basis for further discussion and study of this important topic.

Cost-effectiveness analysis of cochlear dose reduction by proton beam therapy for medulloblastoma in childhood

Background: The aim of this study is to evaluate the cost-effectiveness of proton beam therapy with cochlear dose reduction compared with conventional X-ray radiotherapy for medulloblastoma in childhood. Methods: We developed a Markov model to describe health states of 6-year-old children with medulloblastoma after treatment with proton or X-ray radiotherapy. The risks of hearing loss were calculated on cochlear dose for each treatment. Three types of health-related quality of life (HRQOL) of EQ-5D, HUI3 and SF-6D were used for estimation of quality-adjusted life years (QALYs). The incremental cost-effectiveness ratio (ICER) for proton beam therapy compared with X-ray radiotherapy was calculated for each HRQOL. Sensitivity analyses were performed to model uncertainty in these parameters. Results: The ICER for EQ-5D, HUI3 and SF-6D were $21 716/QALY, $11 773/QALY, and $20 150/QALY, respectively. One-way sensitivity analyses found that the results were sensitive to discount rate, the risk of hearing loss after proton therapy, and costs of proton irradiation. Cost-effectiveness acceptability curve analysis revealed a 99% probability of proton therapy being cost effective at a societal willingness-to-pay value. Conclusions: Proton beam therapy with cochlear dose reduction improves health outcomes at a cost that is within the acceptable cost-effectiveness range from the payer's standpoint.

Trial-based cost-effectiveness analysis comparing surgical and endoscopic drainage in patients with obstructive chronic pancreatitis

ObjectivePublished evidence indicates that surgical drainage of the pancreatic duct was more effective than endoscopic drainage for patients with chronic pancreatitis. This analysis assessed the cost-effectiveness of surgical versus endoscopic...

Mapping to Obtain EQ-5D Utility Values for Use in NICE Health Technology Assessments

Quality-adjusted life-years (QALYs) are widely used as an outcome for the economic evaluation of health interventions. However, preference-based measures used to obtain health-related utility values to produce QALY estimates are not always included in key clinical studies. Furthermore, organizations responsible for reviewing or producing health technology assessments (HTAs) may have preferred instruments for obtaining utility estimates for QALY calculations. Where data using a preference-based measure or the preferred instrument have not been collected, it may be possible to “map” or “crosswalk” from other measures of health outcomes. The aims of this study were 1) to provide an overview of how mapping is currently used as reported in the published literature and in an HTA policy-making context, specifically at the National Institute for Health and Clinical Excellence in the United Kingdom, and 2) to comment on best current practice on the use of mapping for HTA more generally. The review of the National Institute for Health and Clinical Excellence guidance found that mapping has been used since first established but that reporting of the models used to map has been poor. Recommendations for mapping in HTA include an explicit consideration of the generalizability of the mapping function to the target sample, reporting of standard econometric and statistical tests including the degree of error in the mapping model across subsets of the range of utility values, and validation of the model(s). Mapping can provide a route for linking outcomes data collected in a trial or observational study to the specific preferred instrument for obtaining utility values. In most cases, however, it is still advantageous to directly collect data by using the preferred utility-based instrument and mapping should usually be viewed as a “second-best” solution.

Inconsistencies in Nice Guidance for Acupuncture: Reanalysis and Discussion

Acupuncture received a positive recommendation in the National Institute for Health and Clinical Excellence (NICE) clinical guideline for low back pain (LBP). However, no such recommendation was forthcoming in the NICE clinical guideline for osteoarthritis (OA). Importantly, the two guidelines adopted different treatment comparators in their economic analyses of acupuncture; in the LBP guideline 'usual care' was used (with no consideration of placebo/sham interventions), whereas 'sham acupuncture' was the comparator in the OA guideline. To analyse the implications of using different control group comparators when estimating the cost-effectiveness of acupuncture therapy. The NICE OA economic analysis for acupuncture was replicated using 'usual care' (ie, no placebo/sham component) as the treatment comparator. A 'transfer-to-utility' technique was used to transform Western Ontario and McMaster Osteoarthritis scores into EQ-5D utility scores to allow quality-adjusted life year (QALY) gains to be estimated. QALY estimates were combined with direct incremental cost estimates of acupuncture treatment to determine incremental cost-effectiveness ratios (ICERs). When 'usual care' was used as the treatment comparator, ICER point estimates were below £20 000 per QALY gained for each acupuncture trial analysed in the OA clinical guideline. In the original analysis, using placebo/sham acupuncture as the treatment comparator, ICERs were generally above £20 000 per QALY gained. The treatment comparator chosen in economic evaluations of acupuncture therapy is likely to be a strong determinant of the cost-effectiveness results. Different comparators used in the OA and LBP NICE guidelines may have led to the divergent recommendations in the guidelines.

Support and assessment for fall emergency referrals (SAFER 2) research protocol: cluster randomised trial of the clinical and cost effectiveness of new protocols for emergency ambulance paramedics to assess and refer to appropriate community-based care

IntroductionEmergency calls to ambulance services are frequent for older people who have fallen, but ambulance crews often leave patients at the scene without ongoing care. Evidence shows that when left...

SF-6D and EQ-5D result in widely divergent incremental cost-effectiveness ratios in a clinical trial of older women: implications for health policy decisions

Using two instruments (SF-6D and EQ-5D) to estimate quality adjusted life years (QALYs), we conducted an economic evaluation of a 12-month randomized controlled trial with a 12-month follow-up study in older women to evaluate the value for money of two doses of resistance training compared with balance and tone classes. We found that the incremental QALYs estimated from the SF-6D were two- to threefold greater than those estimated from the EQ-5D. Decision makers must continually choose between existing and new interventions. Hence, economic evaluations are increasingly prevalent. The impact of quality-adjusted life year (QALY) estimates using different instruments on the incremental cost-effectiveness ratios (ICERs) is not well understood in older adults. Thus, we compared ICERs, in older women, estimated by the EuroQol-5D (EQ-5D) and the Short Form-6D (SF-6D) to discuss implications on decision making. Using both the EQ-5D and the SF-6D, we compared the incremental cost per QALY gained in a randomized controlled trial of resistance training in 155 community-dwelling women aged 65 to 75 years. The 12-month randomized controlled trial included a subsequent 12-month follow-up. Our focus, the follow-up study, included 123 of the 155 participants from the Brain Power study; 98 took part in the economic evaluation (twice-weekly balance and tone exercises, n = 28; once-weekly resistance training, n = 35; twice-weekly resistance training, n = 35). Our primary outcome measure was the incremental cost per QALY gained of once- or twice-weekly resistance training compared with balance and tone exercises. At cessation of the follow-up study, the incremental QALY was -0.051 (EQ-5D) and -0.144 (SF-6D) for the once-weekly resistance training group and -0.081 (EQ-5D) and -0.127 (SF-6D) for the twice-weekly resistance training group compared with balance and tone classes. The incremental QALYs estimated from the SF-6D were two- to threefold greater than those estimated from the EQ-5D. Given the large magnitude of difference, the choice of preference-based utility instrument may substantially impact health care decisions.

National EQ-5D tariffs and quality-adjusted life-year estimation: comparison of UK, US and Danish utilities in south Swedish rheumatoid arthritis patients

ObjectiveTo study how the choice of national EQ-5D tariff may affect utility and incremental quality-adjusted life-year (QALY) estimates.MethodsSouth Swedish rheumatoid arthritis patients in an observational study, starting and continuing anti-tumour...

The impact of motor and non motor symptoms on health state values in newly diagnosed idiopathic Parkinson’s disease

The aim of the study was to estimate health state utility values in newly diagnosed idiopathic Parkinson's disease (PD) for use in the assessment of health-related quality-of-life (HRQL), and in the estimation of quality-adjusted life-years (QALYs). Data from 162 patients enrolled in a community-based incidence study of PD were used to estimate health state utility values. Self-report data from the EQ-5D, a generic measure of HRQL, were used to derive preference-based health state utility values. The impact of motor and non motor symptoms, and other clinical and demographic factors, on the derived EQ-5D health state values was examined in univariate and multivariate analyses. The mean health state utility value for recently diagnosed PD patients was estimated at 0.65±0.27. Significant reductions in health state values were attributable to pain (-0.18), motor functioning (-0.16), depression (-0.12), and insomnia (-0.11). Depression had its greatest impact (-0.19) in patients in the less severe stages of PD (i.e. Hoehn Yahr stages ≤2.5). This study shows, through the presentation of QALY values, that there is scope to achieve significant health gains in newly diagnosed idiopathic PD patients via improved management of pain, depression and insomnia, alongside the treatment of primary motor symptoms.

Time Trade-Off Derived EQ-5D Weights for Australia

BackgroundCost-utility analyses (CUAs) are increasingly common in Australia. The EuroQol five-dimensional (EQ-5D) questionnaire is one of the most widely used generic preference-based instruments for measuring health-related quality of life for the estimation of quality-adjusted life years within a CUA. There is evidence that valuations of health states vary across countries, but Australian weights have not previously been developed. MethodsConventionally, weights are derived by applying the time trade-off elicitation method to a subset of the EQ-5D health states. Using a larger set of directly valued health states than in previous studies, time trade-off valuations were collected from a representative sample of the Australian general population (n = 417). A range of models were estimated and compared as a basis for generating an Australian algorithm. ResultsThe Australia-specific EQ-5D values generated were similar to those previously produced for a range of other countries, but the number of directly valued states allowed inclusion of more interaction effects, which increased the divergence between Australia's algorithm and other algorithms in the literature. ConclusionThis new algorithm will enable the Australian community values to be reflected in future economic evaluations.

A meta-analysis of health state valuations for people with diabetes: explaining the variation across methods and implications for economic evaluation

To review published studies on the effect of diabetes and its complications on utility scores to establish whether there is systematic variation across studies and to examine the implications for the estimation of quality-adjusted life years (QALYs). A systematic review was performed using studies reporting QALY measures elicited from people with diabetes including those with a history of complications. Meta-analysis was used to obtain the average utility, and meta-regression was employed to examine the impact of study characteristics and elicitation methods on these values. The effect of different utility scores on QALYs was examined using diabetes simulation models. In the meta-analysis based on 45 studies reporting 66 values, the average utility score was 0.76 (95% CI 0.75-0.77). A meta-regression showed significant variation due to age, method of elicitation and the proportion of males. The average utility score for individual complications ranged from 0.48 (95% CI 0.25, 0.71) for chronic renal disease to 0.75 (95% CI 0.73, 0.78) for myocardial infarction, and these differences produced meaningful changes in simulated QALYs. There was significant heterogeneity between studies. We provide summary utility scores for diabetes and its major complications that could help inform economic evaluation and policy analysis.

Toward a more universal approach in health valuation

By polling individual responses to hypothetical scenarios, valuation studies estimate population preferences toward health on a quality-adjusted life year (QALY) scale. The scenarios typically involve trade-offs in time (time trade-off (TTO)), risk (standard gamble (SG)), or number of persons affected (person trade-off (PTO)). This paper revisits the QALY assumptions and provides a coherent health econometric approach that unites TTO, SG, and PTO techniques under a common estimator. The proposed approach avoids the use of ratio statistics in QALY estimation and the common convention of arbitrarily changing trade-off responses. As an example, 34% of the TTO responses from the seminal Measurement and Valuation of Health study were changed in the original UK analysis, which led to substantially lower QALY estimates. As a general rule, if the original estimate is less than 0.5 QALYs, add 0.25 QALYs to get the new estimates.