Randomized controlled trial of MICBT for co-existing alcohol misuse and depression : outcomes to 36-months

Integrated psychological treatment addressing co-existing alcohol misuse and depression has not been compared with single-focused treatment. This trial evaluates changes over 36 months following randomization of 284 outpatients to one of four motivational interviewing and cognitive-behavior therapy (MICBT) based interventions: (1) brief integrated intervention (BI); or BI plus 9 further sessions with (2) an integrated-, (3) alcohol-, or (4) depression-focus. Outcome measures included changes in alcohol consumption, depression (BDI-II: Beck Depression Inventory) and functioning (GAF: Global Assessment of Functioning), with average improvements from baseline of 21.8 drinks per week, 12.6 BDI-II units and 8.2 GAF units. Longer interventions tended to be more effective in reducing depression and improving functioning in the long-term, and in improving alcohol consumption in the short-term. Integrated treatment was at least as good as single-focused MICBT. Alcohol-focused treatment was as effective as depression-focused treatment at reducing depression and more effective in reducing alcohol misuse. The best approach seems to be an initial focus on both conditions followed by additional integrated- or alcohol-focused sessions.

Effect of ramipril on walking times and quality of life among patients with peripheral artery disease and intermittent claudication : a randomized controlled trial

Importance Approximately one-third of patients with peripheral artery disease experience intermittent claudication, with consequent loss of quality of life. Objective To determine the efficacy of ramipril for improving walking ability, patient-perceived walking performance, and quality of life in patients with claudication. Design, Setting, and Patients Randomized, double-blind, placebo-controlled trial conducted among 212 patients with peripheral artery disease (mean age, 65.5 [SD, 6.2] years), initiated in May 2008 and completed in August 2011 and conducted at 3 hospitals in Australia. Intervention Patients were randomized to receive 10 mg/d of ramipril (n = 106) or matching placebo (n = 106) for 24 weeks. Main Outcome Measures Maximum and pain-free walking times were recorded during a standard treadmill test. The Walking Impairment Questionnaire (WIQ) and Short-Form 36 Health Survey (SF-36) were used to assess walking ability and quality of life, respectively. Results At 6 months, relative to placebo, ramipril was associated with a 75-second (95% CI, 60-89 seconds) increase in mean pain-free walking time (P < .001) and a 255-second (95% CI, 215-295 seconds) increase in maximum walking time (P < .001). Relative to placebo, ramipril improved the WIQ median distance score by 13.8 (Hodges-Lehmann 95% CI, 12.2-15.5), speed score by 13.3 (95% CI, 11.9-15.2), and stair climbing score by 25.2 (95% CI, 25.1-29.4) (P < .001 for all). The overall SF-36 median Physical Component Summary score improved by 8.2 (Hodges-Lehmann 95% CI, 3.6-11.4; P = .02) in the ramipril group relative to placebo. Ramipril did not affect the overall SF-36 median Mental Component Summary score. Conclusions and Relevance Among patients with intermittent claudication, 24-week treatment with ramipril resulted in significant increases in pain-free and maximum treadmill walking times compared with placebo. This was associated with a significant increase in the physical functioning component of the SF-36 score. Trial Registration clinicaltrials.gov Identifier: NCT00681226

Long-term azithromycin for Indigenous children with non-cystic-fibrosis bronchiectasis or chronic suppurative lung disease (Bronchiectasis Intervention Study) : a multicentre, double-blind, randomised controlled trial

Background Indigenous children in high-income countries have a heavy burden of bronchiectasis unrelated to cystic fibrosis. We aimed to establish whether long-term azithromycin reduced pulmonary exacerbations in Indigenous children with non-cystic-fibrosis bronchiectasis or chronic suppurative lung disease. Methods Between Nov 12, 2008, and Dec 23, 2010, we enrolled Indigenous Australian, Maori, and Pacific Island children aged 1—8 years with either bronchiectasis or chronic suppurative lung disease into a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial. Eligible children had had at least one pulmonary exacerbation in the previous 12 months. Children were randomised (1:1 ratio, by computer-generated sequence with permuted block design, stratified by study site and exacerbation frequency [1—2 vs ≥3 episodes in the preceding 12 months]) to receive either azithromycin (30 mg/kg) or placebo once a week for up to 24 months. Allocation concealment was achieved by double-sealed, opaque envelopes; participants, caregivers, and study personnel were masked to assignment until after data analysis. The primary outcome was exacerbation (respiratory episodes treated with antibiotics) rate. Analysis of the primary endpoint was by intention to treat. At enrolment and at their final clinic visits, children had deep nasal swabs collected, which we analysed for antibiotic-resistant bacteria. This study is registered with the Australian New Zealand Clinical Trials Registry; ACTRN12610000383066. Findings 45 children were assigned to azithromycin and 44 to placebo. The study was stopped early for feasibility reasons on Dec 31, 2011, thus children received the intervention for 12—24 months. The mean treatment duration was 20·7 months (SD 5·7), with a total of 902 child-months in the azithromycin group and 875 child-months in the placebo group. Compared with the placebo group, children receiving azithromycin had significantly lower exacerbation rates (incidence rate ratio 0·50; 95% CI 0·35—0·71; p<0·0001). However, children in the azithromycin group developed significantly higher carriage of azithromycin-resistant bacteria (19 of 41, 46%) than those receiving placebo (four of 37, 11%; p=0·002). The most common adverse events were non-pulmonary infections (71 of 112 events in the azithromycin group vs 132 of 209 events in the placebo group) and bronchiectasis-related events (episodes or investigations; 22 of 112 events in the azithromycin group vs 48 of 209 events in the placebo group); however, study drugs were well tolerated with no serious adverse events being attributed to the intervention. Interpretation Once-weekly azithromycin for up to 24 months decreased pulmonary exacerbations in Indigenous children with non-cystic-fibrosis bronchiectasis or chronic suppurative lung disease. However, this strategy was also accompanied by increased carriage of azithromycin-resistant bacteria, the clinical consequences of which are uncertain, and will need careful monitoring and further study.

A randomized controlled trial of a 10 percent CPP-ACP cream to reduce mutans streptococci colonization

Purpose The purpose of this study was to investigate the effectiveness of a 10 percent casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) cream to reduce mutans streptococci (MS) colonization and prevent early childhood caries. Methods The cohort was randomized at mean age of 11 days old to receive once-daily CPP-ACP cream (n=102) or no product (comparison group; n=89) from the time of first tooth eruption. All mothers were contacted by telephone at six, 12, and 18 months and advised to brush their children's teeth twice daily with low-dose fluoride toothpaste. At 24 months, all children were examined at a community clinic. Results At 24 months old, one out of 65 (2 percent) children in the CPP-ACP group had caries vs. four out of 58 (seven percent) in the comparison group (difference not statistically significant). There were fewer MS-positive children in the CPP-ACP group (26 percent) vs. the comparison group (47 percent; P=.02). A dose-response effect of CPP-ACP usage on MS was observed, where MS was present in eight percent of regular CPP-ACP users, 28 percent of irregular users, and 47 percent of non-users (P<.02). Conclusions CPP-ACP reduced the percentages of mutans streptococci-positive 24-month-old children, although it did not reduce caries prevalence.

A randomized controlled trial of self-management programme improves health-related outcomes of older people with heart failure

Aims This paper is a report on the effectiveness of a self-management programme based on the self-efficacy construct, in older people with heart failure. Background Heart failure is a major health problem worldwide, with high mortality and morbidity, making it a leading cause of hospitalization. Heart failure is associated with a complex set of symptoms that arise from problems in fluid and sodium retention. Hence, managing salt and fluid intake is important and can be enhanced by improving patients' self-efficacy in changing their behaviour. Design Randomized controlled trial. Methods Heart failure patients attending cardiac clinics in northern Taiwan from October 2006–May 2007 were randomly assigned to two groups: control (n = 46) and intervention (n = 47). The intervention group received a 12-week self-management programme that emphasized self-monitoring of salt/fluid intake and heart failure-related symptoms. Data were collected at baseline as well as 4 and 12 weeks later. Data analysis to test the hypotheses used repeated-measures anova models. Results Participants who received the intervention programme had significantly better self-efficacy for salt and fluid control, self-management behaviour and their heart failure-related symptoms were significantly lower than participants in the control group. However, the two groups did not differ significantly in health service use. Conclusion The self-management programme improved self-efficacy for salt and fluid control, self-management behaviours, and decreased heart failure-related symptoms in older Taiwanese outpatients with heart failure. Nursing interventions to improve health-related outcomes for patients with heart failure should emphasize self-efficacy in the self-management of their disease.

Study protocol : a randomised controlled trial of a theory-based online intervention to improve sun safety among Australian adults

Background The effects of exposure to ultraviolet radiation are a significant concern in Australia which has one of the highest incidences of skin cancer in the world. Despite most skin cancers being preventable by encouraging consistent adoption of sun-protective behaviours, incidence rates are not decreasing. There is a dearth of research examining the factors involved in engaging in sun-protective behaviours. Further, online multi-behavioural theory-based interventions have yet to be explored fully as a medium for improving sun-protective behaviour in adults. This paper presents the study protocol of a randomised controlled trial of an online intervention based on the Theory of Planned Behaviour (TPB) that aims to improve sun safety among Australian adults. Methods/Design Approximately 420 adults aged 18 and over and predominantly from Queensland, Australia, will be recruited and randomised to the intervention (n = 200), information only (n = 200) or the control group (n = 20). The intervention focuses on encouraging supportive attitudes and beliefs toward sun-protective behaviour, fostering perceptions of normative support for sun protection, and increasing perceptions of control/self-efficacy over sun protection. The intervention will be delivered online over a single session. Data will be collected immediately prior to the intervention (Time 1), immediately following the intervention (Time 1b), and one week (Time 2) and one month (Time 3) post-intervention. Primary outcomes are intentions to sun protect and sun-protective behaviour. Secondary outcomes are the participants’ attitudes toward sun protection, perceptions of normative support for sun protection (i.e. subjective norms, group norms, personal norms and image norms) and perceptions of control/self-efficacy toward sun protection. Discussion The study will contribute to an understanding of the effectiveness of a TPB-based online intervention to improve Australian adults’ sun-protective behaviour. Trials registry Australian and New Zealand Trials Registry number ACTRN12613000470796

Can ginger ameliorate chemotherapy-induced nausea? Protocol of a randomized double blind, placebo-controlled trial

Background Preliminary research shows ginger may be an effective adjuvant treatment for chemotherapy-induced nausea and vomiting but significant limitations need to be addressed before recommendations for clinical practice can be made. Methods/Design In a double–blinded randomised-controlled trial, chemotherapy-naïve patients will be randomly allocated to receive either 1.2 g of a standardised ginger extract or placebo per day. The study medication will be administrated as an adjuvant treatment to standard anti-emetic therapy and will be divided into four capsules per day, to be consumed approximately every 4 hours (300 mg per capsule administered q.i.d) for five days during the first three cycles of chemotherapy. Acute, delayed, and anticipatory symptoms of nausea and vomiting will be assessed over this time frame using a valid and reliable questionnaire, with nausea symptoms being the primary outcome. Quality of life, nutritional status, adverse effects, patient adherence, cancer-related fatigue, and CINV-specific prognostic factors will also be assessed. Discussion Previous trials in this area have noted limitations. These include the inconsistent use of standardized ginger formulations and valid questionnaires, lack of control for anticipatory nausea and prognostic factors that may influence individual CINV response, and the use of suboptimal dosing regimens. This trial is the first to address these issues by incorporating multiple unique additions to the study design including controlling for CINV-specific prognostic factors by recruiting only chemotherapy-naïve patients, implementing a dosing schedule consistent with the pharmacokinetics of oral ginger supplements, and independently analysing ginger supplements before and after recruitment to ensure potency. Our trial will also be the first to assess the effect of ginger supplementation on cancer-related fatigue and nutritional status. Chemotherapy-induced nausea and vomiting are distressing symptoms experienced by oncology patients; this trial will address the significant limitations within the current literature and in doing so, will investigate the effect of ginger supplementation as an adjuvant treatment in modulating nausea and vomiting symptoms. Trial registration

A 5- versus 3-day course of oral corticosteroids for children with asthma exacerbations who are not hospitalised : a randomised controlled trial

Objective To determine whether a 5-day course of oral prednisolone is superior to a 3-day course in reducing the 2-week morbidity of children with asthma exacerbations who are not hospitalised. Design, setting and participants Double-blind randomised controlled trial of asthma outcomes following a 5-day course of oral prednisolone (1 mg/kg) compared with a 3-day course of prednisolone plus placebo for 2 days. Participants were children aged 2–15 years who presented to the emergency departments of three Queensland hospitals between March 2004 and February 2007 with an acute exacerbation of asthma, but were not hospitalised. Sample size was defined a priori for a study power of 90%. Main outcome measures Difference in proportion of children who were symptom-free at Day 7, as measured by intention-to-treat (ITT) and per-protocol analysis; quality of life (QOL) on Days 7 and 14. Results 201 children were enrolled, and there was an 82% completion rate. There was no difference between groups in the proportion of children who were symptom-free (observed difference, 0.04 [95% CI, − 0.09 to 0.18] by ITT analysis; 0.04 [95% CI, − 0.17 to 0.09] by per-protocol analysis). There was also no difference between groups in QOL (P = 0.42). The difference between groups for the primary outcome was within the equivalence range calculated post priori. Conclusion A 5-day course of oral prednisolone confers no advantage over a 3-day course for children with asthma exacerbations who are not hospitalised.

Randomised controlled trial of amoxycillin clavulanate in children with chronic wet cough

Background Despite guideline recommendations, there are no published randomised controlled trial data on the efficacy of antibiotics for chronic wet cough in children. The majority of children with chronic wet cough have protracted bacterial bronchitis (PBB), a recognised condition in multiple national guidelines. The authors conducted a parallel 1:1 placebo randomised controlled trial to test the hypothesis that a 2-week course of amoxycillin clavulanate is efficacious in the treatment of children with chronic wet cough. Methods 50 children (median age 1.9 years, IQR 0.9–5.1) with chronic (>3 weeks) wet cough were randomised to 2 weeks of twice daily oral amoxycillin clavulanate (22.5 mg/kg/dose) or placebo. The primary outcome was ‘cough resolution’ defined as a >75% reduction in the validated verbal category descriptive cough score within 14 days of treatment compared with baseline scores, or cessation of cough for >3 days. In selected children, flexible bronchoscopy and bronchoalveolar lavage (BAL) were undertaken at baseline. Results Cough resolution rates (48%) were significantly higher in children who received amoxycillin clavulanate compared with those who received placebo (16%), p=0.016. The observed difference between proportions was 0.32 (95% CI 0.08 to 0.56). Post treatment, median verbal category descriptive score in the amoxycillin clavulanate group of 0.5 (IQR 0.0–2.0) was significantly lower than in the placebo group, 2.25 (IQR 1.15–2.9) (p=0.02). Pre-treatment BAL data were consistent with PBB in the majority of children, with no significant difference between groups. Conclusion A 2-week course of amoxycillin clavulanate will achieve cough resolution in a significant number of children with chronic wet cough. BAL data support the diagnosis of PBB in the majority of these children.

Management based on exhaled nitric oxidelevels adjusted for atopy reduces asthma exacerbations in children : A dual centre randomised controlled trial

While several randomised control trials (RCTs) have evaluated the use of fractional exhaled nitric oxide (FeNO) to improve asthma outcomes, none used FeNO cut-offs adjusted for atopy, a determinant of FeNO levels. In a dual centre RCT, we assessed whether a treatment strategy based on FeNO levels, adjusted for atopy, reduces asthma exacerbations compared with the symptoms-based management (controls). Children with asthma from hospital clinics of two hospitals were randomly allocated to receive an a-priori determined treatment hierarchy based on symptoms or FeNO levels. There was a 2-week run-in period and they were then reviewed ten times over 12-months. The primary outcome was the number of children with exacerbations over 12-months. Sixty-three children were randomised (FeNO=31, controls=32); 55 (86%) completed the study. Although we did achieve our planned sample size, significantly fewer children in the FeNO group (6 of 27) had an asthma exacerbation compared to controls (15 of 28), p=0.021; number to treat for benefit=4 (95%CI 3-24). There was no difference between groups for any secondary outcomes (quality of life, symptoms, FEV1). The final daily inhaled corticosteroids (ICS) dose was significantly (p=0.037) higher in the FeNO group (median 400µg, IQR 250-600) compared to the controls (200, IQR100-400). Taking atopy into account when using FeNO to tailor asthma medications is likely beneficial in reducing the number of children with severe exacerbations at the expense of increased ICS use. However, the strategy is unlikely beneficial for improving asthma control. A larger study is required to confirm or refute our findings.

The ENHANCES study--Enhancing Head and Neck Cancer patients' Experiences of Survivorship: study protocol for a randomized controlled trial

Background Few cancers pose greater challenges than head and neck (H&N) cancer. Residual effects following treatment include body image changes, pain, fatigue and difficulties with appetite, swallowing and speech. Depression is a common comorbidity. There is limited evidence about ways to assist patients to achieve optimal adjustment after completion of treatment. In this study, we aim to examine the effectiveness and feasibility of a model of survivorship care to improve the quality of life of patients who have completed treatment for H&N cancer. Methods This is a preliminary study in which 120 patients will be recruited. A prospective randomised controlled trial of the H&N Cancer Survivor Self-management Care Plan (HNCP) involving pre- and post-intervention assessments will be used. Consecutive patients who have completed a defined treatment protocol for H&N cancer will be recruited from two large cancer services and randomly allocated to one of three study arms: (1) usual care, (2) information in the form of a written resource or (3) the HNCP delivered by an oncology nurse who has participated in manual-based training and skill development in patient self-management support. The trained nurses will meet patients in a face-to-face interview lasting up to 60 minutes to develop an individualised HNCP, based on principles of chronic disease self-management. Participants will be assessed at baseline, 3 and 6 months. The primary outcome measure is quality of life. The secondary outcome measures include mood, self-efficacy and health-care utilisation. The feasibility of implementing this intervention in routine clinical care will be assessed through semistructured interviews with participating nurses, managers and administrators. Interviews with patients who received the HNCP will explore their perceptions of the HNCP, including factors that assisted them in achieving behavioural change. Discussion In this study, we aim to improve the quality of life of a patient population with unique needs by means of a tailored self-management care plan developed upon completion of treatment. Delivery of the intervention by trained oncology nurses is likely to be acceptable to patients and, if successful, will be a model of care that can be implemented for diverse patient populations.

A protocol for a pragmatic randomized controlled trial evaluating outcomes of emergency nurse practitioner service

Aim To evaluate emergency nurse practitioner service effectiveness on outcomes related to quality of care and service responsiveness. Background Increasing service pressures in the emergency setting have resulted in the adoption of service innovation models; the most common and rapidly expanding of these is the emergency nurse practitioner. The delivery of high quality patient care in the emergency department is one of the most important service indicators to be measured in health services today. The rapid uptake of emergency nurse practitioner service in Australia has outpaced the capacity to evaluate this model in outcomes related to safety and quality of patient care. Design Pragmatic randomized controlled trial at one site with 260 participants. Methods This protocol describes a definitive prospective randomized controlled trial, which will examine the impact of emergency nurse practitioner service on key patient care and service indicators. The study control will be standard emergency department care. The intervention will be emergency nurse practitioner service. The primary outcome measure is pain score reduction and time to analgesia. Secondary outcome measures are waiting time, number of patients who did not wait, length of stay in the emergency department and representations within 48 hours. Discussion Scant research enquiry evaluating emergency nurse practitioner service on patient effectiveness and service responsiveness exists currently. This study is a unique trial that will test the effectiveness of the emergency nurse practitioner service on patients who present to the emergency department with pain. The research will provide an opportunity to further evaluate emergency nurse practitioner models of care and build research capacity into the workforce.

A natural oil-based emulsion containing allantoin versus aqueous cream for managing radiation-induced skin reactions in patients with cancer : a phase III double-blind randomised controlled trial

Purpose To investigate the effects of a natural oil-based emulsion containing allantoin versus aqueous cream for preventing and managing radiation induced skin reactions (RISR). Methods and Materials A total of 174 patients were randomised and participated in the study. Patients either received Cream 1 (the natural oil-based emulsion containing allantoin) or Cream 2 (aqueous cream). Skin toxicity, pain, itching and skin-related quality of life scores were collected for up to four weeks after radiation treatment. Results Patients who received Cream 1 had a significantly lower average level of Common Toxicity Criteria at week 3 (p<0.05), but had statistically higher average levels of skin toxicity at weeks 7, 8 and 9 (all p<0.001). Similar results were observed when skin toxicity was analysed by grades. With regards to pain, patients in the Cream 2 group had a significantly higher average level of worst pain (p<0.05) and itching (p=0.046) compared to the Cream 1 group at week 3, however these differences were not observed at other weeks. In addition, there was a strong trend for Cream 2 to reduce the incidence of grade 2 or more skin toxicity in comparison to Cream 1 (p=0.056). Overall, more participants in the Cream 1 group were required to use another topical treatment at weeks 8 (p=0.049) and 9 (p=0.01). Conclusion The natural oil-based emulsion containing allantoin appears to have similar effects for managing skin toxicity compared to aqueous cream up to week 5, however, it becomes significantly less effective at later weeks into the radiation treatment and beyond treatment completion (week 6 and beyond). There were no major differences in pain, itching and skin-related quality of life. In light of these results, clinicians and patients can base their decision on costs and preferences. Overall, aqueous cream appears to be a more preferred option.

A smoking cessation intervention for people with chronic Hepatitis C : a randomised controlled trial

Purpose The purpose of this study was to examine the validity of current practice in smoking cessation for the general population i.e., a telephone counselling and nicotine replacement therapy (NRT) intervention and its applicability to people with chronic hepatitis-C. Methods A randomised controlled trial was conducted over twelve weeks. Following consent, ninety-two smokers (outpatients) with chronic hepatitis-C were recruited by the Nurse Practitioner hepatology, randomly assigned and stratified by number of cigarettes smoked (i.e., 15 and greater; <15) into the intervention group (telephone counselling and NRT) and control group (telephone counselling). Outcomes measured included socio-demographics, nicotine dependence, depression, anxiety and stress and quality of life (QOL). All statistical data were analysed using SPSS. Results After 12 weeks, the intervention group showed a sustained reduction of smoking i.e., 5.8(CI: 2.4,9.3) cigarettes less per day, whereas the control group showed 1.6(CI:-1.9,5.2) cigarette reduction. Although not statistically significantly different (F=2.9, p=0.090) the intervention group on average smoked 4.2 fewer cigarettes compared to the control group. After twelve weeks, seven patients in the intervention group and three patients in the control group reported quitting. Whilst not statistically significant (Fisher’s Exact, p=0.311) this was a clinically significant result. No differences were found for nicotine dependence or depression, anxiety and stress. The intervention group experienced no change in QOL (-0.1,CI:-0.9, 0.6), however, the environmental score for the control group decreased by 1.8(CI:1.0, 2.6,p= 0.001). This was statistically significant. Conclusion A telephone counselling and nicotine replacement therapy intervention from the nurse practitioner, hepatology reduced smoking in patients with chronic hepatitis-C. The intervention group showed a sustained reduction over the 12 weeks. A total of 10 patients quit smoking at the end of the study. QOL deteriorated in the environmental subscale for the control group. These results informed a nurse practitioner model of care for approaches to smoking cessation.

Promoting resilience in children with intellectual disability : a randomized controlled trial in Australian schools

Children with intellectual disability are more vulnerable to adverse developmental outcomes because of the lifelong risks associated with cognitive impairment. Difficulties with learning and adaptive behaviour inevitably produce considerable personal, social and economic disadvantage. Of concern is consistent evidence that psychiatric disorders affect a substantial proportion of people with intellectual disability. The estimated prevalence rate of between 35 and 49 % is three times that found in the general population (Wallander, Dekker, & Koot, 2006). Until recently, mental illness has been relatively neglected for people with intellectual disability, especially in relation to prevention or early detection (Kolaitis, 2008) and most research to date has been descriptive rather than focused on intervention (Bouras, 2013). Yet a considerable body of evidence demonstrates that efficacious interventions do exist for preventing psychopathology and enhancing resilience in typically developing children and adolescents (see Mallin, Walker, & Levin, 2013 for a review). In order to prevent the high comorbidity of intellectual disability and psychopathology, there is a compelling need for evidence-based practices that promote the resilience of individuals with intellectual disability (Matson, Terlonge, & Minshawi, 2008). In this chapter, we describe a randomized controlled trial of an intervention that was designed to enhance the resilience of a group of children with mild intellectual disability as they prepared to make the transition to high school. We report results from our evaluation of this intervention, and reflect on the difficulties of providing successful interventions for children whose lives are complicated not only by intellectual disability, but also by a range of contextual disadvantages.