Reversibility of alexithymia with effective treatment of moderate-to-severe psoriasis: longitudinal data from EPIDEPSO.

BACKGROUND: Alexithymia refers to difficulty in identifying and expressing emotions. Alexithymia is associated with high burden of disease in patients with psoriasis. OBJECTIVES: To investigate whether alexithymia was reversible in patients with psoriasis following real-life therapeutic intervention. METHODS: The Epidemiological Study in Patients with Recently Diagnosed Psoriasis (EPIDEPSO; NCT01964443) was a 1-year multicentre observational study investigating the prevalence of alexithymia and other psychosocial comorbidities in patients with psoriasis with ≤ 10 years' disease duration and eligible for systemic treatment. Alexithymia was assessed using the Toronto Alexithymia Scale (TAS-20) at baseline, 6 months and 1 year. RESULTS: There was a statistically significant decrease in the prevalence of alexithymia in the follow-up cohort, from 26·7% at baseline to 21·2% at 6 months and 18·8% at 1 year. More than half of the patients (n = 77, 53·8%) who were alexithymic at baseline experienced reversion of their alexithymia. Reversion of alexithymia was higher in patients who reached a high level of disease control, defined as ≥ 75% or ≥ 90% improvement in Psoriasis Area and Severity Index. Reversion of alexithymia was associated with dramatic improvement in quality of life, anxiety and depression. Moreover, hazardous alcohol use, highly prevalent in patients with alexithymia, was reduced almost threefold at 1 year. CONCLUSIONS: Alexithymia and associated high disease burden may be reversible in patients with effective treatment of psoriasis. Proactive recognition of patients who are unable to identify and express their feelings is important.

Prevalence of alexithymia in patients with psoriasis and its association with disease burden: a multicentre observational study.

BACKGROUND: Single-centre studies show that alexithymia, defined as difficulty in recognizing and describing emotions, is more prevalent among patients with psoriasis than in the general population. However, its prevalence and the consequences of the association between alexithymia and psoriasis are unclear. OBJECTIVES: The primary objective of this study was to determine the prevalence of alexithymia, as defined by a score ≥ 61 in the 20-item Toronto Alexithymia Scale, in a large sample of patients who had plaque psoriasis for ≤ 10 years and were eligible for phototherapy or systemic treatment. The secondary objectives were to investigate the relationship between alexithymia and the clinical and psychological aspects of psoriasis. METHODS: Data were collected in the framework of an observational, multicentre, international study, the EPidemiological Study In Patients With Recently DiagnosEd PSOriasis (EPIDEPSO), aiming at investigating the prevalence of alexithymia and other psychosocial comorbidities in patients with psoriasis of ≤ 10 years' disease duration. RESULTS: The prevalence of alexithymia within a cohort of 670 patients was 24·8% (95% confidence interval 21·7-28·2). Patients with alexithymia had a higher burden of psoriasis, including significant impairment of quality of life, higher levels of anxiety and depression, a higher risk of alcohol dependency and impairment of work productivity, compared with patients without alexithymia. CONCLUSIONS: It is important to identify alexithymic patients with psoriasis in clinical practice as they experience a higher disease burden and have a lower ability to express their feelings.

Quality of life and patient benefit following transition from methotrexate to ustekinumab in psoriasis.

BACKGROUND: TRANSIT (NCT01059773) compared immediate and gradual transition from methotrexate to ustekinumab in psoriasis patients via multiple measures, including patient-reported outcomes. OBJECTIVE: To evaluate patient perception of treatment benefits in TRANSIT. METHODS: A total of 489 psoriasis patients received ustekinumab, with immediate cessation of methotrexate (Arm 1) or 4 weeks' overlap with decreasing methotrexate dose (Arm 2). Ustekinumab was administered at weeks 0, 4, 16, 28 and 40. Dermatology Life Quality Index (DLQI), EuroQol 5-item (EQ-5D), visual analogue scale (VAS) valuation technique and patient benefit index (PBI) were employed. Mean global PBI and sub-scores were calculated from the sum of the benefit items weighted by their respective relevance at baseline. Patient-relevant benefit was defined as PBI ≥1 (scale: 0 [no benefit] to 4 [maximum benefit]). Correlations of global PBI with Psoriasis Area and Severity Index (PASI) and DLQI were examined. RESULTS: Relationships between PBI and clinical data were evaluable in 340 patients. The most important treatment goals at baseline included: 'be healed of all skin defects', 'have confidence in therapy', 'get better skin quickly' and 'regain control of the disease'. Benefit in PBI global score was achieved at week 4 by 93% of patients in Arm 1 and 91% in Arm 2. Global PBI scores increased in both Arms between weeks 4 and 52. Global PBI correlated weakly with PASI change from baseline (correlation coefficient range: -0.22 to -0.40), and moderately with DLQI (-0.29 to -0.54). Overall DLQI score was lower than baseline at all times; and the percentage of patients with an overall score of 0 or 1 increased with time. Correspondingly, EQ VAS scores increased with time. DLQI and EQ VAS results were similar between arms. CONCLUSIONS: Regardless of the strategy for transitioning from methotrexate, ustekinumab was associated with rapid and sustained improvement in patient-reported outcomes. PBI appears a suitable tool for assessing patient-relevant treatment benefits in psoriasis patients.

One-year safety and efficacy of ustekinumab and results of dose adjustment after switching from inadequate methotrexate treatment: the TRANSIT randomized trial in moderate-to-severe plaque psoriasis.

BACKGROUND: There are limited long-term, 'real-world' data on ustekinumab, or the effect of dose adjustment in suboptimal responders. OBJECTIVES: We describe 52-week data from TRANSIT, which initiated ustekinumab by licensed regimen and investigated exploratory dose adjustment. METHODS: Patients with moderate-to-severe psoriasis and inadequate methotrexate response received ustekinumab, with immediate or gradual methotrexate withdrawal. Outcomes were similar between treatment arms at week 12 (primary endpoint), so week 52 data were pooled. Patients weighing ≤ 100 kg or > 100 kg were administered ustekinumab 45 or 90 mg, respectively. Patients weighing ≤ 100 kg without 75% improvement in Psoriasis Area and Severity Index (PASI 75) response at weeks 28 or 40 received a dose adjustment to 90 mg. The primary analysis used observed data. RESULTS: Overall, 391 and 98 patients received ustekinumab 45 and 90 mg, respectively. Forty-four patients (9%) discontinued before week 52 (0·4% due to adverse events). At week 52 (in the overall population), 369 patients (83%) achieved a PASI score ≤ 5, and 341 patients (77%) achieved PASI 75; the median PASI score decreased from 15 at baseline to 1·8. At weeks 28 and 40, 84 and 31 patients, respectively, did not achieve PASI 75 and received a dose adjustment; by week 52, 35/82 (43%) and 15/31 (48%) of these patients, respectively, achieved PASI 75 (two discontinued between weeks 28 and 40). CONCLUSIONS: Ustekinumab showed sustained 1-year efficacy and was well tolerated when initially administered according to label. Adjusting the ustekinumab dose to 90 mg may result in clinically meaningful improvement in response in patients weighing ≤ 100 kg with suboptimal initial response.

Transition to ustekinumab in patients with moderate-to-severe psoriasis and inadequate response to methotrexate: a randomized clinical trial (TRANSIT).

BACKGROUND: Limited data exist on transitioning patients with psoriasis from conventional systemic agents to biologics. OBJECTIVES: The TRANSIT study aimed to assess the efficacy and safety of two methotrexate-to-ustekinumab transition strategies. METHODS: Patients with moderate-to-severe psoriasis and inadequate methotrexate response were randomized 1 : 1 to receive ustekinumab with immediate (arm 1) or 4-week gradual (arm 2) methotrexate withdrawal. Patients weighing ≤ 100 kg or > 100 kg received ustekinumab 45 mg or 90 mg, respectively. The primary endpoint was the frequency of adverse events (AEs) at week 12. Secondary endpoints included additional safety, efficacy and patient-reported outcomes. We report the 12-week efficacy and safety results. RESULTS: Overall, 244 patients in arm 1 and 245 in arm 2 were randomized and received ustekinumab. Four patients per arm discontinued the trial by week 12. At week 12 in arms 1 and 2, respectively, 61% and 65% of patients experienced an AE, 2·9% and 2·4% had a serious AE, and 1·2% and 0·4% had an AE leading to ustekinumab discontinuation. In arms 1 and 2, respectively, median Psoriasis Area and Severity Index (PASI) score decreased from 15·2 and 15·4 at baseline to 2·9 and 2·8 at week 12; 58% and 62% of patients achieved a 75% reduction from baseline in PASI score (PASI 75) at week 12; median baseline Dermatology Life Quality Index fell from 8 and 9 at baseline to 1 (both arms) at week 16. CONCLUSIONS: Ustekinumab was well tolerated and effective in patients who had an inadequate response to methotrexate. Both transition strategies resulted in similar week 12 safety and efficacy outcomes.

High levels of women's satisfaction and compliance with transdermal contraception: results from a European multinational, 6-month study.

OBJECTIVE: To investigate compliance, satisfaction, and preference in women using a transdermal contraceptive patch. METHODS: Women (18-46 years) from eight European countries used contraceptive patches (norelgestromin 6 mg, ethinylestradiol 600 µg) for six, 4-week treatment cycles. Compliance, satisfaction, and preference were assessed after 3 and 6 cycles and study completion using self-report methods. RESULTS: Of the 778 participants, 36.8% (n = 287) used no contraception at baseline. The most common methods were oral contraceptives (67.9%, n = 334) and barrier methods (21.5%, n = 106). Of oral contraception users, 63.5% (n = 212) were satisfied or very satisfied with their previous method, but compliance was poor with 77.8% (n = 260) reporting missed doses. After 3 and 6 cycles, >80% of all included women were satisfied or very satisfied with the patch. At study completion, most participants (73.7%) reported a preference for the patch compared to their previous method. Of 4107 cycles, 3718 (90.5%) were completed with perfect compliance. Two pregnancies occurred during this study, representing a Pearl Index of 0.63. No new safety issues were identified and the patch was well tolerated. CONCLUSION: Women were highly satisfied with transdermal contraception and preferred this form of family planning over their previous method. Transdermal contraception represents a valuable addition to contraceptive options with potential to offer high compliance and efficacy.

Once-monthly paliperidone palmitate in recently diagnosed and chronic non-acute patients with schizophrenia.

OBJECTIVE: To explore the treatment response, tolerability and safety of once-monthly paliperidone palmitate (PP1M) in non-acute patients switched from oral antipsychotics, stratified by time since diagnosis as recently diagnosed (≤3 years) or chronic patients (>3 years). RESEARCH DESIGN AND METHODS: Post hoc analysis of a prospective, interventional, single-arm, multicentre, open-label, 6-month study performed in 233 recently diagnosed and 360 chronic patients. MAIN OUTCOME MEASURES: The proportion achieving treatment response (defined as ≥20% improvement in Positive and Negative Syndrome Scale [PANSS] total score from baseline to endpoint) and maintained efficacy (defined as non-inferiority in the change in PANSS total score at endpoint [Schuirmann's test]). RESULTS: 71.4% of recently diagnosed and 59.2% of chronic patients showed a ≥20% decrease in PANSS total score (p = 0.0028 between groups). Changes in PANSS Marder factors, PANSS subscales, and the proportion of patients with a Personal and Social Performance scale (PSP) total score of 71-100 were significantly greater in recently diagnosed compared with chronic patients. PP1M was well tolerated, presenting no unexpected safety findings. CONCLUSION: These data show that recently diagnosed patients treated with PP1M had a significantly higher treatment response and improved functioning, as assessed by the PSP total score, than chronic patients.

Paliperidone palmitate in non-acute patients with schizophrenia previously unsuccessfully treated with risperidone long-acting therapy or frequently used conventional depot antipsychotics.

PALMFlexS, a prospective multicentre, open-label, 6-month, phase IIIb interventional study, explored tolerability, safety and treatment response in adults (n = 231) with non-acute but symptomatic schizophrenia switching to flexibly dosed paliperidone palmitate (PP) after unsuccessful treatment with risperidone long-acting injectable therapy (RLAT) or conventional depot antipsychotics (APs). Treatment response was measured by change in Positive and Negative Syndrome Scale (PANSS) total score from baseline (BL) to last-observation-carried-forward (LOCF) endpoint (EP). Safety and tolerability assessments included Extrapyramidal Symptom Rating Scale (ESRS) total score and treatment-emergent adverse events. Significant reductions in mean PANSS total score were observed for all groups (-7.5 to -10.6; p ⩽ 0.01 [BL to LOCF EP]). After switching to PP, more than 50% of all patients achieved ⩾20% and one-third of RLAT-treated patients even achieved ⩾50% improvement in PANSS total score. Across groups, there were significant improvements (p < 0.05) in symptom severity as measured by Clinical Global Impression-Severity (CGI-S; trend for improvement with RLAT; p = 0.0568), subjective well-being, medication satisfaction, and patient functioning with PP. PP was generally well tolerated. Clinically relevant benefits were observed in non-acute patients with schizophrenia switched from RLAT or conventional depot APs to PP.

Dopamine agonists in Parkinson's disease.

The main pathologic hallmark of Parkinson's disease is a degeneration of the dopaminergic cells in the substantia nigra, pars compacta and--to a lesser extent--in the ventral tegmental area. Striatal dopamine concentrations are significantly reduced before clinical symptoms become apparent. Recent neuroanatomic and function studies have revealed that the nigrostriatal dopaminergic projection is only one of the neuronal elements integrated into extensive basal ganglia-thalamocortical circuits that are intimately involved in the regulation of motor activity. The possibilities for therapeutic intervention at the level of the different dopamine receptor subtypes and their effect on the regulation of motor behavior will be briefly reviewed. Dopamine precursors are considered to provide the best symptomatic treatment, whereas dopamine agonists, although less effective, might be important in slowing the progression of the disease. Our results with pergolide as monotherapy and in combination therapy in patients with Parkinson's disease also are discussed.

Olanzapine in the treatment of dopaminomimetic psychosis in patients with Parkinson's disease.

We studied the effect of olanzapine (1 to 15 mg/d) in 15 nondemented parkinsonian patients with drug-induced psychosis. Psychotic symptoms decreased significantly during treatment, and there was no worsening of extrapyramidal symptoms. These results suggest that olanzapine is a well-tolerated and effective treatment for drug-induced psychosis in nondemented patients with Parkinson's disease.

Imaging of dopamine transporters with iodine-123-FP-CIT SPECT in healthy controls and patients with Parkinson's disease.

UNLABELLED: Several SPECT studies reported decreased striatal 123I-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodoph enyl)nortropane ([123I]FP-CIT) binding in patients with Parkinson's disease. For application in routine clinical studies, information on the reliability and reproducibility of the [123I]FP-CIT SPECT technique is critical. This study reports on the reliability and reproducibility of [I23I]FP-CIT SPECT in healthy control subjects and patients with Parkinson's disease using two different analysis protocols: the conventional region of interest (ROI) protocol and a newly developed, fully automatic, operator-independent volume of interest (VOI) protocol. METHODS: We performed repeated [123I]FP-CIT SPECT scans in 6 healthy control subjects and 10 patients with Parkinson's disease to measure scan-to-scan variations. Scintigraphic data were analyzed 3 hr after injection of the radiotracer. RESULTS: In controls, the mean test/retest for the ratio of the striatal-to-nonspecific [123I]FP-CIT uptake were (3.79 +/- 0.67/3.82 +/- 0.74) and (4.16 +/- 0.70/4.08 +/- 0.97) for the ROI and VOI technique, respectively. No significant differences were measured between test/retest studies. The mean test/retest variability for the ROI technique was low (7.25%) with excellent reliability (rho = 0.99). In addition, the mean test/retest variability for the VOI technique was also low (7.47%) with very high reliability (rho = 0.95). In Parkinson's disease patients, we found mean test/retest for the striatal-to-nonspecific [123I]FP-CIT ratio of (1.78 +/- 0.23/1.79 +/- 0.25) and (1.83 +/- 0.31/1.85 +/- 0.35) using the ROI and VOI technique, respectively. Also in patients, these results did not differ significantly between test/retest studies. The mean test/retest variability for the ROI technique was low (7.90%) with excellent reliability (rho = 1.00). In addition, the mean test/retest variability for the VOI technique was also low (7.36%) with high reliability (rho = 0.96). CONCLUSION: Reliable and reproducible results were obtained with the ROI, as well as the VOI technique, for the analysis of striatal dopamine transporters with [123I]FP-CIT SPECT in healthy controls and Parkinson's disease patients. The use of an operator-independent method will be a great advantage in routine clinical studies.

Iodine-123-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iod ophenyl)tropane SPECT in healthy controls and early-stage, drug-naive Parkinson's disease.

UNLABELLED: The aims of this study were to investigate whether the loss of striatal dopamine transporters in early and drug-naive patients with Parkinson's disease could be demonstrated by means of 123I-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodoph enyl)tropane (123I-FP-CIT) SPECT in a 1-day protocol and whether the SPECT measures were correlated with disease severity. METHODS: Twenty-one early-stage and drug-naive Parkinson's disease patients (age range 42-73 yr; mean age 55.5 yr) and 14 healthy controls (age range 28-83 yr; mean age 53.6 yr) were examined. SPECT image acquisition was always performed at 3 hr postinjection. The ratio of specific to nonspecific striatal 123I-FP-CIT binding was used as the outcome measure. RESULTS: All striatal 123I-FP-CIT ratios were significantly lower in the Parkinson's disease group compared to those in the control group. The mean reduction in the putamen was 57% of the control mean, and that in the caudate nucleus was 29% of the control mean. Patients with unilateral Parkinson's disease showed a bilateral loss of striatal 123I-FP-CIT binding. Discriminant function analysis, using the 123I-FP-CIT SPECT data of the ipsilateral and contralateral putamen, predicted group membership in all cases; the contralateral putamen accounted for the greatest difference between the Parkinson's disease patients and the controls. In the control group, a clear decline in 123I-FP-CIT binding was found with aging, amounting to 9.6%/decade. Unexpectedly, in the Parkinson's disease group, regression analysis revealed that neither severity of disease nor age accounted for a significant part of the variance in striatal SPECT measures. CONCLUSION: Our findings indicate that 123I-FP-CIT SPECT is a reliable method to discriminate between early, drug-naive Parkinson's disease patients and healthy controls and to identify patients in the preclinical phase of Parkinson's disease. Possibly due to the relatively homogeneous group of Parkinson's disease patients and the use of a suboptimal outcome measure, no significant correlations were found between striatal 123I-FP-CIT binding ratios and disease severity, such as were established earlier with 123I-beta-CIT. Further research is necessary to interpret these findings.

Treatment of gastro-oesophageal reflux disease with rabeprazole in primary and secondary care: does Helicobacter pylori infection affect proton pump inhibitor effectiveness?

BACKGROUND: The presence of the gastric pathogen, Helicobacter pylori influences acid suppression by proton pump inhibitors and treatment outcome in patients with gastro-oesophageal reflux disease. AIM: To determine the influence of H. pylori infection on effectiveness of rabeprazole in primary and secondary care patients with gastro-oesophageal reflux disease. METHODS: Patients from primary and secondary care centres with uninvestigated gastro-oesophageal reflux disease (based on symptoms only) and investigated gastro-oesophageal reflux disease (endoscopically confirmed oesophagitis or endoscopy-negative reflux disease) were tested for H. pylori and treated with rabeprazole 20 mg once daily for 4-8 weeks in a non-randomized, multicentre, open-label study. Primary end-point for treatment effectiveness was complete resolution of both heartburn and acid regurgitation at 4-8 weeks; secondary end-point was quality of life as registered with the Psychological General Well-being Index. RESULTS: Data of 1787 patients could be analysed; mean duration of treatment was 36.3 days. At the evaluation visit 76.9% were heartburn-free, 77.7% regurgitation-free and 71% had complete symptom resolution. Overall Psychological General Well-being Index scores improved accordingly. Treatment was equally effective in patients with or without H. pylori infection, but more effective in patients with oesophagitis when compared with symptomatic gastro-oesophageal reflux disease. CONCLUSIONS: The effectiveness of rabeprazole in gastro-oesophageal reflux disease is not affected by the presence of H. pylori infection.

Preclinical (premotor) Parkinson's disease.

Parkinson's disease (PD) is an idiopathic disease caused by necrosis and apoptosis of dopaminergic cells in the brainstem, which are probably induced by oxidative stress. Current therapeutic strategies comprise symptomatic and restorative treatment. Neuroprotective treatment, however, is close to becoming reality. As neuroprotective therapy may be of particular benefit to the preclinical and/or very early PD patients, identifying patients in the early stages of the disease is a priority. Both [18F]dopa positron emission tomography (PET) and [123I]beta-CIT single photon emission computed tomography (SPECT) imaging may be useful tools in diagnosing early (preclinical) PD. As screening the whole population for preclinical PD is not realistic, one has to select subjects with a high risk for this disease. Olfactory disturbances, subtle neurocognitive dysfunction, visuomotor control abnormalities and, to a lesser degree, mood and personality disorders, have lately been suggested to precede or accompany early clinical motor hallmarks of PD. In an epidemiological study, 500 first-degree relatives of PD patients were assessed for these signs and symptoms, and [123I]beta-CIT SPECT was performed on patients in the top 10% and the bottom 10% with regard to sense of smell. In this report, the study design and initial data from this ongoing study will be presented.

Drug-naive patients with Parkinson's disease in Hoehn and Yahr stages I and II show a bilateral decrease in striatal dopamine transporters as revealed by [123I]beta-CIT SPECT.

Ten healthy subjects and 16 patients with early Parkinson's disease (PD) were examined with single photon emission computed tomography (SPECT) and [123I]beta-CIT, a ligand for the dopamine (DA) transporter. Only drug-naive patients were examined since the expression of and binding to DA transporters may be influenced by dopaminergic medication. The main finding was a significant reduction in [123I]beta-CIT binding in the ipsi- and contralateral striatal regions, especially in the putamen, which showed a mean reduction of 65% of the control mean. Discriminant function analysis of the putaminal [123I]beta-CIT binding measures classified 100% of the cases in the correct group. Disease severity correlated negatively and highly significantly with the binding measures. Tremor ratings did not correlate with the SPECT measures, whereas rigidity, and to a lesser extent bradykinesia, did. Patients with unilateral PD showed a bilateral loss of striatal DA transporters. Our findings indicate that with [123I]beta-CIT SPECT it is possible to diagnose PD in subjects with very mild symptoms and signs. Moreover, finding a bilateral loss of striatal DA transporters in patients with unilateral PD also suggests that it may be possible to identify subjects in the preclinical phase of the disease.

Whole blood monoamine oxidase activity in Parkinson's disease and multiple system atrophy patients.

Monoamine oxidase type B (MAO-B), which catalyses the breakdown of dopamine (DA) in human brain, is said to be involved in the pathophysiology of Parkinson's disease (PD). Activity of MAO-B in PD has been measured in platelets isolated from blood samples in different studies, with contradictory results, possibly due to the differences in substrate used or to differences in platelet isolation. Therefore we measured MAO activity in whole blood, which is almost identical to MAO-B activity in platelets, in 25 drug-naive PD patients, 25 treated PD patients, 9 multiple system atrophy (MSA) patients and 20 controls, using a spectrofluorimetric method with kynuramin as a substrate. No statistically significant differences between groups were found, nor any correlation with the severity or duration of the disease.

Decreased cerebrospinal fluid nitrate levels in Parkinson's disease, Alzheimer's disease and multiple system atrophy patients.

Nitric oxide (NO) is a recently discovered endogenous mediator of vasodilatation, neurotransmission, and macrophage cytotoxicity. NO is thought to have a function in memory and in long-term potentiation. At high concentrations NO is neurotoxic and may play a role in neurodegeneration. NO is formed from L-arginine by the enzyme NO synthase (NOS), for which tetrahydrobiopterin (BH4) is a necessary co-factor. Alzheimer's disease (AD) and, to a lesser degree, Parkinson's disease (PD) are thought to be associated with increased microglial activity, suggesting that NO production may be increased. Alternatively, in circumstances of reduced levels of intracellular L-arginine or BH4, NO production is diminished and neurotoxic oxygen radicals may be produced. Since BH4 is decreased in AD and PD brains, these diseases may be associated with decreased NO production. We investigated these two alternatives by measuring the NO degradation products nitrite and nitrate in cerebrospinal fluid (CSF) of PD (n = 103), AD (n = 13), and multiple system atrophy (MSA; n = 14) patients and controls (n = 20). We found for all patient groups, compared with controls, significantly decreased levels of nitrate, but not nitrite. This finding seems to indicate a decreased NO production of the central nervous system (CNS) in these neurodegenerative disorders.