Health-related quality-of-life outcome in patients with idiopathic normal-pressure hydrocephalus - a 1-year follow-up study.

BACKGROUND AND PURPOSE: This prospective study explored the factors affecting the health-related quality-of-life (HRQoL) outcome in patients with idiopathic normal-pressure hydrocephalus (iNPH) 1 year after the installation of the cerebrospinal fluid shunt. METHODS: The HRQoL outcome was evaluated using a 15D instrument, in which the minimum clinically significant change/difference has been estimated to be ±0.015. The follow-up data (15D, Mini-Mental State Examination, Beck Depression Inventory, iNPH Grading Scale), frontal cortical biopsy, Charlson Age Comorbidity Index and body mass index of 145 patients diagnosed with iNPH by clinical and radiological examination were analyzed. RESULTS: At 1-year follow-up, 63 (43%) patients had experienced a clinically significant improvement in HRQoL. Multivariate binary logistic regression analysis indicated that the absence of amyloid-ß and hyperphosphorylated tau pathology in the frontal cortical biopsy (53% vs. 33%; absolute risk difference, 20%; adjusted odds ratio, 2.27; 95% confidence interval, 1.07-4.84; P < 0.05) and lower body mass index (adjusted odds ratio, 0.90, 95% confidence interval, 0.82-0.98; P < 0.05) predicted favorable HRQoL outcome 1 year after the shunting. CONCLUSIONS: Less than half of the patients with iNPH experienced clinically significant favorable HRQoL outcome, partly explained by the patient's characteristics and comorbidities. The HRQoL approach reveals aspects that are important for the patient's well-being, but may also improve the quality of the outcome assessment of cerebrospinal fluid shunting. Study results may help clinicians to estimate which patients will benefit shunt surgery.

Health-related quality of life in patients with idiopathic normal pressure hydrocephalus.

BACKGROUND AND PURPOSE: Factors affecting health-related quality of life (HRQoL) were explored in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: Using the 15D instrument HRQoL was evaluated in 132 patients diagnosed with iNPH by clinical and neuroradiological examinations. The severity of iNPH symptoms was measured with the iNPH grading scale (iNPHGS), depressive symptoms with the Beck Depression Inventory (BDI-21) and cognitive impairment with the Mini-Mental State Examination. RESULTS: The mean (SD) 15D score (on a 0-1 scale) of patients with iNPH was significantly lower than that of an age- and gender-matched sample of the general population [0.718 (0.103) vs. 0.870 (0.106); P < 0.001]. The mean 15D score was lower in iNPH patients with moderate or severe depressive symptoms than in patients without depressive symptoms (P = 0.003). According to stepwise multiple linear regression analysis, a higher total iNPHGS score (b = -0.62, P < 0.001) and a higher BDI-21 total score (ß = -0.201, P = 0.025) predicted a lower 15D score; in combination, these explained 51% of the variance in the 15D score (R(2)  = 0.506, P < 0.001). CONCLUSIONS: Idiopathic normal pressure hydrocephalus impairs patients' HRQoL on multiple dimensions, similarly to other chronic diseases. Potentially treatable depressive symptoms contribute greatly to the HRQoL impairment of iNPH patients, but only if they are moderate or severe. The 15D portrayed HRQoL dimensions affected by iNPH in a similar way to broader assessment batteries and thus is a potentially useful tool for treatment evaluation and cost-utility analysis.

Factors associated with life satisfaction in a 6-year follow-up of depressive out-patients.

BACKGROUND: The major goal of mental health services is to improve mental health and thus also life satisfaction. However, studies assessing factors associated with life satisfaction during recovery from depression are lacking. METHODS: A 6-year natural follow-up of 121 depressive out-patients was carried out with questionnaires at baseline, 1/2, 1, 2 and 6 years completed. A structured diagnostic interview was conducted. Throughout the follow-up, clinical status was assessed with several psychometric scales for life satisfaction (LS), depression (BDI, HDRS), hopelessness (HS), functional ability (GAF, SOFAS) and general psychopathology (SCL). RESULTS: Men and women did not differ in their improvement in life satisfaction. Altogether, 77% of the patients at baseline and 22% at the end were dissatisfied. Life satisfaction on 6-year follow-up was associated with baseline lower interpersonal sensitivity (SCL subscale) and concurrently being loved by someone as well as with baseline and concurrent good self-rated health and wealth. The satisfied were better off in terms of all clinical variables, regardless of the measurement time. Depressive symptoms and hopelessness were the strongest concurrent clinical correlates of LS after 6 years. CONCLUSIONS: Mental health was strongly related to life satisfaction throughout the follow-up, while most of the non-clinical factors were not. Alleviating depression and interpersonal sensitivity and supporting social networks should be focused on in psychiatric treatment in order to improve life satisfaction among depressive patients.

5-Year health-related quality of life outcome in patients with idiopathic normal pressure hydrocephalus.

BACKGROUND: Health-related quality of life (HRQoL) is severely impaired in persons with idiopathic normal pressure hydrocephalus (iNPH). The HRQoL improves in a number of patients after the placement of a cerebrospinal fluid (CSF) shunt, but long-term follow-up of HRQoL is rare. METHODS: Extended follow-up (60 months) of a prospective cohort study involving 189 patients with iNPH who underwent shunt surgery. Preoperative variables were used to predict favorable HRQoL outcome (improvement or non-deterioration) measured by the 15D instrument 5 years after shunting. RESULTS: Out of the 189 initially enrolled study participants, 88 had completed 5-year HRQoL follow-up (46%), 64 had died (34%), and 37 (20%) failed to complete the HRQoL follow-up but were alive at the end of the study. After initial post-operative HRQoL improvement, HRQoL deteriorated so that 37/88 participants (42%) had a favorable HRQoL outcome 5 years after shunting. Multivariate binary logistic regression analysis indicated that younger age (adjusted OR 0.86, 95% CI 0.77-0.95; p < 0.005), lower body mass index (adjusted OR 0.87, 95% CI 0.77-0.98; p < 0.05) and better Mini-Mental State Examination performance (adjusted OR 1.16, 95% CI 1.01-1.32; p < 0.05) before surgery predicted favorable 5-year outcome. CONCLUSIONS: This extended follow-up showed that the self-evaluated HRQoL outcome is associated with iNPH patients' pre-operative cognitive status, overweight and age. The post-operative deterioration may reflect the natural progression of iNPH, but also derive from aging and comorbidities. It indicates a need for long-term follow-up.

Serum adiponectin and resistin levels in major depressive disorder.

OBJECTIVE: To examine the role of the adipose-tissue-derived low-grade inflammation markers adiponectin and resistin in major depressive disorder (MDD) in a population-based sample. METHOD: Serum levels of adiponectin and resistin were measured from 70 DSM-IV MDD subjects and 70 healthy controls. Depression severity was assessed with the 29-item Hamilton Depression Rating Scale. RESULTS: The MDD group had lowered serum adiponectin levels. Regression modelling with adjustments for age, gender, overweight, several socioeconomic and lifestyle factors, coronary heart disease and metabolic syndrome showed that each 5.0 microg/ml decrease in serum adiponectin increased the likelihood of MDD by approximately 20% (P = 0.01). The resistin levels correlated with atypical (P = 0.02), but not with typical depressive symptoms (P = 0.12). CONCLUSION: Our findings suggest that the lowered adiponectin levels in MDD are depression-specific and not explained by conventional low adiponectin-related factors such as such as coronary heart disease and metabolic disorders.

Association of depressive symptoms and metabolic syndrome in men.

OBJECTIVE: To explore the relationship between several indicators of depression and metabolic syndrome (MetS). METHOD: A population-based sample with high (HMS group) or low (LMS group) levels of mental symptoms, including those of depression, in three follow-ups participated in a clinical examination in 2005 (n = 223). MetS was determined according to the NCEP criteria. RESULTS: The prevalence of MetS was 49% in men and 21% in women. Men with MetS had higher rates of major depressive disorder than other men. They also displayed higher Hamilton Rating Scale for Depression (HDRS) scores and more often signs of suicidality. In logistic regression analyses, higher HDRS scores (OR 1.31, 95% CI 1.04-1.64) and belonging to the HMS group (OR 10.1, 95% CI 1.98-51.3) were independent associates for MetS but only in men. CONCLUSION: The results highlight that there is an association between long-term depressive symptoms and the emergence of MetS, especially in men.

Short-term and long-term memory in elderly patients with NIDDM.

OBJECTIVE: To determine cognitive and memory dysfunction associated with non-insulin-dependent diabetes mellitus (NIDDM) and its relationship with depression, metabolic control, and serum lipids. RESEARCH DESIGN AND METHODS: We studied a well-characterized group of 20 elderly patients with NIDDM and 22 control subjects with normal glucose tolerance recruited from a larger population-based sample. In addition to clinical and laboratory examinations, self-rating questionnaires that assess minor psychiatric disorder (General Health Questionnaire) and depression (Zung scale) were completed by patients and control subjects. Memory was examined with digit and block-span tests, word-list learning, Heaton Visual Memory Test, and Moss Visual Span Test. Executive functions were examined by Trail-Making A and B test and by Verbal and Category Fluency Tests. Visuoconstructive reasoning was examined with the block design subtest of the Wechsler Adult Intelligence Scale. RESULTS: The NIDDM patients showed preserved memory span, but poor performance in learning tasks compared with control subjects. The patients recalled no fewer words than the control subjects, but the process of of learning seemed to be different in the two groups. The recognition of the learned words was not impaired. Elevated serum total and very-low-density lipoprotein triglyceride levels, measured either before examinations or 5 or 10 years earlier, were associated with effects on retrieval from semantic memory in NIDDM patients. CONCLUSIONS: The NIDDM patients had impaired control of their learning processes. Elevated serum triglyceride levels may be related to control of mental processing in diabetic patients.

Smoking and suicidality among psychiatric patients.

OBJECTIVE: This study investigated the relationship between smoking and suicidality among psychiatric patients. METHOD: All psychiatric patients (N = 1,217) from Kuopio University Hospital in eastern Finland were examined for current smoking, suicidal ideation, previous suicide attempts, and other risk factors by using a cross-sectional, multivariate design. RESULTS: The probability of at least one previous suicide attempt was 100% higher in current smokers than in nonsmokers. Smokers also had a 43% higher risk of experiencing mild to severe suicidal ideation than nonsmokers. CONCLUSIONS: Current smoking was significantly related to suicidality in multiple logistic models, even after several confounding factors were controlled. The independence of this association seems possible, but the subject requires further research.

High serum cholesterol and risk of suicide.

OBJECTIVE: The study was conducted to estimate the association between serum total cholesterol concentration and mortality from suicide. METHOD: The baseline serum total cholesterol concentration of 37,635 adults was determined in five independent population surveys conducted during 1972-1992 in Finland. Mortality from different causes of death was monitored for a mean of 14.6 years after the survey dates. The means for violent suicides (N=130) included hanging, firearms, cutting, jumping, and unspecified means. The means for nonviolent suicides (N=46) included drug overdose, poisoning with gases, and drowning. RESULTS: Serum total cholesterol concentration was positively related to the risk of violent suicide. Among subjects whose serum total cholesterol concentration was in the highest category, the adjusted relative risk was more than twofold compared with the lowest category. The violent/nonviolent suicide ratio increased linearly with increasing cholesterol category. No association between serum total cholesterol concentration and the risk of nonviolent suicide was found. CONCLUSIONS: This is the first study to demonstrate the positive relationship of high serum total cholesterol concentration with increased risk of violent suicide.

Life satisfaction and suicide: a 20-year follow-up study.

OBJECTIVE: The authors investigated whether self-reported life satisfaction predicted suicide over a period of 20 years (1976-1995) in adults unselected for mental health status. METHOD: A nationwide sample of adults aged 18-64 years (N=29,173) from the Finnish Twin Cohort responded to a health questionnaire that included a life satisfaction scale (score range=4-20, with higher scores indicating greater dissatisfaction) that covered four items: interest in life, happiness, general ease of living, and feeling of loneliness. "Dissatisfied" subjects (life satisfaction score=12-20) were compared to "satisfied" subjects (score=4-6). Mortality data were derived from the national registry and analyzed with Cox regression. RESULTS: Dissatisfaction at baseline (life satisfaction score=12-20) was associated with a higher risk of suicide throughout the 20-year follow-up period (age-adjusted hazard ratio=3.02, 95% confidence interval [CI]=1.83-4.98). The association was somewhat stronger in the first decade (hazard ratio=4.46, 95% CI=1.95-10.20) than in the second (hazard ratio=2.34, 95% CI=1.24-4.45). A dose-response relationship was also found. Men with the highest degrees of dissatisfaction (life satisfaction score=19-20) were 24.85 times as prone to commit suicide as satisfied men during the first 10 years of the follow-up period. Throughout the entire follow-up, life dissatisfaction still predicted suicide after adjusting for age, sex, baseline health status, alcohol consumption, smoking status, and physical activity (hazard ratio=1.74, 95% CI=1.02-2.97). Subjects who reported dissatisfaction at baseline and again 6 years later showed a high suicide risk (hazard ratio=6.84, 95% CI=1.99-23.50) compared to those who repeatedly reported satisfaction. CONCLUSIONS: Life dissatisfaction has a long-term effect on the risk of suicide, and this seems to be partly mediated through poor health behavior. Life satisfaction seems to be a composite health indicator.

Pain as a reason to visit the doctor: a study in Finnish primary health care.

This study aims to demonstrate the prevalence of pain as a reason for seeing a physician in primary care. We also performed an analysis of the localization, duration and frequency of pains, as well as the diagnoses of patients having pain. A total of 28 physicians at 25 health centers in Finland collected the data, comprising 5646 patient visits. Pain was identified as the reason for 2237 (40%) of the visits. The most common localizations were in the lower back, abdomen and head. One-fifth of the pain patients had experienced pain for over six months. Analysis of the diagnoses revealed half of the pains to be musculoskeletal. Patients experienced considerable limitations in various activities of life due to pain. A quarter of the pain patients of active working age received sick leave. Our results confirm that pain is a major primary health care problem, which has an enormous impact on public health.

Nightmares as predictors of suicide.

STUDY OBJECTIVES: To examine the relationship between the frequency of nightmares and the risk of suicide. DESIGN AND SETTING: A prospective follow-up study in a general population of Finland starting in 1972. PARTICIPANTS: A total of 36,211 subjects (17,700 men and 18,511 women) aged 25-64 years at baseline. INTERVENTIONS: N/A. MEASUREMENTS: The study included self-administered questionnaires (mainly questions on socio-economic factors, medical history, health behavior, and psychosocial factors) and health examination at the local primary healthcare center. The frequency of nightmares was estimated. The subjects were followed until Dec. 31, 1995, or death. Information on deaths caused by suicide (n=159) or other self-inflicted injury was obtained from the National Death Register by computerized record linkage using the national personal identification code assigned to every Finnish resident. Using the Cox proportional hazards regression model we controlled for several potential confounding factors. RESULTS: The frequency of nightmares was directly related to the risk of suicide. Among subjects having nightmares occasionally the adjusted relative risk of suicide was 57% higher, and among those reporting frequent nightmares 105% higher compared with subjects reporting no nightmares at all. CONCLUSIONS: This is the first study to report a direct and graded association between the frequency of nightmares and death from suicide in a general population.

Striatal dopamine transporter density in major depression.

RATIONALE: There are no previous data available regarding [123I]beta-CIT binding to the dopamine transporter sites in the basal ganglia in depressed patients. OBJECTIVE: The present study tested the hypothesis that the brain DAT density in depressed patients is lower than that in matched healthy controls. METHODS: Fifteen drug-naive outpatients with major depression and 18 healthy controls were investigated using single photon emission computerized tomography (SPECT) with a high-affinity dopamine transporter specific radioligand. 123I-labeled beta-CIT (2beta-carbomethoxy-3beta-(4-iodophenyl-tropane). RESULTS: We found a significantly higher [123I]beta-CIT uptake in both sides of the basal ganglia in patients with major depression than in the controls (Mann-Whitney U-test, P = 0.002 on the right and P = 0.003 on the left). CONCLUSIONS: The radioligand uptake reflecting the DAT density was significantly higher among the patients than in the controls. This finding is unexpected, since it is generally believed that monoaminergic neurotransmission is lower in depression, and therefore it could be assumed that a reduction in dopamine transmission would lead to secondary down-regulation of DAT density. However, it is possible that up-regulation of the DAT may be the primary alteration, which leads to lower intrasynaptic dopamine concentration and to lower dopamine neural transmission.

Joint heavy use of alcohol, cigarettes and coffee and the risk of suicide.

AIMS: To estimate the relationship between joint heavy use of alcohol, cigarettes and coffee, and the risk of suicide in a general population with high rate of suicide. DESIGN: Prospective cohort analyses. SETTING: Finland. PARTICIPANTS: Data from 36,689 adult (age range 25-64 years) men and women who participated in the population surveys between 1972 and 1992. MEASUREMENTS: The mortality of the cohort was monitored for a mean of 14.4 years, which yielded 169 suicides. Criteria for heavy use of each psychoactive substance were defined as follows: alcohol (> 120 g/week), cigarettes (> or = 21/day) and coffee (> or = seven cups/day). FINDINGS: About half the men and 80% of the women did not use any of the psychoactive substances heavily. Every third man and every fifth woman used one substance heavily, and the prevalence for those who exceeded criteria for joint heavy use of two substances was 9% for men and 1% for women. Joint heavy use of all three substances was rare. The adjusted relative risk of suicide increased linearly with increasing level of joint heavy use of alcohol, cigarettes and coffee. Among subjects with heavy use of one substance the risk was 1.55 (95% CI = 1.10, 2.18), with joint heavy use of two substances 2.22 (95% CI = 1.37, 3.61), and with joint heavy use of all three substances 3.99 (95% CI = 1.80, 8.84) compared with no heavy use. CONCLUSIONS: Clustering of the heavy use of alcohol, cigarettes and coffee could serve as a new marker for increased risk of suicide.

SPECT and neuropsychological performance in severe depression treated with ECT.

BACKGROUND: In severe depression, studies of regional cerebral blood flow (rCBF) by SPECT have not produced uniform results. The association between changes in SPECT and electroconvulsive therapy (ECT) has shown somewhat conflicting data. No data are available on benzodiazepine receptor function SPECT studies in ECT. METHODS: Twenty drug-resistant adult inpatients fulfilling the DSM-IIIR criteria for major depression were studied by SPECT (rCBF by relative ECD uptake in all, and benzodiazepine receptor function by iomazenil uptake in five subjects) before and 1 week after clinically successful bitemporal ECT. Clinical and neuropsychological test scores were used as references for the possible changes in SPECT. RESULTS: An increased perfusion after ECT was observed in right temporal and bilateral parietal cortices, whereas no reductions in relative ECD uptake were seen after ECT. Iomazenil-SPECT revealed a highly significant increase in the benzodiazepine receptor uptake in all studied cortical regions except temporal cortices. CONCLUSIONS: Clinically successful ECT was associated with changes in vascular perfusion and GABAergic neurotransmission, providing new evidence for the mechanism of action of ECT and for the neurobiology of severe drug-resistant depression.

Depression is strongly associated with alexithymia in the general population.

OBJECTIVE: This study examines how alexithymia and depression are related to each other in men and women in a sample of Finnish general population (n = 2018). METHODS: Alexithymia was screened using the 20-item version of the Toronto Alexithymia Scale. Level of depression was assessed using the 21-item Beck Depression Inventory (BDI). Life satisfaction was estimated with a structured scale. RESULTS: The prevalence of alexithymia was 12.8% in men and 8.2% in women. However, the prevalence of alexithymia was 32.1% among those having BDI scores of > or = 9, but only 4.3% among the nondepressed subjects (p < 0.001). The BDI scores explained 29.2% of the variation in TAS-20 scores. Alexithymia was associated with several sociodemographic factors if depression was not taken into account. However, after including depression in the logistic regression models, only depression and low life satisfaction were associated with alexithymia, both in men and women. CONCLUSION: These results suggest that alexithymia has a close relationship to depression in the general population. The impact of social factors on alexithymia may be primarily explained by depression. Depression must be taken into account as a confounding factor when studying alexithymia in general populations due to the strong association between alexithymia and depression.

Alexithymia in patients with coronary heart disease.

OBJECTIVE: The aim of this study was to investigate factors associated with alexithymia in patients (n=153) with coronary heart disease (CHD) verified by coronary angiography. METHOD: Self-rated depression was assessed using 21-item Beck Depression Inventory (BDI) and other psychiatric symptoms with Symptom Check List-90 (SCL-90). Life satisfaction was assessed using a separate scale. The Structured Clinical Interview (SCID I and II) for DSM-III-R was used to identify mental disorders. Assessments took place 1 day before angiography. RESULTS: Twenty-one percent of CHD patients (n=32) were assessed as being alexithymic according to the Toronto Alexithymia Scale (TAS-20). Alexithymics were more often blue-collar workers, incapable of working, dissatisfied with life, and depressed than the other CHD patients. Occurrences of mental disorders were not associated with alexithymia. Logistic regression analysis revealed that factors independently associated with alexithymia were currently or previously being a blue-collar worker (adjusted odds ratio, AOR: 4.8), self-rated depression (AOR: 3.2), and dissatisfaction with life (AOR: 2.9). CONCLUSION: In CHD patients alexithymia was unrelated to cardiovascular risk factors or exercise capacity but was related to self-rated depression and decreased life satisfaction. Alexithymia is associated with the enhanced psychosocial burden of suffering CHD. This patient group may need more individual support and attention than other CHD patients.

Heavy drinking is associated with more severe psychosocial dysfunction among girls than boys in Finland.

PURPOSE: To investigate social, psychological, and environmental factors related to heavy drinking by 15-year-old Finnish school pupils. METHODS: Each of 240 pupils completed a questionnaire about alcohol use, smoking, and illicit drug use; an Offer Self-Image Questionnaire; an Inventory of Parent and Peer Attachment; and a Psychosomatic Symptoms Questionnaire. Teachers assessed each pupil according to a Social Skills Rating Scale. Academic achievement was assessed on the basis of report grades. RESULTS: Heavy drinking was associated with smoking, trial of drugs, poor social skills in class, and poor school achievement in both boys and girls. In girls, heavy drinking was associated with psychosomatic symptoms and a negative social self-image. Girls who drank heavily also had more difficulty with concentration and externalizing problems and more problems with teachers than those who were abstinent or consumed alcohol moderately. The self-images of boys who drank heavily were more negative than those of alcohol-abstinent boys. In boys, heavy drinking was associated with higher numbers of peer relationships. CONCLUSIONS: Heavy drinking is associated with more severe psychosocial dysfunction among girls than boys. It may be possible to identify girls at school who drink heavily and guide them toward treatment.

Alexithymia in patients with major depressive disorder and comorbid cluster C personality disorders: a 6-month follow-up study.

The authors examined the association between alexithymia, cluster C personality disorders (CPD), and severity of depression among 121 outpatients with major depressive disorder (MDD) in a 6-month, follow-up study. Diagnosis of depression and CPD was confirmed by means of the Structured Clinical Interviews for DSM-III-R (SCID I and SCID II). Alexithymia was screened using the 20-item version of the Toronto Alexithymia Scale and severity of depression was assessed using the 21-item Beck Depression Inventory. Results indicated that alexithymic features are common in patients with MDD but often alleviated during recovery from depression. Moreover, comorbid CPD and severity of depression seemed to be associated with poorer recovery from alexithymia. The implications of these findings are discussed.

Evolution of postpartum mental health.

We investigated the postpartum mental health of 139 mothers, 4-8 weeks after delivery and 2 years later. The sample consisted of mothers who attended a maternity center for a routine health check-up 1-2 months after delivery. The occurrence of mental disorders was assessed using a 12-item General Health Questionnaire (GHQ). The occurrence of mental disorders (> 2 on the GHQ) was 28.1% in the initial check-up and 19.4% 2 years later. Mental health improved in 27 mothers (19%) but remained impaired (i.e. cases) in 12 (9%). Mental health was normal in 85 mothers (61%) during both examinations. Factors predicting chronicity of mental disorder on univariate analysis were poor financial situation, poor social support, problems with a partner and life events perceived as stressful during follow-up. Those with continuing mental-health problems had more psychiatric problems than the others before pregnancy. Most (92%) of these subjects had not become pregnant again. Using a logistic-regression analysis, independent factors predicting chronicity of mental-health problems were the high Zung score (Odds Ratio (OR) 1.4, 95% confidence interval (CI) 1.16-1.65) and a deterioration in relationship with a partner during pregnancy (OR 29, 95% CI 1.83-460). On the other hand, a low Zung score (OR 1.3, 95% CI 1.14-1.44) after delivery predicted recovery from mental disorder. A postpartum mental disorder usually resolves spontaneously. However, mental symptoms sometimes persist. The postpartum mental-health of mothers should be assessed, and treatment provided, if necessary.