The survey performed in four European countries (Germany, Greece, Italy and Spain) aimed to characterize patients with schizophrenia treated in everyday clinical practice in terms of demographic characteristics, presenting symptomatology, and current antipsychotic treatement. We present here characteristics of patients in long term hospitalization.

A survey involving 744 psychiatrists gathered anonimous retrospective data from 3,996 patients with schizophrenia. To ensure representativeness of participating physicians, the dataset was adjusted post hoc. Principal component analysis was used to structure the patient attributes relevant for antipsychotic choice, identifying two discriminating variables (disease severity and socioeconomic level) accounting for 91% of the variance in the data. Methodology is described in full detail by Gorwood (2010).

Of 3,996 surveyed patients, 15.8% were in long term hospitalization. They had a mean of 7.1 previous episodes and 5.5 previous hospitalizations. They typically presented with positive symptoms, with delusions, hallucinatory behavior and ideas of persecusion being most frequently observed. 78% of subjects were smokers, 19% had drug and 9% alcohol addiction. 36% of subjects had a verified cardiometabolic comorbidity and 22% were obese. 54% of subjects had verified medication non-adherence. Most frequently used antipsychotic was risperidone (in 24% of subjects). Ziprasidone was used in 9% of subjects. 13% of subjects were on depot medication and 17% was receiving orally disintegrating tablets.

Subjects with schizophrenia in long term hospitalization have high rates of positive symptoms despite receiving antipsychotic treatment regularly. Smoking rates were alarmingly high.

Asenapine and olanzapine reduced persistent negative symptoms (PNS) of schizophrenia in 2 double-blind, randomized 26-week studies and subsequent 26-week extensions; superiority of asenapine over olanzapine was observed in neither core study and only 1 extension.

Further explore the efficacy of asenapine on PNS using pooled data.

Demonstrate superiority of asenapine over olanzapine on PNS.

Core study participants were randomized to twice-daily asenapine 5 or 10 mg or once-daily olanzapine 5–20 mg; extension participants continued existing treatment. Changes from core study 16-item Negative Symptom Assessment (NSA-16) Scale baseline at Weeks 26 and 52 were estimated using MMRM.

Of 949 treated participants (asenapine, 485; olanzapine, 464), 613 (277; 336) completed the core studies and 412 (170; 242) completed the extensions. Discontinuation due to lack of therapeutic effect was significantly greater with asenapine vs olanzapine for the first 26 weeks (13.6% vs 7.3%, p = 0.0016) and during the extension (5.5% vs 2.1%, p = 0.0458) for core and extension study participants, respectively. Between-group differences in least squares mean ± SE NSA-16 score change from core study baseline were significantly greater with asenapine at Week 52 for core (-14.6 ± 0.8 vs -12.6 ± 0.7; p = 0.0497) and extension (-16.5 ± 0.9 vs -13.6 ± 0.7; p = 0.0083) participants, but were not significant at Week 26.

In pooled analyses, asenapine and olanzapine reduced PNS, with statistical superiority of asenapine observed at Week 52 but not Week 26. These results should be interpreted in view of the fact that participants who entered the extensions did so without rerandomization.

Asenapine is an FDA-approved atypical antipsychotic (AAP) indicated in adults for treatment of schizophrenia.

Present meta-analyses of asenapine vs placebo and other antipsychotics in acute schizophrenia.

Further demonstrate the efficacy of asenapine in acute schizophrenia.

PANSS total score changes from baseline to week 6 were assessed using last observation carried forward (LOCF) and mixed model for repeated measures (MMRM). Comparisons of asenapine and antipsychotics vs placebo were obtained from 4 placebo-controlled asenapine studies. Head-to-head comparisons among AAPs assessed in the same trials (including those for which no direct comparisons are available) were conducted with network meta-analyses using a published database (Leucht et al, Am J Psychiatry 2009;166:152–166) of 74 studies updated with data from 5 AAP-controlled asenapine trials.

PANSS change from baseline with asenapine exceeded that of placebo (LOCF: 3.7 [95% CI, 1.5–5.9], P = 0.001; MMRM: 4.1 [95% CI, 1.6–6.5], P = 0.001), a treatment effect comparable to other antipsychotics (LOCF: 4.1 [95% CI, 1.7–6.5], P = 0.001; MMRM: 4.6 [95% CI, 1.9–7.3], P = 0.001). Head-to-head network meta-analysis reported comparable efficacy with asenapine and other AAPs; PANSS differences ranged from 3.9 points better than ziprasidone (95% CI, 0.3–7.4) to 2.9 points worse than olanzapine (95% CI, -5.-0.1).

These meta-analyses demonstrate superiority of asenapine over placebo in acute schizophrenia, with treatment effects of asenapine at least comparable to antipsychotics used in the same studies. Further, the network meta-analysis suggests the efficacy of asenapine for acute schizophrenia is comparable to that of established AAPs.

Natural speech perception relies on both, auditory and visual information. Both sensory channels provide redundant and complementary information, such that speech perception is enhanced in healthy subjects, when both information channels are present.

Patients with schizophrenia have been reported to have problems regarding this audiovisual integration process, but little is known about which neural processes are altered.

In this study we investigated functional connectivity of Broca’s area in patients with schizophrenia.

Functional magnetic resonance imaging (fMRI) was performed in 15 schizophrenia patients and 15 healthy controls to study functional connectivity of Broca’s area during perception of videos of bisyllabic German nouns, in which audio and video either matched (congruent condition) or die not match (incongruent; e.g. video = hotel, audio = island).

There were differences in connectivity between experimental groups and between conditions. Broca’s area of the patient group showed connections to more brain areas than the control group. This difference was more prominent in the incongruent condition, for which only one connection between Broca's area and the supplementary motor area was found in control participants, whereas patients showed connections to 8 widely distributed brain areas.

The findings imply that audiovisual integration problems in schizophrenia result from maladaptive connectivity of Broca's area in particular when confronted with incongruent stimuli and are discussed in light of recent audio visual speech models.

Long term hospitalization are often caused by social reasons wich significantly affects the quality of the patients.

Comparing the quality of long-term hospitalized schizophrenic patients in relation to sex.

We have used following rating scale: a brief psychiatric assessment scale BPRS, QLS Quality of life scale, “Lancashir” profile quality of life scale LQOLP, a short questionnaire for the “needs assessment Cambersels” scale CANSAS. Analysis included 80 inpatients, 40 male and 40 female, with Schizophrenia according to ICD 10 criteria. All patients were hospitalized according to ICD 10 criteria. All patients were hospitalized in a Special Hospital For Psychiatric Illness G. Toponica more than two years.

Significant differences in quality of life between male and female patients about what is discussed in further study.

Research has shown that long-term hospitalizing has adverse effects on quality of life of schizophrenic patients of both sexes. His essential that the length of hospital stay should be reduced to the period reduced to the period for reduction of symptoms and provide the patient a stable life in the community after hospital treatment.

Despite comparable antipsychotic exposure, some patients experience involuntary movements yet others do not. Negative symptoms have been associated with tardive dyskinesia, but it is not certain that this is an association with primary negative symptoms.

To determine whether patients with deficit schizophrenia (who have primary negative symptoms) are more likely to experience tardive dyskinesia than those with non-deficit schizophrenia.

In 2006 all the people with a clinical diagnosis of schizophrenia in Nithsdale, South West Scotland, were identified using the ‘key informant’ method. These patients were assessed using the Schedule for the Deficit Syndrome (SDS) and for the presence of dyskinesia using the Abnormal Involuntary Movements Scale (AIMS). Patients were also assessed for akathisia using the Barnes-Akathisia Scale and for extrapyramidal side effects using the Simpson and Angus rating scale.

There is a significant association between deficit and TD when controlling for age. Those with tardive dyskinesia are more likely to have deficit schizophrenia. The odds ratio is 3.08 (95% CI 1.28, 7.37), p = 0.012.

Our findings support the proposal that the pathological process underlying deficit schizophrenia can predispose to the development of tardive dyskinesia.

Thyroid dysfunction is relatively common in patients with schizophrenia.This study seeks to determine the prevalence and pattern of thyroid dysfunction and thyroid antibodies presence in a group of adult psychiatric inpatients with chronic schizophrenia.

Thyroid function tests and thyroid antibodies measurement were performed on 88 patients hospitalized in Psichiatric Clinic of UHC “Mother Teresa” from december 2006 to december 2007.

55 of them (62,5%) were females and 33 of them (37,5%) males. A median age of 43 years (range16 to 70 years) and a median duration of hospitalization of 10 years (range 1 to 30 years) was assessed.

TAb were found in 22 patients (25%), of which 18 females and 4 males. 16% of them resulted with positive anticorps for Hashimoto Thyroiditis; 9% for Graves‘disease.

70% had normal test, 8% had elevated TSH: 3% of them with low thyroid hormones and 5% with normal thyroid hormones. 20% of cases had low TSH: 5% of them with high level of thyroid hormones, 15% with normal thyroid hormones. Hypothyroidism was more frequent in elderly patients ( > 60 years old), and in those treated with Risperidone. Most of cases (73%) with thyroid disorders resulted from endemic geographic areas. 37% of them mentioned familial history for thyroid pathology, and 23% for diabetes mellitus type 1.

Thyroid abnormalities are common in patients with chronic schizophrenia.This fact call for caution in the use and interpretation of thyroid function tests in these patients.

Families of individuals with schizophrenia experience disempowerment and helplessness because of unique stressors in their everyday life, mainly derived from the positive and negative symptoms of the illness (Bauml, et al., 2006). Another line of research provides evidence that working with families of people with schizophrenia is effective in reducing family burden and distress levels, through structured psychoeducational interventions (Falloon, 2003; Bauml, et al., 2006).

Despite evidence of their efficacy, psychoeducational interventions have not been widely implemented in standard clinical practice. The goal of this ongoing research project is to investigate the efficacy of a group psychoeducational intervention for parents of individuals with schizophrenia in reducing family burden and in improving their communication and problem solving skills, as well as their general family functioning.

The theoretical foundations of family psychoeducation is mainly derived from behavioral family therapy. Four couples (all parents of one or two individuals with schizophrenia) participated in this psychoeducational intervention program. Twenty three group sessions were conducted, organized around three primary goals: a) provision of information about the nature and the treatment of schizophrenia b) management of social and self-stigmatization and c) teaching family members problem-solving and communication skills (Solomon, 2000).

Pre and post treatment measures, as well as direct measures during treatment, were used to quantitatively assess family burden, family rituals, knowledge about the nature of the disorder, coping with stigma, communication and problem solving skills and general family functioning. Findings will be discussed.

PSP scale is a reliable and valid instrument for assessing the functioning of patients with with serious and persistent mental illness (SPMI).

To assess PSP performance in patients with SPMI.

Relapse prevention and maintenance of social functioning in the long-term management of SPMI.

Assessments were made at the local CMHC on June, September and December 2009. Clinical and demographic characteristics were recorded.

44 patients’ function per each domain was rated at six levels.

The impact on total PSP scores of the following variables was examined (random intercept model): type of medication, gender, age, marital status, professional status, residence location, everyday living, follow-up visits and time under treatment.

The sample included 35. 80% male, 75% unmarried, 89% pensioners, 82% living with their families, 71% living in villages, 29% living in cities. Paranoid schizophrenia was the most frequent diagnosis.

Statistically significant improvement from baseline to month 3 was showed for self care, personal and social relations subscales of PSP scale. Socially useful actions stabilized between month 3 and month 6, as well.

The mean PSP scores increased from baseline to month 3 by 4.0 units (p = 0.012) and then stabilized. The mean score changed from month 3 to month 6 by approximately 0.1 units (P = 1.00).

The functioning of patients with SPMI improved over time due to the monitoring by trained physicians and caregivers.

The advices offered from the treating physicians towards functioning maintenance seemed to improve patients’ functioning.

The knowledge of pathophysiology of first psychotic episode is still fragmentary.

To investigate some biochemical and biophysical parameters in first-episode, drug-naive schizophrenic (FES) patients.

26 FES patients (ICD-10; F 20.0 and F 20.3) and 15 age-and gender-match volunteers were investigated. Clinical severity of FES patients were assessed by PANSS scale. Platelet monoamine oxidase (MAO) and serum semicarbazide-sensitive amine oxidase (SSAO) activities, middle-mass endotoxic molecules (MMEM) and malondialdehyde (MDA) levels were measured using respective methods. Steady-state and subnanosecond fluorescent spectroscopy were used for the investigation of albumin conformational changes.

Severity of disorder prior the treatment was 75.5 ± 2.2 (PANSS score). FES patients were characterized by significant increase in MAO activity (99%) and MMEM concentration (124%) and significant decrease in SSAO activity (26%) as compared with controls. Changes of albumin conformational and functional parameters (“effective” albumin concentration and “reserve” of albumin binding) estimated by steady-state fluorescent spectroscopy were insignificant. Factor analysis revealed that MAO and SSAO are more tightly connected with pathogenetic mechanisms of FES then MMEM, MDA and albumin functional parameters. Significant conformational changes of albumin of FES patients were detected using pulse fluorescent spectroscopy with subnanosecond resolution. Results are compared with the data received in chronic schizophrenic patients.

From pathophysiological point of view FES is the initial step in development of pathologically disturbed biochemical status characteristic to chronic schizophrenia. The study was supported by grant # 3156 from International Science and Technology Center (ISTC).

This study examined the relation between schizotypy and the encoding style in a sub-clinical sample. We evaluated, first, the level of schizotypy with the Schizotypal Personality Questionnaire (SPQB) (Raine and al, 1995). Three factors are evaluated

1. a) cognitive-perceptual factor,

2. b) b) interpersonal factor and disorganisation.

A total of 184 students (113 women and 71 men) participated at this study. The mean age of the sample was 22,58 years (SD = 1,96). They were test using a French version of the ESQ, the brief SPQB, State-Trait Anxiety Inventory (STAI), The Center for Epidemiologic Studies Depression (CES-D) Scale.

The results demonstrated that we have a positive correlation between internal encoding style, schizotypy, depression and anxiety. Secondly, a high level of internal encoding style means a high level of congnitivo-perceptual and for interpersonal factors with an impact of depression and anxiety.

An internal encoding style is link with a high score in schizotypy.

Quality of life in patients with schizophrenia has been associated with severity of psychotic symptoms, adverse events and insight.

Determine variables related to quality of life. This communication is focused on variables directly related to pharmacological treatment.

Non-interventional, multicentre, cross-sectional study. Outpatients with stable schizophrenia (according to clinical criteria) who had the last acute episode at least 2 months before were included. EuroQol-5D was used to assess quality of life, and GAF to assess functioning.

941 patients were included in the study and 931 patients were analyzed. Mean index EuroQol-5D score (range: from -0.594 to1) was 0.7 (CI95%: 0.7,0.8), on EuroQol-5D Visual Analog Scale (VAS) was 65.4 (CI95%: 64.2,66.6) and GAF mean score was 59.7 (CI95%: 58.7,60.8).

Variables with correlations statistically significant (p < 0.05) on quality of life and functioning were: no. of antipsychotics, length on antipsychotic treatment, no. of non-antipsychotic drugs, no. total of drugs, no. of adverse events (AEs), no. of moderate AEs, no. of severe AEs and severity of AEs (sum of severity of every AEs from 1 to 5).

In this sample a difference in quality of life and functioning in patients based on the number of treatments (antipsychotic and non-antipsychotic), length with antipsychotic treatment and adverse events (any severity) was shown. In order not to impair quality of life and functioning, the least number of drugs should be used and attitude towards medication should be worked.

Study sponsored by AstraZeneca Spain.

The “Puente project”, rises up the adherence rate with 38% (1). The aim of the study was to analyse the economic impact of this disease management prgramme of patients with a schizophrenic disorder.

“Puente” stands for a programme of LAAP with active outreaching of patients with schizophrenia. The details of the data collection and the subjects have been described elsewhere (1).The hospitalisation rate and the length of stay of the 117 case control pairs have been compared. The cost of hospitalisation in Belgium, recently adjusted by De Ridder et al. (2), have been used in order to map the differences.

The number of hospital days totalised by 23 cases, was 2,152 days, in comparison to 6,371 realised by 42 controls,wich gives 18,6 hospital days per year for the cases and 38.9 days for the controls. Given an hospital cost per day in Belgium of 163.8 € per day, a crude saving of 3,328.5 € per case per year can be realised, correespondng with a net diminution of 2,428.5 € per patient year. Enrolling 1,675 cases per year, creates a saving of 4,066,533 € per year, an equivalent of 24,826 hospital days, or the cost of a psychiatric hospital of 85 beds occupied at 80%.

The Puente programme realised a substantial drop in public patient expenditure of 3,328.5 € per patient year. This is a very strong argument to implement, to finance and to support “Puente” like disease programmes in Belgium.

Cardiovascular disease is the most common cause of death in patients with severe mental illness (SMI). Patients are more likely to be overweight and to have hypertension, dyslipidemia, hyperglycemia and diabetes mellitus. Antipsychotic medication can induce or worsen these cardiovascular risk factors.

Accessibility to healthcare and adequate somatic treatment is limited in patients with SMI.

Prevalence of inadequate treatment for metabolic cardiovascular risk factors in patients treated with antipsychotic medication.

A health monitor was introduced as a screening instrument in a schizophrenia treatment and recovery program (so called F-ACT) at the outpatient departments. Assesment included physical and laboratory examination, demographics, DSM-IV diagnoses, remission-criteria, social functioning, use of medication and drugs.

Over a period of 18 months (2009–2010), 520 of the 600 patients included in the F-ACT were evaluated. Preliminary analysis shows that 452 patients met DSM-IV criteria of schizophrenia and other psychotic disorders. All patients were treated with at least one antipsychotic agent. Metabolic syndrome according to ATP-III was present in 50% of patients (60% abdominal obesity, 58% hypertension, 24% hyperglycemia, 52% high triglycerides, 49% low HDL-cholesterol). Rates of non-treatment ranged from 78% for hypertension, 85% for dyslipidemia and 48% for diabetes mellitus. Rates of inadequate treatment ranged from 69% for hypertension and 83% for dyslipidemia.

1. 1. Metabolic cardiovascular risk factors are highly prevalent in patients treated with antipsychotics

2. 2. Inadequate treatment of metabolic cardiovascular risk factors is common

3. 3. There is a need to improve the cooperation between psychiatrists and general practitioners

Psychotic disorders are highly prevalent and are treated with antipsychotics. There are no biological markers to predict or measure treatment effects. Research to neurotrophic proteins Brain Derived Neurotrophic Factor (BDNF) and S100B demonstrated association with psychotic symptoms and suggested association with treatment outcome and symptomatology.

Investigate the relevance of neurotrophic proteins BDNF and S100B in patients with psychotic disorders treated with antipsychotics.

Primary objective is to investigate the relationship between serum levels of BDNF and S100B and symptomatology at baseline and after six weeks of treatment. Furthermore, a detailed evaluation of symptom profile and treatment effect is performed.

80 patients with acute and chronic psychotic disorder were evaluated during six weeks while receiving antipsychotic treatment of any kind. Symptomatology was assessed using CASH, PANSS and CGI-S/I. Biochemical parameters were determined at baseline and after six weeks. Symptomatology and treatment effect were related to biochemical results.

Preliminary analyses show an overall treatment response of 19% (reduction of PANSS). A significant difference was found at baseline between patients with first-episode psychosis and patients with relapse or chronic psychosis (BDNF 12,4 vs. 21,7μg/l P ≤ 0,01, S100B 0,1055 vs. 0,05937 μg/l, P < 0,05). During treatment, serum levels of neurotrophic proteins returned to normal values in both groups.

Six weeks of antipsychotic treatment results in a modest symptomatic improvement. In subgroups with first episode psychosis, S100B levels are higher and BDNF levels are lower. The normalization of both serum levels suggests an effect of antipsychotic treatment on brain neurochemical processes.

In the past, the first goal of schizophrenia treatment was to reduce psychotic symptoms, mainly positive symptoms. Recently, as a result of an emphasis on patient needs, the concept of quality of life (QoL) has been brought into the treatment. The goal has therefore changed from the alleviation of symptoms to improvement of the patient's satisfaction with social activities. Self-evaluations by people with schizophrenia were previously thought to lack reliability because of the presence of psychopathological symptoms and poor awareness of the disease. Recently the importance of evaluating the satisfaction of patients themselves, however, has been recognized in schizophrenia. Studies on this field showed us, that QoL data from patients with chronic mental illness were reliable and concluded that subjective QoL evaluation was applicable to such patients.

The purpose of the present study was to compare the QoL in patients suffering from schizophrenia in clinical remission with healthy controls and examine the extent of the effects of subjective cognitive functioning on QoL in these patients.

Data were obtained using the quality of life questionnaire (Quality of Life Enjoyment and Satisfaction - Q-LES-Q), and subjective questionnaire for cognitive dysfunction (Cognitive Failures Questionnaire - CFQ) for 40 schizophrenia patients in clinical remission and 40 healthy controls.

Cognitive function correlates negatively with subjective QoL in patients with schizophrenia.

Hope is considered as an important factor in recovery from severe mental illness. So far it has been studied in patients with depression, anxiety disorders and post traumatic stress disorder, whereas empirical studies involving people with psychosis are scarce and their results are inconclusive.

We aimed at evaluating the relationship between

• (i) hope and positive as well as negative psychotic symptoms and

• (ii) hope and depression in people with psychosis.

In this cross-sectional study 148 patients with schizophrenia and schizo-affective disorder were interviewed by a psychologist who rated the positive and negative symptoms on the Positive and Negative Syndrome Scale (PANSS). Hope and depression were measured using the self-assessment scales Integrative Hope Scale (IHS) and the Center for Epidemiologic Studies Depression Scale (CES-D).

No statistically significant correlation was found between hope and positive symptoms (r = .071, p = .414). Hope and negative symptoms, however, showed a statistically significant negative correlation (r = -.196, p = .023), as did hope and depression (r = -.255, p = .003). This latter relationship remained significant after controlling for negative symptoms in a partial correlation (r = -.216, p = .013).

While hope appears unrelated to positive symptoms, a significant correlation with negative symptoms and depression was found. These results emphasise the potential importance of hope as a target variable to support recovery in patients with psychosis. However, prospective studies are needed to clarify the causal relationships between hope and symptoms of psychotic disorders.

Motor behavior is altered in schizophrenia. Most patients have less physical activity than the general population. We have shown that actigraphic means of motor activity are influenced by negative syndrome scores, schizophrenia subtype and antipsychotic use.

The neural correlates of reduced motor activity in schizophrenia are widely unknown.

To elucidate possible mechanisms, we correlated objective motor activity with measures of grey and white matter structure, as well as resting state perfusion.

We report the results of four studies from our lab. Schizophrenia patients and controls were scanned using a 3 T MRI scanner assessing resting perfusion (arterial spin labeling), structure and diffusion tensor imaging. In all participants, continuous actigraphy was performed for 24 hours in order to measure motor activity.

Resting perfusion in schizophrenia correlated with activity in bilateral prefrontal areas in patients, while in controls correlations were exclusively in the ventral anterior nucleus of the thalamus. In both groups, white matter integritiy in various frontal regions and the corticospinal tract correlated with motor activity. The group difference, however, was the inverse correlation of integrity and activity underneath the right supplemental motor area in patients. Grey matter volume did not correlate with activity in controls, but it did correlate in the posterior cingulate in patients.

Interindividual differences in brain structure and perfusion are associated with varying motor activity. Multiple imaging approaches point to altered cortical motor control in schizophrenia.

Cognitive dysfunction was thought to be one of the core features of schizophrenia. And the executive function of the patients was paid more attention by more and more researchers and clinicians.

To investigate the executive function and the learning ability of the patients with first-episode schizophrenia, and their relationships with psychiatric symptoms.

Fifty cases of first-episode schizophrenia patients and fifty age- and gender-matched healthy controls were tested by a computerized version of Tower of London (TOL) test. The scores of the Positive and Negative Syndrome Scale(PANSS) in the group of schizophrenia patients were over 60.

The numbers of the correct answer [x1 :(14.62 ± 4.12), x2: (14.80 ± 4.70)] during the first session and the second session of the TOL test of the patients group were significantly lower than that of the control group [x1: (17.48 ± 3.79), x2:(18.68 ± 3.19)], and the reaction times [t1: (9.27 ± 4.37) seconds, t2: (9.51 ± 5.58) seconds] of the two sessions of TOL were longer than the control group [t1: (7.28 ± 2.04) seconds, t2: (6.67 ± 1.51) seconds], P < 0.01. For the control group, x2 was significantly greater than x1, and t2 shorter than t1 (P < 0.01), while for the patients group, there was no difference between the performances of the first session and the second session. The scores of TOL in the schizophrenia patients were correlated with the negative symptom score of PANSS (P < 0.05) and were not correlated with the scores of other subscales of PANSS (P > 0.05).

The executive function and the learning ability of schizophrenia are impaired and the cognitive dysfunction is correlated with negative symptoms.