Adaptations to water stress and pastoralism in the Turkana of northwest Kenya.

The Turkana people inhabit arid regions of east Africa-where temperatures are high and water is scarce-and they practice subsistence pastoralism, such that their diet is primarily composed of animal products. Working with Turkana communities, we sequenced 367 genomes and identified 8 regions putatively involved in adaptation to water stress and pastoralism. One of these regions includes a putative enhancer for STC1-a kidney-expressed gene involved in the response to dehydration and the metabolism of purine-rich foods such as red meat. We show that STC1 is induced by antidiuretic hormone in humans, is associated with urea levels in the Turkana themselves, and is under strong selection in this population (s∼0.041). This work highlights that partnerships with subsistence-level groups can lead to new models of human physiology with biomedical relevance.

Usefulness of interim analyses in portending study results in antipsychotic and antidepressant trials.

It is unknown whether interim analyses portend final study results. Fatigue, pressure to complete trials and recruitment differences may mitigate against this. We examined the similarity of efficacy results of the first and second half of recruited patients to complete trials and explore possible intervening variables. Using data from the NewMeds repository of patient level data from placebo-controlled randomized trials of antipsychotics (AP) (22 studies, n=7056) and antidepressants (AD) (39 studies, n=12,217) we compared treatment effect size (placebo vs. active treatment) of the first and second half of patients recruited in completed trials. We found that in AP studies median difference in treatment effect between cohorts was -0.03, indicating that overall first and second cohorts yielded similar results. In AD studies, median difference between cohorts was 0.04, indicating that overall the second cohort had slightly larger active-placebo-difference. Overall, on average there were minimal differences in effect size between the first and the second cohorts, and in 30 of 39 trials interim results were a good estimate of the results on the 2nd cohort. In AD trials first and second cohort results were more similar when the proportion of patients per study centre and recruitment time of the two cohorts was similar. Results suggest that interim analyses in AD and AP studies may reliably serve to estimate ultimate effects and, at least in AD trials, are more accurate when the same sites are used to a similar extent and recruitment time of the two consequent cohorts is similar.

A rare WNT1 missense variant overrepresented in ASD leads to increased Wnt signal pathway activation.

Wnt signaling, which encompasses multiple biochemical pathways that regulate neural development downstream of extracellular Wnt glycoprotein ligands, has been suggested to contribute to major psychiatric disorders including autism spectrum disorders (ASD). We used next-generation sequencing and Sequenom genotyping technologies to resequence 10 Wnt signaling pathway genes in 198 ASD patients and 240 matched controls. Results for single-nucleotide polymorphisms (SNPs) of interest were confirmed in a second set of 91 ASD and 144 control samples. We found a significantly increased burden of extremely rare missense variants predicted to be deleterious by PolyPhen-2, distributed across seven genes in the ASD sample (3.5% in ASD vs 0.8% in controls; Fisher's exact test, odds ratio (OR)=4.37, P=0.04). We also found a missense variant in WNT1 (S88R) that was overrepresented in the ASD sample (8 A/T in 267 ASD (minor allele frequency (MAF)=1.69%) vs 1 A/T in 377 controls (MAF=0.13%), OR=13.0, Fisher's exact test, P=0.0048; OR=8.2 and P=0.053 after correction for population stratification). Functional analysis revealed that WNT1-S88R is more active than wild-type WNT1 in assays for the Wnt/ß-catenin signaling pathway. Our findings of a higher burden in ASD of rare missense variants distributed across 7 of 10 Wnt signaling pathway genes tested, and of a functional variant at the WNT1 locus associated with ASD, support that dysfunction of this pathway contributes to ASD susceptibility. Given recent findings of common molecular mechanisms in ASD, schizophrenia and affective disorders, these loci merit scrutiny in other psychiatric conditions as well.

Metabolomics in drug target discovery.

Most diseases result in metabolic changes. In many cases, these changes play a causative role in disease progression. By identifying pathological metabolic changes, metabolomics can point to potential new sites for therapeutic intervention. Particularly promising enzymatic targets are those that carry increased flux in the disease state. Definitive assessment of flux requires the use of isotope tracers. Here we present techniques for finding new drug targets using metabolomics and isotope tracers. The utility of these methods is exemplified in the study of three different viral pathogens. For influenza A and herpes simplex virus, metabolomic analysis of infected versus mock-infected cells revealed dramatic concentration changes around the current antiviral target enzymes. Similar analysis of human-cytomegalovirus-infected cells, however, found the greatest changes in a region of metabolism unrelated to the current antiviral target. Instead, it pointed to the tricarboxylic acid (TCA) cycle and its efflux to feed fatty acid biosynthesis as a potential preferred target. Isotope tracer studies revealed that cytomegalovirus greatly increases flux through the key fatty acid metabolic enzyme acetyl-coenzyme A carboxylase. Inhibition of this enzyme blocks human cytomegalovirus replication. Examples where metabolomics has contributed to identification of anticancer drug targets are also discussed. Eventual proof of the value of metabolomics as a drug target discovery strategy will be successful clinical development of therapeutics hitting these new targets.

Myocardial gene delivery using molecular cardiac surgery with recombinant adeno-associated virus vectors in vivo.

We use a novel technique that allows for closed recirculation of vector genomes in the cardiac circulation using cardiopulmonary bypass, referred to here as molecular cardiac surgery with recirculating delivery (MCARD). We demonstrate that this platform technology is highly efficient in isolating the heart from the systemic circulation in vivo. Using MCARD, we compare the relative efficacy of single-stranded (ss) adeno-associated virus (AAV)6, ssAAV9 and self-complimentary (sc)AAV6-encoding enhanced green fluorescent protein, driven by the constitutive cytomegalovirus promoter to transduce the ovine myocardium in situ. MCARD allows for the unprecedented delivery of up to 48 green fluorescent protein genome copies per cell globally in the sheep left ventricular (LV) myocardium. We demonstrate that scAAV6-mediated MCARD delivery results in global, cardiac-specific LV gene expression in the ovine heart and provides for considerably more robust and cardiac-specific gene delivery than other available delivery techniques such as intramuscular injection or intracoronary injection; thus, representing a potential, clinically translatable platform for heart failure gene therapy.

Cyclic-di-GMP-mediated repression of swarming motility by Pseudomonas aeruginosa: the pilY1 gene and its impact on surface-associated behaviors.

The intracellular signaling molecule cyclic-di-GMP (c-di-GMP) has been shown to influence surface-associated behaviors of Pseudomonas aeruginosa, including biofilm formation and swarming motility. Previously, we reported a role for the bifA gene in the inverse regulation of biofilm formation and swarming motility. The bifA gene encodes a c-di-GMP-degrading phosphodiesterase (PDE), and the Delta bifA mutant exhibits increased cellular pools of c-di-GMP, forms hyperbiofilms, and is unable to swarm. In this study, we isolated suppressors of the Delta bifA swarming defect. Strains with mutations in the pilY1 gene, but not in the pilin subunit pilA gene, show robust suppression of the swarming defect of the Delta bifA mutant, as well as its hyperbiofilm phenotype. Despite the ability of the pilY1 mutation to suppress all the c-di-GMP-related phenotypes, the global pools of c-di-GMP are not detectably altered in the Delta bifA Delta pilY1 mutant relative to the Delta bifA single mutant. We also show that enhanced expression of the pilY1 gene inhibits swarming motility, and we identify residues in the putative VWA domain of PilY1 that are important for this phenotype. Furthermore, swarming repression by PilY1 specifically requires the diguanylate cyclase (DGC) SadC, and epistasis analysis indicates that PilY1 functions upstream of SadC. Our data indicate that PilY1 participates in multiple surface behaviors of P. aeruginosa, and we propose that PilY1 may act via regulation of SadC DGC activity but independently of altering global c-di-GMP levels.

Trajectories and antecedents of treatment response over time in early-episode psychosis.

BACKGROUND: Little is known about the extent of heterogeneity of symptomatology in treated early-onset psychosis. The current study aims to quantify the extent of heterogeneity in trajectories of treated symptom severity in early-episode psychosis and their antecedents. METHODS: Data were from 491 persons with early-episode psychosis from a clinical trial of haloperidol and risperidone. Positive and Negative Syndrome Scale (PANSS) administrations were used to measure symptom severity trajectories for (a) rapid treatment response scores over 4 weeks and (b) medium-term course over 24 weeks. Baseline antecedents included sex, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis, age of onset, the Premorbid Adjustment Scale, and a cognitive test battery. Symptom severity trajectories were calculated with mixed mode latent class regression modeling from which groups were derived. RESULTS: Five groups based on PANSS scores over time were identified. Over 4 weeks, 3 groups with varied baseline PANSS scores (54-105) did not surpass 30% PANSS improvement. Another group improved and then was stable (n = 76,15.3%), and another showed marked improvement (n = 94,18.9%). Logistic regression showed that membership in the best response trajectory was associated with not having a diagnosis of schizophrenia, good premorbid functioning, and higher cognitive functioning, whereas membership in the poor response trajectory was associated with earlier age of onset and poorer cognitive functioning. CONCLUSION: Amelioration generally characterizes treated symptom severity. Age of onset, diagnosis, cognitive functioning, and premorbid functioning have prognostic value in predicting treatment response trajectories.

Pathways to functional outcomes in schizophrenia: the role of premorbid functioning, negative symptoms and intelligence.

BACKGROUND: Social and intellectual premorbid functioning are generally estimated retrospectively, and related to clinical or hospitalization outcomes in schizophrenia. Yet the relationship between premorbid functioning assessed prior to psychiatric hospitalization and postmorbid functional outcomes has not been examined. OBJECTIVES: To test competing models of the relationship between (a) functional outcomes with (b) premorbid functioning assessed on nationally administered tests prior to psychiatric hospitalization, postmorbid intellectual functioning and symptomatology using a historical prospective design. METHODS: Ninety one inpatient and outpatient males with schizophrenia or schizoaffective disorder, aged 19 to 35, were examined using the Positive and Negative Syndrome Scale, the WAIS-III and Strauss and Carpenter social and occupational functional outcome scale. Premorbid intelligence and social functioning data were obtained from national standardized tests administered during high school prior to first hospitalization for schizophrenia. RESULTS: Path modeling showed that premorbid intelligence and behavioral functioning directly predicted postmorbid IQ and negative symptoms, and indirectly predicted postmorbid social and occupational functioning via negative symptoms. Item level analysis indicated that better social and occupational outcomes occurred in a group with few negative symptoms. CONCLUSIONS: Premorbid functioning, postmorbid IQ and negative symptoms are related, yet the relationship between premorbid functioning and postmorbid functional outcomes appears to be mediated by postmorbid negative symptoms.

Validity of the premorbid adjustment scale.

BACKGROUND: The aim of the current study was to test the predictive and concurrent validity of the Premorbid Adjustment Scale (PAS) by comparing it with another similar but more elaborate retrospective measure and with data collected during late adolescence. METHODS: We compared PAS late adolescence scores (age 16-18 years) of 91 males with schizophrenia or schizoaffective disorder with data on behavior collected in adolescence, before the first psychotic episode as part of standardized Draft Board screening, and with the same measure readministered during adulthood and modified to collect the same data again retrospectively. RESULTS: The correlation of the PAS social withdrawal and social relations items with the social behavior scale of the Draft Board were .76 and .80, respectively, for the concurrent ratings and .52 and .53, respectively, for the data collected at age 17 years. The correlation of the PAS school achievements and school adjustment items with the functioning in structured environments scale of the Draft Board were .71 and .72, respectively, for the concurrent ratings and .43 and .47, respectively, for the data collected at age 17 years. CONCLUSIONS: Our results support the predictive and concurrent validity of the PAS and the validity of self-reported data on premorbid functioning in persons with schizophrenia.

Accuracy of self-reported premorbid functioning in schizophrenia.

BACKGROUND: Information on premorbid functioning is often based on patients recalling their past. Premorbid functioning is relevant as it is associated with treatment response and other outcomes. The extent to which memory impairments of persons with schizophrenia may bias such reporting has not been investigated. The purpose of the current study was to assess the extent to which persons with schizophrenia might exhibit biased reporting relative to controls. METHODS: Seventy males with schizophrenia or schizoaffective disorder and 51 males with no psychiatric symptoms participated in the study. Contemporaneous and retrospective reports from a behavioral functioning assessment conducted as part of the Israeli Draft Board were compared. This assessment routinely administered to all 17 years old males in the country assesses social functioning, individual autonomy, organizational ability, physical activity and functioning in structured environments. We compared the groups on the Draft Board behavioral measures at age 17 and at re-assessment. We also examined the relationship between symptom severity, neuropsychological performance and differences between age 17 and current behavioral assessment scores. RESULTS: In a repeated measures MANCOVA of the five measures there was no overall significant difference in accuracy of reporting between persons with schizophrenia and those without. Both groups showed a slight tendency to glorify their past. Consistency of reporting was not significantly correlated with neuropsychological performance or levels of psychotic symptoms. CONCLUSIONS: We found that when reporting on personal and social functioning during teen age years persons with schizophrenia report with the same level of consistency as persons without schizophrenia. This suggests that self-report of premorbid functioning of persons with schizophrenia can be trusted as being reasonably accurate.

Cognitive performance of male adolescents is lower than controls across psychiatric disorders: a population-based study.

OBJECTIVE: Psychiatric patients, as well as humans or experimental animals with brain lesions, often concurrently manifest behavioral deviations and subtle cognitive impairments. This study tested the hypothesis that as a group, adolescents suffering from psychiatric disorders score worse on cognitive tests compared with controls. METHOD: As part of the assessment for eligibility to serve in the military, the entire, unselected population of 16-17-year old male Israelis undergo cognitive testing and screening for psychopathology by the Draft Board. We retrieved the cognitive test scores of 19 075 adolescents who were assigned any psychiatric diagnosis, and compared them with the scores of 243 507 adolescents without psychiatric diagnoses. RESULTS: Mean test scores of cases were significantly poorer then controls for all diagnostic groups, except for eating disorders. Effect sizes ranged from 0.3 to 1.6. CONCLUSION: As group, adolescent males with psychiatric disorders manifest at least subtle impairments in cognitive functioning.

Rheumatoid arthritis (RA)-associated HLA-DR alleles form less stable complexes with class II-associated invariant chain peptide than non-RA-associated HLA-DR alleles.

Certain HLA-DR alleles confer strong susceptibility to the autoimmune disease rheumatoid arthritis (RA). We compared RA-associated alleles, HLA-DR*0401, HLA-DR*0404, and HLA-DR*0405, with closely related, non-RA-associated alleles, HLA-DR*0402 and HLA-DR*0403, to determine whether they differ in their interactions with the class II chaperone, invariant chain (Ii). Ii binds to class II molecules in the endoplasmic reticulum, inhibits binding of other ligands, and directs class II-Ii complexes to endosomes, where Ii is degraded to class II-associated Ii peptide (CLIP). To evaluate the interaction of Ii and CLIP with these DR4 alleles, we introduced HLA-DR*0401, *0402, and *0404 alleles into a human B cell line that lacked endogenous HLA-DR or HLA-DM molecules. In a similar experiment, we introduced HLA-DR*0403 and *0405 into an HLA-DM-expressing B cell line, 8.1.6, and its DM-negative derivative, 9.5.3. Surface abundance of DR4-CLIP peptide complexes and their susceptibility to SDS-induced denaturation suggested that the different DR4-CLIP complexes had different stabilities. Pulse-chase experiments showed CLIP dissociated more rapidly from RA-associated DR molecules in B cell lines. In vitro assays using soluble rDR4 molecules showed that DR-CLIP complexes of DR*0401 and DR*0404 were less stable than complexes of DR*0402. Using CLIP peptide variants, we mapped the reduced CLIP interaction of RA-associated alleles to the shared epitope region. The reduced interaction of RA-associated HLA-DR4 molecules with CLIP may contribute to the pathophysiology of autoimmunity in RA.

Association between nonpsychotic psychiatric diagnoses in adolescent males and subsequent onset of schizophrenia.

BACKGROUND: Nonpsychotic psychiatric symptoms may occasionally herald the later development of schizophrenia. This study followed a population-based cohort of adolescents with nonpsychotic, non-major affective psychiatric disorders to ascertain future hospitalization for schizophrenia. METHODS: Results of the medical and mental health assessments on 124 24416- to 17-year-old males screened by the Israeli draft board were cross-linked with the National Psychiatric Hospitalization case registry, which contains data on all psychiatric hospitalizations in the country, during a 4- to 8-year-long follow-up through age 25 years. In the cohort, 9365 adolescents were assigned a nonpsychotic, non-major affective diagnosis by the draft board. RESULTS: After excluding 167 adolescents who were hospitalized before or up to 1 year after the draft board assessment, 1.03% of the adolescents assigned a nonpsychotic, non-major affective psychiatric diagnosis, compared with only 0.23% of the adolescents without any psychiatric diagnosis, were later hospitalized for schizophrenia. Of the patients with schizophrenia, 26.8%, compared with only 7.4% in the general population, had been assigned a nonpsychotic, non-major affective psychiatric diagnosis in adolescence (overall odds ratio [OR], 4.5; 95% confidence interval [CI], 3.6-5.6), ranging from OR, 21.5 (95% CI, 12.6-36.6) for schizophrenia spectrum personality disorders to OR, 3.6 (95% CI, 2.1-6.2) for neurosis. CONCLUSION: These results reflect the relatively common finding of impaired functioning in patients later hospitalized for schizophrenia and the relatively low power of these disorders in predicting schizophrenia.

Rapid onset of therapeutic effect of risperidone versus haloperidol in a double-blind randomized trial.

BACKGROUND: Speed of onset of therapeutic effect is an important dimension of drugs employed to treat psychosis and schizophrenia. Faster onset is desirable to reduce the anguish caused by delusions and hallucinations and to protect patients and others from the consequences of poor judgment associated with psychotic exacerbation. Although sufficient studies have demonstrated that novel antipsychotics have advantages over clinically employed doses of classic drugs in terms of tolerability and aspects of efficacy, less is known about differences in speed of onset of therapeutic effect. This report consists of a post hoc subanalysis of data from a large double-blind, randomized pivotal trial in which we compared onset of therapeutic effect between risperidone and haloperidol. METHOD: During an 8-week period, 227 patients with DSM-III chronic schizophrenia received 4 mg/day of risperidone and 226 patients received 10 mg/day of haloperidol. Symptoms were assessed 6 times (days 0, 7, 14, 28, 42, and 56) using the Positive and Negative Syndrome Scale (PANSS) for schizophrenia and the Clinical Global Impressions-Severity of Illness scale (CGI-S). Data were analyzed using analysis of variance for multiple dependent variables and repeated-measures multivariate analysis of variance. RESULTS: The analyses revealed that patients receiving risperidone improved more rapidly than those receiving haloperidol as measured by PANSS total and CGI-S scores. Differences were most pronounced during the first week of treatment. CONCLUSION: Results suggest that risperidone offers a more rapid response than haloperidol, particularly during the active phase of illness when time to response can be crucial.

Risperidone versus haloperidol in long-term hospitalized chronic patients in a double blind randomized trial: a post hoc analysis.

BACKGROUND: Patients who remain in hospital for an extended time pose a special therapeutic challenge. OBJECTIVES: The goal of this study was to examine whether the acute response of long-term hospitalized schizophrenic patients differs between haloperidol and risperidone based on a post hoc, sub-analysis of data from a large double blind pivotal trial. METHOD: Data on chronic schizophrenic patients who had been hospitalized for at least 60 days (median 351 days) prior to entering this 8-week randomized double blind controlled trial were examined. This included 75 patients treated with 4 mg of risperidone and 69 treated with 10mg of haloperidol. Changes in symptoms were assessed with the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) and the Clinical Global Impression (CGI). Data were analyzed using analysis of variance. RESULTS: The analyses revealed that patients receiving risperidone improved significantly more than those treated with haloperidol. CONCLUSIONS: Results suggest that the most often prescribed dose of risperidone, 4 mg, might be more effective for long-stay chronic schizophrenic patients than haloperidol 10mg.

Elective amniocentesis in low-risk pregnancies: decision making in the era of information and uncertainty.

OBJECTIVES: Rational choice theory was applied to explain women's use of amniocentesis. Variables included knowledge about prenatal diagnostics, attitudes, and emotional preferences. METHODS: Using structured instruments at 9 to 14 and at 29 to 34 weeks' gestation, we interviewed 232 Israeli women who had low-risk pregnancies. RESULTS: Women who had elective amniocentesis (n = 39) were more knowledgeable about prenatal diagnostics, risks of invasive procedures, and probability of fetal abnormality in high maternal age; had fewer children; and had less favorable attitudes toward parenthood than those who had medically indicated amniocentesis (n = 57) and those who did not have amniocentesis (n = 136). CONCLUSIONS: The use and possible overuse of amniocentesis were associated with having more information about prenatal diagnostics and definite emotional preferences.

Post-traumatic stress disorder in primary-care settings: prevalence and physicians' detection.

BACKGROUND: Little is known about the prevalence of PTSD in primary-care settings and regarding the ability of primary-care physicians to detect PTSD. The current study examines prevalence of PTSD in a national sample of primary-care attenders and primary-care physicians' detection of PTSD and general psychological distress in PTSD patients. METHODS: Data are from a national study of 2975 primary-care attenders in Israel. Demographic data, responses to the GHQ-28, PTSD Inventory and physicians' diagnoses were examined. RESULTS: Twenty-three per cent of all patients who attended clinics (N = 684) reported traumatic events, 39% of whom (males 37%, females 40%) met criteria for PTSD on the PTSD Inventory. Eighty per cent of the males and 92% of the females with PTSD were distressed according to the GHQ. According to physicians, 37% of persons who reported trauma (40% of the women, 32% of the men) suffered from psychological distress. Only 2% of patients meeting PTSD criteria on the self-report measure were given a diagnoses of PTSD by physicians. CONCLUSIONS: Many primary-care patients suffer from PTSD, which is usually accompanied by major psychological distress. Attention by primary-care physicians to a history of trauma could improve physicians' detection of this disabling disorder.

Rehospitalization rates of chronically ill schizophrenic patients discharged on a regimen of risperidone, olanzapine, or conventional antipsychotics.

OBJECTIVE: The purpose of this study was to compare the rehospitalization rates of patients discharged from the hospital while being treated with risperidone, olanzapine, or conventional antipsychotics. METHOD: By using Israel's National Psychiatric Hospitalization Case Registry, rehospitalization status was monitored for all patients with schizophrenia who were discharged from any inpatient psychiatric facility in Israel while taking risperidone (N=268) or olanzapine (N=313) between Jan. 1, 1998, and Dec. 31, 1998, and a group of patients discharged during that time who were treated with conventional antipsychotics (N=458). Time to readmission over the course of 2 years was measured by the product-limit (Kaplan-Meier) formula. RESULTS: The readmission rate for patients discharged while taking conventional antipsychotics was higher than the rates for patients treated with either risperidone or olanzapine. At 24 months, 67% of the risperidone-treated patients and 69% of the olanzapine-treated patients remained in the community, as compared to 52% of the patients treated with conventional antipsychotics. CONCLUSIONS: This study suggests that the rehospitalization rates of patients taking the novel antipsychotics risperidone and olanzapine are not different from each other and are considerably lower than the rate for patients treated with conventional antipsychotics. The results confirm findings of previous studies suggesting that the levels of overall effectiveness of risperidone and olanzapine are not very different and offers evidence that these drugs are more effective in preventing rehospitalization than conventional antipsychotic drugs.

Changes in insurance coverage and extent of care during the two years after first hospitalization for a psychotic disorder.

OBJECTIVE: This study examined changes in insurance coverage during the 24 months after first admission for a psychotic disorder and the relationship of insurance type to the extent of care. METHODS: The sample consisted of 443 persons who were enrolled in the Suffolk County (New York) Mental Health Project. Information about coverage-private insurance, Medicaid-Medicare, or no insurance-was obtained from hospital records and interviews. The insurance status groups were compared to examine differences in the percentage of days they received inpatient, outpatient, and day hospital care. RESULTS AND CONCLUSIONS: The proportion of persons with no insurance decreased from baseline to 24 months, from 42 percent to 21 percent. The proportion of persons with private insurance remained similar, 42 and 37 percent. The proportion of those with Medicaid-Medicare increased from 15 percent to 42 percent. Of those with Medicaid-Medicare at baseline (67 persons), 88 percent had such coverage 24 months later. Of those with private insurance at baseline (188 persons), 73 percent had the same coverage 24 months later. Of those with no insurance at baseline (188 persons), 35 percent had no insurance at 24 months, 54 percent had Medicaid-Medicare, and 11 percent had private insurance. Over the 24 months, the Medicaid-Medicare group had the most days of care, the private insurance group had the least inpatient care, and those with no insurance were least likely to receive outpatient care. There was a linear relationship between receiving more outpatient care and spending less time in the hospital and the day hospital.