HEV-Capsid Protein Interacts With Cytochrome P4502C8 and Retinol-Binding Protein 4

Background

Hepatitis E virus (HEV) is a major causative agent of acute clinical hepatitis in adults throughout much of Asia, the Middle East, and Africa. The lack of an efficient cell culture system for HEV has greatly limited our understanding of the mechanisms of infection, replication, and pathogenicity of this virus. The yeast two-hybridization system is considered to be an efficient method for determining protein-protein interactions and screening interactive proteins associated with host cells.

Objectives

In order to identify the host-cell proteins interacting with the HEV-capsid proteins, a fragment of the HEV-capsid protein p239 (amino acids 368–606) was used as bait; human liver cDNA library was used as a source of host-cell proteins, and the screening was performed using the CytoTrap yeast two-hybrid system.

Materials and Methods

The CytoTrap yeast two-hybrid system, which is also called Sos Recruitment System (SRS), was used to analyze the interaction of the p239 fragment with host-cell proteins.

Results

We isolated 2 proteins, cytochrome P4502C8 (CYP4502C8) and retinol-binding protein 4 (RBP4) after 2 rounds of screening. Co-immunoprecipitation assays showed that both the proteins could bind in vitro to the HEV virion in HepG2 cells.

Conclusions

CYP4502C8 and RBP4 screened from liver cDNA library using the CytoTrap yeast two-hybrid system interact with HEV capsid in vitro.     

Hepatitis E Virus Seroprevalence Among Blood Donors in Bushehr,South of Iran

Background:

Although so far several studies have determined the hepatitis E virus (HEV) prevalence in some parts of Iran, no data exists regarding the HEV seroprevalence in Bushehr province as the southernmost point in Iran yet.

Objectives:

The aim of this study was to evaluate the seroprevalence of anti-HEV IgG among the blood donors in Bushehr.

Patients and Methods:

A total of 628 blood donor samples were collected from September to October 2013, after obtaining informed written consents, and analyzed for the presence of anti-HEV IgG using commercial HEV enzyme-linked immunosorbent assay (ELISA) kit. All the samples were tested by two ELISA kits and evaluated for liver function test.

Results:

Overall, 105 (16.7%) blood samples were positive for HEV-specific-IgG antibodies, while 523 (83.8%) were negative. The presence of anti-HEV IgG was not associated with gender; however, it was correlated with age. It was indicated that the anti-HEV prevalence increases by age and there was a significant difference between the age groups regarding HEV seropositivity.

Conclusions:

High HEV seroprevalence (16.7%) was observed among the blood donors in Bushehr province. It appears that exposure to HEV increases with age; although, more people should be examined.     

Persistent Hepatitis E Virus Genotype 4 Infection in a Child With Acute Lymphoblastic Leukemia

Introduction:

In general, the hepatitis E virus (HEV) causes acute, self-limiting hepatitis. Prolonged and chronic infections caused by HEV genotype 3 have been found in some immunosuppressed patients in developed countries.

Case Presentation:

Here we report a Chinese boy with acute lymphoblastic leukemia, who developed hepatitis E during a period of intensive chemotherapy. Twenty months after the initial infection, HEV viremia was reappeared in the patient, with detectable anti-HEV IgM and IgG and modestly elevated serum transaminases. Sequence analysis of the viral RNAs revealed the reactivation of the HEV genotype 4d strain, indicating viral persistence in the patient.

Conclusions:

To our knowledge, this is the first chronic case confirmed by the prolonged presence of HEV RNA in china. It is also the first reported persistent hepatitis E infection caused by HEV genotype 4.     

Seroepidemiology of Hepatitis E Virus Infection in General Population in Rural Durango,Mexico

Background:

The seroepidemiology of hepatitis E virus (HEV) infection in rural areas in Mexico has been poorly studied.

Objectives:

The aim of the study was to determine the seroprevalence and correlates of anti-HEV IgG antibodies in adults in rural areas in Durango, Mexico.

Materials and Methods:

We performed a cross-sectional study to determine the frequency of anti-HEV IgG antibodies in 273 adults living in rural Durango, Mexico using an enzyme-linked immunoassay. In addition, we searched for an association of HEV exposure with the socio-demographic and behavioral characteristics of the subjects studied.

Results:

One hundred (36.6%) of the 273 rural adults (mean age: 39.85 ± 17.15 years) had anti-HEV IgG antibodies. Multivariate analysis of socio-demographic and behavioral characteristics of the participants showed that HEV exposure was associated with increasing age (OR = 1.04; 95% CI: 1.04-1.05; P < 0.001), consumption of untreated water (OR = 1.92; 95% CI: 1.06-3.46; P = 0.03), and availability of water at home (OR = 1.87; 95% CI: 1.07-3.27; P = 0.02). In contrast, other socio-demographic and behavioral characteristics including educational level, occupation, socio-economic status, foreign travel, consumption of unwashed raw fruits, consumption of raw or undercooked meat and raising animals did not show associations with HEV exposure.

Conclusions:

The seroprevalence of HEV infection found in rural Durango is higher than those reported in other Mexican populations. Consumption of untreated water is an important factor for HEV exposure in rural areas in Durango. The correlates of HEV seropositivity found in the present study can be used for an optimal planning of preventive measures against HEV infection.     

LRRFIP1 Inhibits Hepatitis C Virus Replication by Inducing Type I Interferon in Hepatocytes

Background:

Hepatitis C virus infection is one of the leading causes of end stage liver diseases. The innate immune response slows down viral replication by activating cytokines such as type I interferon (IFN-α/β), which trigger the synthesis of antiviral proteins and modulate the adaptive immune system. Recently, leucine-rich repeat (in Flightless I) interacting protein-1 (LRRFIP1) was reported contributing to the production of interferon-β in macrophages.

Objectives:

The aim of this study was to assess the role of LRRFIP1 in induction of IFN-β and inhibition of HCV infection in hepatocytes.

Materials and Methods:

Induction of IFN-β by LRRFIP1 in Huh7 and Huh7.5.1 was determined by real-time PCR and western blotting in vitro. Inhibition of HCV replication by LRRFIP1 overexpression in hepatocytes was assessed.

Results:

LRRFIP1 increased the expression of IFN-β in hepatocytes with or without HCV infection. Induction of IFN-β by LRRFIP1 was enhanced with the presence of hepatitis C virus. Overexpression of LRRFIP1 in hepatocytes inhibited HCV replication. However, HCV infection did not regulate intracellular expression of LRRFIP1.

Conclusions:

LRRFIP1 and its mediated production of type I interferon play a role in controlling HCV infection. The findings of this study provide new target for HCV treatment and contribute to development of anti-HCV drugs.     

Anti-Hepatitis E Antibody in Hemodialysis Patients in Isfahan,Iran: Prevalence and Risk Factors

Background:

Many studies have been performed regarding the prevalence of hepatitis E in the general population, but there is controversial evidence for an increased risk of the infection in patients on maintenance hemodialysis (HD).

Objectives:

The primary end point of the present study was to determine if the prevalence of anti-hepatitis E virus IgG (anti-HEV IgG) is higher in patients on maintenance HD than in the normal population in Isfahan.

Patients and Methods:

In a case-control study performed in Isfahan in June 2012, we compared the seroprevalence of HEV among 274 patients on maintenance HD and 275 otherwise healthy individuals. The patients were recruited from 3 HD centers in Isfahan. Anti-HEV IgG was detected using a Dia Pro Diagnostic HEV enzyme immunoassay (ELISA) kit. Demographic and clinical data (sex, age, blood transfusion history, HD duration, age at HD initiation, and evidence of hepatitis B and hepatitis C infections) were obtained from the medical records of the HD patients.

Results:

Anti-HEV IgG was detected in 27 (9.9%) controls and 78 (28.3%) patients, with the difference being statistically significant (P < 0.05). Furthermore, there was a significant association between positive anti-HEV antibody, HD duration, and blood transfusion history in the HD patients.

Conclusions:

Considering the results, it seems necessary to conduct prospective studies in order to identify factors responsible for the high seroprevalence of HEV in Isfahan HD units.     

Factor VIII and von Willebrand factor are ligands for the carbohydrate-receptor Siglec-5

Background

Factor VIII (FVIII) and von Willebrand factor (VWF) circulate in plasma in a tight non-covalent complex, being critical to hemostasis. Although structurally unrelated, both share the presence of sialylated glycan-structures, making them potential ligands for sialic-acid-binding-immunoglobulin-like-lectins (Siglecs).

Design and Methods

We explored the potential interaction between FVIII/VWF and Siglec-5, a receptor expressed in macrophages using various experimental approaches, including binding experiments with purified proteins and cell-binding studies with Siglec-5 expressing cells. Finally, Siglec-5 was overexpressed in mice via hydrodynamic gene transfer.

Results

In different systems using purified proteins, saturable, dose-dependent and reversible interactions between a soluble Siglec-5 fragment and both hemostatic proteins were found. Sialidase treatment of VWF resulted in a complete lack of Siglec-5 binding. In contrast, sialidase treatment left interactions between FVIII and Siglec-5 unaffected. FVIII and VWF also bound to cellsurface exposed Siglec-5, as was visualized by classical immunostaining as well as by Duolinkproximity ligation assays. Co-localization of FVIII and VWF with early endosomal markers further suggested that binding to Siglec-5 is followed by endocytosis of the proteins. Finally, overexpression of human Siglec-5 in murine hepatocytes following hydrodynamic gene transfer resulted in a significant decrease in plasma levels of FVIII and VWF in these mice.

Conclusions

Our data indicate that FVIII and VWF may act as a ligand for Siglec-5, and that Siglec-5 may contribute to the regulation of plasma levels of the FVIII/VWF complex.Key words: factor VIII, von Willebrand factor, ligand, Siglec-5, interaction     

An Unusual Cause for a Hepatic Flare in a Chronic HBV Carrier

Introduction:

Hepatitis E is an emerging disease in developed countries with an increasing incidence. In developed countries, HEV genotype 3 prevails as a zoonotic disease carried by wild boars or pigs, which usually causes asymptomatic infection.

Case Presentation:

An asymptomatic HBsAg carrier was tested regularly at a German university hospital and showed no signs of chronic hepatitis B (CHB) activity. At a routine visit, elevated aminotransferases were detected while HBV DNA remained low and the patient was clinically asymptomatic. The laboratory signs of acute hepatitis resolved spontaneously. When aminotransferases returned to normal limits, the patient showed a flare of HBV-replication, which resolved spontaneously. In follow-up, further investigations revealed a resolved hepatitis E (HEV) superinfection causing an acute hepatitis before the HBV flare. No potential risk factors for HEV infection were identified.

Conclusions:

Elevated aminotransferases in CHB patients are most commonly caused by exacerbation of CHB. Nevertheless, when HBV DNA is not elevated, other reasons should be excluded. Amongst others, superinfection with another hepatotropic virus can be the reason for decompensation of chronic hepatitis B. This case report describes an asymptomatic HEV superinfection followed by a flare in HBV replication in an HBsAg carrier without signs of HBV replication for eight years. In CHB carriers with signs of acute hepatitis, rare causes should be considered as well. HEV should be a part of routine laboratory evaluation for hepatitis flares given the rising number of infections.     

Acute hepatitis E in India appears to be caused exclusively by genotype 1 hepatitis E virus

Background

Hepatitis E is caused by infection with hepatitis E virus (HEV), which has four well-known genotypes. Genotypes 1 and 2 HEV have been reported from human cases in areas where the disease is highly endemic. By contrast, genotypes 3 and 4 HEV, which primarily infect several animal species worldwide, have been reported mainly from sporadic human cases in non-endemic areas such as Japan and high-income countries of Europe and North America. To determine whether genotype 3/4 HEV cause sporadic disease in India, a disease-endemic area, we determined HEV genotype in a group of patients with such disease.

Methods

A part of the HEV open reading frame (ORF) 1 was amplified and sequenced from sera of 74 patients with sporadic acute viral hepatitis E from four cities in India. The sequences were compared with prototype sequences for various HEV genotypes and subgenotypes and analyzed using phylogenetic tools to determine the genotype of the isolates. For 12 specimens, a part of HEV ORF2 was also similarly analyzed.

Results

Partial ORF1 sequences of all the 74 isolates belonged to genotype 1 HEV, with 88.2% to 100% nucleotide identity with the prototype genotype 1 isolates. Partial ORF2 sequences for all the 12 isolates also belonged to genotype 1 HEV. On phylogenetic analysis, 71 isolates clustered with prototype genotype 1a HEV; the remaining three isolates were located between subgenotypes 1a and 1c but were closer to the former.

Conclusion

Human sporadic acute hepatitis E in India is caused almost exclusively by genotype 1 HEV.

     

Hepatitis C Virus Capsid Protein and Intracellular Lipids Interplay and its Association With Hepatic Steatosis

Background:

Hepatitis C Virus (HCV) is a major causative agent for chronic liver disease worldwide. Hepatic steatosis is a frequent histological feature in patients with chronic HCV. Both host and viral factors are involved in steatosis development. It results from uncontrolled growth of cytoplasmic lipid droplets (LDs) in hepatocytes. LDs are intracellular organelles playing key role in the HCV life cycle. HCV core protein localizes at the LD surface and this localization is crucial for virion production.

Objectives:

We explored in vitro interplay of core and LDs to investigate the role of core in steatosis.

Materials and Methods:

Core expression vectors were transfected in Huh-7 cells. The effect of core protein on LDs content and distribution in the cells was monitored by confocal microscopy. Cells were treated with oleic acid to analyze the effect of increased intracellular LDs on core expression. Core protein expression was monitored by western blot analysis.

Results:

Core expression altered the intracellular lipid metabolism, which resulted in a change in LDs morphology. Core LDs interaction was required for this effect since the mutation of two prolines (P138A, P143A), which impair LDs localization, had no impact on LDs morphology. Conversely, oleic acid induced intracellular LD content resulted in increased core expression.

Conclusions:

Core-LDs interaction may be an underlying molecular mechanism to induce liver steatosis in patients with HCV infection. This interaction is also crucial for efficient viral replication and persistence in infected cells. Steatosis can also interfere with efficient standard interferon therapy treatment. Management of steatosis should be considered along with standard care for achieving higher sustained virological response (SVR) in patients receiving interferon regimen.     

Population Movement and Virus Spreading: HEV Spreading in a Pilgrimage City,Mashhad in Northeast Iran; an Example

Background

Hepatitis E Virus (HEV) infection is a significant public health concern and responsible for large outbreaks of acute hepatitis in poor sanitary and living conditions.

Objectives

To investigate the impact of population movements on virus spreading, a large-scale population-based survey was performed in a pilgrimage- tourism area, the great Mashhad, capital city of Khorasan province.

Patients and Methods

A cross-sectional study was carried out among 1582 randomly selected individuals from general population of Mashhad, north east of Iran, between May to September 2009. Serum samples were tested for total anti-HEV antibody using a specific enzyme linked immunoassay (ELISA) kit.

Results

The prevalence of HEV infection was 14.2% (225/1582) with a maximum of 25.5 % (14/55) in densely populated areas. The highest prevalence was observed in visitant areas (≥ 20%) near the holly shrine with crowded hotels and inns. The differences between these areas and other districts were statistically significant (P < 0.001). The findings indicated that 13.2% (95/718) of males and 15.0% (130/864) of females were HEV positive; this difference is not significant. Seroprevalence increases with age rising , from 12.8% in subjects less than five years to 28.6% in individuals with more than 65 years old. Although, there were no meaningful differences between HEV seropositivity and socio-economic status, Illiterate individuals were significantly at higher risk for infection than educated persons (P < 0.001).

Conclusions

These findings demonstrated that, high prevalence of HEV is related to populated district, which can reach to the highest rate in hotels and inns close to visitants. Traditional sanitation and water supplying systems are the second important factor for the virus transmission. Therefore, it can be concluded that such areas need efficient surveillance systems to prevent the spreading of infectious diseases.     

Comparison of health and effective functioning in Russia and the United States

Background:

Global aging may increase the societal burden of providing more resources to augment elders’ disabilities. The implications of functional disabilities can vary depending on the society in which they occur.

Objective:

To determine differences in US and Russian elder citizens’ function.

Research design:

Convenience sample of persons 60 years and older were surveyed and evaluated.

Subjects:

One hundred community dwelling residents, half from Galesburg, Illinois and half from Moscow, Russia.

Measurements:

An interviewer administered questionnaire and functional assessment examination.

Results:

The Russian sample was younger than the American sample with a mean age of 67 years versus 78 years, and less likely to be widowed or living alone. Sixty percent of Russians took no medications compared with 14% of Americans, but Russians reported more cardiovascular disease, angina, and hypertension. Forty-four percent of Russians screened as being depressed and only 4% of the Americans. Self-assessed health was good for 77% of Americans and only 6% of Russians. The Medical Outcomes Study SF-36 Health Survey (MOS) eight health concepts showed favorable results for the Americans except for physical functioning, which indicated no difference.

Conclusions:

Marked health and functional differences exist between our samples. Russians had more cardiovascular disease, took less medication, drank and smoked more and were much more likely to be depressed than the US subjects.     

Hepatocyte Isolation From Unused/Rejected Livers for Transplantation: Initial Step Toward Hepatocyte Transplantation,the First Experience From Iran

Background

Hepatocyte transplantation is being used in patients with liver-based metabolic disorders and acute liver failure. Hepatocytes can be isolated from unused/rejected livers under sterile conditions.

Objectives

The quality of the hepatocytes is very important and the main and initial step in hepatocyte transplantation is hepatocyte isolation. In this study we tried to set up the methods of hepatocyte isolation in order to use the high quality cells in acute liver failure or congenital metabolic disorders.

Materials and Methods

In this study, during a year, hepatocytes were isolated from 7 unused/rejected livers among more than 300 harvested livers in Shiraz University of Medical Sciences. The two step collagenase perfusion method was used under GMP (Good manufacturing practice) for hepatocyte isolation.

Results

Highly quality hepatocytes with high viability and low contamination were isolated. The mean viability was 71.8% ± 21.7. In the first 4 cases microbial contamination by Staphylococci, Diphtheroid and Klebsiella was detected, however the last 3 cases were free of any micro organisms. After 5 weeks of cryopreservation in -140°C, the cell viability was still acceptable.

Conclusions

Hepatocyte isolation can be performed as the main and initial step for cell transplantation from unused/rejected liver. It is the first experience in Iran.     

Comparative Proteomics of Sera From HCC Patients With Different Origins

Background:

Hepatocellular carcinoma (HCC), a major fatal cancer worldwide, is induced by different etiological factors in the liver.

Objectives:

To gain insight into serum protein profiling of HCC with different etiologies.

Patients and Methods:

We subjected the sera of HBV-HCC, HCV-HCC, non-B non-C-HCC patients, and healthy volunteers to two-dimensional gel electrophoresis (2-DE) and liquid chromatography tandem mass spectrometry (LC-MS/MS).

Results:

We found 30 differentially expressed protein spots (≥ 1.5 fold P < 0.05) between these two analyses; of them 17 protein spots corresponding to 8 proteins were identified by MS. Transthyretin, leucine rich α-2-glycoprotein, and ficolin 3 were differentially expressed between HBV-related HCC and non-B non-C-HCC sera. Moreover, haptoglobin α-2 isoforms were decreased in HCV-HCC compared to non-B non-CHCC.

Conclusions:

Serum proteome analyses of HCC with different origins showed a differential protein pattern, presumably related to different hepatopathogenesis in liver induced by different agents. Further studies are required to clarify the importance of identified proteins for early diagnosis of HCC with different origins.     

High frequency of enterovirus D68 in children hospitalised with respiratory illness in Norway,autumn 2014

Objectives

An unexpectedly high proportion of children were admitted for severe respiratory infections at the Oslo University Hospital, Ullevål, Norway, during September and October, 2014. In light of the ongoing outbreak of enterovirus-D68 (EV-D68) in North America a real-time RT-PCR for screening of enterovirus and enterovirus D68 was established.

Design

We developed a duplex real-time RT-PCR for rapid screening of enterovirus D68. The method target the 5′ non-translated region (NTR) of the HEV genome at a location generally used for enterovirus detection.

Sample

Nasopharyngeal samples (n = 354), from children <15 years of age, received for respiratory virus analysis in OUH during September 1st and October 31nd, 2014, were tested for enterovirus and screened for enterovirus D68.

Main outcome measures and results

The duplex real-time RT-PCR method was an efficient tool for rapid screening for EV-D68 in respiratory specimens. Enterovirus was detected in 66 (22%) of 303 pediatric nasopharyngeal samples collected from children hospitalised with acute respiratory infection within the two-month period. Out of these, 33 (50%) were EV-D68. EV-D68 was associated with acute flaccid paralysis in one child.

Conclusions

An unexpectedly high proportion of children admitted for severe respiratory infections at the Oslo University Hospital, Ullevål, Norway, were diagnosed with EV- D68 during September 1st and October 31nd, 2014. These results emphasise that greater vigilance is required throughout Europe as enteroviruses are cause of severe respiratory disease.     

Screening for iron overload: Lessons from the HEmochromatosis and IRon Overload Screening (HEIRS) Study

BACKGROUND:

The HEmochromatosis and IRon Overload Screening (HEIRS) Study provided data on a racially, ethnically and geographically diverse cohort of participants in North America screened from primary care populations.

METHODS:

A total of 101,168 participants were screened by testing for HFE C282Y and H63D mutations, and measuring serum ferritin concentration and transferrin saturation. In the present review, lessons from the HEIRS Study are highlighted in the context of the principles of screening for a medical disease as previously outlined by the World Health Organization.

RESULTS:

Genetic testing is well accepted, with minimal risk of discrimination. Transferrin saturation has high biological variability and relatively low sensitivity to detect HFE C282Y homozygotes, which limits its role as a screening test. Symptoms attributable to HFE C282Y homozygosity are no more common in individuals identified by population screening than in control subjects.

CONCLUSIONS:

Generalized population screening in a primary care population as performed in the HEIRS Study is not recommended. There may be a role for focused screening in Caucasian men, with some debate regarding genotyping followed by phenotyping, or phenotyping followed by genotyping.     

Occult Hepatitis C Virus Infection in Patients With Autoimmune Hepatitis

Background:

Occult hepatitis C virus infection (OCI) is recognized by finding hepatitis C virus (HCV) RNA in hepatocytes without detectable anti-HCV antibodies and viral RNA in plasma. Autoimmune hepatitis (AIH) is a chronic and generally progressive disease without exactly-identified etiology.

Objectives:

This study aimed to determine the prevalence of OCI among patients with AIH and to evaluate the tests used to rule out HCV infection in diagnosing AIH.

Patients and Methods:

Between July 2012 to February 2013, 35 Iranian patients with AIH who attended Tehran Hepatitis Center were investigated. For identifying OCI, detection of HCV RNA in both ultracentrifuged serum samples and peripheral blood mononuclear cells (PBMCs) was used. Data analysis was performed using SPSS.

Results:

Six males and 29 females with mean disease duration of 77.1 ± 39.5 month and mean age of 43.62 ± 12.67 years were investigated. All cases were negative for anti-HCV antibody and we could not find any HCV RNA in ultracentrifuged serum samples and PBMCs.

Conclusions:

With our laboratory diagnostic method, it seems that there are no cases of OCI in patients with AIH. However, we recommend further studies with more samples and more precise laboratory method.     

Enhancing Care for Hospitalized Older Adults with Cognitive Impairment: A Randomized Controlled Trial

Background

Approximately 40% of hospitalized older adults have cognitive impairment (CI) and are more prone to hospital-acquired complications. The Institute of Medicine suggests using health information technology to improve the overall safety and quality of the health care system.

Objective

Evaluate the efficacy of a clinical decision support system (CDSS) to improve the quality of care for hospitalized older adults with CI.

Design

A randomized controlled clinical trial.

Setting

A public hospital in Indianapolis.

Population

A total of 998 hospitalized older adults were screened for CI, and 424 patients (225 intervention, 199 control) with CI were enrolled in the trial with a mean age of 74.8, 59% African Americans, and 68% female.

Intervention

A CDSS alerts the physicians of the presence of CI, recommends early referral into a geriatric consult, and suggests discontinuation of the use of Foley catheterization, physical restraints, and anticholinergic drugs.

Measurements

Orders of a geriatric consult and discontinuation orders of Foley catheterization, physical restraints, or anticholinergic drugs.

Results

Using intent-to-treat analyses, there were no differences between the intervention and the control groups in geriatric consult orders (56% vs 49%, P = 0.21); discontinuation orders for Foley catheterization (61.7% vs 64.6%, P = 0.86); physical restraints (4.8% vs 0%, P = 0.86), or anticholinergic drugs (48.9% vs 31.2%, P = 0.11).

Conclusion

A simple screening program for CI followed by a CDSS did not change physician prescribing behaviors or improve the process of care for hospitalized older adults with CI.

Electronic supplementary material

The online version of this article (doi:10.1007/s11606-012-1994-8) contains supplementary material, which is available to authorized users.KEY WORDS: cognitive impairment, clinical trial, decision support, hospitalized elders