Nosocomial SARS-CoV-2 transmission in multi-bedded hospital cubicles over successive pandemic waves: Lower mortality but wider spread with Omicron despite enhanced infection-prevention measures.

BACKGROUND: Increased transmissibility of severe-acute-respiratory-syndrome-coronavirus-2(SARS-CoV-2) variants, such as the Omicron-variant, presents an infection-control challenge. We contrasted nosocomial transmission amongst hospitalized inpatients across successive pandemic waves attributed to the Delta- and Omicron variants, over a 9-month period in which enhanced-infection-prevention-measures were constantly maintained. METHODS: Enhanced-infection-prevention-measures in-place at a large tertiary hospital included universal N95-usage, routine-rostered-testing (RRT) for all inpatient/healthcare-workers (HCWs), rapid-antigen-testing (RAT) for visitors, and outbreak-investigation coupled with enhanced-surveillance (daily-testing) of exposed patients. The study-period lasted from 21st June 2021-21st March 2022. Chi-square test and multivariate-logistic-regression was utilized to identify factors associated with onward transmission and 28d-mortality amongst inpatient cases of hospital-onset COVID-19. RESULTS: During the Delta-wave, hospital-onset cases formed 2.7% (47/1727) of all COVID-19 cases requiring hospitalisation; in contrast, hospital onset-cases formed a greater proportion (17.7%, 265/1483; odds-ratio, OR = 7.78, 95%CI = 5.65-10.70) during the Omicron-wave, despite universal N95-usage and other enhanced infection-prevention measures that remained unchanged. The odds of 28d-mortality were higher during the Delta-wave compared to the Omicron-wave (27.7%, 13/47, vs. 10.6%, 28/265, adjusted-odds-ratio, aOR = 2.78, 95%CI = 1.02-7.69). Onward-transmission occurred in 21.2% (66/312) of hospital-onset cases; being on enhanced-surveillance (daily-testing) was independently associated with lower odds of onward-transmission (aOR = 0.18, 95%CI = 0.09-0.38). Costs amounted to $USD7141 per-hospital-onset COVID-19 case. CONCLUSION: A surge of hospital-onset COVID-19 cases was encountered during the Omicron-wave, despite continuation of enhanced infection-prevention measures; mortality amongst hospital-onset cases was reduced. The Omicron variant poses an infection-control challenge in contrast to Delta; surveillance is important especially in settings where infrastructural limitations make room-sharing unavoidable, despite the high risk of transmission.

Linking sporadic hospital clusters during a community surge of the severe acute respiratory coronavirus virus 2 (SARS-CoV-2) B.1.617.2 delta variant: The utility of whole-genome sequencing.

Sporadic clusters of healthcare-associated coronavirus disease 2019 (COVID-19) occurred despite intense rostered routine surveillance and a highly vaccinated healthcare worker (HCW) population, during a community surge of the severe acute respiratory coronavirus virus 2 (SARS-CoV-2) B.1.617.2 δ (delta) variant. Genomic analysis facilitated timely cluster detection and uncovered additional linkages via HCWs moving between clinical areas and among HCWs sharing a common lunch area, enabling early intervention.

Healthcare-associated multispecies outbreaks of OXA-48-positive carbapenemase-producing Enterobacteriaceae in a Singapore tertiary-care hospital.

OBJECTIVE: To describe OXA-48-like carbapenem-producing Enterobacteriaceae (CPE) outbreaks at Singapore General Hospital between 2018 and 2020 and to determine the risk associated with OXA-48 carriage in the 2020 outbreak. DESIGN: Outbreak report and case-control study. SETTING: Singapore General Hospital (SGH) is a tertiary-care academic medical center in Singapore with 1,750 beds. METHODS: Active surveillance for CPE is conducted for selected high-risk patient cohorts through molecular testing on rectal swabs or stool samples. Patients with CPE are isolated or placed in cohorts under contact precautions. During outbreak investigations, rectal swabs are repeated for culture. For the 2020 outbreak, a retrospective case-control study was conducted in which controls were inpatients who tested negative for OXA-48 and were selected at a 1:3 case-to-control ratio. RESULTS: Hospital wide, the median number of patients with healthcare-associated OXA-48 was 2 per month. In the 3-year period between 2018 and 2020, 3 OXA-48 outbreaks were investigated and managed, involving 4 patients with Klebsiella pneumoniae in 2018, 55 patients with K. pneumoniae or Escherichia coli in 2019, and 49 patients with multispecies Enterobacterales in 2020. During the 2020 outbreak, independent risk factors for OXA-48 carriage on multivariate analysis (49 patients and 147 controls) were diarrhea within the preceding 2 weeks (OR, 3.3; 95% CI, 1.1-10.7; P = .039), contact with an OXA-48-carrying patient (OR, 8.7; 95% CI, 1.9-39.3; P = .005), and exposure to carbapenems (OR, 17.2; 95% CI, 2.2-136; P = .007) or penicillin (OR, 16.6; 95% CI, 3.8-71.0; P < .001). CONCLUSIONS: Multispecies OXA-48 outbreaks in our institution are likely related to a favorable ecological condition and selective pressure exerted by antimicrobial use. The integration of molecular surveillance epidemiology of the healthcare environment is important in understanding the risk of healthcare-associated infection to patients.

Sporadic outbreaks of healthcare-associated COVID-19 infection in a highly-vaccinated inpatient population during a community outbreak of the B.1.617.2 variant: The role of enhanced infection-prevention measures.

Sporadic clusters of health care-associated COVID-19 infection occurred in a highly vaccinated health care-workers and patient population, over a 3-month period during ongoing community transmission of the B.1.617.2 variant. Enhanced infection-prevention measures and robust surveillance systems, including routine-rostered-testing of all inpatients and staff and usage of N95-respirators in all clinical areas, were insufficient in achieving zero health care-associated transmission. The unvaccinated and immunocompromised remain at-risk and should be prioritized for enhanced surveillance.

Two-step evolution of the hepatitis B drug-resistant mutations in a patient who developed primary entecavir resistance.

AIM: Few cases of primary entecavir resistance in chronic hepatitis B patients have been reported to date. The serial profiling of the HBV polymerase gene mutations from a treatment-naive patient who developed drug resistance after 32 months of entecavir therapy is presented here. DESIGN: Serum samples were collected at multiple time points from before the start of therapy to virological and biochemical breakthrough. The evolution of the hepatitis B virus polymerase gene mutations was analysed with commercial line probe assay and pyrosequencing. RESULTS: Drug resistance mutation analysis by pyrosequencing revealed a two-step process in the selection of drug resistance. The patient had a good initial response to entecavir 0.5 mg/day. A partially resistant HBV strain first emerged as the predominant species from as early as 2 weeks. After a period of non-compliance to therapy, there was virological breakthrough, which resolved on restarting entecavir. Shortly after, there was secondary failure of entecavir therapy, caused by a new resistant strain carrying all three mutations required. CONCLUSION: In this patient, pre-existence of minor population of partially resistant viral strains and treatment non-compliance probably contributed to his development of primary entecavir resistance.

Are physicians following guidelines? A survey of Hepatitis B management strategies.

PURPOSE: Practice guidelines for chronic hepatitis B (CHB) assist physicians in management; however, there are also areas where they provide no guidance. This paper aimed to examine treatment preferences for CHB among physicians based upon the Asia Pacific Association for the Study of the Liver (APASL) consensus guidelines 2008. METHODS: A questionnaire was prepared consisting of 18 questions grouped into 8 sections: basic information of participants, the proportion and number of CHB patients on treatment, case scenarios of treatment initiation, preferences for antiviral therapy, scenarios for stopping and continuing antiviral therapy, monitoring patients during therapy, and viral resistance management. The questionnaire was introduced to the APASL 2009 conference delegates. RESULTS: A total of 508 participants from 34 countries participated in the survey. Lamivudine or peg-interferon monotherapy was the preferred first-line therapy, while lamivudine/adefovir combination was the drug of choice for rescue therapy. Drug efficacy and cost were the most important factors to consider before initiating treatment, while viral resistance had a low priority. In general, the APASL guideline was strictly followed in about 50-60 % of the scenarios (initiating, stopping, or continuing antiviral therapy). CONCLUSIONS: The survey concluded that clinical management preferences differed from APASL guidelines in many instances.

Do different lamivudine-resistant hepatitis B genotypes carry the same risk of entecavir resistance?

Entecavir switch is one of the treatment options for lamivudine-resistant hepatitis B (HBV) patients in Asia. This study examined the outcome of patients with different baseline resistance genotypes in a cohort study. In this study, 14 patients with chronic HBV were treated with entecavir 1 mg/day for 5 years. Enrolment criteria include: documented lamivudine resistant mutations, treatment with adefovir 10 mg/day for at least 24 weeks, and Child-Pugh score <7. Most had previous failed adefovir therapy and compensated cirrhosis of the liver. Clinical outcomes, liver biochemistries, and HBV DNA were monitored regularly. Patients with virologic breakthrough were rescued with add-on adefovir. At the end of the treatment period, the mean HBV DNA fell from 5.92 × 10(6) (baseline) to 3.67 × 10(1) IU/ml. The presence of a HBV polymerase rtM204V mutation at the baseline was found to be the major risk factor for adverse outcomes. Compared to the patients with the rtM204I mutant, patients with the rtM204V mutant had increased risk of virologic breakthrough (80% vs. 0%, P = 0.010) requiring add-on adefovir, slower virologic responses (log rank test, P = 0.0011), failure to reach undetectable HBV DNA levels (60% vs. 0%, P = 0.045), and higher risk of entecavir-resistance (60% vs. 0%, P = 0.045). All the patients with rtM204I and rtA181 mutants had undetectable HBV DNA from 18th month. In summary, lamivudine-resistant HBV patients with the rtM204V mutation have the highest risk of developing entecavir resistance, and entecavir monotherapy should be avoided. Those with the rtM204I and rtA181V mutations may have lower risks, but regular surveillance for viral breakthrough is required.

Patient preferences for hepatitis B therapy.

BACKGROUND: Little is known about patient preferences for selection of chronic hepatitis B (CHB) treatment. This issue is important as it affects the therapeutic choices available for patients and, in the long term, the health of CHB patients. METHODS: The study was a questionnaire-led survey directed at patients attending a CHB follow-up clinic. Patients were asked questions regarding their knowledge on CHB treatment, preferred route and frequency of administration, duration of treatment, cost, adverse events, viral resistance, efficacy and whether treatment options were discussed with doctors. Patients were also asked to rank their priorities when selecting treatment for CHB. In addition, a summary of the profile of current agents was shown to patients who were then asked to select their preferred therapy. Finally, patients were asked questions regarding their willingness to pay for CHB treatment and expectations of treatment. Questionnaires were self-administered and statistical analysis was performed using SPSS (version 10.0). RESULTS: Lamivudine was the best-known drug among patients. Only 30% of patients were treatment-naive. Most patients preferred oral therapy with once-daily dosing and a fixed duration of treatment. Drug efficacy was considered the most important factor in drug selection. When shown the profile of the different drugs available for the treatment of CHB, entecavir was the preferred choice of therapy. The majority of patients were willing to spend no more than S$10 (USD 8) daily for therapy with expectation of cure for their disease. Overall, 92% of patients would follow doctor's recommendations. CONCLUSIONS: Patients' preferences are important in evaluating drug selection for CHB.

Intragastric balloon significantly improves nonalcoholic fatty liver disease activity score in obese patients with nonalcoholic steatohepatitis: a pilot study.

BACKGROUND: There is no satisfactory treatment for nonalcoholic steatohepatitis (NASH). The Bioenterics intragastric balloon (BIB) can be an effective treatment for weight reduction in obese patients. OBJECTIVE: We evaluated the efficacy of the BIB in improving the histology of NASH in obese patients. DESIGN: Randomized, controlled study. SETTING: University hospital. PATIENTS: Obese patients with body mass indexes (BMI) ≥27 kg/m(2) and who had histologic evidence of NASH were recruited. INTERVENTION: Patients were randomly assigned to a step 1 American Heart Association (AHA) diet plus exercise and BIB placement or step 1 AHA diet plus exercise and sham BIB placement for a period of 6 months. MAIN OUTCOME MEASUREMENTS: Liver histology was the primary outcome measure recorded before and after treatment. RESULTS: A total of 18 patients completed the study. Baseline characteristics of the BIB and sham groups were similar. At 6 months, a significant reduction in the mean BMI was seen in the BIB group (1.52 vs 0.8; P = .0008). The median nonalcoholic fatty liver disease activity scores at the end of treatment were significantly lower in the BIB-treated compared with the sham-treated groups (2 [0.75] vs 4 [2.25]; P = .03). There was a trend toward improvement in the median steatosis scores (1 [0.75] vs 1 [1]; P = .075). There was no change in the median loblular inflammation, hepatocellular ballooning, or fibrosis scores in both groups after treatment. LIMITATIONS: Pilot study with small numbers and short duration. CONCLUSION: Results from this pilot study demonstrated that addition of BIB for 6 months provided a greater loss of BMI and improvement in 2 of 5 histologic parameters of nonalcoholic fatty liver disease. A longer study with larger numbers will be required to prove whether or not the therapy is meaningful in the treatment of NASH.

Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth factor receptor-4 signaling in hepatocellular carcinoma.

BACKGROUND: We had previously demonstrated overexpression of fibroblast growth factor receptor-4 (FGFR4) in hepatocellular carcinoma (HCC). However, additional molecular mechanisms resulting in amplified FGFR4 signaling in HCC remain under-studied. Here, we studied the mechanistic role of its co-receptor klotho-beta (KLB) in driving elevated FGFR4 activity in HCC progression. RESULTS: Quantitative real-time PCR analysis identified frequent elevation of KLB gene expression in HCC tumors relative to matched non-tumor tissue, with a more than two-fold increase correlating with development of multiple tumors in patients. KLB-silencing in Huh7 cells decreased cell proliferation and suppressed FGFR4 downstream signaling. While transient repression of KLB-FGFR4 signaling decreased protein expression of alpha-fetoprotein (AFP), a HCC diagnostic marker, prolonged inhibition enriched for resistant HCC cells exhibiting increased liver stemness. CONCLUSIONS: Elevated KLB expression in HCC tissues provides further credence to the oncogenic role of increased FGFR4 signaling in HCC progression and represents a novel biomarker to identify additional patients amenable to anti-FGFR4 therapy. The restricted tissue expression profile of KLB, together with the anti-proliferative effect observed with KLB-silencing, also qualifies it as a specific and potent therapeutic target for HCC patients. The enrichment of a liver stem cell-like population in response to extended KLB-FGFR4 repression necessitates further investigation to target the development of drug resistance.

Clinical outcomes of lamivudine-adefovir therapy in chronic hepatitis B cirrhosis.

GOALS: To determine the clinical outcome of chronic hepatitis B cirrhotics on antiviral therapy. BACKGROUND: The long-term outcome of hepatitis B cirrhotics on therapy remains to be characterized. METHODS: A large clinic cohort of chronic hepatitis B cirrhotic patients were enrolled in a treatment program of lamivudine ± adefovir therapy. Patients were analyzed for clinical outcomes, and predictors of these outcomes were evaluated by multivariate analysis. Clinical outcomes of ascites, encephalopathy, hepatocellular carcinoma (HCC), and progression in Child-Pugh score, Model for End-stage Liver Disease score, and mortality were assessed. Data were analyzed by Kaplan-Meier graphs, log-rank test, and Cox regression. RESULTS: Of 143 chronic hepatitis B cirrhotics, 19.6% had decompensated cirrhosis. At 5 years, the mean survival was 83.6%, development of ascites, HCC, encephalopathy, and deterioration in Child-Pugh score were 7.0%, 15.9%, 10.8%, and 16.9%, respectively. The overall progression of liver-related complications was 32.8% at 5 years. Multivariate analysis showed that ascites, albumin ≤28 g/L, Child-Pugh score ≥7.9, Model for End-stage Liver Disease score ≥10.9 were significantly associated with liver-related complications. Low albumin and low hepatitis B virus DNA were independent factors for liver-associated mortality. Lamivudine resistance did not affect mortality or liver disease progression. When stratified by Child-Pugh status, the mean survival of those with Child C cirrhosis was worse than Child A and B cirrhosis (P<0.001, log-rank test). Early deaths (≤12 mo) were due to liver failure or sepsis, whereas deaths ≥12 mo were mainly due to HCC. CONCLUSION: Decompensated chronic hepatitis B cirrhotics may suffer early mortality despite antiviral treatment, and therefore should be considered for early liver transplantation.

Alanine aminotransferase is an inadequate surrogate marker for detecting lamivudine resistance.

AIM: To investigate the accuracy of serum alanine aminotransferase (ALT) in diagnosing lamivudine resistance and factors that contributed to abnormal serum ALT. METHODS: This was a retrospective study of chronic hepatitis B patients on lamivudine therapy who were followed for 3-mo with liver function tests and hepatitis B virus (HBV) DNA measurement. Lamivudine resistance was defined as HBV DNA ≥ 1 log from nadir on at least 2 occasions, confirmed by genotyping. Serum ALT levels in patients with lamivudine resistance were compared to serum ALT levels in those without lamivudine resistance. RESULTS: There were 111 patients with and 117 without lamivudine resistance. The area under the receiver operating characteristic of serum ALT to diagnose lamivudine resistance was 0.645 ± 0.037. Serum ALT > 42.5 U/L gave the best diagnostic accuracy with sensitivity = 61%, specificity = 60%, positive predictive value = 60%, negative predictive value = 61%, positive likelihood ratio = 1.53 and negative likelihood ratio = 0.65 for predicting lamivudine resistance, missing 39% of resistant patients. Using other serum ALT cutoffs, diagnostic accuracy was lower. By multivariate analysis, baseline abnormal serum ALT was associated with abnormal ALT during resistance (OR = 5.98, P = 0.003), and males were associated with serum ALT flares during resistance (OR = 8.9, P = 0.016). CONCLUSION: Serum ALT is inadequate for diagnosing lamivudine resistance and has implications where viral resistance testing is suboptimal and for reimbursement of rescue therapy.

C/EBPalpha is up-regulated in a subset of hepatocellular carcinomas and plays a role in cell growth and proliferation.

BACKGROUND & AIMS: C/EBPalpha (cebpa) is a putative tumor suppressor. However, initial results indicated that cebpa was up-regulated in a subset of human hepatocellular carcinomas (HCCs). The regulation and function of C/EBPalpha was investigated in HCC cell lines to clarify its role in liver carcinogenesis. METHODS: The regulation of C/EBPalpha expression was studied by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blotting, immunohistochemistry, methylation-specific PCR, and chromatin immunoprecipitation assays. C/EBPalpha expression was knocked-down by small interfering RNA or short hairpin RNA. Functional assays included colony formation, methylthiotetrazole, bromodeoxyuridine incorporation, and luciferase-reporter assays. RESULTS: Cebpa was up-regulated at least 2-fold in a subset (approximately 55%) of human HCCs compared with adjacent nontumor tissues. None of the up-regulated samples were positive for hepatitis C infection. The HCC cell lines Hep3B and Huh7 expressed high, PLC/PRF/5 intermediate, HepG2 and HCC-M low levels of C/EBPalpha, recapitulating the pattern of expression observed in HCCs. No mutations were detected in the CEBPA gene in HCCs and cell lines. C/EBPalpha was localized to the nucleus and functional in Hep3B and Huh7 cells; knocking-down its expression reduced target-gene expression, colony formation, and cell growth, associated with a decrease in cyclin A and CDK4 concentrations and E2F transcriptional activity. Epigenetic mechanisms including DNA methylation, and the binding of acetylated histone H3 to the CEBPA promoter-regulated cebpa expression in the HCC cells. CONCLUSIONS: C/EBPalpha is up-regulated in a subset of HCCs and has growth-promoting activities in HCC cells. Novel oncogenic mechanisms involving C/EBPalpha may be amenable to epigenetic regulation to improve treatment outcomes.

Profile of tumor antigen-specific CD8 T cells in patients with hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND & AIMS: Tumor and viral antigens are expressed by hepatocellular carcinoma (HCC) in patients with chronic hepatitis B, but little is known about the immunodominance and function of tumor- and virus-specific CD8+ T cells in these patients. METHODS: HLA-A2-restricted T-cell responses to 16 tumor antigens and hepatitis B virus (HBV) proteins were tested using 49 previously described epitopes. Cells from 30 HLA-A2+, HBV-infected patients (10 with HCC, 10 with HBV cirrhosis, and 10 HBV but no cirrhosis) were analyzed, after expansion, by enzyme-linked immunosorbent spot (ELISPOT). Interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-2 production, as well as expression of the degranulation marker CD107a on tumor-specific CD8+ T cells, were evaluated. RESULTS: Cells from all groups had tumor-specific responses. The tumor antigens NY-ESO-1 and SSX-2 were most frequently targeted and were immunogenic in the HLA-A2 subtypes that are characteristic of Asian ethnicity. Tumor-specific T cells had low affinities; T cells from non-HCC patients were polyfunctional (IFN-gamma+, TNF-alpha+, CD107a+) and those from HCC patients displayed an exhausted phenotype (IFN-gamma+, CD107a+). Programmed Death 1 (PD-1) was expressed at higher levels on T cells from tumor and liver than peripheral blood from HCC patients and might contribute to T-cell exhaustion. Blocking PD-1/PD-L1 increased the frequency of tumor-specific T cells in HCC patients but did not restore T cell function. CONCLUSIONS: Patients with or without HCC have a quantitative and functional hierarchy of tumor-specific T cells. HLA-A2-restricted T cells from HCC patients target NY-ESO-1, but exist in an exhausted state that might require additional activation to restore function.

Fibroblast growth factor receptor 4 regulates proliferation, anti-apoptosis and alpha-fetoprotein secretion during hepatocellular carcinoma progression and represents a potential target for therapeutic intervention.

BACKGROUND/AIMS: FGFR4, a member of the fibroblast growth factor receptor family, has been recently associated with progression of melanoma, breast and head and neck carcinoma. Given its uniquely high expression in the liver, we investigated its contributory role to hepatocellular carcinoma (HCC). METHODS: We performed a comprehensive sequencing of full-length FGFR4 transcript in 57 tumor/normal HCC tissue pairs, and quantified their mRNA expressions. Notable mutations and expression patterns were correlated with patient data. Clinically significant trends were examined in in vitro models. RESULTS: We found eight genetic alterations including two highly frequent polymorphisms (V10I and G338R). Secretion of alpha-fetoprotein (AFP), a HCC biomarker, was increased among patients bearing homozygous Arg388 alleles. One-third of these patients exhibited increased FGFR4 mRNA expression in the matched tumor/normal tissue. Subsequent in vitro perturbation of FGFR4 signaling through both FGF19-stimulation and FGFR4 silencing confirmed a mechanistic link between FGFR4 activities and tumor aggressiveness. More importantly, inhibition of FGFR activity with PD173074 exquisitely blocked HuH7 (high FGFR4 expression) proliferation as compared to control cell lines. CONCLUSIONS: FGFR4 contributes significantly to HCC progression by modulating AFP secretion, proliferation and anti-apoptosis. Its frequent overexpression in patients renders its inhibition a novel and much needed pharmacological approach against HCC.

Health-related quality of life in chronic hepatitis B patients.

UNLABELLED: The relationship between stages of chronic hepatitis B liver disease and health-related quality of life (HRQoL) is an important aspect of the overall management of hepatitis B virus (HBV) infection, yet is not well characterized. Consequently we sought to examine HRQoL in HBV patients, stratified by disease severity, compared with normal controls and hypertensive patients, using the Short Form 36 Health Survey (SF-36) and the EQ-5D self-report questionnaire. Univariate and multivariate analyses were then performed. A total of 432 HBV (156 asymptomatic carriers, 142 chronic hepatitis B, 66 compensated cirrhosis, 24 decompensated cirrhosis, 22 hepatocellular carcinoma, and 22 post-liver transplant) patients, 93 hypertensive patients, and 108 normal controls participated in the study. Multivariate analysis showed that normal controls and asymptomatic carriers had similar SF-36 scores, which were better than those for hypertensive patients, but with development of chronic hepatitis B and compensated cirrhosis, showed a significant decrease in general health and the mental dimension, whereas those with advanced liver disease (decompensated cirrhosis and hepatocellular carcinoma) had significantly lower scores in all components (P < 0.05), indicating that the physical component deteriorates only with advanced liver disease. Similar results were obtained with EQ5D. Post-liver transplant patients had similar HRQoL to patients with decompensated cirrhosis and hepatocellular carcinoma, although there was a trend toward improvement. CONCLUSION: Our results showed that HRQoL in asymptomatic carriers is comparable to those of normal controls and better than hypertensive patients, but deteriorates with disease progression, initially in general health and mental dimensions, but with advanced disease all dimensions are affected.