Overt hepatic encephalopathy: development of a novel clinician reported outcome tool and electronic caregiver diary.

Clinical management and clinical trials of patients with overt hepatic encephalopathy (OHE) are compromised by lack of standardized and reproducible tools for its clinical diagnosis or for caregiver (CG) identification of OHE manifestations which merit medical evaluation. Using an iterative Delphi method, Steering Committee and international hepatologist panel, the West Haven (WH) scale was modified to develop and operationalize a clinician tool for OHE identification and grading (HE Grading Instrument, HEGI™). Major diagnostic criteria included disorientation to time, place, and person, asterixis, lethargy, and coma. Minimum HEGI requirements for OHE diagnosis included: (1) disorientation, or (2) presence of both lethargy and asterixis, or (3) coma. Inter- and intra-rater HEGI reproducibility were 97 % and 98 %, respectively. When applied to a phase II clinical trial population of 178 patients with 388 OHE episodes, HEGI demonstrated excellent concordance with investigator judgement. Additionally, a multi-stage study was conducted to develop a daily CG e-diary, based on OHE manifestations recognizable by CG including speech difficulties, unusual behavior, forgetfulness, confusion, disorientation and level of consciousness. The e-diary was designed for use on smart phone, laptop or desktop, utilized branching logic and skip patterns, incorporated automatic daily completion reminders and real time alerts to clinical sites to facilitate daily standardized CG input and was found to be user friendly and understandable. The HEGI and e-diary, which were developed using methodology accepted by regulatory authorities, are designed to facilitate the design and interpretation of clinical trials for OHE and improve outcomes for OHE patients in clinical practice.

William Wilde in the West of Ireland.

It is widely believed that Sir William Wilde's forebears were in Ireland for just two or three generations. This belief stems from a number of short biographies of Wilde which were published during his lifetime. These biographies gave different versions of the origin of the Wilde family and appear to have been generated by the creative imagination of Lady Jane Wilde or, as she was better known by her nom de plume, Speranza. She was equally imaginative in creating narratives about her own family background and in one she claimed descent from the Italian poet Dante Alighieri. So it was not a great challenge for her to invent biographies of her husband which she deemed suitable for a knight living at the prestigious address of 1 Merrion Square, leading many to believe that William and his son Oscar were more English than Irish. It was also important for Speranza to distance Sir William from any connection which the Wilde family might have had with trade. In this paper published and unpublished material are used, together with a careful examination of family deeds in the Registry of Deeds office, to elucidate the real roots of the Wilde family in Dublin and in the West of Ireland.

Prospective Multicenter Observational Study of Overt Hepatic Encephalopathy.

BACKGROUND: Overt hepatic encephalopathy (OHE) is a frequent complication of decompensated cirrhosis. AIMS: A multicenter prospective observational study was performed to assess the most commonly recorded presenting manifestations of OHE and its associated health-care burden. METHODS: Qualifying patients must have experienced ≥1 OHE episode within 30 days of enrollment (qualifying OHE) and were followed for recurrence (on-study OHE). RESULTS: Two hundred and sixty-five patients were enrolled at 30 sites and followed for up to 9 months (mean 72 days). Seventy-two patients experienced 122 on-study episodes; with 72, 23, and 13 having ≥1, ≥2, or ≥3 on-study episodes with median days to occurrence of the 1st, 2nd, and 3rd episode of 34, 19, and 11, respectively. The most frequently recorded OHE manifestations included confusion (78 %), change in mental status (57 %), disorientation (48 %), lethargy (46 %), and asterixis (45 %). West Haven grade was used inconsistently and recorded for only 28 % of episodes. Most qualifying and on-study episodes occurred on rifaximin (60 and 82 %, respectively) and were associated with hospitalization (68 and 85 %, respectively). Twenty-three patients experienced ≥2 on-study episodes within 2 months of enrollment on average (median 45 days) and accounted for 60 % of on-study episodes. CONCLUSIONS: In this prospective study, OHE's most commonly recorded presenting manifestations included confusion, altered mental status, disorientation, lethargy, and asterixis. As reflected by frequent recurrence and hospitalizations, OHE, particularly the approximately 10 % of "high-resource-utilizing" patients with frequent recurrence, continues to pose a major unmet medical need and health-care burden despite the use of rifaximin.

Glutamine and hyperammonemic crises in patients with urea cycle disorders.

UNLABELLED: Blood ammonia and glutamine levels are used as biomarkers of control in patients with urea cycle disorders (UCDs). This study was undertaken to evaluate glutamine variability and utility as a predictor of hyperammonemic crises (HACs) in UCD patients. METHODS: The relationships between glutamine and ammonia levels and the incidence and timing of HACs were evaluated in over 100 adult and pediatric UCD patients who participated in clinical trials of glycerol phenylbutyrate. RESULTS: The median (range) intra-subject 24-hour coefficient of variation for glutamine was 15% (8-29%) as compared with 56% (28%-154%) for ammonia, and the correlation coefficient between glutamine and concurrent ammonia levels varied from 0.17 to 0.29. Patients with baseline (fasting) glutamine values >900 µmol/L had higher baseline ammonia levels (mean [SD]: 39.6 [26.2]µmol/L) than patients with baseline glutamine ≤ 900 µmol/L (26.6 [18.0]µmol/L). Glutamine values >900 µmol/L during the study were associated with an approximately 2-fold higher HAC risk (odds ratio [OR]=1.98; p=0.173). However, glutamine lost predictive significance (OR=1.47; p=0.439) when concomitant ammonia was taken into account, whereas the predictive value of baseline ammonia ≥ 1.0 upper limit of normal (ULN) was highly statistically significant (OR=4.96; p=0.013). There was no significant effect of glutamine >900 µmol/L on time to first HAC crisis (hazard ratio [HR]=1.14; p=0.813), but there was a significant effect of baseline ammonia ≥ 1.0 ULN (HR=4.62; p=0.0011). CONCLUSIONS: The findings in this UCD population suggest that glutamine is a weaker predictor of HACs than ammonia and that the utility of the predictive value of glutamine will need to take into account concurrent ammonia levels.

Comparing the endothelialisation of extracellular matrix bioscaffolds with coated synthetic vascular graft materials.

INTRODUCTION: Existing synthetic vascular grafts have unacceptably high failure rates when replacing below knee arteries. In vitro endothelialisation is a technique, which has been shown to enhance the patency rates of below knee vascular grafts. Synthetic materials are however poor cellular substrates and must be combined with coatings to promote cellular growth and attachment. The most common coating clinically is fibrin-coated ePTFE. The aim of our study was to compare the endothelialisation of fibrin-coated ePTFE with novel extracellular matrix (ECM) biomaterials that we hypothesise will provide a superior substrate for cell growth. METHODS: Human endothelial cells were cultured on ECM scaffolds and fibrin-coated ePTFE. Uncoated Dacron and ePTFE acted as controls. The cells were examined for viability, phenotype, adhesion and proliferation. Cell morphology was accessed using scanning electron microscopy. RESULTS: Cells remained viable and produced von Willebrand factor on all substrates tested. ECM scaffolds and fibrin-modified ePTFE achieved statistically higher attachment efficiency when compared to both uncoated synthetic graft materials (p ≤ 0.001). At 90 min 80 ± 3.6% of cells had attached to the ECM scaffold compared to Dacron (30 ± 4.5%, n = 3) and ePTFE (33 ± 2.5%, n = 3). There was no difference in adhesion rates between ECM scaffolds and fibrin-coated ePTFE (p = 1.00). Endothelial cells proliferated fastest on ECM scaffolds when compared to all other materials tested (p < 0.001) and reached confluency on day seven. CONCLUSION: ECM bioscaffolds offer an improved substrate for promoting rapid endothelialisation compared to fibrin-coated ePTFE by combining firm cellular anchorage and superior cell expansion.

Successful Treatment of Acute on Chronic Mesenteric Ischaemia by Common Iliac to Inferior Mesenteric Artery Bypass.

Chronic mesenteric ischaemia is a rare and potentially fatal condition most commonly due to atherosclerotic stenosis or occlusion of two or more mesenteric arteries. Multivessel revascularisation of both primary mesenteric vessels, the celiac artery and superior mesenteric artery (SMA), is the current mainstay of treatment; however, in a certain cohort of patients, revascularisation one or both vessels may not be possible. Arteries may be technically unreconstructable or the patient may be surgically unfit for the prolonged aortic cross clamping times required. Here we present a case involving a 72-year-old woman with acute on chronic mesenteric ischaemia. She was a high risk surgical patient with severe unreconstructable stenotic disease of the SMA and celiac arteries. She was successfully treated with single vessel revascularisation of the inferior mesenteric artery (IMA) via a common iliac to IMA reversed vein bypass. At two-year follow-up, the graft remains patent and the patient continues to be symptom-free and is maintaining her weight.

Urinary phenylacetylglutamine (U-PAGN) concentration as biomarker for adherence in patients with urea cycle disorders (UCD) treated with glycerol phenylbutyrate.

Urinary phenylacetylglutamine (U-PAGN) concentrations in spot urine samples were analyzed as a dosing biomarker during glycerol phenylbutyrate (GPB) dosing in 68 healthy adults and 66 adult and pediatric patients with urea cycle disorders who participated in GPB clinical trials. Age- and body surface area (BSA)-specific 25th percentile cutoff points for spot U-PAGN concentrations (<~9000 µg/mL for < 2 years old patients, < 7000 µg/mL for > 2 years with BSA ≤ 1.3 m2, and <~5000 µg/mL for > 2 years of age with BSA > 1.3 m2) were determined as an approach to identify patients for whom increased dosing and/or adherence to prescribed dosing should be assessed.

Non-contact in vivo measurement of ocular microtremor using laser speckle correlation metrology.

Ocular microtremor (OMT) is a small involuntary eye movement present in all subjects. In this paper we present the results of in vivo OMT measurement using a novel non-contact laser speckle technique. OMT signals have not previously been measured from the sclera using this laser speckle correlation technique. To verify the system's ability to record eye movements, it is first tested using a large angle eye rotation. Next, the system is tested with a group of 20 subjects and OMT parameters are extracted. The results of OMT measurements gave a mean frequency of 78 ± 3.86 Hz and peak-to-peak amplitude of 21.42 ± 7.01 µrad, these values are consistent with known values from eye-contacting methods.

Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio.

BACKGROUND: Phenylacetic acid (PAA) is the active moiety in sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB, HPN-100). Both are approved for treatment of urea cycle disorders (UCDs) - rare genetic disorders characterized by hyperammonemia. PAA is conjugated with glutamine in the liver to form phenylacetyleglutamine (PAGN), which is excreted in urine. PAA plasma levels ≥ 500 µg/dL have been reported to be associated with reversible neurological adverse events (AEs) in cancer patients receiving PAA intravenously. Therefore, we have investigated the relationship between PAA levels and neurological AEs in patients treated with these PAA pro-drugs as well as approaches to identifying patients most likely to experience high PAA levels. METHODS: The relationship between nervous system AEs, PAA levels and the ratio of plasma PAA to PAGN were examined in 4683 blood samples taken serially from: [1] healthy adults [2], UCD patients of ≥ 2 months of age, and [3] patients with cirrhosis and hepatic encephalopathy (HE). The plasma ratio of PAA to PAGN was analyzed with respect to its utility in identifying patients at risk of high PAA values. RESULTS: Only 0.2% (11) of 4683 samples exceeded 500 µg/ml. There was no relationship between neurological AEs and PAA levels in UCD or HE patients, but transient AEs including headache and nausea that correlated with PAA levels were observed in healthy adults. Irrespective of population, a curvilinear relationship was observed between PAA levels and the plasma PAA:PAGN ratio, and a ratio>2.5 (both in µg/mL) in a random blood draw identified patients at risk for PAA levels>500 µg/ml. CONCLUSIONS: The presence of a relationship between PAA levels and reversible AEs in healthy adults but not in UCD or HE patients may reflect intrinsic differences among the populations and/or metabolic adaptation with continued dosing. The plasma PAA:PAGN ratio is a functional measure of the rate of PAA metabolism and represents a useful dosing biomarker.

Population pharmacokinetic modeling and dosing simulations of nitrogen-scavenging compounds: disposition of glycerol phenylbutyrate and sodium phenylbutyrate in adult and pediatric patients with urea cycle disorders.

Sodium phenylbutyrate and glycerol phenylbutyrate mediate waste nitrogen excretion in the form of urinary phenylacetylglutamine (PAGN) in patients with urea cycle disorders (UCDs); rare genetic disorders characterized by impaired urea synthesis and hyperammonemia. Sodium phenylbutyrate is approved for UCD treatment; the development of glycerol phenylbutyrate afforded the opportunity to characterize the pharmacokinetics (PK) of both compounds. A population PK model was developed using data from four Phase II/III trials that collectively enrolled patients ages 2 months to 72 years. Dose simulations were performed with particular attention to phenylacetic acid (PAA), which has been associated with adverse events in non-UCD populations. The final model described metabolite levels in plasma and urine for both drugs and was characterized by (a) partial presystemic metabolism of phenylbutyric acid (PBA) to PAA and/or PAGN, (b) slower PBA absorption and greater presystemic conversion with glycerol phenylbutyrate, (c) similar systemic disposition with saturable conversion of PAA to PAGN for both drugs, and (d) body surface area (BSA) as a significant covariate accounting for age-related PK differences. Dose simulations demonstrated similar PAA exposure following mole-equivalent PBA dosing of both drugs and greater PAA exposure in younger patients based on BSA.

Medical complications and outcomes at an onsite rehabilitation unit for older people.

BACKGROUND: The rehabilitation of older patients in Ireland after an acute medical event occurs at dedicated onsite hospital units or at offsite centres. Information on medical complications and outcomes is inadequate. AIMS: Enumeration of medical complications of patients admitted to a dedicated onsite rehabilitation unit for older people, and the extent of co-morbidity in the population with the effects that this had on the evolution of medical complications. METHODS: A retrospective analysis of patients admitted to a 58-bed onsite unit over a 1-year period was performed. Information collating co-morbidities, medical complications and functional outcomes was recorded. RESULTS: Medical complications occurred in almost 95% of patients, where full data were available. Over one-third required intravenous therapy. CONCLUSION: Twenty-four hour medical cover is required for older patients managed at onsite rehabilitation units. Further studies on offsite medical rehabilitation facilities for older patients are required.

Discharge of patients to long-term care from a large acute hospital over a 12-year period.

BACKGROUND: Several factors may be important in determining the discharge of patients to long-term care from the acute hospital. AIMS: We aimed to look at factors associated with discharge to long-term care from St. James's Hospital, Dublin between 1997 and 2008. METHODS: Data obtained from a long-term care database within the geriatric service were analysed. This service is responsible for assessing and listing all patients for long-term care within the hospital. RESULTS: 3,107 patients were listed and 2,520 discharged to long-term care during the period. Mean age was 81.7±7.3 years and 64.1% were female. The number listed increased since 1997, but there was no change in age or gender. Median time to discharge was 52 days, but varied by year and was longer for public versus private facilities (mean difference=18 days, P=0.006). Mortality of those awaiting long-term care was 17.0%, but varied significantly by year and ranged form 9.3-29.0%. Mortality was higher in males, in those of older age and during the winter months. CONCLUSIONS: Variation in the time to discharge appears to be associated with changes in the provision of publicly funded private nursing home beds.

Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders.

UNLABELLED: We have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD). STUDY DESIGN: These analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6-17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine. RESULTS: Patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5 to 31.8 g/day and of sodium phenylbutyrate ranging from 1.3 to 31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979% to 5690% for phenylbutyric acid, 843% to 3931% for phenylacetic acid, and 881% to 1434% for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r = 0.730, p < 0.001) or as total 24-hour excretion (r = 0.791 p<0.001), followed by plasma phenylacetylglutamine AUC(24-hour), plasma phenylacetic acid AUC(24-hour) and phenylbutyric acid AUC(24-hour). Plasma phenylacetic acid levels in adult and pediatric patients did not show a consistent relationship with either urinary phenylacetylglutamine or ammonia control. CONCLUSION: The findings are collectively consistent with substantial yet variable pre-systemic (1st pass) conversion of phenylbutyric acid to phenylacetic acid and/or phenylacetylglutamine. The variability of blood metabolite levels during the day, their weaker correlation with dose, the need for multiple blood samples to capture trough and peak, and the inconsistency between phenylacetic acid and urinary phenylacetylglutamine as a marker of waste nitrogen scavenging limit the utility of plasma levels for therapeutic monitoring. By contrast, 24-hour urinary phenylacetylglutamine and morning spot urine phenylacetylglutamine correlate strongly with dose and appear to be clinically useful non-invasive biomarkers for compliance and therapeutic monitoring.

Loneliness and vascular biomarkers: the Dublin Healthy Ageing Study.

BACKGROUND: Loneliness has been associated with poor physical health and a link has been suggested between the presence of loneliness, cardiovascular health and inflammatory markers. OBJECTIVE: To investigate the association between vascular disease biomarkers and loneliness in a community-dwelling non-demented elderly population. DESIGN: cross-sectional community based assessment. PARTICIPANTS: 466 subjects with mean age 75.45 (SD, 6.06) years. 208 (44.6%) were male. RESULTS: Higher levels of HbA1c, but not other vascular biomarkers were independently associated with being lonely. CONCLUSION: Loneliness was associated with raised levels of HbA1c in a community dwelling elderly population. The mechanism for this association has yet to be elucidated but may reflect an abnormal stress response in people who are lonely.

Venous drainage, a simple method to prevent the systemic consequences of ischaemia-reperfusion injury in acute lower limb ischaemia.

BACKGROUND: Ischaemia-reperfusion injury (I-R injury) is a recognised and potentially fatal complication following revascularisation of an ischaemic limb. Prevention of reperfusion injury is the focus of much research, but effective drug regimens have yet to be established into clinical practice. CASE REPORT: Here we present a man with prolonged, severe lower limb ischaemia, successfully treated with a novel surgical technique for preventing I-R injury. Prior to revascularisation, the common femoral vein was cannulated and the harmful venous effluent was drained. The patient made an excellent recovery, the limb was salvaged and no systemic complications were encountered.

Apolipoprotein E promoter polymorphisms (-491A/T and -427T/C) and Alzheimer's disease: no evidence of association in the Irish population.

BACKGROUND: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder with as yet poorly understood aetiology. Both environmental and genetic factors have been implicated as predisposing factors. The APOE e4 allele is an established genetic susceptibility factor for AD for several populations including the Irish. Polymorphisms (-491A/T and -427T/C) at the promoter region of the APOE gene are postulated to affect the expression of the gene through differential binding of transcription factors. AIMS: Two APOE promoter polymorphisms (-491A/T and -427T/C) are examined for possible association with AD. METHODS: Using a case-control study design, a sample of 112 Irish late onset Alzheimer's (LOAD) patients and 107 ethnically matched controls were investigated for association with the above polymorphisms. CONCLUSIONS: No evidence of association between any of the examined markers and AD was observed. Haplotype analysis using markers -491A/T and -427T/C in conjunction with the APOE (Hha I) polymorphism revealed significant associations of three haplotypes with AD. However, this association was mainly due to the highly significant association of the APOE e4 allele with AD and not of the promoter variants.

Survival of patients discharged to long term care.

Data on the life expectancy of elderly people in long term care facilities will be important for effective service planning and monitoring quality of care. To date there are no such data from an Irish perspective. A random sample of patients discharged to long term care between Jan 1st 1997 and December 31st 2003 from a single Dublin hospital was studied. Death by January 1st 2005 was ascertained through the register of births deaths and marriage. Median survival was calculated and factors associated with mortality were determined in a logistic regression. Mean (sd) age was 82 (11) years and 61 (29%) were female. Median survival was 30.3 (95%CI 22.4-45.0) months (mean Irish life expectancy at this age is about 78 months). Three factors were independently associated with death by 2 years: age (Odds ratio 1.11 [95%CI 1.05-1.17, F ratio 15.1, p=0.0001] per year), male gender (Odds ratio 1.52 [95%CI 1.05-3.68, F ratio 5.2, p=0.024]) and discharge to continuing care (Odds ratio 1.96 [1.05-3.68, F ratio 4.4, p=0.037]). These results (which are the first such Irish data) show that patients discharged to long term care are a frail group with a reduced life expectancy. Encouragingly survival for this cohort (25% at 1 year) was similar to that seen in other countries. Data on nursing home survival will allow more accurate planning of long term residential services and help monitor quality of care.

An automated ocular microtremor feature extraction using the Gabor thresholding technique.

Ocular Microtremor (OMT) is a very fine continuous eye movement which has potential in monitoring and identifying a number of clinical conditions. There is a need for improved analysis and processing techniques to extract useful, quantifiable parameters from the OMT signal. A number of papers have shown the clinical significance of looking at the 'bursts' and 'baseling' patterns of the OMT signal. Analysis to date relies on visual inspection alone. This paper introduces an automated approach to burst/baseline identification based on a time-varying filter using the Gabor transform.