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BACKGROUNDNatriuretic peptides are involved in the cascade of pathophysiological eventsoccurring in liver cirrhosis, counterbalancing vasoconstriction and anti-natriuretic factors. The effects of natriuretic peptides as treatment of cirrhotic ascites have been investigated only in small studies, and definitive results are lacking.AIMTo examine the effects and safety of natriuretic peptides in cirrhosis patients with ascites.METHODSWe searched MEDLINE, Web of Science, Scopus, Cochrane Library and Embasefor all available studies applying intravenous administration of any natriureticpeptide to patients suffering from cirrhotic ascites. Inclusion was not limited bytreatment duration or dose, or by follow-up duration. Both randomised controlled trials and non-randomised studies were eligible for inclusion. The primary outcome was change in renal sodium excretion. Secondary outcomes included safety measures and changes in renal water excretion, plasma aldosterone concentration, and plasma renin activity.RESULTSTwenty-two studies were included. Atrial natriuretic peptide (ANP) was the onlyintensively studied treatment. Sodium excretion increased in response to continuous ANP infusion and was more pronounced when infusion rates of > 30 ng/kg/min were administered compared with ≤ 30 ng/kg/min (P < 0.01). Moreover, natriuresis was significantly higher in study subgroups with mild/moderate ascites compared with moderate/severe and refractory ascites (P < 0.01). ANP infusions increased renal water excretion, although withoutreaching a statistically significant dose-response gradient. Plasma aldosterone concentration and plasma renin activity were significantly lower at baseline in study subgroups achieving a negative sodium balance in response to an ANP administration compared with treatment non-responders (P < 0.01). Blood pressure decreases occurred less frequently when ANP doses ≤ 30 ng/kg/minwere applied. The quality of evidence for a natriuretic response to ANP was low, mainly due to small sample sizes and considerable between-study heterogeneity. Data were sparse for the other natriuretic peptides; B-type natriuretic peptide and urodilatin.CONCLUSIONIntravenous ANP infusions increase sodium excretion in patients with cirrhotic ascites. Continuous infusion rates > 30 ng/kg/min are the most effective. However, safety increases with infusion rates ≤ 30 ng/kg/min.

Chronic rheumatological manifestations similar to those of rheumatoid arthritis (RA) are described after chikungunya virus infection. We aimed to compare the relevance of joint counts and symptoms to clinical outcomes in RA and chronic chikungunya disease. Forty patients with chronic chikungunya arthralgia and 40 patients with RA were enrolled in a cross-sectional study. The association of tenderness and swelling, clinically assessed in 28 joints, and patient evaluations of pain and musculoskeletal stiffness with modified Health Assessment Questionnaire (HAQ) and quality of life (QoL) assessments were investigated. Tender and swollen joint counts, pain and stiffness scores were all associated with the HAQ disability index in RA (all r > 0.55, p ≤ 0.0002), but only stiffness was significantly associated with disability in chikungunya (r = 0.38, p = 0.02). Joint counts, pain and stiffness were also associated with most QoL domains in RA patients. In contrast, in chikungunya disease, tender joint counts were associated only with one QoL domain and swollen joints for none, while pain and stiffness were associated with several domains. Our results confirm the relevance of joint counts in RA, but suggest that in chronic chikungunya disease, joint counts have more limited value. Stiffness and pain score may be more important to quantify chikungunya arthritis impact.

BACKGROUND: The risk factors for hepatic hydrothorax are unknown.METHODS: We used data from three randomized trials of satavaptan treatment in patients with cirrhosis and ascites followed for up to 1 year. We excluded patients with previous hepatic hydrothorax or other causes for pleural effusion. The candidate risk factors were age, sex, heart rate, mean arterial pressure, diuretic-resistant ascites, a recurrent need for paracentesis, diabetes, hepatic encephalopathy, International Normalized Ratio, creatinine, bilirubin, albumin, sodium, platelet count, use of non-selective beta-blockers (NSBBs), spironolactone, furosemide, proton pump inhibitors, and insulin. We identified risk factors using a Fine and Gray regression model and backward selection. We reported subdistribution hazard ratios (sHR) for hepatic hydrothorax. Death without hepatic hydrothorax was a competing risk.RESULTS: Our study included 942 patients, of whom 41 developed hepatic hydrothorax and 65 died without having developed it. A recurrent need for paracentesis (sHR: 2.55, 95% CI: 1.28-5.08), bilirubin (sHR: 1.18 per 10 µmol/l increase, 95% CI: 1.09-1.28), diabetes (sHR: 2.49, 95% CI: 1.30-4.77) and non-use of non-selective beta-blockers (sHR: 2.27, 95% CI: 1.13-4.53) were risk factors for hepatic hydrothorax. Development of hepatic hydrothorax was associated with a high mortality-hazard ratio of 4.35 (95% CI: 2.76-6.97).CONCLUSIONS: In patients with cirrhosis and ascites, risk factors for hepatic hydrothorax were a recurrent need for paracentesis, a high bilirubin, diabetes and non-use of NSBBs. Among these patients with cirrhosis and ascites, development of hepatic hydrothorax increased mortality fourfold.

Chikungunya virus (CHIKV) has re-emerged as a significant human pathogen in the 21st century, causing periodic, and sometimes widespread, outbreaks over the past 15 years. Although mortality is very rare, a debilitating arthralgia is very common and may persist for months or years. There are no antivirals that are approved for the treatment of CHIKV infection, and current treatment options consist of supportive care only. Herein, we demonstrate the efficacy of a CHIKV-specific antibody in the prophylactic and therapeutic treatment of CHIKV in mouse models of disease. The fully human anti-CHIKV monoclonal Ab SVIR023 demonstrated broad in vitro activity against representative strains from the three major CHIKV clades. Therapeutic treatment with SVIR023 administered 1- or 3-days post-infection resulted in reduced virus in various tissues in a dose- and time-dependent manner. Prophylactic treatment up to 4 weeks prior to virus challenge was also effective in preventing disease in mice. Mice treated with SVIR023 and infected with CHIKV were resistant to secondary challenge and no evidence of antibody enhancement of disease was observed. Treatment with SVIR023 was effective in mouse models of CHIKV infection and disease and further evaluation towards clinical development is warranted.

This paper presents a concise framework for achieving sustainable and well-grounded mini-grid system across rural communities by interpreting various critical determinants which directly/indirectly affect a localized energy grid and draws a co-relation between them. The end product is a matrix that guides private sectors to rate an area in terms of its viability to cater an autonomous energy generation system by blending technology with economic and social aspects. More importantly the framework also addressed methodology for scaling a plant – circumstances such as post-grid arrival, rise in energy demand, conjunction with new generation plants required to meet the rise. Furthermore, the paper provides a commentary on business models and blend of financial indices suitable for decentralized system for long term financial viability for private sectors. GoN has been supporting rural micro-grids through Alternative Energy Promotion Centre (AEPC). Until recently, rural off-grid areas of Nepal had community led projects that would become defunct after arrival of national grid, fragmented planning, substandard technology, O&M issues etc. Now, with concept of private sector led projects opening up, the paper provides a skeleton for establishing mini-grid systems designed by negating those downsides that are practically feasible. This study was performed in various micro-grid sites in Makawanpur District. Research was carried out beforehand via online technology. This was to gain a sense of understanding before visiting the district. A field visit took place from April 24-26, 2018 to verify the research and to perform further analysis. Details were gathered firsthand through empathizing with locals, who filled out a questionnaire set Benchmarks were established in relation to technology, economics and social factors. Analysis was carried out, with the villages ranked against each other.

Clinical trials; Liver transplant; Quality of life Ensayos clínicos; Trasplante de hígado; Calidad de vida Assaigs clínics; Trasplantament de fetge; Qualitat de vida Management of decompensated cirrhosis is currently geared towards the treatment of complications once they occur. To date there is no established disease-modifying therapy aimed at halting progression of the disease and preventing the development of complications in patients with decompensated cirrhosis. The design of clinical trials to investigate new therapies for patients with decompensated cirrhosis is complex. The population of patients with decompensated cirrhosis is heterogeneous (i.e., different etiologies, comorbidities and disease severity), leading to the inclusion of diverse populations in clinical trials. In addition, primary endpoints selected for trials that include patients with decompensated cirrhosis are not homogeneous and at times may not be appropriate. This leads to difficulties in comparing results obtained from different trials. Against this background, the LiverHope Consortium organized a meeting of experts, the goal of which was to develop recommendations for the design of clinical trials and to define appropriate endpoints, both for trials aimed at modifying the natural history and preventing progression of decompensated cirrhosis, as well as for trials aimed at managing the individual complications of cirrhosis.

Highlights • This study investigated the duration of persistence of chikungunya-related arthralgia. • Statisticalanalysis of multiple cohorts of chikungunya patients was performed. • First estimates of the average rate of chronic chikungunya virus arthralgia resolution were calculated. • Varying rates of arthralgia resolution are associated with age and other factors., Background Arthralgia, persistent pain or stiffness of the joints, is the hallmark symptom of chronic chikungunya virus (CHIKV) disease. Associated with significant disability and reduced quality of life, arthralgia can persist for many months following CHIKV infection. Understanding the expected duration of arthralgia persistence is important for managing clinical expectations at the individual-level as well as for estimating long-term burdens on population health following a CHIKV epidemic. Methods A review of cohort studies reporting the prevalence of arthralgia post-CHIKV infection over multiple time points was conducted. Generalized linear models were used to estimate the average rate of arthralgia resolution following CHIKV infection. Results Sixteen cohort studies matching the inclusion criteria were identified and included in the analysis. An average rate of arthralgia resolution of 10.85% (95% confidence interval (CI) 9.05–12.66%) per month was estimated across studies, corresponding to an expected median time to arthralgia resolution of 6.39 months (95% CI 5.48–7.66 months) and an expected arthralgia prevalence of 72.21% (95% CI 68.40–76.23%) at 3 months post-CHIKV infection. Conclusions Estimates of the average rate of arthralgia resolution and the expected prevalence of arthralgia over time post-CHIKV infection were derived. These can help inform expectations regarding the long-term public health burdens associated with CHIKV epidemics.

INTRODUCTION Ascites is a frequent complication to cirrhosis. When ascites becomes refractory to standard diuretic pharmacotherapy, patients are facing a median survival of less than one year and most likely a need for frequent hospitalisations due to large-volume paracentesis or complications. An unmet need exists for new and improved treatments of refractory ascites and the present study investigates the potential of the natriuretic peptide ularitide for this indication. METHODS We aim to investigate the effects, safety and tolerability of ularitide as treatment of refractory ascites in cirrhosis patients in a randomised, double-blind, placebo-controlled trial. Participants receive ularitide or placebo as a continuous intravenous infusion during hospitalisation as an add-on to any diuretic treatment. Clinical end points include increase in diuresis and natriuresis, reduction in body weight and waist circumference, safety end points, as well as changes in plasma concentrations of renal and systemic response biomarkers and hormones. CONCLUSION This study will provide evidence concerning the potential of ularitide in treating cirrhosis patients with refractory ascites. FUNDING This investigator-initiated trial is supported by ADS AIPHIA Development Services AG. TRIAL REGISTRATION Clinicaltrials.gov (NCT04311489) and EU Drug Regulating Authorities Clinical Trials (EudraCT: 2019-002268-28). The trial will be conducted in accordance with good clinical practice, the Declaration of Helsinki and applicable demands from Danish authorities. INTRODUCTION Ascites is a frequent complication to cirrhosis. When ascites becomes refractory to standard diuretic pharmacotherapy, patients are facing a median survival of less than one year and most likely a need for frequent hospitalisations due to large-volume paracentesis or complications. An unmet need exists for new and improved treatments of refractory ascites and the present study investigates the potential of the natriuretic peptide ularitide for this indication. METHODS We aim to investigate the effects, safety and tolerability of ularitide as treatment of refractory ascites in cirrhosis patients in a randomised, double-blind, placebo-controlled trial. Participants receive ularitide or placebo as a continuous intravenous infusion during hospitalisation as an add-on to any diuretic treatment. Clinical end points include increase in diuresis and natriuresis, reduction in body weight and waist circumference, safety end points, as well as changes in plasma concentrations of renal and systemic response biomarkers and hormones. CONCLUSION This study will provide evidence concerning the potential of ularitide in treating cirrhosis patients with refractory ascites. FUNDING This investigator-initiated trial is supported by ADS AIPHIA Development Services AG. TRIAL REGISTRATION Clinicaltrials.gov (NCT04311489) and EU Drug Regulating Authorities Clinical Trials (EudraCT: 2019-002268-28). The trial will be conducted in accordance with good clinical practice, the Declaration of Helsinki and applicable demands from Danish authorities.

Objective.To determine the frequency of chronic joint pain and stiffness 3 years after infection with chikungunya virus (CHIKV) in a Latin American cohort.Methods.A cross-sectional followup of 120 patients from an initial cohort of 500 patients who reported joint pain 2 years after infection from the Atlántico Department, Colombia. Patients were clinically diagnosed as having CHIKV during the 2014–2015 epidemic, and baseline and followup symptoms at 40 months were evaluated in serologically confirmed cases.Results.Of the initial 500 patients enrolled in the study, 482 had serologically confirmed chikungunya infection. From this group, 123 patients reported joint pain 20 months after infection, and 54% of those patients reported continued joint pain 40 months after infection. Therefore, 1 out of every 8 people who tested serologically positive for CHIKV infection had persistent joint pain 3 years after infection. Participants who followed up in person were predominantly adult (mean ± SD age 51 ± 14 yrs) and female (86%). The most common type of pain reported in these patients at 40 months post-infection was pain with periods of relief and subsequent reoccurrence, and over 75% reported stiffness after immobility, with 39% experiencing morning stiffness.Conclusion.To our knowledge, this is the first report to describe persistent joint pain and stiffness 40 months after viral infection. The high frequency of chronic disease highlights the need to develop prevention and treatment methods. Further studies should be conducted to understand the similarities between post-chikungunya joint pain and rheumatoid arthritis.

Background: Severe ascites is associated with both a poor health-related quality of life (HRQL) and a mortality in excess of that captured by current prognostic clinical scores. Aim: To determine the association between HRQL and mortality in patients with severe ascites. Methods: The HRQL data from previously published randomised controlled trials examining the efficacy of satavaptan in ascites were retrospectively evaluated. Results: Of the 496 patients randomised who completed the SF-36, 405 patients had complete datasets and were included in the analysis (difficult-to-treat ascites, n = 164 or refractory ascites, n = 241). Overall, patients reported poor HRQL, in particular the physical component score (PCS) of SF-36. The physical component score (PCS) correlated with the mental component score (MCS) of SF-36 (Spearman rank correlation = 0.68) but not with markers of severity of liver disease. The PCS, but not the MCS, was significantly lower in patients who died (P = 0.01 and P = 0.84, respectively). After confounder-adjustment, the hazard ratio for a 10-point increase in the physical component score was 0.83 (95% CI; 0.72-0.97) for all-cause mortality and 0.84 (95% CI; 0.71-0.99) for cirrhosis-related deaths only, indicating that patients with better physical HRQL live longer on average. Conclusions: Poor physical component score (PCS) of SF-36 is an independent predictor of 12-month mortality in patients with severe ascites independent of current prognostic clinical scores. It holds promise not only in prognostic modelling but also as an endpoint in the evaluation of therapies targeting ascites.

The risk factors for hepatic hydrothorax are unknown.We used data from three randomized trials of satavaptan treatment in patients with cirrhosis and ascites followed for up to 1 year. We excluded patients with previous hepatic hydrothorax or other causes for pleural effusion. The candidate risk factors were age, sex, heart rate, mean arterial pressure, diuretic-resistant ascites, a recurrent need for paracentesis, diabetes, hepatic encephalopathy, International Normalized Ratio, creatinine, bilirubin, albumin, sodium, platelet count, use of non-selective beta-blockers (NSBBs), spironolactone, furosemide, proton pump inhibitors, and insulin. We identified risk factors using a Fine and Gray regression model and backward selection. We reported subdistribution hazard ratios (sHR) for hepatic hydrothorax. Death without hepatic hydrothorax was a competing risk.Our study included 942 patients, of whom 41 developed hepatic hydrothorax and 65 died without having developed it. A recurrent need for paracentesis (sHR: 2.55, 95% CI: 1.28-5.08), bilirubin (sHR: 1.18 per 10 µmol/l increase, 95% CI: 1.09-1.28), diabetes (sHR: 2.49, 95% CI: 1.30-4.77) and non-use of non-selective beta-blockers (sHR: 2.27, 95% CI: 1.13-4.53) were risk factors for hepatic hydrothorax. Development of hepatic hydrothorax was associated with a high mortality-hazard ratio of 4.35 (95% CI: 2.76-6.97).In patients with cirrhosis and ascites, risk factors for hepatic hydrothorax were a recurrent need for paracentesis, a high bilirubin, diabetes and non-use of NSBBs. Among these patients with cirrhosis and ascites, development of hepatic hydrothorax increased mortality fourfold.

Introduction/Objective: Musculoskeletal stiffness is a common feature in rheumatologic inflammatory diseases but little is known about background joint stiffness in the healthy population. The aim of this survey was to determine the variation in musculoskeletal stiffness with age in a cohort of healthy adults using a patient reported outcome instrument designed to assess stiffness in rheumatoid arthritis.Methods: Healthy subjects >= 18 years old were enrolled at two sites. Those with a diagnosis of rheumatological disease were excluded. Each subject completed a 21-item questionnaire designed to evaluate the severity of musculoskeletal stiffness, its physical impact and psychosocial impact, and to provide an overall stiffness score, expressed as a percentage. Scores were analyzed by age group.Results: Two hundred eighty-two subjects were included with a mean age of 42 years (+/- 17, range 18-85). More than 50% of subjects reported stiffness in each age group but with a low median overall stiffness score of 5.4% (IQR 0, 12.6). Scores were markedly higher in those aged >= 60 years, median 10.0% (IQR 2.6, 21.9), and only in this age group did the majority of subjects report a physical or psychosocial impact of stiffness. Scores in males and females were similar.Conclusion: The prevalence of musculoskeletal stiffness in healthy subjects of all ages is not negligible, and the high frequency of stiffness and greater severity in the upper age cohort suggest that the background joint stiffness amongst older subjects should be considered when interpreting stiffness in rheumatologic patients.

The Amazon region of Brazil experienced a large epidemic of East Central South African (ECSA) chikungunya virus (CHIKV) in 2017 and continuous transmission of CHIKV persists. The impact of chronic arthritis caused by ECSA CHIKV is unknown.The study aim was to describe the duration, severity, and characteristics of CHIKV arthritis in Roraima, Brazil, in comparison with local controls to further understand the long-term rheumatologic impact of ECSA CHIKV infection.We performed a cross-sectional analysis comparing clinical arthritis outcomes among 40 cases with chronic ( 3 months) arthritis attributed to their CHIKV disease (n = 40) with control participants who were exposed to CHIKV but did not develop chronic arthritis (n = 40), rheumatoid arthritis controls (n = 40), and healthy controls lacking CHIKV exposure and arthritis (n = 40).Our primary finding is that over 2 years post-infection, patients report moderate arthritis disease severity comparable with rheumatoid arthritis with the most significant impact on decreased quality of life from pain.These findings suggest that chronic arthritis caused by ECSA CHIKV infection has had a moderate impact in the Americas. Key Points • Chikungunya infection is responsible for moderate arthritis disease severity. • The East Central South African (ECSA) strain of CHIKV is a cause of persistent arthritis in Roraima, Brazil.

Patients with cirrhosis are at increased risk for cardiovascular death [1]. At the same time, they have a prolonged electrocardiographic QT interval, which is a sign of delayed ventricular repolari...

Background: Musculoskeletal stiffness is reported to be frequent following chikungunya infection and can persist for many months after infection. However, stiffness severity and its impact is not well characterised in this disease. A stiffness patient reported outcome instrument has been developed for use in rheumatoid arthritis. Objectives: Our objective was to assess the use of this questionnaire and importance of musculoskeletal stiffness in a cohort of chikungunya patients with chronic joint symptoms in the Atlantico Department of Colombia. Methods: Sixty-seven patients with chronic arthralgia and 15 patients without arthralgia were followed up a mean of 40 months after chikungunya infection. The patients came from a larger cohort of 500 patients previously followed up 20 months after infection. Those consenting to a 40-month in-person follow-up were included here. Tender joint counts, a pain intensity visual analogue scale (VAS), Health Assessment Questionnaire-Disability Index (HAQ-DI) and the EuroQol overall health VAS (EQ-VAS) were completed. A 21-item musculoskeletal stiffness questionnaire (MSQ) was completed and summarized as percentage scores for overall stiffness and its components: stiffness severity, physical impact and psychosocial impact. Results: The 82 patients (12 male and 70 female) had a mean age 51±14 years. Forty-two out of sixty-seven patients with arthralgia and 3/15 patients without arthralgia reported musculoskeletal stiffness. Stiffness in those patients had a median severity of 28% (IQR 0-42). An impact of their stiffness on physical activities was reported by 39/45 patients (87%) and psychosocial impact by 32/45 patients (71%). Overall MSQ score was a median of 16% (IQR 0-34). Mean tender joint count in patients reporting arthralgia was 6.2±7.1, mean pain intensity 65±20 out of 100, mean HAQ-DI = 0.54±0.52, and a mean EQ-VAS = 68±62 out of 100. Overall stiffness scores were poorly correlated with tender joint counts (r2=0.17) and pain intensity (r2=0.22). Stiffness scores were more strongly associated with the HAQ-DI (r2=0.52) and EQ-VAS overall health VAS scores (r2=0.46), whereas tender joint counts were not: r2=0.22 for HAQ-DI and r2=0.21 for EQ-VAS. Conclusion: Musculoskeletal stiffness following chikungunya infection is distinct from the persistent arthralgia usually reported. It does not necessarily occur in the same patients and is poorly correlated with joint pain severity. Stiffness, as measured by this questionnaire, may be more strongly associated than arthralgia with overall health and disability indices in patients with chikungunya disease. The MSQ is a potentially useful instrument for assessing symptoms in chronic chikungunya disease. Disclosure of Interests: Hugh Watson Shareholder of: Sanofi, Employee of: Sanofi, Sarah Tritsch: None declared, Liliana Encinales: None declared, Andres Cadena: None declared, Carlos Cure: None declared, Alexandra Porras: None declared, Alejandro Rico Mendoza: None declared, Aileen Chang: None declared

Background: A patient questionnaire for evaluating musculoskeletal stiffness (MSQ) has been developed for rheumatoid arthritis (RA) (Halls 2015) and also tested in chikungunya disease. Joint stiffness is associated with older age in adults. Objectives: The aim of this study was to evaluate the variation in MSQ scores with age in a cohort of healthy adults. Methods: Subjects ≥18 years old were enrolled at two sites. Subjects were engaged in, or had completed, tertiary education. Subjects with a diagnosis of joint disease, Parkinson’s disease or multiple sclerosis were excluded. Each subject completed a 21-item questionnaire designed to evaluate the severity of musculoskeletal stiffness, its physical impact and psychosocial impact, and to provide an overall stiffness score. Results are expressed as a percentage of the maximum possible score. Results: Two hundred and fifty-eight subjects were included, 120 males and 138 females. Subjects were >95% Caucasian. The mean age of subjects was 40±16 years. No differences were seen in the stiffness scores between males and females. The percentage of subjects reporting any stiffness was over 50% in every age group, and markedly higher in those aged ≥60 years (Table). The average overall MSQ scores and those of its three components were low and showed little variation between the three lower age cohorts, but scores increased in the upper age cohort (Table). Conclusion: The prevalence of musculoskeletal stiffness in healthy subjects as measured with this questionnaire is not negligible. Overall stiffness scores in this study were low in the subjects aged 18-59 years when compared to those in RA and chikungunya disease. However, the high frequency of stiffness and the higher average scores in the upper age cohort suggest that the background joint stiffness amongst older subjects should be considered when interpreting stiffness scores in patients. References [1] Halls S, Dures E, Kirwan J, et al. AB1128-HPR Developing A New Rheumatoid Arthritis (RA) Stiffness Patient Reported Outcome Measure (PROM). Ann Rheum Dis2016; 75: 1317 Disclosure of Interests: Hugh Watson Shareholder of: Sanofi, Employee of: Sanofi, Amalie Lynggard: None declared, Lars-Erik Bartels: None declared

Background and Aim: Hyponatremia is associated with development of hepatic encephalopathy (HE), but the nature of the relationship between serum sodium and HE incidence is unknown. We examined the association between serum sodium, changes in serum sodium, and HE incidence using data from three randomized trials of satavaptan in cirrhosis patients with ascites. Methods: During follow-up, patients were examined for HE, and serum sodium was measured regularly. We used fractional polynomials to estimate the nature of the association between current serum sodium and hazard rate of HE (e.g. with a linear, logarithmic, or exponential slope) and Cox regression to adjust for confounders. Moreover, we examined the association between serum sodium at inclusion and 30-day and 1-year cumulative risk of HE. Finally, we examined the effect of “change in serum sodium since inclusion” on the hazard rate of HE. Results: We included 1116 patients of whom 302 developed HE. Median serum sodium at inclusion was 137 (interquartile range, 134–139). The lower the current serum sodium, the higher the rate of HE. Specifically, the confounder-adjusted HE hazard rate increased linearly by 8% (adjusted hazard ratio = 1.08, 95% confidence interval: 1.06–1.10) for every mmol/L decrease in serum sodium over the range of measured values. Current serum sodium had a stronger effect on the HE rate than the changes in serum sodium since inclusion. Conclusion: The hazard rate of HE development increased by 8% for every mmol/L decrease in serum sodium. Further, current serum sodium had a stronger effect on the HE rate than changes in serum sodium.

BACKGROUND AND AIM: Hyponatremia, a cause of brain dysfunction and risk factor for hepatic encephalopathy, is frequent in patients with advanced cirrhosis and ascites. The interdependence of liver failure and hyponatremia makes it difficult to separate the effects of each on cognitive function. The objective was to assess whether an increase in plasma sodium in patients with cirrhosis and ascites leads to an improvement in cognitive function.METHODS: This is a post-hoc analysis of 250 cirrhosis patients without overt hepatic encephalopathy randomized to receive either placebo or satavaptan, a vasopressin V2 antagonist. The exposure was plasma sodium, and the outcome was the trail-making test (TMT) parts A and B, which assesses speed of information processing, performed before the study starts and after 14 days. The results were analyzed by initial and change to final sodium concentration.RESULTS: At entry, the patients with normonatremia exhibited better results on both the TMT-A (median 56 vs 77.5 s for patients with sodium ≤ 130 mmol/L [P = 0.0059]) and the TMT-B (median 127 vs 170 s for patients with sodium ≤ 130 mmol/L [P = 0.0066]), unrelated to age. Improvement of hyponatremia was more common in patients who received satavaptan (59.7%) than placebo (18.5%). Correction of hyponatremia did not shorten the simple TMT-A but markedly improved the complex TMT-B by an average of 20 s compared with 6.5 s in those with continuing hyponatremia (P = 0.02). Liver status measures remained stable during the period reported.CONCLUSIONS: These data suggest that improvement of hyponatremia in patients with cirrhosis leads to an increase in the speed of complex information processing.

Background:Chronic rheumatological manifestations similar to those of rheumatoid arthritis (RA) have been described after chikungunya virus infection. However, the clinical significance of the symptoms and disease severity in the two conditions has not been directly compared.Objectives:To compare, using identical measures of disease severity and patient outcomes, the impact of disease severity measures and symptoms on outcomes in RA and chronic chikungunya disease.Methods:Forty patients with chronic chikungunya arthralgia two years post-infection and 40 matched patients with RA were enrolled in Roraima, Brazil. Twenty-eight joints were assessed for tenderness and swelling, a pain intensity visual analogue scale, musculoskeletal stiffness questionnaire, modified Health Assessment Questionnaire and the EuroQol EQ5D-5L quality of life assessment were completed. The importance of the various measures of disease severity were analysed using Spearman’s rank correlation and regression analysis.Results:Tender and swollen joint counts, pain and stiffness were all predictive of the HAQ disability index in RA, but only stiffness was significantly associated with disability in chikungunya patients (Table 1). Tender and swollen joint counts, pain and stiffness were predictive for all EQ5D quality of life domains (except anxiety/depression) in RA patients. In contrast, in chikungunya disease, tender joint counts were predictive only of usual daily activities; pain was predictive of impaired mobility, self-care and discomfort, while stiffness was predictive for the mobility and anxiety/depression domains (Figure 1). Swollen joint counts were not associated with any of the patient outcomes in chikungunya disease. Linear regression analysis confirmed (p=0.003) that the effect of swollen joint count on the HAQ disability index depends on the underlying disease.Table 1.Association of disease severity with HAQ disability index in rheumatoid and CHIKV+ arthritisSeverity measureRheumatoid arthritisCHIKV+ arthritisr (p)r (p)Tender joint count0.56 (0.0002)0.24 (0.14)Swollen joint count0.60 (0.002 (0.99)Joint pain (VAS)0.55 (0.0002)0.29 (0.07)Stiffness severity0.57 (0.0001)0.38 (0.02)Figure 1.Association of disease severity with quality of life domains in rheumatoid and CHIKV+ arthritisConclusion:The value of all the disease severity measures tested in RA were confirmed, but tender joint counts may have more limited value in the assessment of chronic chikungunya disease. Joint swelling appears to have little impact for chikungunya patients, while stiffness appears to be an important metric to quantify chikungunya arthritis disease severity.Disclosure of Interests:Hugh Watson Shareholder of: Sanofi, Employee of: Sanofi, Ramão Luciano Nogueira-Hayd: None declared, Maony Rodrigues-Moreno: None declared, Felipe Naveca: None declared, Giulia Calusi: None declared, Richard Amdur: None declared, Karol Suchowiecki: None declared, Gary S. Firestein: None declared, Gary Simon: None declared, Aileen Chang: None declared

Background & aims Many patients with cirrhosis use proton pump inhibitors. We aimed to determine their effects on the risk and prognosis of infections in patients with cirrhosis and ascites. Methods We used data from three 1-year trials of satavaptan treatment of ascites (N = 1198) to compare incidence and 90-day mortality of first-time infections between users and nonusers of proton pump inhibitors. With standard and marginal structural Cox models, we adjusted for differences in gender, age, cirrhosis aetiology, Model for End-stage Liver Disease score, serum albumin, lactulose use, severity of ascites, and history of spontaneous bacterial peritonitis or variceal bleeding. Results During the follow-up, 446 patients had an infection. At inclusion, 524 patients (44%) used proton pump inhibitors, and 645 (54%) used them at some point during the follow-up. Proton pump inhibitor use increased the rate of infections overall (adjusted hazard ratio = 1.43, 95% CI 1.18-1.74), and it also increased the rate of all specific types of infections except upper respiratory tract infections of presumably viral origin. The estimated cumulative risk of infections was 36.4% for proton pump inhibitor users vs 25.1% for nonusers at 6 months (relative risk = 1.45, 95% CI 1.22-1.73), and 45.2% vs 37.7% at 1 year (relative risk = 1.20, 95% 0.97-1.40). Use of proton pump inhibitors did not affect mortality during the 90 days following infection (adjusted hazard ratio = 0.83, 95% CI 0.53-1.31). Conclusions Approximately half of patients with cirrhosis and ascites use proton pump inhibitors. This use increases their risk of bacterial infections, but does not affect their prognosis after an infection occurs.

BACKGROUND & AIMS: Acute episodes of renal dysfunction or acute kidney injury (AKI) in cirrhotic patients with ascites are mostly precipitated by an acute event. The prevalence of un-precipitated AKI in stable ascitic cirrhotic patients is unknown. The aims of this study were to determine (i) the prevalence of un-precipitated AKI in stable cirrhotics with ascites and (ii) any predictive factors for its development.METHODS: A total of 1115 stable cirrhotic patients with mild liver and renal dysfunction but varying degrees of ascites severity from 3 previous satavaptan vs placebo randomized controlled trials (Group A, ascites requiring diuretics but not paracentesis; Group B, ascites requiring frequent paracentesis; Group C, refractory ascites) were included. AKI was diagnosed when there was either an increase of ≥0.3 mg/dL in ≤48 hours or a 50% increase in serum creatinine, and staged according to the fold increase of the serum creatinine. Two serum creatinine levels measured maximally 7 days apart at screening and at randomization of the satavaptan studies with no acute intervening events were used.RESULTS: The prevalence of un-precipitated AKI was 1.8% overall, with the prevalence rising with increasing severity of ascites. Ninety-five per cent of cases were stage 1, with 15% progression rate, 3 reaching the severity of type 1 acute hepatorenal syndrome. Ascites severity was the most powerful predictor for un-precipitated AKI development, which did not predict overall mortality.CONCLUSIONS: Increased prevalence of AKI with more severe ascites despite minimal baseline liver and renal dysfunction suggests that frequent monitoring of renal function in these patients is mandatory.

BackgroundThere is limited evidence to support the belief that benzodiazepines increase cirrhosis patients’ risk of hepatic encephalopathy (HE).ObjectiveWe aimed to examine the association between benzodiazepine use and HE development in cirrhosis patients.MethodsWe used data on 865 cirrhosis patients with ascites from three trials to study the effect of benzodiazepine use on development of first-time HE. For each patient, we classified periods of benzodiazepine use by the number of days since initiation. We used Cox regression to compare the risk of HE in current benzodiazepine users vs. non-users adjusting for confounders.ResultsCirrhosis patients were not at increased risk of HE for the first two days of benzodiazepine use, but then faced a five-fold increased risk of HE during days 3 to 10 of benzodiazepine use. The risk of HE was not increased for those who had been using benzodiazepines for more than 28 days.ConclusionCirrhosis patients who had begun using benzodiazepines between 3 and 10 days previously had a markedly increased risk of developing first-time HE. Cirrhosis patients who had been using benzodiazepines for just one or two days or continued use for more than 28 days did not have such an excess risk.

Satavaptan, a vasopressin V2-receptor antagonist, has been shown to improve hyponatraemia in patients with cirrhosis. Hyponatraemia has been associated with an increased risk of hepatic encephalopathy. The objective is to evaluate the efficacy of satavaptan in reducing the risk of new episodes of hepatic encephalopathy. 1,200 patients with cirrhosis and uncomplicated ascites were included in three randomised double-blind studies comparing satavaptan (5-10 mg/day) vs placebo over a one-year treatment period. Effects on incidence of hepatic encephalopathy episodes in individual study and pooled databases were determined with analyses adjusted for hyponatraemia and previous episodes of encephalopathy. Hyponatraemia was improved by satavaptan. Three hundred and ninety-five hepatic encephalopathy episodes were recorded. The risk of an episode and the mean number of episodes were not reduced by satavaptan in any of the three studies in the overall population or in patients who were hyponatraemic on entry. These findings were confirmed in analysis of the pooled data. Satavaptan did not reduce the frequency of hepatic encephalopathy in patients with cirrhosis and ascites.

UNLABELLED: Proton pump inhibitors (PPIs) may be a risk factor for hepatic encephalopathy (HE) in patients with cirrhosis, possibly through translocation of gut bacteria, which can also lead to spontaneous bacterial peritonitis (SBP). We examined the associations between PPIs and development of HE or SBP in patients with cirrhosis with ascites. We used data from three 1-year trials of satavaptan for ascites control. We used Cox regression to compare HE and SBP rates between users and nonusers of PPIs. At inclusion, 39% of the 865 patients with cirrhosis with ascites used PPIs, 52% used them at some point during the follow-up, and the proportion of current users was always in the 30%-39% range. There were 189 first-time HE episodes during the follow-up, and the cumulative 1-year risk was 31% for those who used PPIs at baseline versus 25% for those who did not. The confounder-adjusted hazard ratio (HR) of HE for current PPI use versus current nonuse was 1.36 (95% confidence interval [CI], 1.01-1.84). The HR for overt HE was higher (adjusted HR = 1.88; 95% CI, 1.21-1.91). During the follow-up, 86 patients developed SBP. The adjusted HR of SBP for current PPI users versus nonusers was 1.72 (95% CI, 1.10-2.69).CONCLUSION: PPIs were used by 52% of this international cirrhosis cohort during a 1-year period and was a risk factor for developing HE and SBP. These findings are consistent with the hypothesis that PPIs may increase translocation of gut bacteria. (Hepatology 2016;64:1265-1272).

BACKGROUND: Epilepsy is associated with an increased mortality among cirrhosis patients, but the reasons are unknown. We aimed to determine whether epilepsy is a risk factor for developing hepatic encephalopathy (HE), which is a strong predictor of mortality.METHODS: We used data from three randomized 1-year trials of satavaptan in cirrhosis patients with ascites. With Cox regression, we compared the hazard rates of HE grade 1-4 between those cirrhosis patients who did or did not have epilepsy. We adjusted for confounding by gender, age, cirrhosis etiology, diabetes, history of HE, Model for Endstage Liver Disease (MELD) score, serum sodium, albumin, lactulose use, rifaximin use, and benzodiazepine/barbiturate sedation. In a supplementary analysis we examined the association between epilepsy and the hazard rate of HE grade 2-4.RESULTS: Of the 1120 cirrhosis patients with ascites, 21 (1.9 %) were diagnosed with epilepsy. These patients had better liver function at inclusion than the patients without epilepsy (median MELD score 7.9 vs. 11.4), and only one died during the trials. Nevertheless, seven patients with epilepsy had an HE episode during the follow-up, and the adjusted hazard ratio of HE grade 1-4 for patients with epilepsy vs. controls was 2.12 (95 % CI 0.99-4.55). The corresponding hazard ratio of HE grade 2-4 was 3.83 (95 % CI 1.65-8.87).CONCLUSIONS: Our findings suggest that epilepsy is associated with an increased risk of HE in patients with cirrhosis.

The safety of nonselective β-blockers (NSBBs) in advanced cirrhosis has been questioned. We used data from three satavaptan trials to examine whether NSBBs increase mortality in cirrhosis patients with ascites. The trials were conducted in 2006-2008 and included 1198 cirrhosis patients with ascites followed for 1 year. We used Cox regression to compare all-cause mortality and cirrhosis-related mortality between patients who did and those who did not use NSBBs at randomization, controlling for age, gender, Model for End-Stage Liver Disease score, Child-Pugh score, serum sodium, previous variceal bleeding, cirrhosis etiology, and ascites severity. Moreover, we identified clinical events predicting that a patient would stop NSBB treatment. At randomization, the 559 NSBB users were more likely than the 629 nonusers to have a history of variceal bleeding but less likely to have Child-Pugh class C cirrhosis, hyponatremia, or refractory ascites. The 52-week cumulative all-cause mortality was similar in the NSBB user and nonuser groups (23.2% versus 25.3%, adjusted hazard ratio = 0.92, 95% confidence interval 0.72-1.18), and NSBBs also did not increase mortality in the subgroup of patients with refractory ascites (588 patients, adjusted hazard ratio = 1.02, 95% confidence interval 0.74-1.40) or in any other subgroup. Similarly, NSBBs did not increase cirrhosis-related mortality (adjusted hazard ratio = 1.00, 95% confidence interval 0.76-1.31). During follow-up, 29% of initial NSBB users stopped taking NSBBs, and the decision to stop NSBB treatment marked a sharp rise in mortality and coincided with hospitalization, variceal bleeding, bacterial infection, and/or development of hepatorenal syndrome. Conclusion: This large and detailed data set on worldwide nonprotocol use of NSBBs in cirrhosis patients with ascites shows that NSBBs did not increase mortality; the decision to stop NSBB treatment in relation to stressful events may have added to the safety. (Hepatology 2016;63:1968-1976).

Hyponatremia in cirrhosis is associated with significant morbidity and mortality and complicates ascites management. Vasopressin receptor antagonists improve serum sodium concentration by increasing renal solute-free water excretion, but their effects on the management of ascites have not been assessed. Our aim was to investigate the effects of satavaptan, a highly selective vasopressin V2 receptor antagonist, on ascites management and serum sodium in hyponatremic patients with cirrhosis. A total of 110 patients with cirrhosis, ascites, and hyponatremia (serum sodium ≤130 mmol/L) were included in a multicenter, double-blind, randomized, controlled study comparing three fixed doses of satavaptan (5 mg, 12.5 mg, or 25 mg once daily) versus placebo. Duration of treatment was 14 days and all patients received spironolactone at 100 mg/day. Satavaptan treatment was associated with improved control of ascites, as indicated by a reduction in body weight (mean change at Day 14 was +0.49 kg [±4.99] for placebo versus +0.15 kg [±4.23], −1.59 kg [±4.60] and −1.68 kg [±4.98] for the 5 mg, 12.5 mg, and 25 mg doses, respectively; P = 0.05 for a dose-effect relationship overall) and a parallel reduction in abdominal girth. This beneficial effect on ascites was associated with improvements in serum sodium (mean change from baseline to day 5 was 1.3 ± 4.2, 4.5 ± 3.5, 4.5 ± 4.8, and 6.6 ± 4.3 mmol/L for the placebo group and the groups on satavaptan at 5 mg, 12.5 mg, and 25 mg/day, respectively; P < 0.01 for all compared to placebo). Thirst was significantly more common in patients treated with satavaptan compared to those treated with placebo, whereas the frequency of other adverse events was similar among groups. Conclusion: The V2 receptor antagonist satavaptan improves the control of ascites and increases serum sodium in patients with cirrhosis, ascites, and hyponatremia under diuretic treatment. (HEPATOLOGY 2008.)

BACKGROUND & AIMS: It remains unclear whether diabetes increases the risk for hepatic encephalopathy (HE) in cirrhotic patients. We examined this question using data from three randomized trials of satavaptan, a vasopressin receptor antagonist that does not affect HE risk, in cirrhotic patients with ascites.METHODS: The trials included 1198 patients, and we excluded those with HE before or at randomization and followed the remaining patients for the one year duration of the trials. They were examined for HE regularly, and we compared rates of first-time overt HE between diabetics and non-diabetic patients using Cox regression, adjusting for gender, age, ascites severity, cirrhosis etiology, Child-Pugh class, creatinine, bilirubin, INR, sodium, potassium, albumin, platelets, lactulose use, benzodiazepine/barbiturate use, spironolactone dose, furosemide dose, potassium-sparing diuretic dose, and CirCom comorbidity score.RESULTS: We included 862 patients of whom 193 (22%) had diabetes. In total, they experienced 115 first-time episodes of overt HE during the follow-up. Fewer diabetics than non-diabetic patients were in Child-Pugh class C at baseline (13% vs. 23%), yet they had higher cumulative risk of first-time overt HE (26.0% vs. 15.8% after 1 year), and their episodes of first-time overt HE were more likely to progress beyond grade 2 (64% vs. 42% of episodes progressed to grade 3 or 4, p=0.01 for independence between diabetes and highest HE grade). After the confounder adjustment, the hazard ratio of first-time overt HE for diabetics vs. non-diabetic patients was 1.86 (95% CI 1.20-2.87).CONCLUSIONS: Diabetes increased the risk of first-time overt HE among cirrhotic patients with ascites.

A number of multi-agency co-located teams have now been established across the country. A small-scale study was conducted which aimed to learn from the professionals working in these teams. Specifically, the study sought to investigate which factors are perceived by members of these teams as most important in facilitating multi-agency team development. It further aimed to investigate the areas in which new multi-agency co-located teams might most usefully benefit from external support (by way of professional time, resources, expertise, training, etc.). Factors perceived as most important in facilitating multi-agency team development are identified. A number of key areas in which applied psychologists might support multi-agency teams are also identified and discussed, including helping such teams to establish a shared vision, to understand the roles and responsibilities of team members and to evaluate the outcomes of their work, and helping teams in relation to joint training.