APASL clinical practice guidelines on the management of acute kidney injury in acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a syndrome that is characterized by the rapid development of organ failures predisposing these patients to a high risk of short-term early death. The main causes of organ failure in these patients are bacterial infections and systemic inflammation, both of which can be severe. For the majority of these patients, a prompt liver transplant is still the only effective course of treatment. Kidneys are one of the most frequent extrahepatic organs that are affected in patients with ACLF, since acute kidney injury (AKI) is reported in 22.8-34% of patients with ACLF. Approach and management of kidney injury could improve overall outcomes in these patients. Importantly, patients with ACLF more frequently have stage 3 AKI with a low rate of response to the current treatment modalities. The objective of the present position paper is to critically review and analyze the published data on AKI in ACLF, evolve a consensus, and provide recommendations for early diagnosis, pathophysiology, prevention, and management of AKI in patients with ACLF. In the absence of direct evidence, we propose expert opinions for guidance in managing AKI in this very challenging group of patients and focus on areas of future research. This consensus will be of major importance to all hepatologists, liver transplant surgeons, and intensivists across the globe.

Prevention of mother-to-child transmission of hepatitis B virus: An observation of routine practice in a tertiary liver centre before and after the introduction of the global health sector strategy on viral hepatitis.

INTRODUCTION: Worldwide, around 296 million people have hepatitis B virus (HBV) infection, most commonly transmitted from mother-to-child. Global Health Sector Strategy on Viral Hepatitis (GHSSVH) was introduced in May 2016, calling for elimination of viral hepatitis by 2030. This study aims to compare practice in a tertiary liver centre before and after GHSSVH introduction for prevention of mother-to-child transmission (MTCT). MATERIALS AND METHODS: This retrospective cohort study was performed in a tertiary referral liver centre in Malaysia, using data from electronic medical record from January 2015 to December 2019. A total of 1457 medical records of female with HBV infection were screened. The inclusion criteria of the study were pregnant women with HBsAg positive or known to have HBV infection during the study period. We excluded patients with co-infections of other types of viral hepatitis or human immunodeficiency virus, concurrent liver diseases (e.g.: autoimmune hepatitis, Wilson's disease), previous organ transplant and malignancy­except for hepatocellular carcinoma (HCC). RESULTS: This study included 117 pregnancies and 21/117 (17.9%) were on antiviral therapy (AVT) for HBV. In 2017­ 2019, 13/18 (72.2%) of those with HBV DNA >200,000IU/ml were on AVT, compared to 5/9 (55.6%) for 2015­2016, indicating 58% (95% CI −63% to 568%) higher odds of being on AVT in post GHSSVH group after accounting for HBV DNA. CONCLUSION: Uptake of maternal AVT for the prevention of MTCT shows an increased trend since the introduction of GHSSVH, with room for improvement.

Clinical evaluation of serological IgG antibody response on the Abbott Architect for established SARS-CoV-2 infection.

OBJECTIVE: This study aimed to evaluate the diagnostic performance of the Abbott Architect SARS-CoV-2 IgG assay in COVID-19 patients. METHODS: Residual sera from 177 symptomatic SARS-CoV-2-positive patients and 163 non-COVID-19 patients were tested for antibody with the Abbott SARS-CoV-2 IgG assay (Abbott Diagnostics, Chicago, USA). Clinical records for COVID-19 patients were reviewed to determine the time from onset of clinical illness to testing. RESULTS: Specificity of the assay was 100.0% (95%CI: 97.1-100.0%). The clinical sensitivity of the assay varied depending on time from onset of symptoms, increasing with longer periods from the onset of clinical illness. The clinical sensitivity at ≤6 days was 8.6% (7/81; 95%CI: 3.8-17.5%), at 7-13 days 43.6% (17/39; 95%CI: 28.2-60.2%), at 14-20 days 84.0% (21/25; 95%CI: 63.1-94.7%), and at ≥21 days 84.4% (27/32; 95%CI: 66.5-94.1%). Clinical sensitivity was higher in the ≥14-day group compared to <14 days. There were no differences between the 14-20-day and ≥21-days groups; the combined clinical sensitivity for these groups (≥14 days) was 84.2% (49/57; 71.6-92.1%). CONCLUSION: The Abbott SARS-CoV-2 IgG test has high specificity. Clinical sensitivity was limited in the early stages of disease but improved from 14 days after the onset of clinical symptoms.

Bioequivalence and pharmacokinetic comparison of two fixed dose combination of Metformin/ Glibenclamide formulations in healthy subjects under fed condition.

AIM: This study is conducted to compare the pharmacokinetic profiles of two fixed dose combination of metformin/glibenclamide tablets (500mg/5 mg per tablet). MATERIALS AND METHODS: This is a single-center, single-dose, open-label, randomized, 2-treatment, 2-sequence and 2- period crossover study with a washout period of 7 days. All 28 adult male subjects were required to fast for at least 10 hours prior to drug administration and they were given access to water ad libitum during this period. Thirty minutes prior to dosing, all subjects were served with a standardized high-fat and high-calorie breakfast with a total calorie of 1000 kcal which was in accordance to the EMA Guideline on the Investigation of Bioequivalence. Subsequently, subjects were administered either the test or reference preparation with 240mL of plain water in the first trial period. During the second trial period, they received the alternate preparation. Plasma levels of glibenclamide and metformin were analysed separately using two different high performance liquid chromatography methods. RESULTS: The 90% confidence interval (CI) for the ratio of the AUC0-t, AUC0-∞, and Cmax of the test preparation over those of the reference preparation were 0.9693-1.0739, 0.9598- 1.0561 and 0.9220 - 1.0642 respectively. Throughout the study period, no serious drug reaction was observed. However, a total of 26 adverse events (AE)/side effects were reported, including 24 that were definitely related to the study drugs, namely giddiness (n=17), while diarrheoa (n=3), headache (n=2) and excessive hunger (n=2) were less commonly reported by the subjects. CONCLUSION: It can be concluded that the test preparation is bioequivalent to the reference preparation.

Ubiquitin Regulation of Trk Receptor Trafficking and Degradation.

The regulation of Trk receptors is critical for orchestrating multiple signalling pathways required for developing and maintaining neuronal networks. Activation of Trk receptors results in signalling, internalisation and subsequent degradation of the protein. Although ubiquitination of TrkA by Nedd4-2 has been identified as an important degradation pathway, much less is known about the pathways regulating the degradation of TrkB and TrkC. Critical to the interaction between TrkA and Nedd4-2 is a PPxY motif present within TrkA but absent in TrkB and TrkC. Given the absence of this interaction motif, it remains to be determined how TrkB and TrkC are ubiquitinated. Here we report that the adaptor protein Ndfip1 can interact with all three Trk receptors and show for TrkB the recruitment of Nedd4-2 through PPxY motifs present in Ndfip1. Ndfip1 mediates the ubiquitination of TrkB, resulting in receptor trafficking predominantly on Rab7 containing late endosomes, highlighting a pathway for TrkB degradation at the lysosome. In vitro, overexpression of Ndfip1 increased TrkB ubiquitination and decreased viability of BDNF-dependent primary neurons. In vivo, conditional genetic deletion of Ndfip1 increased TrkB in the brain and resulted in enlargement of the granular cell layer of the dentate gyrus.

Human leukocyte antigen (HLA) class II association in chronic hepatitis B patients with hepatocellular carcinoma in a Malay population: A pilot study.

Asian countries account for almost three quarter of hepatocellular carcinoma (HCC) reported globally and chronic hepatitis B infection is one of the main contributors. Clinical observations show that Malay patients with chronic hepatitis B and HCC tend to have a worse outcome, when compared to other two major races in Malaysia. The objectives of this study was to determine the frequency of human leukocyte antigen (HLA) class II alleles in chronic hepatitis B patients with HCC among Malays compared to the general population to identify potential associations of HLA alleles with this disease. HLA class II typing was performed in chronic hepatitis B patients with hepatocellular carcinoma (n=12) by -polymerase chain reaction, sequence specific primer (PCR-SSP) method. There were higher allelic frequencies of certain HLA-DQB1 and HLA-DRB1 alleles; HLA-DQB1*03 (07) (41.7%), and HLA-DRB1*12 (41.7% vs 28.6%) and compared to controls (41.7% vs 29.7%). However, there was no significant statistical correlation found when compared with the normal healthy general population. This study provides an insight into the HLA Class II association with chronic hepatitis B and hepatocellular carcinoma in Malays. However, findings from this study should be validated with a larger number of samples using a high resolution HLA typing.

Pharmacist interventions during patient rounds in two intensive care units: Clinical and financial impact.

INTRODUCTION: The risk of prescribing errors and related adverse drug events (ADE) on the intensive care unit (ICU) is high. Based on studies carried out in North America or the UK, a clinical pharmacy service can reduce ADEs and lower overall costs. This study looks into the clinical and financial impact of interventions made by pharmacists during patient rounds in two ICU settings in the Netherlands. MATERIALS AND METHODS: A quality improvement study was performed in a general teaching hospital (GTH) and a university hospital (UH) in the Netherlands. The improvement consisted of a review of medication orders and participation in patient rounds by an ICU-trained pharmacist. The main outcome measure was the proportion of accepted pharmacist interventions. Secondary outcome measures were the clinical relevance of the accepted interventions, the proportion of prevented potential ADEs (pADE) and a cost-benefit ratio. RESULTS: In the GTH 160 patients and in the UH 174 patients were included. A total of 332 and 280 interventions were analysed. Acceptance of the interventions was 67.3% in the GTH and 61.8% in the UH. The accepted interventions were mostly scored as clinically relevant, resulting in 0.16 and 0.11 prevented pADEs per patient. The cost benefit was €119 (GTH) and €136 (UH) per accepted intervention. CONCLUSION: This clinical pharmacy service in two ICUs resulted in high numbers of accepted and clinically relevant interventions. Our model appeared to be cost-effective in both ICU settings.

The present and future disease burden of hepatitis C virus infections with today's treatment paradigm: Volume 4.

Factors influencing the morbidity and mortality associated with viremic hepatitis C virus (HCV) infection change over time and place, making it difficult to compare reported estimates. Models were developed for 17 countries (Bahrain, Bulgaria, Cameroon, Colombia, Croatia, Dominican Republic, Ethiopia, Ghana, Hong Kong, Jordan, Kazakhstan, Malaysia, Morocco, Nigeria, Qatar and Taiwan) to quantify and characterize the viremic population as well as forecast the changes in the infected population and the corresponding disease burden from 2015 to 2030. Model inputs were agreed upon through expert consensus, and a standardized methodology was followed to allow for comparison across countries. The viremic prevalence is expected to remain constant or decline in all but four countries (Ethiopia, Ghana, Jordan and Oman); however, HCV-related morbidity and mortality will increase in all countries except Qatar and Taiwan. In Qatar, the high-treatment rate will contribute to a reduction in total cases and HCV-related morbidity by 2030. In the remaining countries, however, the current treatment paradigm will be insufficient to achieve large reductions in HCV-related morbidity and mortality.

Liver failure determines the outcome in patients of acute-on-chronic liver failure (ACLF): comparison of APASL ACLF research consortium (AARC) and CLIF-SOFA models.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a progressive disease associated with rapid clinical worsening and high mortality. Early prediction of mortality and intervention can improve patient outcomes. We aimed to develop a dynamic prognostic model and compare it with the existing models. METHODS: A total of 1402 ACLF patients, enrolled in the APASL-ACLF Research Consortium (AARC) with 90-day follow-up, were analyzed. An ACLF score was developed in a derivation cohort (n = 480) and was validated (n = 922). RESULTS: The overall survival of ACLF patients at 28 days was 51.7%, with a median of 26.3 days. Five baseline variables, total bilirubin, creatinine, serum lactate, INR and hepatic encephalopathy, were found to be independent predictors of mortality, with AUROC in derivation and validation cohorts being 0.80 and 0.78, respectively. AARC-ACLF score (range 5-15) was found to be superior to MELD and CLIF SOFA scores in predicting mortality with an AUROC of 0.80. The point scores were categorized into grades of liver failure (Gr I: 5-7; II: 8-10; and III: 11-15 points) with 28-day cumulative mortalities of 12.7, 44.5 and 85.9%, respectively. The mortality risk could be dynamically calculated as, with each unit increase in AARC-ACLF score above 10, the risk increased by 20%. A score of ≥11 at baseline or persisting in the first week was often seen among nonsurvivors (p = 0.001). CONCLUSIONS: The AARC-ACLF score is easy to use, dynamic and reliable, and superior to the existing prediction models. It can reliably predict the need for interventions, such as liver transplant, within the first week.

The clinical features and treatment outcome of chronic hepatitis C with pegylated interferon and ribavirin in routine care.

AIM: To describe the clinical characteristic of hepatitis C (HCV) patients and the results of pegylated interferon and ribavirin (PegIFN/RBV) therapy in a routine clinical practice. METHODS: A retrospective review of consecutive HCV patients treated with PegIFN/RBV in 2004 to 2012. RESULTS: A total of 273 patients received treatment. The mean age was 44.16 ± 10.5 years and 76% were male. The top 2 self-reported risks were blood or blood product transfusion before 1994 and injection drug use, found in 57.1% of patients. The predominant HCV genotype (GT) was 3 at 60.6%, second was GT1 at 36.1% and other GTs were uncommon at about 1% or less. About half of our patients have high baseline viral load (>800,000 iu/ml), 18.3% had liver cirrhosis and 22.3% had HIV co-infection. Co-morbid illness was found in 42.9%, hypertension and type 2 diabetes were the two most common. The overall sustained virological response (SVR) by intention-to-treat analysis were 54.9% (n=150/273), 41.2% (40/97) for GT1, 100% (5/5) for GT2 and 62% (101/163) for GT3. Subgroup analysis for HCV monoinfected, treatment naïve showed SVR of 49.2% (31/63) for GT1, 100% (5/5) for GT2 and 67% (69/103) for GT3. In HCV mono-infected and treatment experienced (n=29), the SVR was 28.6% (4/14) for GT1, 21.4% (69/103) for GT3. In the HIV/HCV co-infected, treatment naïve (n=56), the SVR was 28.6% (4/14) for GT1 and 64.3% (27/42) for GT3. Treatment naïve GT3 mono-infected patients had a statistically significant higher SVR compared to treatment experienced patients (P=0.001). In GT3 patients who achieved rapid virological response, the SVR was significantly higher at 85.2% (P< 0.001). The SVR for cirrhotics were low especially for GT1 at 21% (4/19) and 31% (4/13) based on all patients and treatment naïve HCV monoinfected respectively. In GT3 cirrhotics the corresponding SVR were 57.1% (16/28) and 60.9% (14/23). Premature discontinuation rate was 21.2% with the majority due to intolerable adverse events at 12.1%. CONCLUSIONS: In our routine clinical practice, the HCV patients we treated were young, predominantly of GT3 and many had difficult-to-treat clinical characteristics. The SVR of our patients were below those reported in Asian clinical trials but in keeping with some "real world" data.

Cost-utility of exercise therapy in patients with hip osteoarthritis in primary care.

OBJECTIVE: To determine the cost-effectiveness (CE) of exercise therapy (intervention group) compared to 'general practitioner (GP) care' (control group) in patients with hip osteoarthritis (OA) in primary care. METHOD: This cost-utility analysis was conducted with 120 GPs in the Netherlands from the societal and healthcare perspective. Data on direct medical costs, productivity costs and quality of life (QoL) was collected using standardised questionnaires which were sent to the patients at baseline and at 6, 13, 26, 39 and 52 weeks follow-up. All costs were based on Euro 2011 cost data. RESULTS: A total of 203 patients were included. The annual direct medical costs per patient were significantly lower for the intervention group (€ 1233) compared to the control group (€ 1331). The average annual societal costs per patient were lower in the intervention group (€ 2634 vs € 3241). Productivity costs were higher than direct medical costs. There was a very small adjusted difference in QoL of 0.006 in favour of the control group (95% CI: -0.04 to +0.02). CONCLUSION: Our study revealed that exercise therapy is probably cost saving, without the risk of noteworthy negative health effects. TRIAL REGISTRATION NUMBER: NTR1462.

Treating hepatitis C in HIV/HCV co-infected patients in Malaysia - the outcomes and challenges.

BACKGROUND: Co-infection by human immunodeficiency and hepatitis C viruses (HIV/HCV) is common and results in significant morbidity and mortality despite effective antiretroviral therapies (ART). METHOD: A retrospective and prospective evaluation of the efficacy and safety of pegylated interferon alfa 2a/2b plus ribavirin (PEG-IFN/RBV) in consecutive HIV/HCV co-infected patients treated in real life clinical practice in Malaysia. RESULTS: Forty-five HIV/HCV co-infected patients with a median age (interquartile range, IQR) of 41 years (37; 47) were assessed for treatment with PEG-IFN/RBV. All except one are of male gender and the most common risk behaviour was injecting drug use. At baseline 75.5% was on ART and the median (IQR) CD4 count was 492 cells/µl (376; 621). The HCV genotypes (GT) were 73 % GT3 and 27% GT1. Liver biopsies in forty patients showed 10% had liver cirrhosis and another 50% had significant liver fibrosis. The treatment completion rate was 79.5% with 15.9% dropped out of treatment due to adverse effects (AE) or default and 4.6% due to lack of early virological response. The AE causing premature discontinuations were neuropsychiatric and haematological. The overall sustained virological response (SVR) was 63.6% with a trend towards higher SVR in GT3 compared with GT1 (71.9% vs. 41.7%; p=0.064). In patients with bridging fibrosis plus occasional nodules or cirrhosis on liver biopsy, the SVR was significantly lower at 20% (p=0.030) compared to those with milder fibrosis. CONCLUSION: HIV/HCV co-infected patients can be successfully and safely treated with PEG-IFN/RBV achieving high rates of SVR except in cirrhotic patients.

Big Data and Analytics in Healthcare.

This editorial is part of the Focus Theme of Methods of Information in Medicine on "Big Data and Analytics in Healthcare". The amount of data being generated in the healthcare industry is growing at a rapid rate. This has generated immense interest in leveraging the availability of healthcare data (and "big data") to improve health outcomes and reduce costs. However, the nature of healthcare data, and especially big data, presents unique challenges in processing and analyzing big data in healthcare. This Focus Theme aims to disseminate some novel approaches to address these challenges. More specifically, approaches ranging from efficient methods of processing large clinical data to predictive models that could generate better predictions from healthcare data are presented.

Integrins as Therapeutic Targets for Respiratory Diseases.

Integrins are a large family of transmembrane heterodimeric proteins that constitute the main receptors for extracellular matrix components. Integrins were initially thought to be primarily involved in the maintenance of cell adhesion and tissue integrity. However, it is now appreciated that integrins play important roles in many other biological processes such as cell survival, proliferation, differentiation, migration, cell shape and polarity. Lung cells express numerous combinations and permutations of integrin heterodimers. The complexity and diversity of different integrin heterodimers being implicated in different lung diseases present a major challenge for drug development. Here we provide a comprehensive overview of the current knowledge of integrins from studies in cell culture to integrin knockout mouse models and provide an update of results from clinical trials for which integrins are therapeutic targets with a focus on respiratory diseases (asthma, emphysema, pneumonia, lung cancer, pulmonary fibrosis and sarcoidosis).

¹8F-FDG PET/CT in inflammation of unknown origin: a cost-effectiveness pilot-study.

PURPOSE: Patients with increased inflammatory parameters, nonspecific signs and symptoms without fever and without a diagnosis after a variety of diagnostic procedures are a diagnostic dilemma and are referred to as having inflammation of unknown origin (IUO). The objective of this pilot study was to compare the cost-effectiveness of a diagnostic work-up/strategy with and without (18)F-FDG PET/CT in patients with IUO using a published dataset as a reference. METHODS: IUO patients without (18)F-FDG PET/CT (group A, 46 patients) and IUO patients referred for (18)F-FDG PET/CT (group B, 46 patients) were selected. IUO was defined as the combination of nonspecific signs and symptoms and a prolonged erythrocyte sedimentation rate (ESR), defined as ≥age/2 in men and ≥(age + 10)/2 in women (ESR in millimetres per hour and age in years), and/or C-reactive protein (CRP) ≥15 mg/l. The costs of all tests and procedures and the number of hospitalization days in each patient to reach a diagnosis were calculated using current Dutch tariffs. RESULTS: In group A a diagnosis was reached in 14 of the 46 patients. The mean cost per patient of all the diagnostic procedures was 2,051, and including the cost of hospitalization was 12,614. In group B a diagnosis was reached in 32 of the 46 patients. The mean cost per patient of all the diagnostic procedures was 1,821, significantly lower than in group A (p < 0.0002), and including the cost of hospitalization was 5,298. CONCLUSION: In IUO (18)F-FDG PET/CT has the potential to become a cost-effective routine imaging technique indicating the direction for further diagnostic decisions thereby allowing unnecessary, invasive and expensive diagnostic investigations to be avoided and possibly the duration of hospitalization to be reduced. However, a prospective multicentre "bottom-up microcosting" cost-effectiveness study is warranted before these preliminary data can be extrapolated to clinical practice.

Real-world resource use and costs of adjuvant treatment for stage III colon cancer.

Since the generalisability of trial-based economic evaluations may be limited, there is an increasing focus on real-world cost-effectiveness. Real-world studies involve evaluating the effects and costs of treatments in daily clinical practice. This study reports on the real-world resource use and costs of adjuvant treatments of stage III colon cancer in a population-based observational study. Analyses were based on a detailed retrospective medical chart review which was conducted for 206 patients with colon cancer treated in 2005 and 2006 in the Netherlands. Mean total costs per patient were €9681 for 5-FU/LV, €9736 for capecitabine, €32,793 for FOLFOX and €18,361 for CAPOX. Drug costs and the costs related to hospitalisations for chemotherapy administration were the main cost drivers. We identified a potential for substantial cost-savings when the 48 h administration of 5FU/LV in the FOLFOX regimen were to take place in an outpatient setting or be replaced by oral capecitabine as in the CAPOX regimen. This analysis based on detailed real-life data clearly indicates that clinical choices made in oncology based on efficacy of therapy have economic consequences. Considering today's reality of finite healthcare resources, these economic consequences deserve a formal role in clinical decision making, for instance in guideline development.

Health-related quality of life and productivity losses in patients with depression and anxiety disorders.

OBJECTIVES: To assess the explanatory power of disease severity and health-related quality of life (HRQOL) on absenteeism and presenteeism in a working population suffering from depression and/or anxiety disorders. METHODS: We used data of a large, multicenter, randomized trial (n = 644). Pearson chi-squared tests, analysis of variance, and multinomial logistic regression analyses were performed to explore associations of the type of the disorder and HRQOL with different types of productivity losses. Multivariate regression analyses were performed to assess associations with the duration of absenteeism. RESULTS: The type of the disorder, disease severity, and HRQOL were associated with different types of productivity losses. Health-related quality of life and age were significantly associated with the duration of absenteeism. CONCLUSIONS: Our findings indicate that HRQOL may significantly explain the type of productivity loss as well as the duration of absenteeism.

Estimated hospital health costs of chronic abdominal pain in the Netherlands.

UNLABELLED: aim: Calculation of the hospital costs of chronic abdominal pain in the Netherlands. DESIGN: Cross-sectional study. METHODS: We selected 'Diagnosis-Related Groups' (DRG) of disorders that are associated with chronic abdominal pain from a large teaching hospital and a tertiary referral centre. For each DRG we determined the percentage of patients that can present with abdominal pain. The total costs for both hospitals were calculated using the registered quantity of the DRGs. Each DRG was categorised by somatic and functional origin. The results were subsequently extrapolated to the entire Dutch population demanding hospital care for chronic abdominal pain. Finally, the percentage and associated costs were calculated for patients who had two or more separate diagnoses for chronic abdominal pain in the field of gastroenterology, gynaecology, internal medicine and urology. RESULTS: The yearly outpatient and (day) clinical health costs for patients with chronic abdominal pain in the Netherlands were approximately €623 million (gastroenterology €226 million; gynaecology €303 million; internal medicine €63 million; and urology €31 million). Of these diagnoses, 53.6% were related to functional disorders, which accounts for approximately €220 million per year. The yearly costs of patients who had at least two separate diagnoses within one year for chronic abdominal pain were estimated at €23.5 million per year. CONCLUSION: Chronic abdominal pain is a common problem that entails significant healthcare costs in the Netherlands of which functional diagnoses compromise a significant amount.