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Chronic hepatitis C virus ( HCV) infection is a major cause of chronic liver disease and liver-related death. Recently, multiple regimens of different direct-acting antiviral agents ( DAAs) have been registered. Although treatment with sofosbuvir ( SOF) and simeprevir ( SMV) is registered for the treatment of genotype 4 patients in some countries, data on efficacy of this combination are lacking. We aimed to assess the efficacy of SOF and SMV with or without RBV during 12 weeks in a real-life cohort of genotype 4 HCV patients. A retrospective multicentre observational study was conducted in 4 hospitals in Amsterdam, the Netherlands, including patients with advanced liver fibrosis or liver cirrhosis treated with SOF plus SMV with or without RBV during 12 weeks for a genotype 4 chronic HCV infection from 1 January 2015 to 1 August 2015. Sustained viral response ( SVR) was established at week 12 after end of treatment. A total of 53 patients with genotype 4 HCV infection, treatment naïve and experienced, were included. SVR was achieved in 49 of 53 patients (92%). The four failures all had a virological relapse and did not receive ribavirin. Three were nonresponder to earlier interferon-based treatment, and one was treatment naive. In this real-life cohort of patients with HCV genotype 4 infection and advanced liver fibrosis/cirrhosis, we show that treatment with SOF and SMV is effective. The addition of RBV could be considered in treatment-experienced patients as recommended in guidelines. [ABSTRACT FROM AUTHOR]

Background/objective: To gain insight into both patients' and relatives' experiences with spiritual care (SC) in the intensive care unit (ICU)., Methods: Method used was qualitative interviewing. This was a thematic, topic-centered, biographical, and narrative approach, using semistructured interviews with thematic analysis. A purposive sampling method was used to select a sample of ICU patients and ICU patients' relatives. An interview guide facilitated individual, semistructured interviews. The interview data were recorded by means of note-taking and audio-recording. Verbatim transcripts were compiled for analysis and interpretation., Results: All 12 participants-7 ICU patients and 5 family members of 5 other ICU patients-experienced ICU admission as an existential crisis. Participants would appreciate the signaling of their spiritual needs by ICU health care professionals (HCPs) at an early stage of ICU admission and subsequent SC provision by a spiritual caregiver. They regarded the spiritual caregiver as the preferred professional to address spiritual needs, navigate during their search for meaning and understanding, and provide SC training in signaling spiritual needs to ICU HCPs., Discussion: Early detection of existential crisis signals with ICU patients and relatives contributes to the mapping of spiritual and religious needs. Spiritual care training of ICU HCPs in signaling spiritual needs by ICU patients and relatives is recommended. Effective SC contributes to creating room for processing emotions, spiritual well-being, and satisfaction with integrated SC as part of daily ICU care., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: HBV can integrate in the host genome of the hepatocyte and recent findings suggest that integrated HBV contributes to the persistent production of viral proteins. Here, we quantified the levels of integrated HBV in patients with chronic hepatitis B (CHB) and analyzed the relation between HBV integration, virological activity (plasma HBV DNA and HBsAg levels), and clinical outcomes., Approach and Results: We developed and validated a multistep Arthrobacter luteus (Alu)-PCR that specifically amplifies integrated HBV and RT-Alu-PCR detecting mRNA transcripts derived from integrated HBV. Pretreatment liver biopsy samples and baseline characteristics of 124 patients with CHB either treated for 48 weeks with pegylated interferon plus adefovir or tenofovir or receiving no treatment were available for analysis. Integrated HBV sequences containing open reading frame S and X (but not C) and S and X mRNA transcripts derived from integrated HBV could be detected and quantified in liver biopsies. Integrated HBV levels correlated with HBV DNA, HBsAg, alanine aminotransferase plasma levels, and the liver histology activity index but not to levels of intrahepatic covalently closed circular DNA (cccDNA), plasma pregenomic RNA, or hepatitis B core-related antigen. Multivariable logistic regression analysis showed that lower baseline HBV integration levels were independently associated with HBsAg loss (functional cure) within 5 years follow-up., Conclusions: Integrated HBV levels are strongly correlated with surrogate markers for virological activity but not to cccDNA levels and are predictive for HBsAg loss. Our data suggest that integrated HBV is closely related to HBV replication and may therefore be an important tool in the evaluation and development of treatment modalities aiming to cure CHB., (© 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Successful treatment of chronic hepatitis C with direct-acting antiviral agents (DAAs) is expected to lead to improvement in liver fibrosis in most of the patients. However, limited data are available on the improvement of advanced liver fibrosis and cirrhosis, measured by transient elastography after treatment. This study assessed the change in liver stiffness measurements after successful treatment with DAAs in patients with pre-treatment advanced fibrosis or cirrhosis., Methods: This observational retrospective cohort study included 514 mono-infected chronic hepatitis C patients, treated with all possible DAA-regimes in the Amsterdam region, the Netherlands. Liver stiffness was measured using FibroScan® at baseline and during follow-up. Cut-off values for staging liver fibrosis were ≥ 9.5 kPa for advanced fibrosis (F3) and ≥ 14.6 kPa for cirrhosis (F4)., Results: Liver stiffness decreased significantly from a median of 15.6 kPa (IQR 11.4-25.4) to 9.4 kPa (IQR 6.2-17.0) in 197 patients with pre-treated advanced fibrosis or cirrhosis. In 50.3% of these patients, liver stiffness improved to a value fitting with mild to moderate fibrosis (< 9.5 kPa, F0-F2) after successful treatment. Multivariate analysis demonstrated that a pre-treatment FibroScan® value of ≥ 20.0 kPa was associated with persisting advanced fibrosis or cirrhosis after treatment (OR 29.07, p < 0.001)., Conclusion: Liver stiffness improves significantly after successful direct-acting antiviral agent treatment in chronic hepatitis C patients with advanced fibrosis or cirrhosis prior to DAA treatment. Long-term outcomes regarding occurrence of hepatocellular carcinoma (HCC) in these patients are required to determine whether they can be safely discharged from HCC surveillance.

In patients with non-tuberculous mycobacterial cervicofacial lymphadenitis, incomplete surgical removal of infected lymph nodes leads to delayed healing and a higher recurrence rate, with eventual spontaneous drainage through the skin. However, complete surgical removal is not always achievable due to the extent of the infected tissue and proximity to vulnerable structures, such as the facial or accessory nerve. The aim of this study was to identify the clinical determinants of the (in)ability to perform complete surgical removal. The electronic health records of patients aged 0-15 years with bacteriologically proven non-tuberculous mycobacterial cervicofacial lymphadenitis, who underwent surgical treatment and preoperative sonographic imaging, were analysed. This was a case-control study. A total of 103 patients met the inclusion criteria. Most of the infections were unilateral, submandibular, and caused by Mycobacterium avium. Multiple logistic regression analysis revealed that higher age (odds ratio 1.24, 95% confidence interval 1.04-1.47) and fistulization (odds ratio 3.15, 95% confidence interval 1.13-8.75) were significantly associated with a limited ability to surgically remove all infected tissue. However, a larger sonographic lymph node size was not significantly associated. These findings could aid clinicians when informing the parent(s)/guardian(s) of the patient preoperatively and in properly estimating the intraoperative and postoperative course., (Copyright © 2020 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Purpose: The aim of this study is to review the literature for three major domains in relation to spiritual care in the ICU, namely Quality of Life (QoL), Quality of Care (QoC), and Education (E)., Method: An integrative literature research., Results: The 113 selected articles reveal that spirituality is an essential component of QoL and that complementary and effective spiritual care (SC) relieves distress of patients and their relatives. Furthermore, the contribution of SC to quality of care is: 1) diagnosing and addressing spiritual and emotional needs among patients and their relatives; 2) offering spiritual comfort to the patient in distress; 3) increased spiritual well-being of both patients and their relatives; 4) increased family satisfaction in general and by shared decision-making. Finally, the literature reveals the necessity to improve SC knowledge and skills of ICU healthcare professionals (IC HCPs) through relevant training courses., Conclusion: SC contributes to QoL and QoC. The literature indicates that IC HCPs acknowledge the need to improve their SC knowledge and skills to enhance complementary, effective SC. Further research on SC as an integrated part of daily ICU care is necessary to improve QoL and QoC of patients and their relatives., Competing Interests: Declaration of Competing Interest To the best of our knowledge, no conflict of interest, financial or other, exists., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic hepatitis C virus (HCV) infection is a global public health issue, which is associated with high rates of morbidity and mortality. The development of direct acting antivirals (DAAs) has transformed treatment: they offer us highly-effective therapy with superior tolerability compared to interferon-containing regimens. In 2016, the World Health Organization (WHO) therefore adopted several ambitious viral hepatitis elimination targets, aiming for a 90% reduction in new infections and a 65% reduction in mortality by 2030. The ultimate goal is to eliminate HCV completely. It is reasonable that these goals may be achieved in the Netherlands due to the low prevalence of chronic HCV, the availability of DAAs, and excellent healthcare infrastructure. This paper describes a national effort to curtail the HCV epidemic in the Netherlands through an HCV retrieval and linkage to care project (CELINE: Hepatitis C Elimination in the Netherlands).

Objectives: Widespread controversy exists regarding correct diagnosing nontuberculous mycobacterial cervicofacial (NTM) lymphadenitis. This study intends to gather the available evidence with respect to diagnosing NTM cervicofacial lymphadenitis., Methods: A review protocol was developed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-statement (www.prisma-statement.org). A comprehensive search was performed in the bibliographic databases PubMed, Embase.com and Wiley/Cochrane Library. 10 Articles fulfilled the inclusion criteria and were included in the review. Assessing risk of bias of the articles was done using the revised Quality Assessment of Diagnostic Accuracy (QUADAS-2) tool., Results: This systematic review shows that diagnostic studies of high methodological quality are scarce. Diagnostic accuracy of polymerase chain reaction (PCR), culture, skin testing, auramine staining, Ziehl-Neelsen staining, and immunodiagnostic assays was studied. Culture sensitivity proved to be 41,8%, while polymerase chain reaction has a sensitivity of 71,6%. Both methods showed a specificity of 100%. Sensitivity of Immunodiagnostic assays ranged between 87,5% and 100% and specificity between 81% and 100%. Overall sensitivity of skin tests containing purified protein derivative (PPD-S) was 70% (95% CI [62%-78%]) with an overall specificity of 94% (95% CI [88%-100%])., Conclusions: In patients with a high clinical suspicion for NTM cervicofacial lymphadenitis, a positive PPD-S skin is indicative for the diagnosis of NTM cervicofacial lymphadenitis. Either PCR or culture is necessary to confirm the diagnosis. Interferon-γ release assays with purified protein derivative stimulation appear to provide good sensitivity and specificity as a non-invasive pre-operative test, but the evidence is weak. More studies of high methodological quality are needed to validate the results of this systematic review., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Since there are no scientific data available about the role of spiritual care (SC) in Dutch ICUs, the goal of this quantitative study was twofold: first, to map the role of SC as a part of daily adult ICU care in The Netherlands from the perspective of intensivists, ICU nurses, and spiritual caregivers and second, to identify similarities and differences among these three perspectives. This study is the quantitative part of a mixed methods approach. To conduct empirical quantitative cohort research, separate digital questionnaires were sent to three different participant groups in Dutch ICUs, namely intensivists, ICU nurses, and spiritual caregivers working in academic and general hospitals and one specialist oncology hospital. Overall, 487 participants of 85 hospitals (99 intensivists, 290 ICU nurses, and 98 spiritual caregivers) responded. The majority of all respondents (>70%) considered the positive effects of SC provision to patients and relatives: contribution to mental well-being, processing and channeling of emotions, and increased patient and family satisfaction. The three disciplines diverged in their perceptions of how SC is currently evolving in terms of information, assessment, and provision. Nationwide, SC is not implemented in daily ICU care. The majority of respondents, however, attached great importance to interdisciplinary collaboration. In their view SC contributes positively to the well-being of patients and relatives in the ICU. Further qualitative research into how patients and relatives experience SC in the ICU is required in order to implement and standardize SC as a scientifically based integral part of daily ICU care.

Background: An increasing number of transitions due to substitution of care of more complex patients urges insight in and improvement of transitional medication safety. While lack of documentation of prescription changes and/or lack of information exchange between settings likely cause adverse drug events, frequency of occurrence of these causes is not clear. Therefore, we aimed at determining the frequency of in-hospital patients’ prescription changes that are not or incorrectly documented in their primary care provider’s (PCP) medical record., Methods: A medical record review study was performed in a database linking patients’ medical records of hospital and PCP. A random sample (n = 600) was drawn from all 1399 patients who were registered at a participating primary care practice as well as the gastroenterology or cardiology department in 2013 of the University Medical Center Utrecht, the Netherlands. Outcomes were the number of in-hospital prescription changes that was not or incorrectly documented in the medical record of the PCP, and timeliness of documentation., Results: Records of 390 patients included one or more primary-secondary care transitions; in total we identified 1511 transitions. During these transitions, 408 in-hospital prescription changes were made, of which 31% was not or incorrectly documented in the medical record of the PCP within the next 3 months. In case changes were documented, the median number of days between hospital visit and documentation was 3 (IQR 0–18)., Conclusions: One third of in-hospital prescription changes was not or incorrectly documented in the PCP’s record, which likely puts patients at risk of adverse drug events after hospital visits. Such flawed reliability of a routine care process is unacceptable and warrants improvement and close monitoring.

Background: miR-122 is an important host factor for hepatitis C virus (HCV) replication. The aim of this study was to assess the safety and tolerability, pharmacokinetics, and antiviral effect of a single dose of RG-101, a hepatocyte targeted N-acetylgalactosamine conjugated oligonucleotide that antagonises miR-122, in patients with chronic HCV infection with various genotypes., Methods: In this randomised, double-blind, placebo-controlled, multicentre, phase 1B study, patients were randomly assigned to RG-101 or placebo (7:1). We enrolled men and postmenopausal or hysterectomised women (aged 18-65 years) with chronic HCV genotype 1, 3, or 4 infection diagnosed at least 24 weeks before screening who were either treatment naive to or relapsed after interferon-α based therapy. Patients with co-infection (hepatitis B virus or HIV infection), evidence of decompensated liver disease, or a history of hepatocellular carcinoma were excluded. Randomisation was done by an independent, unblinded, statistician using the SAS procedure Proc Plan. The first cohort received one subcutaneous injection of 2 mg/kg RG-101 or placebo; the second cohort received one subcutaneous injection of 4 mg/kg or placebo. Patients were followed up for 8 weeks (all patients) and up to 76 weeks (patients with no viral rebound and excluding those who were randomised to the placebo group) after randomisation. The primary objective was safety and tolerability of RG-101. This trial was registered with EudraCT, number 2013-002978-49., Findings: Between June 4, 2014, and Oct 27, 2014, we enrolled 32 patients with chronic HCV genotype 1 (n=16), 3 (n=10), or 4 (n=6) infections. In the first cohort, 14 patients were randomly assigned to receive 2 mg/kg RG-101 and two patients were randomly assigned to receive placebo, and in the second cohort, 14 patients were randomly assigned to receive 4 mg/kg RG-101 and two patients were randomly assigned to receive placebo. Overall, 26 of the 28 patients dosed with RG-101 reported at least one treatment-related adverse event. At week 4, the median viral load reduction from baseline was 4·42 (IQR 3·23-5·00) and 5·07 (4·19-5·35) log 10 IU/mL in patients dosed with 2 mg/kg RG-101 or 4 mg/kg RG-101. Three patients had undetectable HCV RNA levels 76 weeks after a single dose of RG-101. Viral rebound at or before week 12 was associated with the appearance of resistance associated substitutions in miR-122 binding regions in the 5' UTR of the HCV genome., Interpretation: This study showed that one administration of 2 mg/kg or 4 mg/kg RG-101, a hepatocyte targeted N-acetylgalactosamine conjugated anti-miR-122 oligonucleotide, was well tolerated and resulted in substantial viral load reduction in all treated patients within 4 weeks, and sustained virological response in three patients for 76 weeks., Funding: Regulus Therapeutics, Inc., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background & Aims: Prevalence of hepatitis C virus (HCV) infection in the Netherlands is low (anti-HCV prevalence 0.22%). All-oral treatment with direct-acting antivirals (DAAs) is tolerable and effective but expensive. Our analysis projected the future HCV-related disease burden in the Netherlands by applying different treatment scenarios., Methods: Using a modelling approach, the size of the HCV-viraemic population in the Netherlands in 2014 was estimated using available data and expert consensus. The base scenario (based on the current Dutch situation) and different treatment scenarios (with increased efficacy, treatment uptake, and diagnoses) were modelled and the future HCV disease burden was predicted for each scenario., Results: The estimated number of individuals with viraemic HCV infection in the Netherlands in 2014 was 19,200 (prevalence 0.12%). By 2030, this number is projected to decrease by 4 5% in the base scenario and by 85% if the number of treated patients increases. Furthermore, the number of individuals with hepatocellular carcinoma and liver-related deaths is estimated to decrease by 19% and 27%, respectively, in the base scenario, but may both be further decreased by 68% when focusing on treatment of HCV patients with a fibrosis stage of ≥ F2., Conclusions: A substantial reduction in HCV-related disease burden is possible with increases in treatment uptake as the efficacy of current therapies is high. Further reduction of HCV-related disease burden may be achieved through increases in diagnosis and preventative measures. These results might inform the further development of effective disease management strategies in the Netherlands.

In this work, a reliable and robust vacuum-outlet gas chromatography-mass spectrometry (GC-MS) method is introduced for the identification and quantification of impurities in trinitrotoluene (TNT). Vacuum-outlet GC-MS allows for short analysis times; the analysis of impurities in TNT was performed in 4min. This study shows that impurity profiling of TNT can be used to investigate relations between TNT samples encountered in forensic casework. A wide variety of TNT samples were analyzed with the developed method. Dinitrobenzene, dinitrotoluene, trinitrotoluene and amino-dinitrotoluene isomers were detected at very low levels (<1wt.%) by applying the MS in selected-ion monitoring (SIM) mode. Limits of detection ranged from 6ng/mL for 2,6-dinitrotoluene to 43ng/mL for 4-amino-2,6-dinitrotoluene. Major impurities in TNT were 2,4-dinitrotoluene and 2,3,4-trinitrotoluene. Impurity profiles based on seven compounds showed to be useful to TNT samples from different sources. Statistical analysis of these impurity profiles using likelihood ratios demonstrated the potential to investigate whether two questioned TNT samples encountered in forensic casework are from the same source., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Introduction: Interferon-g-inducible protein-10 (IP-10) serum levels are associated with IL28B genotype and may predict response to interferon÷ribavirin-based therapy in chronic hepatitis C patients. Our aim was to relate IP-10 levels before and during treatment to treatment outcome, viral HCV-RNA kinetics and IL28B genotype., Patients and Methods: A cohort of chronic hepatitis C patients was treated with high-dose interferon for six weeks, followed by standard peginterferon÷ ribavirin for 24 or 48 weeks. IP-10 and HCV-RNA levels were frequently determined before, during and after treatment., Results: IP-10 levels increased from log2.56 pg÷ml at baseline to log3.48 pg÷ml at Day 1 and gradually diminished thereafter. IP-10 levels at any time point were not statistically different between patients with or without sustained viral response (SVR). Patients with IL28B CC genotype had significantly lower baseline IP-10 levels (p = 0.019) and a higher increase of IP-10 levels from baseline to Day 1 than patients with IL28B non-CC genotypes (p = 0.015). Patients with HCV-RNA decline &#8805; 2.28log10 at Day 1 had significantly lower baseline IP-10 levels (p = 0.016) and a higher increase of IP-10 levels from baseline to Day1 (p = 0.047) than patients with HCV-RNA decline of < 2.28log10 at Day 1., Conclusions: In patients treated with high induction dose interferon, IP-10 levels at any time point were not predictive for SVR. Low baseline IP-10 levels and a higher increase of IP-10 levels from baseline to Day 1 were associated with IL28B CC genotype and HCV-RNA decline &#8805; 2.28log10 at Day 1. This suggests that, in our cohort, for prediction of SVR the added value of IP-10 to IL28B genotype and early viral kinetics is limited.