Clinical characteristics and risk factors of preventable hospital readmissions within 30 days.

Knowledge regarding preventable hospital readmissions is scarce. Our aim was to compare the clinical characteristics of potentially preventable readmissions (PPRs) with non-PPRs. Additionally, we aimed to identify risk factors for PPRs. Our study included readmissions within 30 days after discharge from 1 of 7 hospital departments. Preventability was assessed by multidisciplinary meetings. Characteristics of the readmissions were collected and 23 risk factors were analyzed. Of the 1120 readmissions, 125 (11%) were PPRs. PPRs occurred equally among different departments (p = 0.21). 29.6% of PPRs were readmitted by a practitioner of a different medical specialty than the initial admission (IA) specialist. The PPR group had more readmissions within 7 days (PPR 54% vs. non-PPR 44%, p = 0.03). The median LOS was 1 day longer for PPRs (p = 0.16). Factors associated with PPR were higher age (p = 0.004), higher socio-economic status (p = 0.049), fewer prior hospital admissions (p = 0.004), and no outpatient visit prior to readmission (p = 0.025). This study found that PPRs can occur at any department in the hospital. There is not a single type of patient that can easily be pinpointed to be at risk of a PPR, probably due to the multifactorial nature of PPRs.

Deep sequencing identifies hepatitis B virus core protein signatures in chronic hepatitis B patients.

BACKGROUND: We aimed to identify HBc amino acid differences between subgroups of chronic hepatitis B (CHB) patients. METHODS: Deep sequencing of HBc was performed in samples of 89 CHB patients (42 HBeAg positive, 47 HBeAg negative). Amino acid types were compared using Sequence Harmony to identify subgroup specific sites between HBeAg-positive and -negative patients, and between patients with combined response and non-response to peginterferon/adefovir combination therapy. RESULTS: We identified 54 positions in HBc where the frequency of appearing amino acids was significantly different between HBeAg-positive and -negative patients. In HBeAg negative patients, 22 positions in HBc were identified which differed between patients with treatment response and those with non-response. The fraction non-consensus sequence on selected positions was significantly higher in HBeAg-negative patients, and was negatively correlated with HBV DNA and HBsAg levels. CONCLUSIONS: Sequence Harmony identified a number of amino acid changes associated with HBeAg-status and response to peginterferon/adefovir combination therapy.

Immune responses in DAA treated chronic hepatitis C patients with and without prior RG-101 dosing.

BACKGROUND&AIMS: With the introduction of DAA's, the majority of treated chronic hepatitis C patients (CHC) achieve a viral cure. The exact mechanisms by which the virus is cleared after successful therapy, is still unknown. The aim was to assess the role of the immune system and miRNA levels in acquiring a sustained virological response after DAA treatment in CHC patients with and without prior RG-101 (anti-miR-122) dosing. METHODS: In this multicenter, investigator-initiated study, 29 patients with hepatitis C virus (HCV) genotype 1 (n = 11), 3 (n = 17), or 4 (n = 1) infection were treated with sofosbuvir and daclatasvir ± ribavirin. 18 patients were previously treated with RG-101. IP-10 levels were measured by ELISA. Ex vivo HCV-specific T cell responses were quantified in IFN-γ-ELISpot assays. Plasma levels of miR-122 were measured by qPCR. RESULTS: All patients had an SVR12. IP-10 levels rapidly declined during treatment, but were still elevated 24 weeks after treatment as compared to healthy controls (median 53.82 and 39.4 pg/mL, p = 0.02). Functional IFN-γ HCV-specific T cell responses did not change by week 12 of follow-up (77.5 versus 125 SFU/106 PBMC, p = 0.46). At follow-up week 12, there was no difference in plasma miR-122 levels between healthy controls and patients with and without prior RG-101 dosing. CONCLUSIONS: Our data shows that successful treatment of CHC patients with and without prior RG-101 dosing results in reduction of broad immune activation, and normalisation of miR-122 levels (EudraCT: 2014-002808-25). TRIAL REGISTRATION: EudraCT: 2014-002808-25.

Plasma MicroRNA Levels Are Associated With Hepatitis B e Antigen Status and Treatment Response in Chronic Hepatitis B Patients.

Background: Hepatitis B virus (HBV) modulates microRNA (miRNA) expression to support viral replication. The aim of this study was to identify miRNAs associated with hepatitis B e antigen (HBeAg) status and response to antiviral therapy in patients with chronic hepatitis B (CHB) , and to assess if these miRNAs are actively secreted by hepatoma cells. Methods: Plasma miRNA levels were measured by reverse-transcription quantitative polymerase chain reaction in healthy controls (n = 10) and pretreatment samples of an identification cohort (n = 24) and a confirmation cohort (n = 64) of CHB patients treated with peginterferon/nucleotide analogue combination therapy. Levels of HBV-associated miRNAs were measured in cells, extracellular vesicles, and hepatitis B surface antigen (HBsAg) particles of hepatoma cell lines. Results: HBeAg-positive patients had higher plasma levels of miR-122-5p, miR-125b-5p, miR-192-5p, miR-193b-3p, and miR-194-5p compared to HBeAg-negative patients, and levels of these miRNAs were associated with HBV DNA and HBsAg levels. Pretreatment plasma levels of miR-301a-3p and miR-145-5p were higher in responders (combined response or HBsAg loss) compared to nonresponders. miR-192-5p, miR-193b-3p, and miR-194-5p were present in extracellular vesicles and HBsAg particles derived from hepatoma cells. Conclusions: We identified miRNAs that are associated with HBeAg status, levels of HBV DNA and HBsAg, and treatment response in CHB patients. We demonstrated that several of these miRNAs are present in extracellular vesicles and HBsAg particles secreted by hepatoma cells.

Immune phenotype and function of natural killer and T cells in chronic hepatitis C patients who received a single dose of anti-MicroRNA-122, RG-101.

MicroRNA-122 is an important host factor for the hepatitis C virus (HCV). Treatment with RG-101, an N-acetylgalactosamine-conjugated anti-microRNA-122 oligonucleotide, resulted in a significant viral load reduction in patients with chronic HCV infection. Here, we analyzed the effects of RG-101 therapy on antiviral immunity. Thirty-two chronic HCV patients infected with HCV genotypes 1, 3, and 4 received a single subcutaneous administration of RG-101 at 2 mg/kg (n = 14) or 4 mg/kg (n = 14) or received a placebo (n = 2/dosing group). Plasma and peripheral blood mononuclear cells were collected at multiple time points, and comprehensive immunological analyses were performed. Following RG-101 administration, HCV RNA declined in all patients (mean decline at week 2, 3.27 log10 IU/mL). At week 8 HCV RNA was undetectable in 15/28 patients. Plasma interferon-γ-induced protein 10 (IP-10) levels declined significantly upon dosing with RG-101. Furthermore, the frequency of natural killer (NK) cells increased, the proportion of NK cells expressing activating receptors normalized, and NK cell interferon-γ production decreased after RG-101 dosing. Functional HCV-specific interferon-γ T-cell responses did not significantly change in patients who had undetectable HCV RNA levels by week 8 post-RG-101 injection. No increase in the magnitude of HCV-specific T-cell responses was observed at later time points, including 3 patients who were HCV RNA-negative 76 weeks postdosing. CONCLUSION: Dosing with RG-101 is associated with a restoration of NK-cell proportions and a decrease of NK cells expressing activation receptors; however, the magnitude and functionality of ex vivo HCV-specific T-cell responses did not increase following RG-101 injection, suggesting that NK cells, but not HCV adaptive immunity, may contribute to HCV viral control following RG-101 therapy. (Hepatology 2017;66:57-68).

Safety, tolerability, and antiviral effect of RG-101 in patients with chronic hepatitis C: a phase 1B, double-blind, randomised controlled trial.

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) log10 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.

Long-term safety and efficacy of microRNA-targeted therapy in chronic hepatitis C patients.

BACKGROUND AND AIMS: MicroRNA-122 (miR-122) is an important host factor for hepatitis C virus (HCV) and promotes HCV RNA accumulation. Decreased intra-hepatic levels of miR-122 were observed in patients with hepatocellular carcinoma, suggesting a potential role of miR-122 in the development of HCC. Miravirsen targets miR-122 and resulted in a dose dependent and prolonged decrease of HCV RNA levels in chronic hepatitis C patients. The aim of this study was to establish the sustained virological response rate to peginterferon (P) and ribavirin (R) following miravirsen dosing and to assess long-term safety in patients treated with miravirsen. METHODS: In this multicenter, retrospective follow-up study we included 36 treatment naïve patients with chronic hepatitis C genotype 1 who received five weekly subcutaneous injections with miravirsen or placebo over a 29-day period in a phase 2a study. Patients were offered PR therapy 3weeks (3mg/kg group) or 6weeks (5 or 7mg/kg group) after completion of miravirsen or placebo dosing. RESULTS: PR therapy was started in 14/36 patients of whom 12 had received miravirsen. SVR was achieved in 7/12 patients previously dosed with miravirsen. All patients dosed with 7mg/kg miravirsen who were subsequently treated with PR achieved SVR. One patient had a prolonged undetectable HCV RNA period from week 14 to week 29 after baseline without subsequent antiviral therapy and relapsed thereafter. None of the patients treated with anti-miR-122 developed HCC or other liver-related complications. CONCLUSION: No long-term safety issues were observed among 27 miravirsen-treated patients. Targeting miR-122 may be an effective and safe treatment strategy for HCV infection and should be investigated in larger clinical trials.

MicroRNAs: role and therapeutic targets in viral hepatitis.

MicroRNAs regulate gene expression by binding to the 3'-untranslated region (UTR) of target messenger RNAs (mRNAs). The importance of microRNAs has been shown for several liver diseases, for example, viral hepatitis. MicroRNA-122 is highly abundant in the liver and is involved in the regulation of lipid metabolism. MicroRNA-122 is also an important host factor for the HCV and promotes HCV replication. In contrast to HCV, microRNA-122 inhibits replication of the HBV. MicroRNA-122 acts as a tumour suppressor and reduced levels of microRNA-122 are associated with hepatocellular carcinoma. MicroRNAs other than microRNA-122 have been linked to viral hepatitis, fibrosis and inflammation. In this review, we discuss function and clinical implications of microRNA-122 and other microRNAs in liver diseases, especially viral hepatitis.

Functional outcome of very preterm-born and small-for-gestational-age children at school age.

BACKGROUND: Our aim was to determine functional outcome of very preterm-born and small-for-gestational-age (SGA) children as compared with matched controls at school age. METHODS: We included 28 very preterm SGA children (GA <32 wk, birth weight (BW) <10th percentile), born in 2000-2001. We also included 28 very preterm but appropriate-for-gestational-age (AGA) children, matched for GA, gender, and birth year, as controls. We assessed motor skills, intelligence quotient (IQ), attention, verbal memory, visual perception, visuomotor integration, executive functioning, and behavior of both sets of children at school age. RESULTS: The SGA children had a median GA of 29.7 wk and BW of 888 g, whereas the controls had a median GA of 29.4 wk and BW of 1,163 g. At 8.6 y, the median total IQ of the SGA children was 94 as compared with 95 in the controls (not significant). Performance IQ was significantly lower in SGA children (89 vs. 95, P = 0.043), whereas verbal IQ was not (95 vs. 95). Total motor skills (P = 0.048) and fine motor skills (P = 0.021) were worse in SGA children. Furthermore, SGA children scored lower on selective attention (P = 0.026) and visual perception (P = 0.025). Other scores did not differ significantly between groups. CONCLUSION: The differences we found between the groups were small. This suggests that the impaired functioning of very preterm-born SGA children is attributable to their having been born very preterm rather than to being SGA.

Functional impairments at school age of children with necrotizing enterocolitis or spontaneous intestinal perforation.

We aimed to determine motor, cognitive, and behavioral outcome at school age of children who had either necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP). This case-control study included infants with NEC Bell's stage IIA onward, infants with SIP, and matched controls (1996-2002). At school age, we assessed motor skills, intelligence, visual perception, visuomotor integration, verbal memory, attention, behavior, and executive functions. Of 93 infants with NEC or SIP, 28 (30%) died. We included 52 of 65 survivors for follow-up. At mean age of 9 y, we found that 68% of the children had borderline or abnormal scores on the Movement Assessment Battery for Children (versus 45% of controls). Their mean total intelligence quotient (IQ) was 86 ± 14 compared with 97 ± 9 in the controls. In addition, attention and visual perception were affected (p < 0.01 and p = 0.02). In comparison to controls, surgically treated children were at highest risk for adverse outcome. In conclusion, at school age, the motor functions and intelligence of many children with NEC or SIP were borderline or abnormal and, specifically, attention and visual perception were impaired. Children with NEC or SIP form a specific risk group for functional impairments at school age even though the majority does not have overt brain pathology.