Citations

Abstract Chronic hepatitis C can lead to cirrhosis and hepatocellular carcinoma. We studied the safety and immunogenicity of a novel therapeutic hepatitis C virus (HCV) genotype 1a/1b consensus DNA vaccine, INO-8000, encoding HCV NS3, NS4A, NS4B, and NS5A proteins alone or co-administered with DNA-encoding IL12 (INO-9012), a human cytokine that stimulates cellular immune function, in individuals with chronic hepatitis C. This was a phase I, multisite dose-escalation trial with an expansion cohort evaluating doses of 0, 0.3, 1.0, and 3.0 mg of INO-9012 (IL12 DNA) as an addition to 6.0 mg of (INO-8000; HCV DNA vaccine). Vaccines were administered by intramuscular injection followed by electroporation at study entry and at weeks 4, 12, and 24. HCV-specific CD4+ and CD8+ T-cell immune responses were measured by IFNγ ELISpot and flow cytometry–based assays. Transient, mild-to-moderate injection site reactions unrelated to IL12 DNA dose were common. Increases in HCV-specific IFNγ production occurred in 15/20 (75%) participants. Increases in the frequency of HCV-specific CD4+ and CD8+ T cells occurred at all dose levels, with the greatest increases seen at 1.0 mg of INO-9012. HCV-specific CD8+ and CD4+ T-cell activities increased in 16/18 (89%) and 14/17 (82%) participants with available data, respectively. The vaccine regimen was safe and induced HCV-specific CD4+ and CD8+ cellular immune responses of modest magnitude in most HCV-infected participants. The addition of 1.0 mg of IL12 DNA provided the best enhancement of immune responses. The vaccine regimen had little effect on controlling HCV viremia. Prevention Relevance: The administration of IL12 DNA along with a hepatitis C viral antigen DNA vaccine enhanced the HCV-specific immune responses induced by the vaccine in individuals with chronic hepatitis C, an important cause of hepatocellular carcinoma. IL12 could be an effective adjuvant in vaccines targeting HCV and other oncogenic viruses.

AbstractTransthyretin‐mediated amyloidosis (ATTR) is a rare, under‐recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition of amyloid transthyretin (TTR) fibrils in multiple organs and tissues throughout the body. TTR is predominantly synthesized by the liver and normally circulates as a homotetramer, while misfolded monomers aggregate to form amyloid fibrils. One strategy to treat ATTR amyloidosis is to reduce the amount of TTR produced by the liver using drugs that directly target the TTR mRNA or gene. This narrative review focuses on how TTR gene silencing tools act to reduce TTR production, describing strategies for improved targeted delivery of these agents to hepatocytes where TTR is preferentially expressed. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), termed RNA silencers, cause selective degradation of TTR mRNA, while a TTR gene editing tool reduces TTR expression by introducing nonsense mutations into the TTR gene. Two strategies to facilitate tissue‐specific delivery of these nucleic acid‐based drugs employ endogenous receptors expressed by hepatocytes. Lipid nanoparticles (LNPs) that recruit apolipoprotein E support low‐density lipoprotein receptor‐mediated uptake of unconjugated siRNA and are now used for CRISPR gene editing tools. Additionally, conjugating N‐acetylgalactosamine (GalNAc) moieties to ASOs or siRNAs facilitates receptor‐mediated uptake by the asialoglycoprotein receptor. In summary, ATTR is a progressive disease with various clinical manifestations due to TTR aggregation, deposition, and amyloid formation. Receptor‐targeted ligands (eg, GalNAc) and nanoparticle encapsulation (eg, LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to hepatocytes, the primary location of TTR synthesis.

Objective: To investigate whether dexmedetomidine (DEX), as adjunctive therapy to benzodiazepine (BZD), is superior to BZD alone in critically ill patients with alcohol withdrawal syndrome (AWS). Data Sources: PubMed Central, Cochrane CENTRAL, ClinicalTrials.gov and Google Scholar were used as search databases. Specific keywords and MeSH terms were “dexmedetomidine,” “benzodiazepine,” and “alcohol withdrawal syndrome.” The last search was on September 16, 2022. Study Selection and Data Extraction: Randomized controlled trials (RCTs) and nonrandomized/cohort studies exploring the use of DEX in the management of AWS were included. A total of 12 studies were included in the systematic review and 7 in the meta-analysis. Data Synthesis: The intensive care unit length of stay (ICU LOS) was found to have a mean difference (MD) of 48.06 [37.48, 58.64], P = <0.001 for the cohort subgroup, significantly favoring the DEX arm, but, in contrast, pooled RCT data showed a result of –20.07 [–36.86, –3.28], P = 0.02, a shorter ICU LOS for the DEX arm. Bradycardia and hypotension incidence significantly favored the BZD arm in both subgroups. This study compares the effectiveness of adjunctive DEX in clinical practice and aims to help providers in critical decision-making by compiling and analyzing the best current available evidence of its use in AWS. Conclusions: Based on low to very low level of evidence, adjunctive DEX showed no significant difference for ICU LOS when compared with BZD alone. Pooled randomized trials potentially show a benefit but are similarly limited by their low quality of evidence.

Abstract Introduction Pericardial effusion (PE) in patients with infective endocarditis (IE) has been shown to be an independent risk factor for severe complications, however no significant association with mortality has been established. Our study aims to study the significance of pericardial effusion in patients with IE. Methods We performed a retrospective analysis using the United States National Inpatient Sample (NIS) database to identify all the hospital admissions with IE using ICD 10 codes and divided them into two groups based on the presence of PE. The outcomes of interest were in-hospital mortality, in-hospital complications, need for cardiac surgery, and length of stay (LOS). Results A total of 381,300 patients were hospitalized from 2016 to 2019 with IE, of whom 10,370 developed PE. Mean age of patients in the PE group was 51 years and in non-PE group was 61 years with males and Caucasian race being predominant in both groups. PE group had higher rates of in-hospital death (12.7% vs 9%, P≤0.001) and longer in-hospital stay (12 days vs 7 days, P≤0.001) compared to non-PE group. The rates of cardiac surgery were higher in PE group (26.1% vs 8.4%, P≤0.001). The rates of heart failure, heart block, renal failure, cardiogenic shock, and embolic stroke were higher in PE group [Table 1]. Conclusion Our study shows that presence of PE in patients with IE is a predictor for in-hospital mortality, length of stay, and need for cardiac surgery. Also, these patients are at higher risk for heart failure, heart block, cardiogenic shock and embolic stroke. Funding Acknowledgement Type of funding sources: None.

Background Rotational and orbital coronary atherectomy (CA) are commonly utilized to treat complex calcified coronary lesions. We conducted a meta-analysis to evaluate sex differences in procedural complications and clinical outcomes after CA. Methods PubMed, Google Scholar, and Cochrane databases were searched for all studies comparing sex differences in procedural and clinical outcomes following CA. The outcomes of interest were procedural complications (coronary dissection, stroke, major bleeding, coronary perforation, cardiac tamponade, and slow or no flow in target vessel) and the clinical outcomes (including early mortality, mid-term all-cause mortality, stroke, myocardial infarction, and target vessel revascularization). Pooled risk ratios (RRs) with their corresponding 95% confidence intervals (CIs) were calculated using the Mantel–Haenszel random-effects model. Results Six observational studies with 3517 patients (2420 men and 1035 women) were included in this meta-analysis. While there was no significant difference in the early mortality (RR, 1.14; 95% CI, 0.37–3.53; P = 0.83) between men and women, at a mean follow-up of 2.9 years, all-cause mortality was significantly higher in women (RR, 1.29; 95% CI, 1.11–1.49; P = 0.0009). Women had an increased risk of procedure-related stroke (RR, 3.98; 95% CI, 1.06–14.90; P = 0.04), coronary dissection (RR, 2.10; 95% CI, 1.23–3.58; P = 0.006), and bleeding (RR, 2.26; 95% CI, 1.30–3.93; P = 0.004), whereas the rates of coronary perforation, cardiac tamponade, and the risk of slow or no flow in the revascularized artery were similar in both. Conclusion In our analysis, women undergoing CA are at increased risk of mid-term mortality and procedure-related complications including stroke, coronary dissection, and major bleeding.

We aimed to evaluate the feasibility of a tailored physical activity (PA) prescription in overweight and obese people in a tertiary hospital in Lima, Peru. A feasibility pre–post-pilot study was conducted using mixed methods. Participants received a tailored prescription scheme for PA that lasted twelve weeks. It included two prescription sessions, three follow-up phone calls, and three evaluations. Primary feasibility outcomes were recruitment, visits, and phone call adherence. Primary intervention outcomes were self-reported PA levels and the 6 min walk test. Out of 228 people invited to participate, 30 were enrolled and received the first session of prescription, 11 went to the second session, and 21 went to the final evaluation; phone call participation decreased progressively during follow-up. There were no differences in the 6th week and the 12th week compared to the baseline for all the measures, except in the 6 min walk test. The participants considered the intervention was well designed, but they suggested complementing it with dietary instructions. The prescription of PA in overweight and obese people is feasible for promoting PA, but its implementation requires refinements to anticipate possible barriers to changing behavior.