Merits and potential downsides of the 2013 ACC/AHA cholesterol management guidelines.

New guidelines from the American College of Cardiology and the American Heart Association on cholesterol management introduced substantial changes from the previous Adult Treatment Panel III guidelines and generated an immediate storm of controversy upon their release in November 2013. Four categories of individuals that can benefit from statin therapy, including three high-risk groups, have been identified. The fourth category of primary prevention has proven to be the most contentious, with criticism centering on the algorithm used to estimate ten-year risk for atherosclerotic cardiovascular disease and the optimal threshold for statin therapy. Although the risk assessment algorithm can be further refined, it represents an improvement from the previous calculator since it better captures risk in women and African Americans. However, the elimination of lipid targets in the new guidelines discounts a wealth of clinical trial and epidemiological evidence indicating that, with regards to low-density lipoprotein cholesterol, "lower is better." Recommendations regarding the use of nonstatin drugs, while appropriate, could potentially be revised in the future. In general, the new guidelines stress the necessity of addressing the multiple factors that contribute to cardiovascular risk, and they provide a valuable opportunity for physicians to address the importance of lifestyle modifications to lower a patient's overall risk.

A Phase 1 clinical trial of Hantaan virus and Puumala virus M-segment DNA vaccines for haemorrhagic fever with renal syndrome delivered by intramuscular electroporation.

Haemorrhagic fever with renal syndrome (HFRS) is endemic in Asia, Europe and Scandinavia, and is caused by infection with the hantaviruses Hantaan (HTNV), Seoul (SEOV), Puumala (PUUV), or Dobrava (DOBV) viruses. We developed candidate DNA vaccines for HFRS expressing the Gn and Gc genes of HTNV or PUUV and evaluated them in an open-label, single-centre Phase 1 study. Three groups of nine participants each were vaccinated on days 0, 28 and 56 with the DNA vaccines for HTNV, PUUV, or a mixture of both vaccines using the Ichor Medical Systems TriGrid Intramuscular Delivery System. All vaccinations consisted of a total dose of 2.0 mg DNA in an injected volume of 1 mL saline. For the combined vaccine, the mixture contained equal amounts (1.0 mg) of each DNA vaccine. There were no study-related serious adverse events. Neutralizing antibody responses were measured by a plaque reduction neutralization test. Neutralizing antibody responses were detected in five of nine and seven of nine individuals who completed all three vaccinations with the HTNV or PUUV DNA vaccines, respectively. In the combined vaccine group, seven of the nine volunteers receiving all three vaccinations developed neutralizing antibodies to PUUV. The three strongest responders to the PUUV vaccine also had strong neutralizing antibody responses to HTNV. These results demonstrate that the HTNV and PUUV DNA vaccines delivered by electroporation separately or as a mixture are safe. In addition, both vaccines were immunogenic, although when mixed together, more participants responded to the PUUV than to the HTNV DNA vaccine.

Interference of hepatitis C virus replication in cell culture by antisense peptide nucleic acids targeting the X-RNA.

The RNA-dependent RNA polymerase (RdRp) of hepatitis C virus (HCV) is the essential catalytic enzyme for viral genome replication. It initiates minus-strand RNA synthesis from a highly conserved 98-nt sequence, called the X-RNA, at the 3'-end of the plus-strand viral genome. In this study, we evaluated the antiviral effects of peptide nucleic acids (PNAs) targeting the X-RNA. Our in vitro RdRp assay results showed that PNAs targeting the three major stem-loop (SL) domains of X-RNA can inhibit RNA synthesis initiation. Delivery of X-RNA-targeted PNAs by fusing the PNAs to cell-penetrating peptides (CPPs) into HCV-replicating cells effectively suppressed HCV replication. Electrophoretic mobility shift assays revealed that the PNA targeting the SL3 region at the 5'-end of X-RNA dissociated the viral RdRp from the X-RNA. Furthermore, delivery of the SL3-targeted PNA into HCV-infected cells resulted in the suppression of HCV RNA replication without activation of interferon ß expression. Collectively, our results indicate that the HCV X-RNA can be effectively targeted by CPP-fused PNAs to block RNA-protein and/or RNA-RNA interactions essential for viral RNA replication and identify X-RNA SL3 as an RdRp binding site crucial for HCV replication. In addition, the ability to inhibit RNA synthesis initiation by targeting HCV X-RNA using antisense PNAs suggests their promising therapeutic potential against HCV infection.

A phase 1 study of a meningococcal native outer membrane vesicle vaccine made from a group B strain with deleted lpxL1 and synX, over-expressed factor H binding protein, two PorAs and stabilized OpcA expression.

This phase I clinical trial assessed the safety and immunogenicity of a native outer membrane vesicle (NOMV) vaccine prepared from an lpxL1(-) synX(-) mutant of strain 8570(B:4:P1.19,15:L8-5) of Neisseria meningitidis. Additional mutations enhance the expression of factor H binding protein variant 1 (fHbp v.1), stabilize expression of OpcA and introduce a second PorA (P1.22,14). Thirty-six volunteers were assigned to one of four dose groups (10, 25, 50 and 75 mcg, based on protein content) to receive three intramuscular injections at six week intervals with aluminum hydroxide adjuvant. Specific local and systemic adverse events were solicited by diary and at visits on days 2, 7, and 14 after each vaccination. Blood chemistries, complete blood count, and coagulation studies were measured on each vaccination day and again 2 and 14 days later. Blood for ELISA and serum bactericidal assays was drawn two and six weeks after each vaccination. The proportion of volunteers who developed a fourfold or greater increase in bactericidal activity to the wild type parent of the vaccine strain at two weeks after the third dose was 27 out of 34 (0.79, 95% C.I. 0.65-0.93). Against four other group B strains the response rate ranged from 41% to 82% indicating a good cross reactive antibody response. Depletion assays show contributions to bactericidal activity from antibodies to lipooligosaccharide (LOS), fHbp v.1 and OpcA.

Sero-epidemiology of hepatitis A virus infection among healthcare workers in Korean hospitals.

Hepatitis A virus (HAV) has been increasingly reported in Korea as has an outbreak in Korean healthcare workers (HCWs). This 2008 study evaluated the sero-epidemiology of HAV infections among 3696 HCWs in four Korean hospitals. HCWs were tested for immunoglobulin G anti-HAV antibodies using commercially available kits. Data including demographic characteristics, occupation, workplace and serological status for other hepatitis viruses were collected. Statistical analyses were conducted to identify variables related to HAV seropositivity. Among the 3696 participants, 2742 (74%) were women and the majority (96%) were aged 20-39 years (median: 28; range: 19-68). Eighteen percent were physicians, 46% nurses, 10% nurses' aides, 11% paramedical technicians and 15% administrative staff. Seropositivity for HAV significantly increased with age (P<0.001): 1.8% for < or =24 years, 14.7% for 25-29 years, 41.8% for 30-34 years, 75.5% for 35-39 years, and 93.7% for > or =40 years. Among those aged 20-39 years, age-specific HAV seroprevalence was significantly lower in physicians than in the other occupational groups (P<0.001). In Korea, mass vaccination to HCWs aged < or =29 years or screening for seropositivity and vaccinating non-immune subjects aged 30-39 years should be considered, especially in physicians.