Week 4 viral load predicts long-term suppression of hepatitis B virus DNA during antiviral therapy: improving hepatitis B treatment in the real world.

BACKGROUND: Entecavir and tenofovir potently suppress hepatitis B virus (HBV) replication so that serum HBV DNA levels <20 IU/mL can be achieved after 2 years. Despite this, inadequate suppression is reported in >20% of cases for unclear reasons. AIM: We tested whether 4-week viral load (VL) assessment could improve 96-week treatment outcome. METHODS: Data on all chronic hepatitis B patients treated with entecavir or tenofovir between 2005 and 2014 were entered prospectively. Full data capture included pre-treatment, weeks 4, 24, 48 and 96 HBV DNA titre, HBeAg, age, gender, antiviral agent and dose escalation. Compliance data were compiled from pharmacy records, doctors' letters and clinic bookings/attendance. Time to achieve complete viral suppression (HBV DNA < 20 IU/mL) was graphed using Kaplan-Meier curves. Factors affecting this were examined using a multivariate Cox Proportional Hazard model. RESULTS: Among 156 patients treated, 72 received entecavir and 84 tenofovir. Pre-treatment HBV DNA titre, 4-week assessment and compliance impacted significantly on time to complete viral suppression. At 96 weeks, 90% of those assessed as compliant by 4-week HBV DNA had complete viral suppression versus 50% followed by 6-month VL estimation. Continuing care by the same physician was related to 4-week VL testing and optimal compliance. CONCLUSIONS: Medium-term outcomes of HBV antiviral therapy are improved by early on-treatment VL testing, facilitating patient engagement and improved compliance. The observation that 90% complete viral suppression after 2 years monotherapy is achievable in a routine clinic setting questions the need for combination therapy in HBV cases with suboptimal response.

Interpreting febrile neutropenia rates from randomized, controlled trials for consideration of primary prophylaxis in the real world: a systematic review and meta-analysis.

BACKGROUND: Guidelines recommend primary prophylaxis (PP) with granulocyte-colony-stimulating factors (G-CSF) for patients above a febrile neutropenia (FN) risk threshold of 20%. Practitioners often use FN rates of regimens based on data from randomized, controlled trials (RCTs), which are often comprised of highly selected patients. Patients in the community setting may be at higher risk of FN. MATERIALS AND METHODS: A systematic literature search was conducted for full-length articles reporting FN rates for breast cancer-related chemotherapies between January 1996 and February 2014. A regimen was included if there was at least one RCT and one observational study. Meta-regression was used to model the odds of FN. RESULTS: 130 studies involving 29 regimens and 50 069 patients were identified. Sixty-five observational study (n = 7812) and 110 RCT (n = 42 257) cohorts were included. The unadjusted FN rate was 11.7% in observational and 7.9% in RCT cohorts. The univariable odds ratio (OR) for FN in the observational study compared with RCT cohorts was 1.58 [95% confidence interval (CI) 1.09-2.28; P = 0.017]. The FN rates remained significantly higher in the observational study compared with RCT cohorts (OR = 1.74; 95% CI 1.15-2.62; P = 0.012) after adjusting for age, chemotherapy intent, and regimen; this meant that a 13% (95% CI 8.7% to 17.9%) FN rate in RCT would translate into 20% FN rate in observational study. CONCLUSIONS: FN rates in the observational studies are significantly higher than suggested by RCTs. Guidelines should clarify how FN rates from RCTs should be applied in clinical practice. Large population-based studies are needed to confirm FN rates in the real world.

Assessment of changes in cardiac index and fluid responsiveness: a comparison of Nexfin and transpulmonary thermodilution.

BACKGROUND: The Nexfin device uses non-invasive photoplethysmography to monitor cardiac output and respiratory variations in pulse pressure and stroke volume. The aim of this study was to compare rapid changes in cardiac index after fluid challenge between Nexfin and bolus transpulmonary thermodilution and the ability to predict fluid responsiveness of dynamic indices given by Nexfin. METHODS: Simultaneous comparative cardiac index were collected from transpulmonary thermodilution and Nexfin before and after fluid challenge in 45 patients following conventional cardiac surgery. Correlations, Bland-Altman analyses and percentage errors were calculated. Pulse pressure variations and stroke volume variations before fluid challenge were collected to assess their discrimination in predicting fluid responsiveness. RESULTS: Eight (18%) patients were excluded. A weak positive relationship was found between rapid changes in cardiac index after fluid challenge given by both technologies (n = 37, r = 0.39, P = 0.019). Bias, precision and limits of agreements were 0.20 l/min/m(2) (95% confidence interval (CI) 0.02-0.40), 0.57 l/min/m(2) and ± 1.12 l/min/m(2) before fluid challenge, and 0.01 l/min/m(2) (95% CI -0.24 to 0.26), 0.74 l/min/m(2) and ± 1.45 l/min/m(2) after fluid challenge. Percentage errors between Nexfin and transpulmonary thermodilution were 55% and 58% before and after fluid challenge, respectively. Pulse pressure variations and stroke volume variations given by Nexfin were not discriminant to predict fluid responsiveness: areas under receiver operating characteristics curves 0.57 (95% CI 0.40-0.73) and 0.50 (0.33-0.67), respectively. CONCLUSIONS: The Nexfin cannot be used to measure rapid changes in cardiac index following fluid challenge and to predict fluid responsiveness after cardiac surgery.

Simple approach to improving vancomycin dosing in intensive care: a standardised loading dose results in earlier therapeutic levels.

BACKGROUND: Patients in the Intensive Care Unit (ICU) often have sub-therapeutic vancomycin levels in the initial stages of therapy. Loading doses have been demonstrated to overcome this problem. AIM: The aim of this study was to determine the impact of a standardised loading dose and increased clinician awareness of under-dosing on the achievement of early therapeutic vancomycin trough concentrations in the ICU. METHODS: A pre- and post-intervention observational study was conducted in the ICU following the introduction of a 2-g vancomycin loading dose and demonstration of local under-dosing. All initial vancomycin trough levels were examined, except those from neurosurgical patients. Primary outcome measures were the proportion of patients achieving therapeutic vancomycin levels and mean trough concentrations. A year after introduction, a review was conducted to further assess the impact and sustainability of the intervention. RESULTS: There were 31 courses of vancomycin in the pre-intervention period (no loading doses given) and 21 courses in the post-intervention period, of which 11 had a loading dose. In the pre-intervention group, 13% of courses achieved therapeutic concentrations. This increased to 33% in the post-intervention group (P= 0.08). A statistically significant increase in mean trough concentration, from 9.8 ± 6.6 mg/L to 14.9 ± 6.3 mg/L (P= 0.01), between the pre- and post-intervention groups was observed. During the follow-up period, results were similar to the post-intervention audit. CONCLUSION: A standardised loading dose is a simple and sustainable intervention that may improve early achievement of therapeutic vancomycin levels in critically ill patients. The clinical significance of this requires further study.

Vaccine-preventable meningitis in French children with incorrect vaccination status from 2011 to 2013.

The objective of this study was to determine the number of cases of pediatric meningitis or purpura fulminans associated with an incorrect vaccination status from 2011 to 2013 in France. A total of 48 children with vaccine-preventable meningitis or purpura fulminans, including three deaths, had an incorrect vaccination status: 26 cases were due to Neisseria meningitidis group C (54.2%), 19 to Streptococcus pneumoniae (39.6%), and three to Haemophilus influenzae type b (6.3%). The majority of patients (n=35, 72.9%) had received no injection of the vaccine concerned. Over a 3-year period, 48 cases of bacterial meningitis or purpura fulminans in children could have been avoided if the French immunization schedule had been followed.

Current concepts in electrical defibrillation.

The electrical defibrillator has been proven to be a life-saving device in the treatment of cardiac arrest due to ventricular tachycardia or ventricular fibrillation. An understanding of the physiology and technology behind this device is useful for providers of emergency care. In this article, we review the current concepts in electrical defibrillation and briefly discuss the developmental history. The physiology and the technical considerations will make up the bulk of the discussion. The latest developments in electrical defibrillation also will be reviewed.

Concentrations and chiral signatures of POPs in soils and sediments: a comparative urban versus rural study in Canada and UK.

Surface soils and sediments were collected in Toronto, Canada to investigate the concentrations and enantiomeric signatures of urban versus rural locations. Samples were analyzed for polychlorinated biphenyls (PCBs), polyaromatic hydrocarbons (PAHs) and organochlorine pesticides (OCs). In soils, the sum of 10 PCB congeners (Sigma PCB 28, 52, 95, 101, 118, 136, 138, 149, 153, 180) and 15 PAHs (Sigma PAHs) ranged from 0.76-58 to 58-3200 ng g(-1), respectively. The most abundant OCs detected were DDTs, followed by chlordanes and endosulfans. Sigma PAHs exhibited an urban-rural gradient of up to 60 times but a gradient was not observed for Sigma PCBs and OCs which may reflect local sources of these chemicals. In sediments, Sigma PCBs and Sigma PAHs ranged from 0.03-23 ng g(-1) to 42-3300 ng g(-1), respectively. Sigma PCBs, Sigma PAHs, chlordanes and DDTs exhibited weak urban-rural gradients. Chiral signatures of PCB 95, 136, 149, trans-chlordane (TC), cis-chlordane (CC) and o,p-DDT were characterized to study the enantiomeric degradation in urban versus rural areas and its relation to contaminant levels. Supplementary to these data, we also report on the chiral signatures of PCBs in UK lake sediments from a variety of urban and rural locations. The extent of enantiomeric degradation was expressed as the enantiomeric excess (EE%) which is defined as 100x(E1-E2)/(E1+E2), where E1 is always the most abundant enantiomer and E2 is the least abundant enantiomer. The EE% of PCB 149 in the UK sediments was negatively correlated (p<0.05) with Sigma PAHs suggesting either more recent emissions of this PCB congener in the more contaminated urban locations and hence a more racemic signature or less enantiomeric degradation of the congener in more contaminated urban soils. However, no significant correlation was observed between EE% of any of the chiral chemicals and contaminant levels in the Toronto soils.

A splice variant of the ITF-2 transcript encodes a transcription factor that inhibits MyoD activity.

Proteins of the basic helix-loop-helix (bHLH) family are transcription factors that bind DNA containing the E box motif (CANNTG) found in the promoters of many muscle-specific genes. ITF-2 is a bHLH protein with widespread expression that is thought to form active heterodimers with MyoD, a muscle-specific bHLH transcription factor. We have isolated cDNAs derived from two alternatively spliced forms of mouse ITF-2, termed MITF-2A and -2B. These proteins differ in their N termini. Neither MITF-2A nor -2B transactivated the cardiac alpha-actin promoter, which contains an E box, when transfected into nonmuscle cells. In fact, MITF-2B inhibited MyoD activation of the cardiac alpha-actin promoter. This inhibitory activity required the N-terminal 83 amino acids since MITF-2A showed no inhibitory activity, and a mutant MITF-2B with deletion of the N-terminal 83 amino acids failed to inhibit MyoD-mediated transcriptional activation. MyoD activity was also inhibited by Id, a HLH protein, and this inhibition was reversed by the addition of excess E12 or MITF-2A. However, the inhibition of MyoD activity by MITF-2B was not reversed with E12 or MITF-2A. While Id is thought to inhibit MyoD by binding and sequestering potential dimerization partners, MITF-2B appears to inhibit MyoD activity by forming an inactive heterodimer with MyoD. Thus, differentially spliced transcripts of mouse ITF-2 encode different proteins that appear to dimerize with MyoD and activate or repress transcription.

Identification of two novel HLA class II alleles, DQB1*030503 and DRB1*0447.

Two novel human leukocyte antigen (HLA) class II alleles have been identified in routine typing of bone marrow donors for the Australian Bone Marrow Donor Registry in Sydney, Australia. Sequence analysis of exon 2 of both the DQB1 and DRB1 genes revealed the novel polymorphism. A silent substitution of G to A at nucleotide position 210 has been identified for the DQB1*030503 allele when compared to the closest matched allele, DQB1*030501. There is no associated amino acid difference between the translated products of the two alleles. The second new allele is a variant of the DRB1 gene. The DRB1*0447 allele was identified with three nucleotide substitutions compared to the closest matched allele DRB1*0436. There is a silent mutation at nucleotide position 303, G to C and two substitutions at adjacent nucleotide positions 344 and 345, T to G and G to T, respectively. The latter two substitutions result in an amino acid change from valine to glycine at position 86, implicating a different specificity and affinity of antigen binding.

A new HLA-B allele, B*1565, identified in three unrelated samples.

Anew human leukocyte antigen-B allele, B*1565, has been identified during routine typing of cord blood samples. Subsequently, two individuals from the same family as the first cord blood sample plus two unrelated Australian Bone Marrow Donor Registry samples have been found to carry this novel allele.