OBJECTIVES AND DESIGN:Hepatitis C virus (HCV) has been recognized as an emerging sexually transmitted infection (STI) among HIV-positive MSM. However, HIV-negative MSM at high risk for HIV might also ...be at increased risk for HCV. We studied the HCV prevalence in HIV-negative MSM who start preexposure prophylaxis (PrEP) in Amsterdam. Phylogenetic analysis was used to compare HCV strains obtained from HIV-negative and HIV-positive MSM.
METHODS:At enrolment in the Amsterdam PrEP demonstration project, HIV-negative MSM were tested for the presence of HCV antibodies and HCV RNA. If positive for HCV RNA, an HCV NS5B gene fragment (709 bp) was sequenced and compared with HCV isolates from HIV-positive MSM (n = 223) and risk groups other than MSM (n = 153), using phylogenetic analysis.
RESULTS:Of 375 HIV-negative MSM enrolled in Amsterdam PrEP, 18 (4.8%, 95% confidence interval 2.9–7.5%) of participants were anti-HCV and/or HCV RNA positive at enrolment; 15 of 18 (83%) had detectable HCV RNA. HCV genotyping showed genotype 1a (73%), 4d (20%), and 2b (7%). All HCV-positive MSM starting PrEP were part of MSM-specific HCV clusters containing MSM with and without HIV.
CONCLUSION:HCV prevalence among HIV-negative MSM who started PrEP was higher than previously reported. All HIV-negative HCV-positive MSM were infected with HCV strains already circulating among HIV-positive MSM. The increasing overlap between sexual networks of HIV-positive and HIV-negative MSM might result in an expanding HCV-epidemic irrespective of HIV-status. Hence, routine HCV testing should be offered to MSM at high risk for HIV, especially for those enrolling in PrEP programs.
Purpose: Imatinib, a BCR-ABL tyrosine kinase inhibitor, is a substrate of the efflux transporters P-glycoprotein (P-gp; ABCB1 ) and ABCG2 (breast cancer resistance protein), and its brain ...accumulation is restricted by both transporters. For dasatinib,
an inhibitor of SCR/BCR-ABL kinases, in vivo interactions with P-gp and ABCG2 are not fully established yet.
Experimental Design: We used Abcb1a/1b â/â , Abcg2 â/â , and Abcb1a/1b;Abcg2 â/â mice to establish the roles of P-gp and ABCG2 in the pharmacokinetics and brain accumulation of dasatinib.
Results: We found that oral uptake of dasatinib is limited by P-gp. Furthermore, relative brain accumulation, 6 hours after administration,
was not affected by Abcg2 deficiency, but absence of P-gp resulted in a 3.6-fold increase after oral and 4.8-fold higher accumulation
after i.p. administration. Abcb1a/1b;Abcg2 â/â mice had the most pronounced increase in relative brain accumulation, which was 13.2-fold higher after oral and 22.7-fold
increased after i.p. administration. Moreover, coadministration to wild-type mice of dasatinib with the dual P-gp and ABCG2
inhibitor elacridar resulted in a similar dasatinib brain accumulation as observed for Abcb1a/1b;Abcg2 â/â mice.
Conclusions: Brain accumulation of dasatinib is primarily restricted by P-gp, but Abcg2 can partly take over this protective function
at the blood-brain barrier. Consequently, when both transporters are absent or inhibited, brain uptake of dasatinib is highly
increased. These findings might be clinically relevant for patients with central nervous system Philadelphia chromosomeâpositive
leukemia, as coadministration of an inhibitor of P-gp and ABCG2 with dasatinib might result in better therapeutic responses
in these patients.
Summary
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.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
In patients with ischaemic cardiomyopathy and viable myocardium, left ventricular ejection fraction (LVEF) does not always improve after revascularisation. Whether this may affect prognosis is ...unclear.
To evaluate the prognosis of viable patients with and without improvement of LVEF after coronary revascularisation.
Before revascularisation, radionuclide ventriculography (RNV) and dobutamine stress echocardiography were performed to assess LVEF and myocardial viability, respectively. Nine to 12 months after revascularisation, LVEF improvement was assessed by RNV. Patients were divided into three groups: group 1, viable patients with LVEF improvement (n = 27); group 2, viable patients without LVEF improvement (n = 15), group 3, non-viable patients (n = 48). Cardiac events were evaluated during a 4-year follow-up.
After revascularisation, the mean (SD) LVEF improved from 32 (9)% to 42 (10)% in group 1, but did not change significantly in group 2 and in group 3, p<0.001 by analysis of variance (ANOVA). Heart failure symptoms improved in both groups 1 (mean (SD) NYHA class from 3.1 (0.9) to 1.7 (0.7)) and 2 (from 3.2 (0.7) to 1.7 (0.9)), but not in group 3 (from 2.8 (1.0) to 2.7 (0.5)), p<0.001 by ANOVA. During follow-up, the cardiac event rate was low (4%) in group 1, intermediate (21%) in group 2 and high (33%) in group 3 (p = 0.01).
The best prognosis after revascularisation may be expected in those viable patients whose LVEF improves. Conversely, viable patients without functional improvement have an intermediate prognosis.
Immediate initiation of antiretroviral therapy (ART) regardless of CD4 cell count reduces risk for AIDS and non-AIDS-related events in asymptomatic, HIV-positive persons and is the standard of care. ...However, most HIV-positive persons initiate ART when their CD4 count decreases below 500 × 10
cells/L. Consequences of delayed ART on risk for non-AIDS-defining and AIDS-defining cancer, one of the most common reasons for death in HIV, are unclear.
To estimate the long-term risk difference for cancer with the immediate ART strategy.
Multinational prospective cohort study.
The D:A:D (Data collection on Adverse events of anti-HIV Drugs) study, which included HIV-positive persons from Europe, Australia, and the United States.
8318 HIV-positive persons with at least 1 measurement each of CD4 cell count and viral load while ART-naive (study period, 2006 to 2016).
The parametric g-formula was used, with adjustment for baseline and time-dependent confounders (CD4 cell count and viral load), to assess the 10-year risk for non-AIDS-defining and AIDS-defining cancer of immediate versus deferred (at CD4 counts <350 and <500 × 10
cells/L) ART initiation strategies.
During 64 021 person-years of follow-up, 231 cases of non-AIDS-defining cancer and 272 of AIDS-defining cancer occurred among HIV-positive persons with a median age of 36 years (interquartile range, 29 to 43 years). With immediate ART, the 10-year risk for non-AIDS-defining cancer was 2.97% (95% CI, 2.37% to 3.50%) and that for AIDS-defining cancer was 2.50% (CI, 2.37% to 3.38%). Compared with immediate ART initiation, the 10-year absolute risk differences when deferring ART to CD4 counts less than 500 × 10
cells/L and less than 350 × 10
cells/L were 0.12 percentage point (CI, -0.01 to 0.26 percentage point) and 0.29 percentage point (CI, -0.03 to 0.73 percentage point), respectively, for non-AIDS-defining cancer and 0.32 percentage point (CI, 0.21 to 0.44 percentage point) and 1.00 percentage point (CI, 0.67 to 1.44 percentage points), respectively, for AIDS-defining cancer.
Potential residual confounding due to observational study design.
In this young cohort, effects of immediate ART on 10-year risk for cancer were small, and further supportive data are needed for non-AIDS-defining cancer.
Highly Active Antiretroviral Therapy Oversight Committee.
The Murchison Wide-Field Array (MWA) is a low-frequency radio telescope, currently under construction, intended to search for the spectral signature of the epoch of reionization (EOR) and to probe ...the structure of the solar corona. Sited in western Australia, the full MWA will comprise 8192 dipoles grouped into 512 tiles and will be capable of imaging the sky south of 40° declination, from 80 MHz to 300 MHz with an instantaneous field of view that is tens of degrees wide and a resolution of a few arcminutes. A 32 station prototype of the MWA has been recently commissioned and a set of observations has been taken that exercise the whole acquisition and processing pipeline. We present Stokes
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integrations of a field 20° wide centered on Pictoris A. These images demonstrate the capacity and stability of a real-time calibration and imaging technique employing the weighted addition of warped snapshots to counter extreme wide-field imaging distortions.
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BFBNIB, NMLJ, NUK, PNG, UL, UM, UPUK
In the present study the authors compared the incidence and risk factors for external drainage-related bacterial meningitis (ED-BM) by using ventricular and lumbar catheters.
A cohort of 230 ...consecutive patients with ED was evaluated. Cerebrospinal fluid samples were obtained daily for microbiological culture, and ED-BM was defined based on culture results in combination with clinical symptoms. The incidence of ED-BM was 7% in lumbar and 15% in ventricular drains. Independent risk factors included site leakage, drain blockage, and most importantly duration of ED. Despite a higher infection rate, ventricular catheters did not have a significant higher risk of infection after correcting for duration of drainage.
Analysis of data in the present study showed that the incidence of ED-associated death is low (0.45%) in patients who do not receive continuous antibiotic prophylaxis during ED.
Interannual changes in the occurrence of Bryde’s whale (Balaenoptera edeni) have been observed in La Paz Bay (southwestern Gulf of California, Mexico) over the last 20 years. We suggest that these ...changes could be driven by natural fluctuations in food resources that are related to climate variability. We compared monthly Bryde’s whale occurrence in La Paz Bay from 1988 to 2006 to climate variability at seasonal and interannual time scales and its effect on prey availability. The results showed that Bryde’s whales do not have a well-defined pattern of seasonal occurrence; however, large numbers of whales were consistently recorded during La Niña conditions when the Gulf of California sardine population is distributed further south within the gulf. In contrast, fewer whales were recorded during El Niño and neutral conditions. This indicates that changes in the occurrence of Bryde’s whales at La Paz Bay are driven by the El Niño-Southern Oscillation interannual variability and are probably mediated by their prey availability.
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