Susceptibility of influenza B viruses to neuraminidase inhibitors: findings from the first 4 years (2008–2012) of the global Influenza Resistance Information Study (IRIS)

Poster Session: Antiviral Drugs and ResistanceBackground: Type B influenza virus infections continue to account for a substantial proportion of clinical illness. Little is known about comparative disease profiles by virus lineage. A global observational trial (the Influenza Resistance Information Study or IRIS; NCT00884117) was initiated to study neuraminidase inhibitor (NAI) susceptibility and the clinical and virological course of influenza in treated and untreated patients. Materials and Methods: Patients in the northern and southern hemispheres (USA, France, Germany, Poland, Norway, Hong Kong, Australia) with influenza-like illness and/or a positive rapid influenza test result were enrolled. Throat/nasal swabs were performed on Days 1, 3 (self-swab), 6 and 10 and tested for influenza A and B viruses by RT-PCR. Influenzapositive samples collected on Days 1, 6 or 10 were cultured and subsequently sequenced (HA and NA) and phenotypically tested for NAI susceptibility. The lineage of B viruses was determined from sequencing. Clinical information, including the scoring of seven influenza symptoms (scale: 0 [absent], 1 [mild], 2 [moderate], 3 [severe]), was recorded on diary cards by the patient or the patient’s legal guardian (Days 1–12). Symptoms were also assessed by the investigator at each visit. The decision to prescribe an NAI was left to the physician’s discretion. Results: In the first 4 years of IRIS (December 2008 to March 2012), 2262 influenza-positive (RT-PCR) patients were enrolled, of whom 697 presented with a type B influenza virus infection (564 Victoria, 98 Yamagata, 35 undetermined lineage). Most type B patients (402; 58%) were children aged < 13 years. A total of 330 (47%) type B patients were treated with oseltamivir (as monotherapy) within 2 days of symptom onset; a further 26 started oseltamivir 2 days after symptom onset. Eleven patients received zanamivir, one received amantadine and another received rimantidine. A total of 328 (47%) did not receive any influenza antiviral. Symptoms were mild to moderate on Day 1 (mean total score: 12.8, treated; 12.9, untreated), and the mean temperature on Day 1 was 38.2°C. All viruses obtained at baseline or postbaseline were susceptible to NAIs: mean (SD) IC50 values for oseltamivir were 4.8 nM (2.5 nM) and 5.5 nM (2.3 nM) for the Victoria and Yamagata viruses, respectively; the corresponding values for zanamivir were 2.0 nM (1.4 nM) and 2.9 nM (1.6 nM), respectively. No known NAI resistance mutations were detected by NA or HA population sequencing. The proportion of RT-PCR–positive patients on Day 6 was 130/309 (42.1%) for patients treated with oseltamivir and 152/312 (48.7%) for untreated patients. In Kaplan–Meier analyses, no significant differences in median time to influenza RNA clearance were found between oseltamivir-treated and -untreated patients, either in adults or children. The time to symptom resolution (all symptom scores ≤ 1) was 5 days (95% CI, 4–5 days) in oseltamivir-treated children and 6 days (95% CI, 5–6 days) in untreated children (P = .026), but no significant difference in symptom resolution time was found in adults (Kaplan–Meier analysis). Conclusions: Analysis of type B influenza viruses obtained globally between 2008 and 2012 showed that all pre-treatment B/Victoria and B/Yamagata viruses were susceptible to oseltamivir and zanamivir. Moreover, no resistant viruses were detected during treatment. Given the non-randomised design of this study, no definitive conclusions can be drawn with regard to the clinical benefit of oseltamivir in patients infected with type B influenza viruses.published_or_final_versio

Measurement of Permanent Electric Dipole Moments of Charged Hadrons in Storage Rings

Permanent Electric Dipole Moments (EDMs) of elementary particles violate two fundamental symmetries: time reversal invariance (T) and parity (P). Assuming the CPT theorem this implies CP-violation. The CP-violation of the Standard Model is orders of magnitude too small to be observed experimentally in EDMs in the foreseeable future. It is also way too small to explain the asymmetry in abundance of matter and anti-matter in our universe. Hence, other mechanisms of CP violation outside the realm of the Standard Model are searched for and could result in measurable EDMs. Up to now most of the EDM measurements were done with neutral particles. With new techniques it is now possible to perform dedicated EDM experiments with charged hadrons at storage rings where polarized particles are exposed to an electric field. If an EDM exists the spin vector will experience a torque resulting in change of the original spin direction which can be determined with the help of a polarimeter. Although the principle of the measurement is simple, the smallness of the expected effect makes this a challenging experiment requiring new developments in various experimental areas. Complementary efforts to measure EDMs of proton, deuteron and light nuclei are pursued at Brookhaven National Laboratory and at Forschungszentrum Juelich with an ultimate goal to reach a sensitivity of 10^{-29} e cm.Comment: 8 pages, 2 figure

Sensitivity of the Atlantic meridional overturning circulation to South Atlantic freshwater anomalies

The sensitivity of the Atlantic Meridional Overturning Circulation (AMOC) to changes in basin integrated net evaporation is highly dependent on the zonal salinity contrast at the southern border of the Atlantic. Biases in the freshwater budget strongly affect the stability of the AMOC in numerical models. The impact of these biases is investigated, by adding local anomaly patterns in the South Atlantic to the freshwater fluxes at the surface. These anomalies impact the freshwater and salt transport by the different components of the ocean circulation, in particular the basin-scale salt-advection feedback, completely changing the response of the AMOC to arbitrary perturbations. It is found that an appropriate dipole anomaly pattern at the southern border of the Atlantic Ocean can collapse the AMOC entirely even without a further hosing. The results suggest a new view on the stability of the AMOC, controlled by processes in the South Atlantic. <br/

Parity- and Time-Reversal-Violating Moments of Light Nuclei

I present the calculation of parity- and time-reversal-violating moments of the nucleon and light nuclei, originating from the QCD theta term and effective dimension-six operators. By applying chiral effective field theory these calculations are performed in a unified framework. I argue that measurements of a few light-nuclear electric dipole moments would shed light on the mechanism of parity and time-reversal violation.Comment: 8 pages, contribution to the proceedings of the 5th International Symposium on Symmetries in Subatomic Physics (SSP2012), June 18-22, 2012, Groningen, The Netherland

Men who have sex with men more often chose daily than event-driven use of pre-exposure prophylaxis: baseline analysis of a demonstration study in Amsterdam.

The Amsterdam PrEP project is a prospective, open-label demonstration study at a large sexually transmitted infection (STI) clinic. We examined the uptake of PrEP; the baseline characteristics of men who have sex with men (MSM) and transgender persons initiating PrEP; their choices of daily versus event-driven PrEP and the determinants of these choices

Suppression of HBV by Tenofovir in HBV/HIV coinfected patients : a systematic review and meta-analysis

Background: Hepatitis B coinfection is common in HIV-positive individuals and as antiretroviral therapy has made death due to AIDS less common, hepatitis has become increasingly important. Several drugs are available to treat hepatitis B. The most potent and the one with the lowest risk of resistance appears to be tenofovir (TDF). However there are several questions that remain unanswered regarding the use of TDF, including the proportion of patients that achieves suppression of HBV viral load and over what time, whether suppression is durable and whether prior treatment with other HBV-active drugs such as lamivudine, compromises the efficacy of TDF due to possible selection of resistant HBV strains. Methods: A systematic review and meta-analysis following PRISMA guidelines and using multilevel mixed effects logistic regression, stratified by prior and/or concomitant use of lamivudine and/or emtricitabine. Results: Data was available from 23 studies including 550 HBV/HIV coinfected patients treated with TDF. Follow up was for up to seven years but to ensure sufficient power the data analyses were limited to three years. The overall proportion achieving suppression of HBV replication was 57.4%, 79.0% and 85.6% at one, two and three years, respectively. No effect of prior or concomitant 3TC/FTC was shown. Virological rebound on TDF treatment was rare. Interpretation: TDF suppresses HBV to undetectable levels in the majority of HBV/HIV coinfected patients with the proportion fully suppressed continuing to increase during continuous treatment. Prior treatment with 3TC/FTC does not compromise efficacy of TDF treatment. The use of combination treatment with 3TC/FTC offers no significant benefit over TDF alone

Influence of climatic variables on crown condition in pine forests of Northern Spain

Producción CientíficaThe aim of this study was to find relationships between crown condition and some climatic parameters to identify which are those having a main influence on crown condition, and how this influence is shown in the tree (crown transparency), and to contribute to the understanding of how these parameters will affect under future climate change scenarios

Age-related gene and miRNA expression changes in airways of healthy individuals

© 2019, The Author(s). Knowledge on age-related miRNA changes in healthy individuals and their interaction with mRNAs is lacking. We studied age-related mRNA and miRNA expression changes and their interactions in normal airways. RNA and small RNA sequencing was performed on bronchial biopsies of 86 healthy individuals (age: 18–73) to determine age-related expression changes. Per age-related miRNA we determined the enrichment of age-related predicted targets and their correlation. We identified 285 age-related genes and 27 age-related miRNAs. Pathway enrichment showed that genes higher expressed with age were involved in synapse-related processes. Genes lower expressed with age were involved in cell cycle regulation, the immune system and DNA damage/repair. MiR-146a-5p, miR-146b-5p and miR-142-5p were lower expressed with increasing age and we found a significant enrichment for predicted targets of these miRNAs among genes that were higher expressed with age. The expression levels of the enriched predicted targets RIMS2 and IGSF1 were negatively correlated with both miR-146a-5p and miR-146b-5p. RIMS2 was present in the enriched process, i.e. positive regulation of synaptic transmission. In conclusion, genes decreased with ageing are involved in several of the ageing hallmarks. Genes higher expressed with ageing were involved in synapse-related processes, of which RIMS2 is potentially regulated by two age-related miRNAs

A human-like bile acid pool induced by deletion of hepatic Cyp2c70 modulates effects of FXR activation in mice[S]

Bile acids (BAs) facilitate intestinal absorption of lipid-soluble nutrients and modulate various metabolic pathways through the farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5. These receptors are targets for therapy in cholestatic and metabolic diseases. However, dissimilarities in BA metabolism between humans and mice complicate translation of preclinical data. Cytochrome P450 family 2 subfamily c polypeptide 70 (CYP2C70) was recently proposed to catalyze the formation of rodent-specific muricholic acids (MCAs). With CRISPR/Cas9-mediated somatic genome editing, we generated an acute hepatic Cyp2c70 knockout mouse model (Cyp2c70ako) to clarify the role of CYP2C70 in BA metabolism in vivo and evaluate whether its activity modulates effects of pharmacologic FXR activation on cholesterol homeostasis. In Cyp2c70ako mice, chenodeoxycholic acid (CDCA) increased at the expense of βMCA, resulting in a more hydrophobic human-like BA pool. Tracer studies demonstrated that, in vivo, CYP2C70 catalyzes the formation of βMCA primarily by sequential 6β-hydroxylation and C7-epimerization of CDCA, generating βMCA as an intermediate metabolite. Physiologically, the humanized BA composition in Cyp2c70ako mice blunted the stimulation of fecal cholesterol disposal in response to FXR activation compared with WT mice, predominantly due to reduced stimulation of transintestinal cholesterol excretion. Thus, deletion of hepatic Cyp2c70 in adult mice translates into a human-like BA pool composition and impacts the response to pharmacologic FXR activation. This Cyp2c70ako mouse model may be a useful tool for future studies of BA signaling and metabolism that informs human disease development and treatment