Resilience to resistance of HIV-1 protease inhibitors: profile of darunavir

The current effectiveness of HAART in the management of HIV infection is compromised by the emergence of extensively cross-resistant strains of HIV-1, requiring a significant need for new therapeutic agents. Due to its crucial role in viral maturation and therefore HIV-1 replication and infectivity, the HIV-1 protease continues to be a major development target for antiretroviral therapy. However, new protease inhibitors must have higher thresholds to the development of resistance and cross-resistance. Research has demonstrated that the binding characteristics between a protease inhibitor and the active site of the HIV-1 protease are key factors in the development of resistance. More specifically, the way in which a protease inhibitor fits within the substrate consensus volume, or substrate envelope , appears to be critical. The currently available inhibitors are not only smaller than the native substrates, but also have a different shape. This difference in shape underlies observed patterns of resistance because primary drug-resistant mutations often arise at positions in the protease where the inhibitors protrude beyond the substrate envelope but are still in contact with the enzyme. Since all currently available protease inhibitors occupy a similar space (in spite of their structural differences) in the active site of the enzyme, the specific positions where the inhibitors protrude and contact the enzyme correspond to the locations where most mutations occur that give rise to multidrug-resistant HIV-1 strains. Detailed investigation of the structure, thermodynamics, and dynamics of the active site of the protease enzyme is enabling the identification of new protease inhibitors that more closely fit within the substrate envelope and therefore decrease the risk of drug resistance developing. The features of darunavir, the latest FDA-approved protease inhibitor, include its high binding affinity (Kd = 4.5 x 10-12 M) for the protease active site, the presence of hydrogen bonds with the backbone, and its ability to fit closely within the substrate envelope (or consensus volume). Darunavir is potent against both wild-type and protease inhibitor-resistant viruses in vitro, including a broad range of over 4,000 clinical isolates. Additionally, in vitro selection studies with wild-type HIV-1 strains have shown that resistance to darunavir develops much more slowly and is more difficult to generate than for existing protease inhibitors. Clinical studies have shown that darunavir administered with low-dose ritonavir (darunavir/ritonavir) provides highly potent viral suppression (including significant decreases in HIV viral load in patients with documented protease inhibitor resistance) together with favorable tolerability. In conclusion, as a result of its high binding affinity for and overall fit within the active site of HIV-1 protease, darunavir has a higher genetic barrier to the development of resistance and better clinical efficacy against multidrug-resistant HIV relative to current protease inhibitors. The observed efficacy, safety and tolerability of darunavir in highly treatment-experienced patients makes darunavir an important new therapeutic option for HIV-infected patients

Laser-induced fluorescence studies of HfF+ produced by autoionization

Autoionization of Rydberg states of HfF, prepared using the optical-optical double resonance (OODR) technique, holds promise to create HfF+ in a particular Zeeman level of a rovibronic state for an electron electric dipole moment (eEDM) search. We characterize a vibronic band of Rydberg HfF at 54 cm-1 above the lowest ionization threshold and directly probe the state of the ions formed from this vibronic band by performing laser-induced fluorescence (LIF) on the ions. The Rydberg HfF molecules show a propensity to decay into only a few ion rotational states of a given parity and are found to preserve their orientation qualitatively upon autoionization. We show empirically that we can create 30% of the total ion yield in a particular |J+,M+> state and present a simplified model describing autoionization from a given Rydberg state that assumes no angular dynamics.Comment: 8 pages, 5 figure

EPICA Dome C electronic control system

AbstractA new deep drill has been developed within the framework of the European Programme for Ice Coring in Antarctica (EPICA). Several versions of the EPICA drill exist. The version used at Dome Concordia (75˚06'1" S, 123˚23'71" E) was operated with a new electronic control system developed by the Ente per le Nuove tecnologie, l'Energia e l'Ambiente (ENEA) Research Center in Brasimone, Italy. This electronic control system was used for the first time during the 1997/98 Antarctic summer season

Real-world utilization and outcomes of systemic therapy among patients with advanced or recurrent endometrial cancer in the United States

OBJECTIVE: Evaluate systemic therapy utilization patterns and outcomes by line of therapy among patients with advanced/recurrent endometrial cancer (EC) treated in the United States. METHODS: This retrospective observational study used the Optum Clinformatics Extended Data Mart Date of Death database (1 January 2004-31 December 2019) and included de-identified data from adult patients with advanced/recurrent EC who were treated with first-line (1L) platinum-based chemotherapy and initiated second-line (2L) anti-neoplastic therapy. The index date was the date of 1L therapy initiation. The number and sequence of treatments received and the proportion of patients who received each type of treatment for each line of therapy were evaluated. To account for new drug approvals, patients first treated in 2018 or 2019 were also assessed separately. RESULTS: Among the 1317 patients who met all eligibility criteria, 520 (39.5%) and 235 (17.8%) patients received 3 or 4+ lines of treatment, respectively, during a median total follow-up time of 25.2 months (range, 2.5-173.3 months) following the index date. Chemotherapy, including platinum- and non-platinum-based regimens, was the most common treatment across all lines of therapy: 2L, 80.0%; 3L, 66.2%; 4L+, 80.4%. Overall, 2.5%, 2.3%, and 8.9% of 2L, 3L, and 4L + patients, respectively, received anti-program death 1 (anti-PD-1) immunotherapies. In patients first treated in 2018 and 2019 ( CONCLUSIONS: Among patients with advanced/recurrent EC treated with 1L platinum-based therapy in clinical practice, chemotherapy was the most common treatment choice across all lines of therapy. Immunotherapy use was low overall but increased in patients who started treatment in 2018 or 2019. Overall, median TTNT decreased as lines of therapy increased

Etude des variabilités cycliques dans le cylindre d'un moteur essence à injection directe par la PIV haute cadence

International audienceLes résultats obtenus à partir des mesures expérimentales par PIV haute cadence dans la chambre de combustion d'un moteur essence à injection directe ont été analysés à l'aide de la décomposition propre orthogonale (POD) dans le but d'isoler les structures cohérentes au cours d'un cycle moteur et identifier leurs variabilités cycliques. Des investigations basées sur l'analyse de la position du centre du tumble en fonction de la phase moteur, i.e. à un degré vilebrequin déterminé, montrent que les plus fortes variations apparaissent lors de la compression. Il a été démontré que les dispersions aérodynamiques dans la chambre de combustion se comportent différemment en fonction de l'ouverture de la tubulure d'admission

Erectile dysfunction is frequent in systemic sclerosis and associated with severe disease: a study of the EULAR Scleroderma Trial and Research group

Introduction: Erectile dysfunction (ED) is common in men with systemic sclerosis (SSc) but the demographics, risk factors and treatment coverage for ED are not well known. Method: This study was carried out prospectively in the multinational EULAR Scleroderma Trial and Research database by amending the electronic data-entry system with the International Index of Erectile Function-5 and items related to ED risk factors and treatment. Centres participating in this EULAR Scleroderma Trial and Research substudy were asked to recruit patients consecutively. Results: Of the 130 men studied, only 23 (17.7%) had a normal International Index of Erectile Function-5 score. Thirty-eight per cent of all participants had severe ED (International Index of Erectile Function-5 score ≤ 7). Men with ED were significantly older than subjects without ED (54.8 years vs. 43.3 years, P < 0.001) and more frequently had simultaneous non-SSc-related risk factors such as alcohol consumption. In 82% of SSc patients, the onset of ED was after the manifestation of the first non-Raynaud's symptom (median delay 4.1 years). ED was associated with severe cutaneous, muscular or renal involvement of SSc, elevated pulmonary pressures and restrictive lung disease. ED was treated in only 27.8% of men. The most common treatment was sildenafil, whose efficacy is not established in ED of SSc patients. Conclusions: Severe ED is a common and early problem in men with SSc. Physicians should address modifiable risk factors actively. More research into the pathophysiology, longitudinal development, treatment and psychosocial impact of ED is needed

Availability of Advance Care Planning Documentation for Older Emergency Department Patients: A Cross-Sectional Study

Introduction: Increasing advance care planning (ACP) among older adults is a national priority. Documentation of ACP in the electronic health record (EHR) is particularly important during emergency care

Understanding young people's transitions in university halls through space and time

This article contributes to the theoretical discussion about young people's transitions through space and time. Space and time are complex overarching concepts that have creative potential in deepening understanding of transition. The focus of this research is young people's experiences of communal living in university halls. It is argued that particular space-time concepts draw attention to different facets of experience and in combination deepen the understanding of young people's individual and collective transitions. The focus of the article is the uses of the space-time concepts 'routine', 'representation', 'rhythm' and 'ritual' to research young people's experiences. The article draws on research findings from two studies in the North of England. © 2010 SAGE Publications

REMPI Spectroscopy of HfF

The spectrum of electronic states at 30000--33000 cm$^{-1}$ in hafnium fluoride has been studied using (1+1) resonance-enhanced multi-photon ionization (REMPI) and (1+1$'$) REMPI. Six $\Omega' = 3/2$ and ten $\Pi_{1/2}$ vibronic bands have been characterized. We report the molecular constants for these bands and estimate the electronic energies of the excited states using a correction derived from the observed isotope shifts. When either of two closely spaced $\Pi_{1/2}$ electronic states is used as an intermediate state to access autoionizing Rydberg levels, qualitatively distinct autoionization spectra are observed. The intermediate state-specificity of the autoionization spectra bodes well for the possibility of using a selected $\Pi_{1/2}$ state as an intermediate state to create ionic HfF$^+$ in various selected quantum states, an important requirement for our electron electric dipole moment (eEDM) search in HfF$^+$.Comment: 11 pages, 8 figures, 1 tabl

Deep soils modify environmental consequences of increased nitrogen fertilizer use in intensifying Amazon agriculture

Agricultural intensification offers potential to grow more food while reducing the conversion of native ecosystems to croplands. However, intensification also risks environmental degradation through emissions of the greenhouse gas nitrous oxide (N2O) and nitrate leaching to ground and surface waters. Intensively-managed croplands and nitrogen (N) fertilizer use are expanding rapidly in tropical regions. We quantified fertilizer responses of maize yield, N2O emissions, and N leaching in an Amazon soybean-maize double-cropping system on deep, highly-weathered soils in Mato Grosso, Brazil. Application of N fertilizer above 80 kg N ha−1 yr−1 increased maize yield and N2O emissions only slightly. Unlike experiences in temperate regions, leached nitrate accumulated in deep soils with increased fertilizer and conversion to cropping at N fertilization rates \u3e80 kg N ha−1, which exceeded maize demand. This raises new questions about the capacity of tropical agricultural soils to store nitrogen, which may determine when and how much nitrogen impacts surface waters