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At week 48 in the phase IIIb DAWNING study, the integrase strand transfer inhibitor (INSTI) dolutegravir plus 2 nucleoside reverse transcriptase inhibitors demonstrated superiority to ritonavir-boosted lopinavir in achieving virologic suppression in adults with HIV-1 who failed first-line therapy. Here, we report emergent HIV-1 drug resistance and mechanistic underpinnings among dolutegravir-treated adults in DAWNING. Population viral genotyping, phenotyping, and clonal analyses were performed on participants meeting confirmed virologic withdrawal (CVW) criteria on dolutegravir-containing regimens. Dolutegravir binding to and structural changes in HIV-1 integrase-DNA complexes with INSTI resistance-associated substitutions were evaluated. Of participants who received dolutegravir through week 48 plus an additional 110 weeks for this assessment, 6 met CVW criteria with treatment-emergent INSTI resistance-associated substitutions and 1 had R263R/K at baseline but not at CVW. All 7 achieved HIV-1 RNA levels of 10-fold and reduced viral replication capacity versus baseline levels. This study demonstrates that the pathway to dolutegravir resistance is a challenging balance between HIV-1 phenotypic change and associated loss of viral fitness. (This study has been registered at ClinicalTrials.gov under identifier NCT02227238.)

P1093 is a multicenter, open-label, phase I/II study of pharmacokinetics, safety, and tolerability of dolutegravir plus an optimized background regimen in pediatric participants aged 4 weeks to

Data caching in the cloud is an efficient way to improve the QoS of diverse data applications. However, this benefit is not freely available, given monetary cost to manage the caches in the cloud. In this paper, we study the data caching problem in the cloud that is driven by the monetary cost reduction, instead of the hit rate under limited capacity as in traditional cases. In particular, given a stream of requests $\mathcal{R}$ to a shared data item, we present a shortest-path based optimal algorithm that can minimize the total transfer and caching costs within O(mn) time for off-line case, here m represents the number of nodes in the network, while n is the length of the request stream. The cost model in this computation is semi-homo, which indicates that all pairs of nodes have the same transfer cost, but each cache server node has its own caching cost rate. Our off-line algorithm improves the previous results not only in reducing the time complexity from O(m2n) to O(mn), but also in relaxing the cost model to be semi-homogeneous, rendering the algorithm more practical in reality. Furthermore, we also study this problem in its online form, and by extending the anticipatory caching idea, we propose a 2-competitive online algorithm based on the same cost model and show its tightness by giving a lower bound of the competitive ratio as 2 − o(1) for any deterministic online algorithm. We provably achieve these results with our deep insights into the problem and careful analysis of the solution algorithms, together with a trace-based study to evaluate their performance in reality.

Two keepers at the San Francisco Zoo begin a relationship after one kills Tatiana the tiger, the zoo's famous cat who mauled the boys taunting her before her escape.

The hepatitis C virus (HCV) NS4B protein is an antiviral therapeutic target for which small-molecule inhibitors have not been shown to exhibit in vivo efficacy. We describe here the in vitro and in vivo antiviral activity of GSK8853, an imidazo[1,2- a ]pyrimidine inhibitor that binds NS4B protein. GSK8853 was active against multiple HCV genotypes and developed in vitro resistance mutations in both genotype 1a and genotype 1b replicons localized to the region of NS4B encoding amino acids 94 to 105. A 20-day in vitro treatment of replicons with GSK8853 resulted in a 2-log drop in replicon RNA levels, with no resistance mutation breakthrough. Chimeric replicons containing NS4B sequences matching known virus isolates showed similar responses to a compound with genotype 1a sequences but altered efficacy with genotype 1b sequences, likely corresponding to the presence of known resistance polymorphs in those isolates. In vivo efficacy was tested in a humanized-mouse model of HCV infection, and the results showed a 3-log drop in viral RNA loads over a 7-day period. Analysis of the virus remaining at the end of in vivo treatment revealed resistance mutations encoding amino acid changes that had not been identified by in vitro studies, including NS4B N56I and N99H. Our findings provide an in vivo proof of concept for HCV inhibitors targeting NS4B and demonstrate both the promise and potential pitfalls of developing NS4B inhibitors.

In this paper we consider the data caching problem in next generation data services in the cloud, which is characterized by using monetary cost and access trajectory information to control cache replacements, instead of exploiting capacityoriented strategies as in traditional research. In particular, given a stream of requests to a shared data item with respect to a homogeneous cost model, we first propose a fast off-line algorithm using dynamic programming techniques. The proposed algorithm can generate optimal schedule within O(mn) timespace complexity to cache, migrate as well as replicate the shared data item to serve an n-length request sequence with minimum cost in a fully connected m-node network, substantially improving the previous results. Additionally, we also study this problem in its online form, and present a 3-competitive online algorithm by leveraging a speculative caching idea. The algorithm can serve an online request in constant time, and is space efficient in O(m) as well, rendering it to be more practical in reality. Our research complements the shortage of similar research in literature on this problem.

GSK2485852 (referred to here as GSK5852) is a hepatitis C virus (HCV) NS5B polymerase inhibitor with 50% effective concentrations (EC 50 s) in the low nanomolar range in the genotype 1 and 2 subgenomic replicon system as well as the infectious HCV cell culture system. We have characterized the antiviral activity of GSK5852 using chimeric replicon systems with NS5B genes from additional genotypes as well as NS5B sequences from clinical isolates of patients infected with HCV of genotypes 1a and 1b. The inhibitory activity of GSK5852 remained unchanged in these intergenotypic and intragenotypic replicon systems. GSK5852 furthermore displays an excellent resistance profile and shows a

GSK2336805 is an orally bioavailable hepatitis C virus (HCV) inhibitor working through an NS5A-mediated mechanism. This first-time-in-human study was conducted to assess the safety, tolerability, pharmacokinetics, metabolism, and efficacy of GSK2336805 in healthy subjects and subjects infected with HCV genotype 1. We performed a three-part, randomized, double-blind, placebo-controlled study in 46 healthy subjects and 23 HCV-infected subjects. After an overnight fast, healthy subjects received GSK2336805 as 10 mg, 30 mg, 30 mg plus food, and 60 mg in a single dose and 10 mg (7 days), 30 mg (7 days), and 75 mg (14 days) in a once-daily multiple dose. Subjects with HCV received GSK2336805 as a 1- to 120-mg single dose. In subjects with HCV, reductions in HCV RNA were observed within 4 h and a single dose of GSK2336805 of ≥10 mg resulted in a statistically significant ≥2-log reduction in HCV RNA compared with placebo at 24 h postdose. GSK2336805 was readily absorbed in all subjects, and the half-life ( t 1/2 ) was suitable for once-daily dosing. Administration of GSK2336805 with food had no effect on plasma GSK2336805 exposure; however, absorption was delayed, with a median t max (time to maximum concentration of drug in serum) of 4.5 versus 2.0 h. Twenty subjects who received GSK2336805 experienced mild to moderate adverse events; none were serious. GSK2336805 was well tolerated and exhibited rapid, significant antiviral activity after a single dose in HCV-infected subjects. These results support the conduct of further studies evaluating GSK2336805 administered once daily for longer durations in combination with peginterferon, ribavirin, and other direct-acting antivirals. (This study has been registered at ClinicalTrials.gov under registration no. NCT01277692.)

A zanamivir postapproval efficacy study was conducted in children ( n = 279) in Japan during three influenza seasons. Pharyngeal swab specimens ( n = 714) were obtained for detailed resistance analysis. From 371 cultured viruses, 3 viruses (A/H1N1) from two subjects showed reduced susceptibility to zanamivir at day 1 (before treatment), 1 had an N74S amino acid substitution (fold shift, 46), and 2 (day 1 and day 2) had a Q136K amino acid substitution (fold shifts, 292 and 301). Q136K was detected only in cultured virus and not in the swab. From the remaining 118 cultured viruses obtained during or after treatment with zanamivir, no shifts in virus susceptibility were detected. Neuraminidase (NA) population sequencing showed that viruses from 12 subjects had emergent amino acid substitutions, but 3 with susceptibility data were not zanamivir resistant. The remainder may be natural variants. Further analysis is planned. Hemagglutinin (HA) sequencing showed that viruses from 20 subjects had 9 HA amino acid substitutions that were previously implicated in resistance to neuraminidase inhibitors in in vitro assays or that were close to the receptor binding site. Their role in in vivo resistance appears to be less important but is not well understood. NA clonal sequence analysis was undertaken to determine if minority species of resistant viruses were present. A total of 1,682 clones from 90 subjects were analyzed. Single clones from 12 subjects contained amino acid substitutions close to the NA active site. It is unclear whether these single amino acid substitutions could have been amplified after drug pressure or are just chance mutations introduced during PCR.

The majority of HIV-1 integrase amino acid sites are highly conserved, suggesting that most are necessary to carry out the critical structural and functional roles of integrase. We analyzed the 34 most variable sites in integrase (>10% variability) and showed that prevalent polymorphic amino acids at these positions did not affect susceptibility to the integrase inhibitor dolutegravir (S/GSK1349572), as demonstrated both in vitro (in site-directed mutagenesis studies) and in vivo (in a phase IIa study of dolutegravir monotherapy in HIV-infected individuals). Ongoing clinical trials will provide additional data on the virologic activity of dolutegravir across subject viruses with and without prevalent polymorphic substitutions.

Background HIV clonal genotypic analysis (CG) was used to investigate whether a more sensitive analysis method would detect additional low-abundance mutations compared with population genotyping (PG) in antiretroviral-naive patients who experienced virological failure (VF) during treatment with abacavir/lamivudine/zidovudine and tenofovir. Methods HIV was analysed by PG and CG (771 baseline and 657 VF clones) from subjects with VF (confirmed HIV RNA ≥ 400 copies/mL at 24–48 weeks). Results Fourteen of 123 subjects (11%) met VF criteria; their median baseline HIV RNA was 5.4 log10 copies/mL, and 4.0 log10 copies/mL at VF. By baseline PG, 2/14 had HIV-1 with nucleoside reverse transcriptase inhibitor (NRTI) or non-NRTI mutations. By baseline CG, 9/14 had HIV-1 with NNRTI and/or NRTI mutations; 7/9 had study drug-associated mutations. By PG at VF, 10/14 had selected for resistance mutations [2, K65R; 1, M184V; and 7, thymidine analogue mutations (TAMs) ± M184V]. By CG at VF, for subjects with TAMs, T215F was more commonly detected (5/14 samples) than T215Y (2/14). For one subject who selected K65R at VF, both K65R-containing clones and TAM-containing clones (both T215A and T215F) were observed independently but not conjunctively in the same clone in a post-VF sample. Conclusions The majority of subjects with VF had major and minor mutations detected at VF; CG detected additional low-abundance variants at baseline and VF that could have influenced mutation selection pathways. Both PG and CG data suggest TAMs, not K65R selection, are the preferred resistance route, biased towards 215F selection. No HIV clone contained both K65R and T215F/Y mutations, suggesting in vivo antagonism between the two mutations. The once-daily zidovudine usage and high baseline viraemia may also have contributed to rapid selection of HIV with multiple mutations in VFs.

PurposeThe purpose of this article is to share with readers details of this consortium's multicultural virtual teaming project implementation and the lessons learned from experiences of the participating students and professors.Design/methodology/approachTo establish a preliminary relationship, virtual student teams exchange e‐mail messages with team mates at participating universities that provide introductions for each member of the team. Each team member uses these individual introductions to write a brief paper that introduces all team mates. Next, the students virtually interview one another to obtain answers to culture‐specific questions for each culture that is represented on the team. In some courses, this information is analysed using Hofstede's four dimensions of culture: power distance, individualism versus collectivism, uncertainty avoidance, and masculinity versus femininity.FindingsBased on participants' experiences in these virtual teaming projects, the following recommendations are presented: emphasise relationship building; solicit widespread input for planning; and balance individual control with shared objectives.Originality/valueThese cultural virtual teaming projects proved to be valuable learning experiences for both the students and faculty who were involved.

Colander (1995) identifies four main explanations of the inverse relationship between the price level and aggregate demand: the Pigou effect, the Keynes effect, the international price level effect, and the intertemporal price level effect. This paper examines whether any of these explanations can be justified. All four are found to at least potentially suffer from some form of the fallacy of composition. These problems are the result of the fallacious use of microeconomic principles to draw conclusions about the macroeconomy. The effect of price changes on aggregate demand appears to be ambiguous or negligible.

Factors that contribute to the transmission of human immunodeficiency virus type 1 (HIV-1), especially drug-resistant HIV-1 variants remain a significant public health concern. In-depth phylogenetic analyses of viral sequences obtained in the screening phase from antiretroviral-naive HIV-infected patients seeking enrollment in EPZ108859, a large open-label study in the USA, Canada and Puerto Rico (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00440947","term_id":"NCT00440947"}}NCT00440947) were examined for insights into the roles of drug resistance and epidemiological factors that could impact disease dissemination. Viral transmission clusters (VTCs) were initially predicted from a phylogenetic analysis of population level HIV-1 pol sequences obtained from 690 antiretroviral-naive subjects in 2007. Subsequently, the predicted VTCs were tested for robustness by ultra deep sequencing (UDS) using pyrosequencing technology and further phylogenetic analyses. The demographic characteristics of clustered and non-clustered subjects were then compared. From 690 subjects, 69 were assigned to 1 of 30 VTCs, each containing 2 to 5 subjects. Race composition of VTCs were significantly more likely to be white (72% vs. 60%; p = 0.04). VTCs had fewer reverse transcriptase and major PI resistance mutations (9% vs. 24%; p = 0.002) than non-clustered sequences. Both men-who-have-sex-with-men (MSM) (68% vs. 48%; p = 0.001) and Canadians (29% vs. 14%; p = 0.03) were significantly more frequent in VTCs than non-clustered sequences. Of the 515 subjects who initiated antiretroviral therapy, 33 experienced confirmed virologic failure through 144 weeks while only 3/33 were from VTCs. Fewer VTCs subjects (as compared to those with non-clustering virus) had HIV-1 with resistance-associated mutations or experienced virologic failure during the course of the study. Our analysis shows specific geographical and drug resistance trends that correlate well with transmission clusters defined by HIV sequences of similarity. Furthermore, our study demonstrates the utility of molecular and epidemiological analysis of VTCs for identifying population-specific risks associated with HIV-1 transmission and developing effective local healthcare strategies.

Rent control is a public policy which fails on both normative and positive economic grounds. In the former case, it violates all canons of equity, of both right (private property rights are sacrosanct) and left (it does not promote egalitarianism, rather, often, it enriches rich tenants and impoverishes poor landlords). In the latter, it leads to inefficiency, deterioration of rental housing, reduces incentives for upkeep and maintenance, reduces labor mobility, exacerbates landlord tenant relations, promotes housing abandonment and homelessness, and misallocates resources away from residential rental units. This sovietization of housing has effects similar to the sovietization of anything else: farming, factories, industry, forestry, whatever.

A number of explanations are commonly presented in public finance texts as reasons why government intervention in the economy will improve performance. This chapter questions the validity of each of them. The chapter examines the merit goods argument, equity considerations, growth and development, and stabilization, and finds the arguments offered in their behalf to be unpersuasive. Public finance as presented in textbooks is seen as relying on rather dubious normative arguments.

No Abstract. African Journal of Finance and Management Vol. 14(1) 2005: 52-59

The search for direct acting antiviral (DAA) compounds that act against targets on the Hepatitis C virus or host proteins that play a crucial role in the replication of this virus is of high importance since the current standard of care does not achieve a sustained virological response (SVR) in many patients even after an extended treatment period. GSK2485852 is an inhibitor of the HCV NS5B polymerase and is highly active with EC50 values in the low nanomolar range in the genotype 1 and 2 subgenomic replicon system as well as the infectious HCV cell-culture system. In an attempt to elucidate potency of GSK2485852 beyond the standard replicon assays, we used chimeric replicon systems with NS5B genes from different genotypes as well as NS5B sequences from clinical isolates of patients infected with HCV of genotype 1a and 1b. The inhibitory activity of GSK2485852 remained unchanged on these intergenotypic and intragenotypic replicon systems. GSK2485852 furthermore displays an excellent resistance profile and shows less than a five-fold potency loss across clinically important NS5B resistance mutations like S282T, P495L, M423T, C316Y or Y448H. A diverse mutant panel tested also revealed a lack of cross resistance against known resistance mutations against other viral proteins. Data from both 454 and population sequencing showed a pattern of mutations arising in the NS5B RNA dependent RNA polymerase. GSK2485852 shows superior viral RNA reductions of up to five logs in genotype 1b replicons.

There are great opportunities to improve the standard of living of the people of North America. The smaller nations of the area especially stand to gain from these opportunities. The essential requirements are to improve productivity by increasing the size of the market, to encourage investment where it is most productive, and to facilitate the movement of workers to productive employment. The achievement of each of these goals requires that governments reduce the barriers which they have established to inhibit the free movement of people, capital, and ideas among the nations of North America. The United States has a special opportunity to play a leadership role in education and in financing the development of the area.