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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.

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.

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.)

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.

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.

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

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.