Limits to potent antiretroviral therapy.

The availability of potent combination antiretroviral therapy (ART), also known as highly active antiretroviral therapy or HAART has changed the prognosis of HIV infection. However, the benefits have to be seen in the context of deficiencies of current therapy: failure to eradicate the virus, the slow and potentially incomplete recovery of the immune system, the high prevalence of resistance, and the potential for long-term toxicity. Treatment strategies need to take into account these limits to better target those HIV-infected patients who could benefit the most from antiretroviral therapy.

Opening Education Beyond the Property Relation: From Commons to Communism

Open Education, and specifically the OER movement, seeks to provide universal access to knowledge, undermining the historical enclosure and the increasing privatisation of the public education system. In this paper we examine this aspiration by submitting the implicit theoretical assumptions of Open Education to the test of critical political economy. We acknowledge the Open Education movement's revolutionary potential but outline the inherent limitations of its current focus on the commons (property relations) rather than the social relations of capitalist production (wage work, the company) and because of this, argue that it will only achieve limited, rather than revolutionary, impact.

Added Value of Deep Sequencing Relative to Population Sequencing in Heavily Pre-Treated HIV-1-Infected Subjects.

OBJECTIVE: To explore the potential of deep HIV-1 sequencing for adding clinically relevant information relative to viral population sequencing in heavily pre-treated HIV-1-infected subjects. METHODS: In a proof-of-concept study, deep sequencing was compared to population sequencing in HIV-1-infected individuals with previous triple-class virological failure who also developed virologic failure to deep salvage therapy including, at least, darunavir, tipranavir, etravirine or raltegravir. Viral susceptibility was inferred before salvage therapy initiation and at virological failure using deep and population sequencing genotypes interpreted with the HIVdb, Rega and ANRS algorithms. The threshold level for mutant detection with deep sequencing was 1%. RESULTS: 7 subjects with previous exposure to a median of 15 antiretrovirals during a median of 13 years were included. Deep salvage therapy included darunavir, tipranavir, etravirine or raltegravir in 4, 2, 2 and 5 subjects, respectively. Self-reported treatment adherence was adequate in 4 and partial in 2; one individual underwent treatment interruption during follow-up. Deep sequencing detected all mutations found by population sequencing and identified additional resistance mutations in all but one individual, predominantly after virological failure to deep salvage therapy. Additional genotypic information led to consistent decreases in predicted susceptibility to etravirine, efavirenz, nucleoside reverse transcriptase inhibitors and indinavir in 2, 1, 2 and 1 subject, respectively. Deep sequencing data did not consistently modify the susceptibility predictions achieved with population sequencing for darunavir, tipranavir or raltegravir. CONCLUSIONS: In this subset of heavily pre-treated individuals, deep sequencing improved the assessment of genotypic resistance to etravirine, but did not consistently provide additional information on darunavir, tipranavir or raltegravir susceptibility. These data may inform the design of future studies addressing the clinical value of minority drug-resistant variants in treatment-experienced subjects.

Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure.

PURPOSE: To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor patients after imatinib failure; to assess correlative angiogenesis biomarkers with patient outcomes. EXPERIMENTAL DESIGN: Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore cross-over impact. Circulating levels of angiogenesis biomarkers were analyzed. RESULTS: In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 vs. 64.9 weeks; HR, 0.876; P = 0.306) as expected, given the cross-over design. RPSFT analysis estimated median OS for placebo of 39.0 weeks (HR, 0.505, 95% CI, 0.262-1.134; P = 0.306). No new safety concerns emerged with extended sunitinib treatment. No consistent associations were found between the pharmacodynamics of angiogenesis-related plasma proteins during sunitinib treatment and clinical outcome. CONCLUSIONS: The cross-over design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following cross-over, there was no statistical difference in OS. RPSFT analysis modeled the absence of cross-over, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events.

Syphilis in HIV-infected patients: Predictors for serological failure and serofast state.

Purpose: HIV-infected patients treated for syphilis may be at increased risk for serological failure and serofast state. Our aim was to analyse serological response to treatment in HIV-infected patients diagnosed with syphilis, and factors associated with serological cure and serofast state. Methods: Open-label, no controlled study of a series of HIV- patients diagnosed with syphilis during 2004-2011. Patients were categorized by rapid plasma reagin titer (RPR) into success (4-fold decrease in RPR by 12 or 24 months after treatment of early or late syphilis), serofast (success with persistently stable reactive RPR), and failure/ re-infection ( failure to decrease 4-fold in RPR by 12 or 24 months after treatment or sustained 4-fold increase in RPR after treatment response). Results: 141 HIV- patients were diagnosed with syphilis during the study period (104 early syphilis, 36 late or indeterminate latent syphilis). The mean age was 36.3 years, 98.5% were male, and 87.2% homosexual men. In 46 (32.6%) cases, HIV and syphilis infection diagnosis were coincident (mean CD4 457/mm3 and HIV-VL 4.72 log10). Among patients with prior known HIV infection, 65 were on antiretroviral therapy (ART) at syphilis diagnosis (mean CD4 469/ mm3, 76.9% undetectable HIV-VL). 116 patients satisfied criteria for serological response analysis (89 early, 24 late/indeterminate). At 12 months of early syphilis treatment (89.2% penicillin) there were 16 (18%) failures, and at 24 months of late/indeterminate syphilis (91.7% penicillin) there were 5 (18.5%) failures. Overall, 36 (31.0%) patients presented serofast state. Treatment failure was related with lower CD4 count (295 vs 510/μL; p=0.045) only in patients with coincident diagnosis. Serofast state was related with older age (41 vs 36 years; p=0.024), and lower CD4 count (391 vs 513/mm3; p=0.026). Conclusions: In this series of HIV-infected patients, with many patients on ART and with good immunological and virological parameters, serological failure and serofast state were frequent. Immunological status, and age could influence on serological response to syphilis treatment in HIV-infected patients.

Interleukin-10 rs1800896 and CXCR2 rs1126579 polymorphisms modulate the predisposition to septic shock

Despite major improvements in its treatment and diagnosis, sepsis is still a leading cause of death and admittance to the intensive care unit (ICU). Failure to identify patients at high risk of developing septic shock contributes to an increase in the sepsis burden and rapid molecular tests are currently the most promising avenue to aid in patient risk determination and therapeutic anticipation. The primary goal of this study was to evaluate the genetic susceptibility that affects sepsis outcome in 72 sepsis patients admitted to the ICU. Seven polymorphisms were genotyped in key inflammatory response genes in sepsis, including tumour necrosis factor-α,interlelukin (IL)-1β, IL-10,IL-8, Toll-like receptor 4, CXCR1and CXCR2. The primary finding showed that patients who were homozygous for the major A allele in IL-10rs1800896 had almost five times higher chance to develop septic shock compared to heterozygotes. Similarly, selected clinical features and CXCR2rs1126579 single nucleotide polymorphisms modulated septic shock susceptibility without affecting survival. These data support the hypothesis that molecular testing has clinical usefulness to improve sepsis prognostic models. Therefore, enrichment of the ICU portfolio by including these biomarkers will aid in the early identification of sepsis patients who may develop septic shock.

Impaired antibody memory to varicella zoster virus in HIV-infected children: low antibody levels and avidity*.

OBJECTIVE: HIV-infected children have impaired antibody responses after exposure to certain antigens. Our aim was to determine whether HIV-infected children had lower varicella zoster virus (VZV) antibody levels compared with HIV-infected adults or healthy children and, if so, whether this was attributable to an impaired primary response, accelerated antibody loss, or failure to reactivate the memory VZV response. METHODS: In a prospective, cross-sectional and retrospective longitudinal study, we compared antibody responses, measured by enzyme-linked immunosorbent assay (ELISA), elicited by VZV infection in 97 HIV-infected children and 78 HIV-infected adults treated with antiretroviral therapy, followed over 10 years, and 97 age-matched healthy children. We also tested antibody avidity in HIV-infected and healthy children. RESULTS: Median anti-VZV immunoglobulin G (IgG) levels were lower in HIV-infected children than in adults (264 vs. 1535 IU/L; P<0.001) and levels became more frequently unprotective over time in the children [odds ratio (OR) 17.74; 95% confidence interval (CI) 4.36-72.25; P<0.001]. High HIV viral load was predictive of VZV antibody waning in HIV-infected children. Anti-VZV antibodies did not decline more rapidly in HIV-infected children than in adults. Antibody levels increased with age in healthy (P=0.004) but not in HIV-infected children. Thus, antibody levels were lower in HIV-infected than in healthy children (median 1151 IU/L; P<0.001). Antibody avidity was lower in HIV-infected than healthy children (P<0.001). A direct correlation between anti-VZV IgG level and avidity was present in HIV-infected children (P=0.001), but not in healthy children. CONCLUSION: Failure to maintain anti-VZV IgG levels in HIV-infected children results from failure to reactivate memory responses. Further studies are required to investigate long-term protection and the potential benefits of immunization.

Does T Helper Differentiation Correlate with Resistance or Susceptibility to Infection with L. major? Some Insights From the Murine Model.

The murine model of Leishmania major infection has been an invaluable tool in understanding T helper differentiation in vivo. The initial evidence for a role of distinct CD4(+) T helper subsets in the outcome of infection was first obtained with this experimental model. The development of CD4(+) Th1 cells was associated with resolution of the lesion, control of parasite replication, and resistance to re-infection in most of the mouse strains investigated (i.e., C57BL/6). In contrast, differentiation of CD4(+) Th2 cells correlated with the development of unhealing lesions, and failure to control parasite load in a few strains (i.e., BALB/c). Since these first reports, an incredible amount of effort has been devoted to understanding the various parameters involved in the differentiation of these, and more recently discovered T helper subsets such as Th17 and T regulatory cells. The discovery of cross-talk between T helper subsets, as well as their plasticity force us to reevaluate the events driving a protective/deleterious T helper immune response following infection with L. major in mice. In this review, we describe the individual contributions of each of these CD4(+) T helper subsets following L. major inoculation, emphasizing recent advances in the field, such as the impact of different substrains of L. major on the pathogenesis of disease.

Transmit diversity vs. spatial multiplexing in modern MIMO systems

A contemporary perspective on the tradeoff between transmit antenna diversity andspatial multiplexing is provided. It is argued that, in the context of most modern wirelesssystems and for the operating points of interest, transmission techniques that utilizeall available spatial degrees of freedom for multiplexing outperform techniques that explicitlysacrifice spatial multiplexing for diversity. In the context of such systems, therefore,there essentially is no decision to be made between transmit antenna diversity and spatialmultiplexing in MIMO communication. Reaching this conclusion, however, requires thatthe channel and some key system features be adequately modeled and that suitable performancemetrics be adopted; failure to do so may bring about starkly different conclusions. Asa specific example, this contrast is illustrated using the 3GPP Long-Term Evolution systemdesign.

An ontology to clarify homology-related concepts.

Although homology is a fundamental concept in biology and is one of the shared channels of communication universal to all biology, it is difficult to find a consensus definition. Indeed, the interpretations of homology have changed as biology has progressed. New terms, such as paramorphism, have been introduced into the literature with mixed success. In addition, different research fields operate with different definitions of homology, for example the mechanistic usage of evo-devo is not strictly historical and would not be acceptable in cladistics. This makes a global understanding of homology complex, whereas the integration of evolutionary concepts into bioinformatics and genomics is increasingly important. We propose an ontology organizing homology and related concepts and hope this solution will also facilitate the integration and sharing of knowledge among the community.

International nursing : cultivating a culture of empowerment

International nursing has been a growing phenomenon throughout the globe. International nurses have been found to be an asset to healthcare organizations and an important part of the health care team. However, growing concern for the plight of international nurses facing obstacles such as professional stagnation and exploitation has spurred the development of strategies to mitigate and ameliorate the experiences of nurses working abroad. In this respect, the purpose of this study was to explore the management-influenced factors and the nurse team-influenced factors that promote the empowerment of the international nurse in the health care setting. The methodology used in this study was a systemic review. After a rigorous search for relevant empirical studies using OVID database, eight empirical research studies were selected using systematic review methodology to collect, analyze and synthesize data. The selected eight empirical studies were then subjected to a content analysis. The results suggested that the empowerment of an international nurse is inseparable from the empowerment of the health care organization. Based on the findings in this study, strategies to promote international nurses were found to mirror strategies evidenced to empower the nursing organization. Some of the management-influenced factors which were found to facilitate empowerment included a diversity rich work culture, transformational leadership at the management level, and a responsibility to foster the values of the organization. The team-influenced factors which were found to contribute to the empowerment of the international nurse included a united mutually-interdependent nurse team, shared accountability among the members of the nurse team, and the building of trust in work relationships. To conlude, this study indicates that efforts to empower international nurses without considering the work culture and the organization as a whole are futile because empowerment cannot take place in an environment that lacks antecedent conditions. Strategies to empower the international nurse should not focus on the deficits and special needs of the international nurse, but should focus on the similarities and commonalities of the nursing body. Empowerment of the international nurse mean open honest communication, supportive work environment, and a firm policy to quell disruptive elements that threaten the organization's values, mission, and philosophy of care.

Evaluation of oxidative stress parameters and metabolic activities of nurses working day and night shifts

The aim of this study was to evaluate the oxidative stress and metabolic activities of nurses working day and night shifts. Intensive care unit (ICU) (n=70) and ordinary service (OS) nurses (n=70) were enrolled in the study. Just before and the end of the shifts, blood samples were obtained to measure the participants' oxidative stress parameters. Metabolic activities were analyzed using the SenseWear Armband. Oxidative stress parameters were increased at the end of the shifts for all OS and ICU nurses compared to the beginning of the shifts. Compared to the OS nurses, the ICU nurses' TAS, TOS, and OSI levels were not significantly different at the end of the day and night shifts. The metabolic activities of the OS and ICU nurses were found to be similar. As a result, the OS and ICU nurses' oxidative stress parameters and metabolic activities were not different, and all of the nurses experienced similar effects from both the day and night shifts.

Pre-play communication and credibility: A test of Aumann's conjecture

The effectiveness of pre-play communication in achieving efficientoutcomes has long been a subject of controversy. In some environments,cheap talk may help to achieve coordination. However, Aumannconjectures that, in a variant of the Stag Hunt game, a signal forefficient play is not self-enforcing and concludes that an "agreementto play [the efficient outcome] conveys no information about what theplayers will do." Harsanyi and Selten (1988) cite this example as anillustration of risk-dominance vs. payoff-dominance. Farrell and Rabin(1996) agree with the logic, but suspect that cheap talk willnonetheless achieve efficiency. The conjecture is tested with one-waycommunication. When the sender first chooses a signal and then anaction, there is impressive coordination: a 94% probability for thepotentially efficient (but risky) play, given a signal for efficientplay. Without communication, efforts to achieve efficiency wereunsuccessful, as the proportion of B moves is only 35%. I also test ahypothesis that the order of the action and the signal affects theresults, finding that the decision order is indeed important. WhileAumann s conjecture is behaviorally disconfirmed when the signal isdetermined initially, the signal s credibility seems to be much moresuspect when the sender is known to have first chosen an action, andthe results are not statistically distinguishable from those whenthere is no signal. Some applications and issues in communication andcoordination are discussed.

Vocal sib-sib interactions: how siblings adjust signaling level to each other

Game theory states that iterative interactions between individuals are necessary to adjust behaviour optimally to one another. Although our understanding of the role of begging signals in the resolution of parent-offspring conflict over parental investment rests on game theory implying repeated interactions between family members, empiricists usually consider interactions at the exact moment when parents allocate food among the brood. Therefore, the mechanisms by which siblings adjust signalling level to one another remain unclear. We tackled this issue in the barn owl, Tyto alba. In the absence of parents, hungry nestlings signal vocally to siblings their intention to contest vigorously the next, indivisible, food item. Such behaviour deters siblings from competing and begging when parents return to the nest. In experimental two-chick broods, nestlings producing the longest calls in the absence of parents, a signal of hunger level, were more successful at monopolizing the food item at the first parental feeding visit of the night. Moreover, nestlings increased (versus decreased) call duration when their sibling produced longer (versus shorter) calls, and an individual was more likely to call again if its sibling began to vocalize before or just after it had ended its previous call. These results are in agreement with the hypothesis that siblings challenge each other vocally to reinforce the honesty of sib-sib communication and to resolve conflicts over which individual will have priority of access to the next delivered food item. Siblings challenge each other vocally to confirm that the level of signalling accurately reflects motivation.

IPERS 2005 to 2009 Experience Study, June 2010

It is a pleasure to submit this report of our investigation of the experience of the Iowa Public Employees’ Retirement System for the period of July 1, 2005 through June 30, 2009. The set of assumptions recommended as a result of this study will be used in the June 30, 2010 actuarial valuation of IPERS which will be used to analyze the funding status of the system, calculate the actuarial and statutory employer contribution rates, and disclose employer liabilities for financial statements. The purpose of this report is to communicate the results of our review of the actuarial methods and assumptions to be used in the completion of the upcoming valuation. Our recommendations represent changes from the prior methods or assumptions, which are intended to better anticipate the emerging experience of the System. Actual future experience, however, may differ from these assumptions. In preparing this report, we relied without audit on information supplied by IPERS staff. In our examination, we have found the data to be reasonably consistent and comparable with data used for other purposes. It should be noted that if any data or other information is inaccurate or incomplete, our calculations might need to be revised. We would like to acknowledge the help given by IPERS staff in the preparation of this report. We hereby certify that, to the best of our knowledge and belief, this report is complete and accurate and has been prepared in accordance with generally recognized and accepted actuarial principles and practices which are consistent with the principles prescribed by the Actuarial Standards Board (ASB) and the Code of Professional Conduct and qualification Standards for Public Statements of Actuarial Opinion of the American Academy of Actuaries.