Emergent resistance to dolutegravir among INSTI-naïve patients on first-line or second-line antiretroviral therapy : a review of published cases

None of the licensing studies of dolutegravir (DTG) reported any treatment-emergent resistance among DTG-treated individuals, though virological failure in treatment-naïve and treatment-experienced, integrase strand transfer inhibitor (INSTI)-naïve individuals has been reported in clinical practice. While the spectrum of dolutegravir-selected mutations and their effects on clinical outcome have been described, the clinical characteristics of these rare but important virological failure cases are often overlooked. In this perspective piece, we focus on key clinical aspects of emergent resistance to DTG among treatment-naïve and treatment-experienced INSTI-naïve patients, with an aim to inform clinical decision-making. Poor adherence and HIV disease factors contribute to emergent drug resistance, even in regimens with high resistance barriers. Patients with severe immunosuppression or poor adherence are under-represented in licensing studies, and these patients may be at higher risk of treatment failure with DTG resistance, which requires close clinical and laboratory follow-up.Publisher PDFPeer reviewe

Developing Beginner-Friendly Programming Error Messages

The motivation for our work is to introduce a recently developed programming language, Clojure, in a beginner computer science (CSci) class at the University of Minnesota, Morris. Clojure is an industryaccepted programming language that provides significant benefits for beginner programmers, such as focus on a functional approach to programming which, in UMM experience, provides a good foundation for subsequent CSci curriculum. Learning Clojure in an introductory class opens opportunities for students to collaborate on numerous worldwide projects, as well as take advantage of improvements in modern computing hardware. However, Clojure is challenging to use because of its complicated handling of programmers’ mistakes. Mistakes in computer programming are a natural part of developing software. When a mistake happens, there is a system to notify the programmer of an error. The specific information that the programmer receives, known as an error message, may or may not be helpful in identifying the issue. Clojure error messages are notorious for being confusing to beginners. We are developing a system that intercepts the existing Clojure error messages and automatically rephrases them for beginner programmers. We will conduct usability tests by observing the interactions between beginner programmers and our system, and the feedback we receive will be used to further improve our project. We present our new error message handling and discuss testing our system with new programmers.https://digitalcommons.morris.umn.edu/urs_2015/1005/thumbnail.jp

Linking the ovarian cancer transcriptome and immunome

<p>Abstract</p> <p>Background</p> <p>Autoantigens have been reported in a variety of tumors, providing insight into the interplay between malignancies and the immune response, and also giving rise to novel diagnostic and therapeutic concepts. Why certain tumor-associated proteins induce an immune response remains largely elusive.</p> <p>Results</p> <p>This paper analyzes the proposed link between increased abundance of a protein in cancerous tissue and the increased potential of the protein for induction of a humoral immune response, using ovarian cancer as an example. Public domain data sources on differential gene expression and on autoantigens associated with this malignancy were extracted and compared, using bioinformatics analysis, on the levels of individual genes and proteins, transcriptional coregulation, joint functional pathways, and shared protein-protein interaction networks. Finally, a selected list of ovarian cancer-associated, differentially regulated proteins was tested experimentally for reactivity with antibodies prevalent in sera of ovarian cancer patients.</p> <p>Genes reported as showing differential expression in ovarian cancer exhibited only minor overlap with the public domain list of ovarian cancer autoantigens. However, experimental screening for antibodies directed against antigenic determinants from ovarian cancer-associated proteins yielded clear reactions with sera.</p> <p>Conclusion</p> <p>A link between tumor protein abundance and the likelihood of induction of a humoral immune response in ovarian cancer appears evident.</p

Metabolic effects of darunavir/ritonavir versus atazanavir/ritonavir in treatment-naive, HIV Type 1-infected subjects over 48 weeks

We assessed metabolic changes for darunavir/ritonavir (DRV/r) once daily (qd) versus atazanavir/ritonavir (ATV/r) qd with fixed-dose tenofovir/emtricitabine. This was a phase 4, multicenter, open-label, randomized exploratory study. Treatment-naive, HIV-1-infected adults received DRV/r 800/100 mg qd or ATV/r 300/100 mg qd, both with emtricitabine/tenofovir 200/300 mg qd. Primary end point: change in triglyceride levels from baseline to week 12. Secondary end points: week 12 and week 48 changes in lipid parameters, insulin sensitivity, inflammatory/coagulation/bacterial translocation biomarkers, viral load, CD4(+) cell count, and week 48 changes in adipose tissue distribution and subjects' perceptions of body changes. In the DRV/r arm, 32/34 and 29/34 subjects completed weeks 12 and 48, respectively; in the ATV/r arm, 30/31 and 25/31 subjects completed weeks 12 and 48, respectively. Small changes in lipid parameters from baseline to weeks 12 and 48 were observed in both arms. Differences were noted between arms in mean changes in total cholesterol (DRV/r, 20.3 mg/dl; ATV/r, 4.6 mg/dl) and apolipoprotein A1 (DRV/r, 10.7 mg/dl; ATV/r, –0.7 mg/dl) at week 12. At week 48, no clinically relevant differences between arms were noted for changes in any lipid parameter, fasting glucose, or insulin sensitivity. Biomarkers generally decreased and efficacy parameters improved in both arms over 48 weeks. Changes in adipose tissue were small and comparable between arms. Subjects' perceptions of body changes generally improved in both study arms. This first pilot comparison in HIV-1-infected subjects suggests that DRV/r has a metabolic profile similar to ATV/r over 48 weeks of treatment. Further randomized studies are warranted

On the Nose

A 67-year-old man presented with a 3-day history of chest tightness, wheezing, coughing, and dyspnea. He had a history of asthma but had not had major exacerbations for 20 years. He did not have fever, sputum production, hemoptysis, orthopnea, or edema

Are conservation organizations configured for effective adaptation to global change?

© The Ecological Society of America. Conservation organizations must adapt to respond to the ecological impacts of global change. Numerous changes to conservation actions (eg facilitated ecological transitions, managed relocations, or increased corridor development) have been recommended, but some institutional restructuring within organizations may also be needed. Here we discuss the capacity of conservation organizations to adapt to changing environmental conditions, focusing primarily on public agencies and nonprofits active in land protection and management in the US. After first reviewing how these organizations anticipate and detect impacts affecting target species and ecosystems, we then discuss whether they are sufficiently flexible to prepare and respond by reallocating funding, staff, or other resources. We raise new hypotheses about how the configuration of different organizations enables them to protect particular conservation targets and manage for particular biophysical changes that require coordinated management actions over different spatial and temporal scales. Finally, we provide a discussion resource to help conservation organizations assess their capacity to adapt

Generalizing Evidence from Randomized Trials using Inverse Probability of Sampling Weights

Results obtained in randomized trials may not easily generalize to target populations. Whereas in randomized trials the treatment assignment mechanism is known, the sampling mechanism by which individuals are selected to participate in the trial is typically not known and assuming random sampling from the target population is often dubious. We consider an inverse probability of sampling weighted (IPSW) estimator for generalizing trial results to a target population. The IPSW estimator is shown to be consistent and asymptotically normal. A consistent sandwich-type variance estimator is derived and simulation results are presented comparing the IPSW estimator to a previously proposed stratified estimator. The methods are then utilized to generalize results from two randomized trials of HIV treatment to all people living with HIV in the US

Lower Pill Burden and Once-Daily Antiretroviral Treatment Regimens for HIV Infection: A Meta-Analysis of Randomized Controlled Trials

Background. Contemporary antiretroviral treatment regimens are simpler than in the past, with lower pill burden and once-daily dosing frequency common. We performed a meta-analysis of randomized controlled trials (RCTs) to investigate the impact of pill burden and once-daily vs twice-daily dosing on ART adherence and virological outcomes. Methods. A literature search of 4 electronic databases through 31 March 2013 was used. RCTs comparing once-daily vs twice-daily ART regimens that also reported on adherence and virological suppression were included. Study design, study population characteristics, intervention, outcome measures, and study quality were extracted. Study quality was rated using the Cochrane risk-of-bias tool. Results. Nineteen studies met our inclusion criteria (N = 6312 adult patients). Higher pill burden was associated with both lower adherence rates (P = .004) and worse virological suppression (P < .0001) in both once-daily and twice-daily subgroups, although the association with adherence in the once-daily subgroup was not statistically significant. The average adherence was modestly higher in once-daily regimens than twice-daily regimens (weighted mean difference = 2.55%; 95% confidence interval [CI], 1.23 to 3.87; P = .0002). Patients on once-daily regimens did not achieve virological suppression more frequently than patients on twice-daily regimens (relative risk [RR] = 1.01; 95% CI, 0.99 to 1.03; P = .50). Both adherence and viral load suppression decreased over time, but adherence decreased less with once-daily dosing than with twice-daily dosing. Conclusions. Lower pill burden was associated with both better adherence and virological suppression. Adherence, but not virological suppression, was slightly better with once- vs twice-daily regimens