Collective Oscillations of Vortex Lattices in Rotating Bose-Einstein Condensates

The complete low-energy collective-excitation spectrum of vortex lattices is discussed for rotating Bose-Einstein condensates (BEC) by solving the Bogoliubov-de Gennes (BdG) equation, yielding, e.g., the Tkachenko mode recently observed at JILA. The totally symmetric subset of these modes includes the transverse shear, common longitudinal, and differential longitudinal modes. We also solve the time-dependent Gross-Pitaevskii (TDGP) equation to simulate the actual JILA experiment, obtaining the Tkachenko mode and identifying a pair of breathing modes. Combining both the BdG and TDGP approaches allows one to unambiguously identify every observed mode.Comment: 5 pages, 4 figure

A Collaboratory, Multi-Disciplinary Approach to Risk Mitigation during HIV Analytical Treatment Interruption

Analytic treatment interruptions (ATIs) are currently the standard for assessing the impact of experimental interventions aimed at inducing sustained antiretroviral therapy (ART)-free remission in trials related to HIV cure. ATIs are associated with substantial risk to both study participants and their sexual partner(s). Two documented HIV transmissions occurring in the context of ATIs have been recently reported, but recommendations for mitigating the risk of such events during ATIs are limited. We outline a practical approach to risk mitigation during ATI studies and describe strategies we are utilising in an upcoming clinical trial that may be applicable to other centres

Considerations for designing and implementing combination HIV cure trials: findings from a qualitative in-depth interview study in the United States

Background: An increasing number of HIV cure trials involve combining multiple potentially curative interventions. Until now, considerations for designing and implementing complex combination HIV cure trials have not been thoroughly considered. Methods: We used a purposive method to select key informants for our study. Informants included biomedical HIV cure researchers, regulators, policy makers, bioethicists, and community members. We used in-depth interviews to generate ethical and practical considerations to guide the design and implementation of combination HIV cure research. We analyzed the qualitative data using conventional content analysis focused on inductive reasoning. Results: We interviewed 11 biomedical researchers, 4 community members, 2 regulators, 1 policy researcher, and 1 bioethicist. Informants generated considerations for designing and implementing combination interventions towards an HIV cure, focused on ethical aspects, as well as considerations to guide trial design, benefit/risk determinations, regulatory requirements, prioritization and sequencing and timing of interventions, among others. Informants also provided considerations related to combining specific HIV cure research modalities, such as broadly neutralizing antibodies (bNAbs), cell and gene modification products, latency-reversing agents and immune-based interventions. Finally, informants provided suggestions to ensure meaningful therapeutic improvements over standard antiretroviral therapy, overcome challenges of designing combination approaches, and engage communities around combination HIV cure research. Conclusion: The increasing number of combination HIV cure trials brings with them a host of ethical and practical challenges. We hope our paper will inform meaningful stakeholder dialogue around the use of combinatorial HIV cure research approaches. To protect the public trust in HIV cure research, considerations should be periodically revisited and updated with key stakeholder input as the science continues to advance

Human Galectin-9 Is a Potent Mediator of HIV Transcription and Reactivation.

Identifying host immune determinants governing HIV transcription, latency and infectivity in vivo is critical to developing an HIV cure. Based on our recent finding that the host factor p21 regulates HIV transcription during antiretroviral therapy (ART), and published data demonstrating that the human carbohydrate-binding immunomodulatory protein galectin-9 regulates p21, we hypothesized that galectin-9 modulates HIV transcription. We report that the administration of a recombinant, stable form of galectin-9 (rGal-9) potently reverses HIV latency in vitro in the J-Lat HIV latency model. Furthermore, rGal-9 reverses HIV latency ex vivo in primary CD4+ T cells from HIV-infected, ART-suppressed individuals (p = 0.002), more potently than vorinostat (p = 0.02). rGal-9 co-administration with the latency reversal agent "JQ1", a bromodomain inhibitor, exhibits synergistic activity (p<0.05). rGal-9 signals through N-linked oligosaccharides and O-linked hexasaccharides on the T cell surface, modulating the gene expression levels of key transcription initiation, promoter proximal-pausing, and chromatin remodeling factors that regulate HIV latency. Beyond latent viral reactivation, rGal-9 induces robust expression of the host antiviral deaminase APOBEC3G in vitro and ex vivo (FDR<0.006) and significantly reduces infectivity of progeny virus, decreasing the probability that the HIV reservoir will be replenished when latency is reversed therapeutically. Lastly, endogenous levels of soluble galectin-9 in the plasma of 72 HIV-infected ART-suppressed individuals were associated with levels of HIV RNA in CD4+ T cells (p<0.02) and with the quantity and binding avidity of circulating anti-HIV antibodies (p<0.009), suggesting a role of galectin-9 in regulating HIV transcription and viral production in vivo during therapy. Our data suggest that galectin-9 and the host glycosylation machinery should be explored as foundations for novel HIV cure strategies

Operationalizing Human Immunodeficiency Virus Cure-related Trials with Analytic Treatment Interruptions During the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Pandemic: A Collaborative Approach

Efforts to recognize and minimize the risk to study participants will be necessary to safely and ethically resume scientific research in the context of the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. These efforts are uniquely challenging in the context of human immunodeficiency virus (HIV) cure clinical trials, which often involve complex experimental therapy regimens and perhaps analytic treatment interruption, in which participants pause antiretroviral therapy. In this viewpoint, we discuss our approach to reopening an HIV cure trial in this context, with a focus on key considerations regarding study design, informed consent and participant education, and study implementation. These recommendations might be informative to other groups seeking to resume HIV cure research in settings similar to ours

SARS-CoV-2 Vaccination in the Context of Ongoing HIV Cure-Related Research Studies

To the Editors: The SARS-CoV-2 pandemic has affected research efforts worldwide. Previously, we described our strategy to mitigate COVID-19 transmission risk during an ongoing HIV cure-related clinical trial. SARS-CoV-2 vaccines recently have been authorized for emergency use and will become available to people with HIV imminently. As a result, researchers must determine how to adjust study protocols to incorporate the likelihood that participants may be vaccinated

Stratified medicine in European Medicines Agency licensing : a systematic review of predictive biomarkers

OBJECTIVES: Stratified medicine is often heralded as the future of clinical practice. Key part of stratified medicine is the use of predictive biomarkers, which identify patient subgroups most likely to benefit (or least likely to experience harm) from an intervention. We investigated how many and what predictive biomarkers are currently included in European Medicines Agency (EMA) licensing. SETTING: EMA licensing. PARTICIPANTS: Indications and contraindications of all drugs considered by the EMA and published in 883 European Public Assessment Reports and Pending Decisions. PRIMARY AND SECONDARY OUTCOME MEASURES: Data were collected on: the type of the biomarker, whether it selected a subgroup of patients based on efficacy or toxicity, therapeutic area, marketing status, date of licensing decision, date of inclusion of the biomarker in the indication or contraindication and on orphan designation. RESULTS: 49 biomarker–indication–drug (B-I-D) combinations were identified over 16 years, which included 37 biomarkers and 41 different drugs. All identified biomarkers were molecular. Six drugs (relating to 10 B-I-D combinations) had an orphan designation at the time of licensing. The identified B-I-D combinations were mainly used in cancer and HIV treatment, and also in hepatitis C and three other indications (cystic fibrosis, hyperlipoproteinaemia type I and methemoglobinaemia). In 45 B-I-D combinations, biomarkers were used as predictive of drug efficacy and in four of drug toxicity. It appeared that there was an increase in the number of B-I-D combinations introduced each year; however, the numbers were too small to identify any trends. CONCLUSIONS: Given the large body of literature documenting research into potential predictive biomarkers and extensive investment into stratified medicine, we identified relatively few predictive biomarkers included in licensing. These were also limited to a small number of clinical areas. This might suggest a need for improvement in methods of translation from laboratory findings to clinical practice

Primary care REFerral for EchocaRdiogram (REFER) in heart failure: a diagnostic accuracy study.

BACKGROUND: Symptoms of breathlessness, fatigue, and ankle swelling are common in general practice but deciding which patients are likely to have heart failure is challenging. AIM: To evaluate the performance of a clinical decision rule (CDR), with or without N-Terminal pro-B type natriuretic peptide (NT-proBNP) assay, for identifying heart failure. DESIGN AND SETTING: Prospective, observational, diagnostic validation study of patients aged >55 years, presenting with shortness of breath, lethargy, or ankle oedema, from 28 general practices in England. METHOD: The outcome was test performance of the CDR and natriuretic peptide test in determining a diagnosis of heart failure. The reference standard was an expert consensus panel of three cardiologists. RESULTS: Three hundred and four participants were recruited, with 104 (34.2%; 95% confidence interval [CI] = 28.9 to 39.8) having a confirmed diagnosis of heart failure. The CDR+NT-proBNP had a sensitivity of 90.4% (95% CI = 83.0 to 95.3) and specificity 45.5% (95% CI = 38.5 to 52.7). NT-proBNP level alone with a cut-off <400 pg/ml had sensitivity 76.9% (95% CI = 67.6 to 84.6) and specificity 91.5% (95% CI = 86.7 to 95.0). At the lower cut-off of NT-proBNP <125 pg/ml, sensitivity was 94.2% (95% CI = 87.9 to 97.9) and specificity 49.0% (95% CI = 41.9 to 56.1). CONCLUSION: At the low threshold of NT-proBNP <125 pg/ml, natriuretic peptide testing alone was better than a validated CDR+NT-proBNP in determining which patients presenting with symptoms went on to have a diagnosis of heart failure. The higher NT-proBNP threshold of 400 pg/ml may mean more than one in five patients with heart failure are not appropriately referred. Guideline natriuretic peptide thresholds may need to be revised

CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome.

Multiple genome-wide studies have identified associations between outcome of human immunodeficiency virus (HIV) infection and polymorphisms in and around the gene encoding the HIV co-receptor CCR5, but the functional basis for the strongest of these associations, rs1015164A/G, is unknown. We found that rs1015164 marks variation in an activating transcription factor 1 binding site that controls expression of the antisense long noncoding RNA (lncRNA) CCR5AS. Knockdown or enhancement of CCR5AS expression resulted in a corresponding change in CCR5 expression on CD4+ T cells. CCR5AS interfered with interactions between the RNA-binding protein Raly and the CCR5 3' untranslated region, protecting CCR5 messenger RNA from Raly-mediated degradation. Reduction in CCR5 expression through inhibition of CCR5AS diminished infection of CD4+ T cells with CCR5-tropic HIV in vitro. These data represent a rare determination of the functional importance of a genome-wide disease association where expression of a lncRNA affects HIV infection and disease progression

When to Start Antiretroviral Therapy

The question of when to start combination antiretroviral therapy for treatment-naïve patients has always been controversial. This is particularly true in the current era, with major guidelines recommending very different treatment strategies. Despite a lack of clarity regarding the optimal time to begin therapy, there has been a recent shift toward earlier initiation. This more aggressive approach is driven by several observations. First, effective viral suppression with therapy can prevent non-AIDS-related morbidity and mortality. Second, therapy can prevent irreversible harm to the human immune system. Third, therapy may prevent transmission of HIV to others, and thus have a potential public health benefit. For patients who are motivated and willing to initiate early treatment, the collective benefits of early therapy may outweigh the well-documented risks of antiretroviral medications