Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1

Massive research efforts are now underway to develop a cure for HIV infection, allowing patients to discontinue lifelong combination antiretroviral therapy (ART). New latency-reversing agents (LRAs) may be able to purge the persistent reservoir of latent virus in resting memory CD4+ T cells, but the degree of reservoir reduction needed for cure remains unknown. Here we use a stochastic model of infection dynamics to estimate the efficacy of LRA needed to prevent viral rebound after ART interruption. We incorporate clinical data to estimate population-level parameter distributions and outcomes. Our findings suggest that approximately 2,000-fold reductions are required to permit a majority of patients to interrupt ART for one year without rebound and that rebound may occur suddenly after multiple years. Greater than 10,000-fold reductions may be required to prevent rebound altogether. Our results predict large variation in rebound times following LRA therapy, which will complicate clinical management. This model provides benchmarks for moving LRAs from the lab to the clinic and can aid in the design and interpretation of clinical trials. These results also apply to other interventions to reduce the latent reservoir and can explain the observed return of viremia after months of apparent cure in recent bone marrow transplant recipients and an immediately-treated neonate.Comment: 8 pages main text (4 figures). In PNAS Early Edition http://www.pnas.org/content/early/2014/08/05/1406663111. Ancillary files: SI, 24 pages SI (7 figures). File .htm opens a browser-based application to calculate rebound times (see SI). Or, the .cdf file can be run with Mathematica. The most up-to-date version of the code is available at http://www.danielrosenbloom.com/reboundtimes

Quantifying uptake and completion of pulmonary rehabilitation programs in people with chronic obstructive pulmonary disease known to tertiary care

Background: People with symptomatic chronic obstructive pulmonary disease (COPD) benefit from pulmonary rehabilitation programs (PRPs), but program attrition is common. Methods: For people with COPD who presented to tertiary care and appeared appropriate for a PRP, we prospectively mapped their PRP journey, explored factors influencing attendance to pre-program assessment and captured program attrition. Results: Of the 391 participants, 31% (95% CI 27 to 36) were referred to a PRP (n = 123; age 68 ± 10years, 62 males [50%], FEV1 45 ± 19%predicted). Of those referred, 94 (76% [69 to 84]) attended a pre-program assessment. Ex-smokers and those who had a healthcare professional (HCP) explain they would be referred were more likely to attend a pre-program assessment (odds ratio [95%CI]; 2.6 [1.1 to 6.1]; and 4.7 [1.9 to 11.7], respectively). Of the 94 who attended, 63 (67% [58 to 77]) commenced; and of those who commenced, 35 (56% [43 to 68]) completed a PRP. All who completed (n = 35, 100%) were provided at least one strategy to maintain training-related gains. Conclusion: Attrition occurs throughout the PRP journey. Interactions with HCPs about PRPs positively influenced attendance. Understanding how HCPs can best contextualise PRPs to encourage referral acceptance and uptake is an important area for further work

Quantifying the effect of monitor wear time and monitor type on the estimate of sedentary time in people with COPD: Systematic review and meta-analysis

In studies that have reported device-based measures of sedentary time (ST) in people with chronic obstructive pulmonary disease (COPD), we explored if the monitor type and monitor wear time moderated the estimate of this measure. Five electronic databases were searched in January 2021. Studies were included if \u3e70% of participants had stable COPD, and measures of ST (min/day) were collected using wearable technology. Meta-regression was used to examine the influence of moderators on ST, monitor type, and wear time. The studies identified were a total of 1153, and 36 had usable data for meta-analyses. The overall pooled estimate of ST (mean [95% CI]) was 524 min/day [482 to 566] with moderate heterogeneity among effect sizes (I2 = 42%). Monitor wear time, as well as the interaction of monitor wear time and monitor type, were moderators of ST (p \u3c 0.001). The largest difference (−318 min; 95% CI [−212 to −424]) was seen between studies where participants wore a device without a thigh inclinometer for 24 h (and removed sleep during analysis) (675 min, 95% CI [589 to 752]) and studies where participants wore a device with a thigh inclinometer for 12 h only (356 min; 95% CI [284 to 430]). In people with COPD, the monitor wear time and the interaction of the monitor wear time and the monitor type moderated the estimate of ST

Interventions with a clear focus on achieving behaviour change are important for maintaining training-related gains in people with chronic obstructive pulmonary disease: a systematic review

Questions: In people with chronic obstructive pulmonary disease (COPD) who complete an exercise training program (ETP) offered at a sufficient dose to result in training-related gains, to what extent are these gains maintained 12 months after program completion? Do variables such as the application of behaviour change techniques moderate the maintenance of these training-related gains? Design: Systematic review, meta-analysis and meta-regression of randomised controlled trials. Participants: People with stable COPD. Intervention: Trials were included if they applied ≥ 4 weeks of a whole-body ETP and reported outcome data immediately following program completion and 12 months after initial program completion. The control group received usual care that did not include a formal exercise training component. Outcome measures: Exercise tolerance, health-related quality of life and dyspnoea during activities of daily living. Data sources: EMBASE, PEDro, PubMed and the Cochrane Library. Results: Nineteen randomised trials with 2,103 participants were found, of which 12 had a sufficiently similar design to be meta-analysed. At 12 months after ETP completion, compared with the control group, the experimental group demonstrated better exercise tolerance (SMD 0.48, 95% CI 0.19 to 0.77) and quality of life (SMD 0.22, 95% CI 0.03 to 0.41) with no clear effect on dyspnoea. Meta-regression using data from all 19 trials demonstrated that the magnitude of between-group differences at the 12-month follow-up was moderated by: behaviour change being a core aim of the strategies implemented following completion of the ETP; the experimental group receiving more behaviour change techniques during the program; and the magnitude of between-group change achieved from the program. Conclusion: At 12 months after completion of an ETP of ≥ 4 weeks, small gains were maintained in exercise tolerance and health-related quality of life. Applying behaviour change techniques with a clear focus on participants integrating exercise into daily life beyond initial program completion is important to maintain training-related gains. Registration: CRD42020193833

Real-Time Predictions of Reservoir Size and Rebound Time during Antiretroviral Therapy Interruption Trials for HIV

Monitoring the efficacy of novel reservoir-reducing treatments for HIV is challenging. The limited ability to sample and quantify latent infection means that supervised antiretroviral therapy (ART) interruption studies are generally required. Here we introduce a set of mathematical and statistical modeling tools to aid in the design and interpretation of ART-interruption trials. We show how the likely size of the remaining reservoir can be updated in real-time as patients continue off treatment, by combining the output of laboratory assays with insights from models of reservoir dynamics and rebound. We design an optimal schedule for viral load sampling during interruption, whereby the frequency of follow-up can be decreased as patients continue off ART without rebound. While this scheme can minimize costs when the chance of rebound between visits is low, we find that the reservoir will be almost completely reseeded before rebound is detected unless sampling occurs at least every two weeks and the most sensitive viral load assays are used. We use simulated data to predict the clinical trial size needed to estimate treatment effects in the face of highly variable patient outcomes and imperfect reservoir assays. Our findings suggest that large numbers of patients—between 40 and 150—will be necessary to reliably estimate the reservoir-reducing potential of a new therapy and to compare this across interventions. As an example, we apply these methods to the two “Boston patients”, recipients of allogeneic hematopoietic stem cell transplants who experienced large reductions in latent infection and underwent ART-interruption. We argue that the timing of viral rebound was not particularly surprising given the information available before treatment cessation. Additionally, we show how other clinical data can be used to estimate the relative contribution that remaining HIV+ cells in the recipient versus newly infected cells from the donor made to the residual reservoir that eventually caused rebound. Together, these tools will aid HIV researchers in the evaluating new potentially-curative strategies that target the latent reservoir

Associations of symptomatic knee OA with histopathologic features in subchondral bone

© 2019, American College of Rheumatology Objective: Subchondral bone and the osteochondral junction are thought to contribute to osteoarthritis (OA) knee pain. We undertook this study to identify osteochondral pathologies specifically associated with symptomatic human knee OA. Methods: Medial tibial plateau samples from 2 groups of subjects (n = 31 per group) were matched for macroscopic chondropathy scores. The symptomatic chondropathy group had undergone total knee replacement for OA knee pain, at which time specimens of the medial tibial plateau were obtained. The asymptomatic chondropathy group included subjects who died of unrelated illness (specimens were obtained at postmortem examination) and who had not previously sought help for knee pain. OA histopathology, immunoreactivity for nerve growth factor (NGF) and CD68 (macrophages), tartrate-resistant acid phosphatase–positive subchondral osteoclasts, and synovitis were compared between groups. Results: Mankin scores, subchondral bone density, and subchondral CD68-immunoreactive macrophage infiltration were similar between the 2 groups. NGF-like immunoreactivity was found in subchondral mononuclear cells and osteoclasts, as well as in chondrocytes. NGF in osteochondral channels and osteoclast densities in subchondral bone were higher in the symptomatic chondropathy group than in the asymptomatic chondropathy group (P < 0.01 and P = 0.02, respectively), as were synovitis scores (P < 0.01). Osteochondral pathology was not significantly associated with synovitis score. The differences in NGF expression and in osteoclast density remained significant after adjustment for age and synovitis score (P = 0.01 and P = 0.04, respectively). Osteochondral NGF and osteoclast densities, together with synovitis scores, explained ~28% of sample allocation to symptomatic or asymptomatic groups. Conclusion: Subchondral pathology was associated with symptomatic knee OA, independent of chondropathy and synovitis. Increased NGF expression in osteochondral channels and increased osteoclast density appear to be key features associated with bone pain in knee OA

Galactic periodicity and the oscillating G model

We consider the model involving the oscillation of the effective gravitational constant that has been put forward in an attempt to reconcile the observed periodicity in the galaxy number distribution with the standard cosmological models. This model involves a highly nonlinear dynamics which we analyze numerically. We carry out a detailed study of the bound that nucleosynthesis imposes on this model. The analysis shows that for any assumed value for $\Omega$ (the total energy density) one can fix the value of $\Omega_{\rm bar}$ (the baryonic energy density) in such a way as to accommodate the observational constraints coming from the $^4{\rm He}$ primordial abundance. In particular, if we impose the inflationary value $\Omega=1$ the resulting baryonic energy density turns out to be $\Omega_{\rm bar}\sim 0.021$. This result lies in the very narrow range $0.016 \leq \Omega_{\rm bar} \leq 0.026$ allowed by the observed values of the primordial abundances of the other light elements. The remaining fraction of $\Omega$ corresponds to dark matter represented by a scalar field.Comment: Latex file 29 pages with no figures. Please contact M.Salgado for figures. A more careful study of the model appears in gr-qc/960603

Antiretroviral dynamics determines HIV evolution and predicts therapy outcome

Despite the high inhibition of viral replication achieved by current anti-HIV drugs, many patients fail treatment, often with emergence of drug-resistant virus. Clinical observations show that the relationship between adherence and likelihood of resistance differs dramatically across drug class. We developed a mathematical model that explains these observations and makes novel predictions. Our model incorporates drug properties, fitness differences between susceptible and resistant strains, mutation, and adherence. We show that antiviral activity falls quickly for drugs with sharp dose-response curves and short half-lives, such as boosted protease inhibitors, limiting the time when resistance can be selected. We find that poor adherence to such drugs causes failure via growth of susceptible virus, explaining puzzling clinical observations. Furthermore, our model predicts that certain single-pill combination therapies can prevent resistance regardless of patient adherence. Our approach represents a first step for simulating clinical trials and may help select novel drug regimens for investigation.MathematicsPhysic

A fluorescent nanosensor paint detects dopamine release at axonal varicosities with high spatiotemporal resolution

The neurotransmitter dopamine (DA) controls multiple behaviors and is perturbed in several major brain diseases. DA is released from large populations of specialized structures called axon varicosities. Determining the DA release mechanisms at such varicosities is essential for a detailed understanding of DA biology and pathobiology but has been limited by the low spatial resolution of DA detection methods. We used a near-infrared fluorescent DA nanosensor paint, adsorbed nanosensors detecting release of dopamine (AndromeDA), to detect DA secretion from cultured murine dopaminergic neurons with high spatial and temporal resolution. We found that AndromeDA detects discrete DA release events and extracellular DA diffusion and observed that DA release varies across varicosities. To systematically detect DA release hotspots, we developed a machine learning–based analysis tool. AndromeDA permitted the simultaneous visualization of DA release for up to 100 dopaminergic varicosities, showing that DA release hotspots are heterogeneous and occur at only ∼17% of all varicosities, indicating that many varicosities are functionally silent. Using AndromeDA, we determined that DA release requires Munc13-type vesicle priming proteins, validating the utility of AndromeDA as a tool to study the molecular and cellular mechanism of DA secretion