It is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure ...prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART.
Colorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection.
We report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.
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Remote sensing change detection (RSCD) aims to explore surface changes from co-registered pair of images. However, the high cost of memory and computation in previous CNN-based methods prevent their ...successes from being applied to real-world applications. Therefore, we propose a novel lightweight network, which identifies changes based on the features extracted by mobile networks via progressive feature aggregation and supervised attention, termed as A2Net. Considering the less powerful representation capability of mobile networks, we design a neighbor aggregation module (NAM) to fuse features within nearby stages of the backbone to strengthen the representation capability of temporal features. Then, we propose a progressive change identifying module (PCIM) to extract temporal difference information from bi-temporal features. Besides, we design a supervised attention module (SAM) to re-weight features for effectively aggregating multi-level features from high levels to low levels. With NAM, PCIM and SAM incorporated, A2Net can achieve favorable results compared with state-of-the-art methods on three challenging RSCD datasets with fewer parameters (3.78M) and lower computation costs (6.02G). The demo code of this work is publicly available at https://github.com/guanyuezhen/ A2Net.
Albeit great success has been achieved in image defocus blur detection, there are still several unsolved challenges, e.g., interference of background clutter, scale sensitivity and missing boundary ...details of blur regions. To deal with these issues, we propose a deep neural network which recurrently fuses and refines multi-scale deep features (DeFusionNet) for defocus blur detection. We first fuse the features from different layers of FCN as shallow features and semantic features, respectively. Then, the fused shallow features are propagated to deep layers for refining the details of detected defocus blur regions, and the fused semantic features are propagated to shallow layers to assist in better locating blur regions. The fusion and refinement are carried out recurrently. In order to narrow the gap between low-level and high-level features, we embed a feature adaptation module before feature propagating to exploit the complementary information as well as reduce the contradictory response of different feature layers. Since different feature channels are with different extents of discrimination for detecting blur regions, we design a channel attention module to select discriminative features for feature refinement. Finally, the output of each layer at last recurrent step are fused to obtain the final result. We collect a new dataset consists of various challenging images and their pixel-wise annotations for promoting further study. Extensive experiments on two commonly used datasets and our newly collected one are conducted to demonstrate both the efficacy and efficiency of DeFusionNet.
Studies of daily emtricitabine-tenofovir disoproxil fumarate (FTC-TDF) for HIV preexposure prophylaxis (PrEP) in men who have sex with men (MSM) modeled intracellular tenofovir-diphosphate (TFV-DP) ...in dried blood spots (DBS) to assess adherence and corresponding PrEP outcomes. We conducted a prospective, randomized, crossover pharmacokinetic study of TFV-DP in DBS during 33%, 67%, or 100% of daily dosing under directly observed therapy (DOT). Participants were assigned to two 12-week dosing regimens, separated by a 12-week washout. Forty-eight adults (25 women) from Denver and San Francisco were included. TFV-DP exhibited a median half-life of 17 days, reaching steady state in 8 weeks. TFV-DP was dose proportional with mean (SD) steady-state concentrations of 530 (159), 997 (267), and 1,605 (405) fmol/punch for the 33%, 67%, and 100% arms, respectively. Prior work in MSM demonstrated clinically meaningful TFV-DP thresholds of 350, 700, and 1,250 fmol/punch, which were estimated 25th percentiles for 2, 4, and 7 doses/week. In the present study, corresponding TFV-DP was within 3% of the prior estimates, and subgroups by site, race, and sex were within 14% of prior estimates, although males had 17.6% (95% confidence intervals CIs, 6.5, 27.4%) lower TFV-DP than females. The thresholds of 350, 700, and 1,250 fmol/punch were achieved by 75% of men taking ≥1.2, 3.2, and 6 doses/week and 75% of women taking ≥0.6, 2.0, and 5.3 doses/week, indicating that lower dosing reached these thresholds for both sexes. In conclusion, TFV-DP arising from DOT was similar to previous estimates and is useful for interpreting PrEP adherence and study outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT02022657.).
Prediction of the future location of vehicles and other mobile targets is instrumental in intelligent transportation system applications. In fact, networking schemes and protocols based on machine ...learning can benefit from the results of such accurate trajectory predictions. This is because routing decisions always need to be made for the future scenario due to the inevitable latency caused by the processing and propagation of the routing request and response. Thus, to predict the high-precision trajectory beyond the state of the art, we propose a generative adversarial network (GAN)-based vehicle trajectory prediction method, GAN-VEEP, for urban roads. The proposed method consists of three components: 1) vehicle coordinate transformation for data set preparation; 2) neural network prediction model trained by GAN; and 3) vehicle turning model to adjust the prediction process. The vehicle coordinate transformation model is introduced to deal with the complex spatial dependence in the urban road topology. Then, the neural network prediction model learns from the behavior of vehicle drivers. Finally, the vehicle turning model can refine the driving path based on the driver's psychology. Compared with its counterparts, the experimental results show that GAN-VEEP exhibits higher effectiveness in terms of the average accuracy, mean absolute error, and root-mean-squared error.
Preexposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) reduced HIV acquisition in the iPrEx trial among men who have sex with men and transgender women. ...Self-reported sexual risk behavior decreased overall, but may be affected by reporting bias. We evaluated potential risk compensation using biomarkers of sexual risk behavior.
Sexual practices were assessed at baseline and quarterly thereafter; perceived treatment assignment and PrEP efficacy beliefs were assessed at 12 weeks. Among participants with ≥1 follow-up behavioral assessment, sexual behavior, syphilis, and HIV infection were compared by perceived treatment assignment, actual treatment assignment, and perceived PrEP efficacy.
Overall, acute HIV infection and syphilis decreased during follow-up. Compared with participants believing they were receiving placebo, participants believing they were receiving FTC/TDF reported more receptive anal intercourse partners prior to initiating drug (12.8 vs. 7.7, P = 0.04). Belief in receiving FTC/TDF was not associated with an increase in receptive anal intercourse with no condom (ncRAI) from baseline through follow-up (risk ratio RR 0.9, 95% confidence interval CI: 0.6-1.4; P = 0.75), nor with a decrease after stopping study drug (RR 0.8, 95% CI: 0.5-1.3; P = 0.46). In the placebo arm, there were trends toward lower HIV incidence among participants believing they were receiving FTC/TDF (incidence rate ratio IRR 0.8, 95% CI: 0.4-1.8; P = 0.26) and also believing it was highly effective (IRR 0.5, 95% CI: 0.1-1.7; P = 0.12).
There was no evidence of sexual risk compensation in iPrEx. Participants believing they were receiving FTC/TDF had more partners prior to initiating drug, suggesting that risk behavior was not a consequence of PrEP use.
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Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of ...adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults.
A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ≥3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs).
Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60-93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair.
This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs.
ClinicalTrials.gov NCT00903084.
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In this paper, we focus on price bidding strategies of multiple users competition for resource usage in cloud computing. We consider the problem from a game theoretic perspective and formulate it ...into a non-cooperative game among the multiple cloud users, in which each cloud user is informed with incomplete information of other users. For each user, we design a utility function which combines the net profit with time efficiency and try to maximize its value. We design a mechanism for the multiple users to evaluate their utilities and decide whether to use the cloud service. Furthermore, we propose a framework for each cloud user to compute an appropriate bidding price. At the beginning, by relaxing the condition that the allocated number of servers can be fractional, we prove the existence of Nash equilibrium solution set for the formulated game. Then, we propose an iterative algorithm (<inline-formula> <tex-math notation="LaTeX">\mathcal {IA}</tex-math> <inline-graphic xlink:type="simple" xlink:href="liu-ieq1-2495120.gif"/> </inline-formula>), which is designed to compute a Nash equilibrium solution. The convergency of the proposed algorithm is also analyzed and we find that it converges to a Nash equilibrium if several conditions are satisfied. Finally, we revise the obtained solution and propose a near-equilibrium price bidding algorithm ( <inline-formula><tex-math notation="LaTeX">\mathcal {NPBA}</tex-math> <inline-graphic xlink:type="simple" xlink:href="liu-ieq2-2495120.gif"/> </inline-formula>) to characterize the whole process of our proposed framework. The experimental results show that the obtained near-equilibrium solution is close to the equilibrium one.
Introduction
Oral sotalol initiation requires a multiple‐day, inpatient admission to monitor for QT prolongation during loading. A 1‐day intravenous (IV) sotalol loading protocol was approved by the ...United States Food and Drug Administration in March 2020, but limited data on clinical use and administration currently exists. This study describes implementation of an IV sotalol protocol within an integrated health system, provides initial efficacy and safety outcomes, and examines length of stay (LOS) compared with oral sotalol initiation.
Methods
IV sotalol was administered according to a prespecified initiation protocol to adult patients with refractory atrial or ventricular arrhythmias. Baseline characteristics, safety and feasibility outcomes, and LOS were compared with patients receiving oral sotalol over a similar time period.
Results
From January 2021 to June 2022, a total of 29 patients (average age 66.0 ± 8.6 years, 27.6% women) underwent IV sotalol load and 20 patients (average age 60.4 ± 13.9 years, 65.0% women) underwent oral sotalol load. The load was successfully completed in 22/29 (75.9%) patients receiving IV sotalol and 20/20 (100%) of patients receiving oral sotalol, although 7/20 of the oral sotalol patients (35.0%) required dose reduction. Adverse events interrupting IV sotalol infusion included bradycardia (seven patients, 24.1%) and QT prolongation (three patients, 10.3%). No patients receiving IV or oral sotalol developed sustained ventricular arrhythmias before discharge. LOS for patients completing IV load was 2.6 days shorter (mean 1.0 vs. 3.6, p < .001) compared with LOS with oral load.
Conclusion
IV sotalol loading has a safety profile that is similar to oral sotalol. It significantly shortens hospital LOS, potentially leading to large cost savings.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Preexposure prophylaxis (PrEP), in which HIV-uninfected persons with ongoing HIV risk use antiretroviral medications to reduce their risk of acquiring HIV infection, is an efficacious and promising ...new HIV prevention strategy. The past 2 years have seen significant new advances in knowledge regarding PrEP, including definitive demonstration that PrEP reduces the risk of HIV acquisition, regulatory approval of combination oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) as the first PrEP agent with a label indication for sexual HIV prevention, and the development of normative guidance for clinical prescribing of PrEP. In PrEP clinical trials, HIV protection was strongly correlated with PrEP adherence; therefore, understanding and supporting adherence to PrEP are key to maximizing its public health impact. As would be expected for any new HIV prevention approach, questions remain, including how to motivate uptake of and sustain adherence to PrEP for HIV prevention in high-risk populations, how much use is sufficient to achieve HIV protection, and the potential of “next-generation” PrEP agents to improve this effective prevention strategy. At this important transition point—from demonstration of efficacy in clinical trials to thinking about implementation and effectiveness—this review addresses where we have been and where we are going with PrEP for HIV prevention.
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