scholarly journals Timing HIV infection with a simple and accurate population viral dynamics model

2021 ◽  
Vol 18 (179) ◽  
pp. 20210314
Author(s):  
Daniel B. Reeves ◽  
Morgane Rolland ◽  
Bethany L. Dearlove ◽  
Yifan Li ◽  
Merlin L. Robb ◽  
...  
Keyword(s):  
Present Model ◽  
Simulated Data ◽  
Infection Model ◽  
Strongly Correlated ◽  
Dynamics Model ◽  
Timing Accuracy ◽  
Viral Loads ◽  
Prevention Trials ◽  
Study Participants ◽  
Infection Timing

Clinical trials for HIV prevention can require knowledge of infection times to subsequently determine protective drug levels. Yet, infection timing is difficult when study visits are sparse. Using population nonlinear mixed-effects (pNLME) statistical inference and viral loads from 46 RV217 study participants, we developed a relatively simple HIV primary infection model that achieved an excellent fit to all data. We also discovered that Aptima assay values from the study strongly correlated with viral loads, enabling imputation of very early viral loads for 28/46 participants. Estimated times between infecting exposures and first positives were generally longer than prior estimates (average of two weeks) and were robust to missing viral upslope data. On simulated data, we found that tighter sampling before diagnosis improved estimation more than tighter sampling after diagnosis. Sampling weekly before and monthly after diagnosis was a pragmatic design for good timing accuracy. Our pNLME timing approach is widely applicable to other infections with existing mathematical models. The present model could be used to simulate future HIV trials and may help estimate protective thresholds from the recently completed antibody-mediated prevention trials.

scholarly journals RECRUITMENT INTO THE ALZHEIMER PREVENTION TRIALS (APT) WEBSTUDY FOR A TRIAL-READY COHORT FOR PRECLINICAL AND PRODROMAL ALZHEIMER’S DISEASE (TRCPAD)

2020 ◽  
pp. 1-7
Author(s):  
S. Walter ◽  
T.B. Clanton ◽  
O.G. Langford ◽  
M.S. Rafii ◽  
E.J. Shaffer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Effective Means ◽  
Web Based ◽  
The Us ◽  
Study Team ◽  
Prodromal Alzheimer’S Disease ◽  
Prevention Trials ◽  
Study Participants ◽  
The Impact

BACKGROUND: The Alzheimer Prevention Trials (APT) Webstudy is the first stage in establishing a Trial-ready Cohort for Preclinical and Prodromal Alzheimer’s disease (TRC-PAD). This paper describes recruitment approaches for the APT Webstudy. Objectives: To remotely enroll a cohort of individuals into a web-based longitudinal observational study. Participants are followed quarterly with brief cognitive and functional assessments, and referred to Sites for in-clinic testing and biomarker confirmation prior to enrolling in the Trial-ready Cohort (TRC). Design: Participants are referred to the APT Webstudy from existing registries of individuals interested in brain health and Alzheimer’s disease research, as well as through central and site recruitment efforts. The study team utilizes Urchin Tracking Modules (UTM) codes to better understand the impact of electronic recruitment methods. Setting: A remotely enrolled online study. Participants: Volunteers who are at least 50 years old and interested in Alzheimer’s research. Measurements: Demographics and recruitment source of participant where measured by UTM. Results: 30,650 participants consented to the APT Webstudy as of April 2020, with 69.7% resulting from referrals from online registries. Emails sent by the registry to participants were the most effective means of recruitment. Participants are distributed across the US, and the demographics of the APT Webstudy reflect the referral registries, with 73.1% female, 85.0% highly educated, and 92.5% Caucasian. Conclusions: We have demonstrated the feasibility of enrolling a remote web-based study utilizing existing registries as a primary referral source. The next priority of the study team is to engage in recruitment initiatives that will improve the diversity of the cohort, towards the goal of clinical trials that better represent the US population.

scholarly journals Saliva viral load is a dynamic unifying correlate of COVID-19 severity and mortality

2021 ◽  
Author(s):  
Julio Silva ◽  
Carolina Lucas ◽  
Maria Sundaram ◽  
Benjamin Israelow ◽  
Patrick Wong ◽  
...  
Keyword(s):  
Viral Load ◽  
Disease Severity ◽  
T Cell Subsets ◽  
Temporal Association ◽  
Strongly Correlated ◽  
Immunological Parameters ◽  
Viral Loads ◽  
Patient Demographics ◽  
Over Time

While several clinical and immunological parameters correlate with disease severity and mortality in SARS-CoV-2 infection, work remains in identifying unifying correlates of coronavirus disease 2019 (COVID-19) that can be used to guide clinical practice. Here, we examine saliva and nasopharyngeal (NP) viral load over time and correlate them with patient demographics, and cellular and immune profiling. We found that saliva viral load was significantly higher in those with COVID-19 risk factors; that it correlated with increasing levels of disease severity and showed a superior ability over nasopharyngeal viral load as a predictor of mortality over time (AUC=0.90). A comprehensive analysis of immune factors and cell subsets revealed strong predictors of high and low saliva viral load, which were associated with increased disease severity or better overall outcomes, respectively. Saliva viral load was positively associated with many known COVID-19 inflammatory markers such as IL-6, IL-18, IL-10, and CXCL10, as well as type 1 immune response cytokines. Higher saliva viral loads strongly correlated with the progressive depletion of platelets, lymphocytes, and effector T cell subsets including circulating follicular CD4 T cells (cTfh). Anti-spike (S) and anti-receptor binding domain (RBD) IgG levels were negatively correlated with saliva viral load showing a strong temporal association that could help distinguish severity and mortality in COVID-19. Finally, patients with fatal COVID-19 exhibited higher viral loads, which correlated with the depletion of cTfh cells, and lower production of anti-RBD and anti-S IgG levels. Together these results demonstrated that viral load – as measured by saliva but not nasopharyngeal — is a dynamic unifying correlate of disease presentation, severity, and mortality over time.

scholarly journals Plasma-derived HIV Nef+ exosomes persist in ACTG384 study participants despite successful virological suppression

2019 ◽  
Author(s):  
Andrea D. Raymond ◽  
Michelle J. Lang ◽  
Jane Chu ◽  
Tamika Campbell-Sims ◽  
Mahfuz Khan ◽  
...  
Keyword(s):  
Virological Suppression ◽  
Cell Recovery ◽  
Viral Loads ◽  
Aids Clinical Trial Group ◽  
Immunodeficiency Virus ◽  
Immunological Recovery ◽  
Clinical Associations ◽  
Study Participants ◽  
Cd4 Cell

AbstractHuman Immunodeficiency Virus (HIV) accessory protein Negative factor (Nef) is detected in the plasma of HIV+ individuals associated with exosomes. The role of Nef+ exosomes (exNef) in HIV pathogenesis is unknown. We perform a retrospective longitudinal analysis to determine correlative clinical associations of exNef plasma levels in ARV-treated HIV+ patients with or without immune recovery. exNef concentration in a subset of AIDS Clinical Trial Group (ACTG) 384 participants with successful virological suppression and with either high (Δ >100 CD4 cell recovery/High Immunological Responders (High-IR) or low (Δ ≤100 CD4 cell recovery/ Low Immunologic Responders (Low-IR) immunologic recovery was measured and compared for study weeks 48, 96, and 144. CD4 recovery showed a negative correlation with exNef at study week 144 (r = −0.3573, *p=.0366). Plasma exNef concentration in high IRs negatively correlated with naïve CD4 count and recovery (r = −0.3249, *p = 0. 0348 (High-IR); r =0.2981, *p= #0.0513 (Low-IR)). However, recovery of CD4 memory cells positively correlated with exNef (r =.4534, *p=.0358) in Low-IRs but not in High-IRs. Regimen A (Didanosine, Stavudine, Efavirenz) lowered exNef levels in IRs by 2-fold compared to other regimens. Nef+ exosomes persist in ART-treated HIV+ individuals despite undetectable viral loads, negatively correlates with naive and memory CD4 T cell restoration and may be associated with reduced immunological recovery. Taken together, these data suggest that exNef may represent a novel mechanism utilized by HIV to promote immune dysregulation.

scholarly journals 43. SARS-CoV-2 Cycle threshold (Ct) values predict future COVID-19 cases

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S31-S32
Author(s):  
Matthew Phillips ◽  
David Quintero ◽  
Susan Butler-Wu
Keyword(s):  
Los Angeles ◽  
Temporal Trends ◽  
The United States ◽  
Viral Rna ◽  
Strongly Correlated ◽  
Large Hospital ◽  
Cycle Threshold ◽  
Viral Loads ◽  
Leading Indicator ◽  
Asymptomatic Patients

Abstract Background The threat of surging COVID-19 cases prompted many hospitals in the United States to preemptively suspend elective procedures throughout the pandemic. Utilizing samples from a large hospital in Los Angeles, we sought to determine if temporal trends in SARS-CoV-2 Cycle threshold (Ct) values (proxy for viral RNA loads) were predictive for the number of future COVID-19 cases. Methods Nasopharyngeal specimens on symptomatic patients and asymptomatic admissions were tested using the Xpert Xpress SARS-CoV-2 and SARS-CoV-2/Flu/RSV assays (Cepheid). Ct values for all SARS-CoV-2 detections between October 2020 to March 2021 were compiled for analysis. Results A total of 2,114 SARS-CoV-2-positive samples were included. The number of tests performed per week increased dramatically in December peaking the first week of January before returning to pre-surge numbers by Mid-February. Ct values fell during this same period with values in December and January (25.6±7.8 and 27±7.9, respectively) significantly lower than those of the other months (30±9.3 to 37.7±6.3). Average weekly Ct values for all patients were significantly, negatively correlated with the number of tests run the following week (R= -0.71, P< 0.001) and two weeks later (R= -0.75, P< 0.0001). Ct values for patients who were asymptomatic at the time of testing most strongly correlated with total number of tests performed one month later (R= -0.86, P< 0.0001). Average weekly Ct values and number of test run As cases (light grey) increased during December and January, there was a significant decrease in Ct values (dark grey) during that same time period. Average Ct values are a leading indicator of cases Average weekly Ct values for all patients (light grey) were significantly, negatively correlated with the number of tests run the following week (R= -0.71, P<0.001) and two weeks later (R= -0.75, P<0.0001). Ct values for patients who were asymptomatic at the time of testing (dark grey) most strongly correlated with total number of tests performed one month later (R= -0.86, P<0.0001). Conclusion Lower Ct values, representing higher levels of viral RNA, have been associated with risk of intubation and infectivity. During the winter surge, we observed significantly lower Ct values suggesting that the increased transmission and morbidity of COVID-19 was temporarily associated with higher viral loads. Interestingly, Ct values for asymptomatic patients were most strongly associated with number of cases observed 1 months in the future, suggesting that asymptomatic viral load may be a leading indicator for forthcoming outbreaks. Given this association, Ct values may be a useful tool for predicting regional outbreaks of COVID-19 and more judicious cessation of elective procedures. Disclosures All Authors: No reported disclosures

scholarly journals Viral Load of SARS-CoV-2 in Respiratory Aerosols Emitted by COVID-19 Patients while Breathing, Talking, and Singing

2021 ◽  
Author(s):  
Kristen K. Coleman ◽  
Douglas Jie Wen Tay ◽  
Kai Sen Tan ◽  
Sean Wei Xiang Ong ◽  
Than The Son ◽  
...  
Keyword(s):  
Viral Load ◽  
Significant Role ◽  
N Gene ◽  
Exhaled Breath ◽  
Indoor Environments ◽  
Future Studies ◽  
Viral Loads ◽  
Asymptomatic Patients ◽  
Gene Copies ◽  
Study Participants

Background: Multiple SARS-CoV-2 superspreading events suggest that aerosols play an important role in driving the COVID-19 pandemic. However, the detailed roles of coarse (>5μm) and fine (≤5μm) respiratory aerosols produced when breathing, talking, and singing are not well-understood. Methods: Using a G-II exhaled breath collector, we measured viral RNA in coarse and fine respiratory aerosols emitted by COVID-19 patients during 30 minutes of breathing, 15 minutes of talking, and 15 minutes of singing. Results: Among the 22 study participants, 13 (59%) emitted detectable levels of SARS-CoV-2 RNA in respiratory aerosols, including 3 asymptomatic patients and 1 presymptomatic patient. Viral loads ranged from 63 - 5,821 N gene copies per expiratory activity. Patients earlier in illness were more likely to emit detectable RNA, and loads differed significantly between breathing, talking, and singing. The largest proportion of SARS-CoV-2 RNA copies was emitted by singing (53%), followed by talking (41%) and breathing (6%). Overall, fine aerosols constituted 85% of the viral load detected in our study. Virus cultures were negative. Conclusions: Fine aerosols produced by talking and singing contain more SARS-CoV-2 copies than coarse aerosols and may play a significant role in the transmission of SARS-CoV-2. Exposure to fine aerosols should be mitigated, especially in indoor environments where airborne transmission of SARS-CoV-2 is likely to occur. Isolating viable SARS-CoV-2 from respiratory aerosol samples remains challenging, and whether this can be more easily accomplished for emerging SARS-CoV-2 variants is an important enquiry for future studies.

Using baseline target moderation to guide decisions on adapting prevention programs

2019 ◽  
Vol 31 (5) ◽  
pp. 1777-1788 ◽  
Author(s):  
George W. Howe
Keyword(s):  
Preventive Intervention ◽  
Simulated Data ◽  
Control Group ◽  
Untreated Control Group ◽  
Protective Mechanisms ◽  
Program Adaptation ◽  
Group Outcomes ◽  
Program Effects ◽  
Prevention Trials ◽  
Preventive Effects

AbstractTom Dishion, a pioneer in prevention science, was one of the first to recognize the importance of adapting interventions to the needs of individual families. Building towards this goal, we suggest that prevention trials be used to assess baseline target moderated mediation (BTMM), where preventive intervention effects are mediated through change in specific targets, and the resulting effect varies across baseline levels of the target. Four forms of BTMM found in recent trials are discussed including compensatory, rich-get-richer, crossover, and differential iatrogenic effects. A strategy for evaluating meaningful preventive effects is presented based on preventive thresholds for diagnostic conditions, midpoint targets and proximal risk or protective mechanisms. Methods are described for using the results from BTMM analyses of these thresholds to estimate indices of intervention risk reduction or increase as they vary over baseline target levels, and potential cut points are presented for identifying subgroups that would benefit from program adaptation because of weak or potentially iatrogenic program effects. Simulated data are used to illustrate curves for the four forms of BTMM effects and how implications for adaptation change when untreated control group outcomes also vary over baseline target levels.

scholarly journals Global Properties of a General Latent Pathogen Dynamics Model with Delayed Pathogenic and Cellular Infections

2019 ◽  
Vol 2019 ◽  
pp. 1-18 ◽  
Author(s):  
A. M. Elaiw ◽  
A. A. Almatrafi ◽  
A. D. Hobiny ◽  
K. Hattaf
Keyword(s):  
Global Stability ◽  
Infection Model ◽  
Global Dynamics ◽  
Dynamics Model ◽  
Pathogen Dynamics ◽  
Global Properties ◽  
Latently Infected ◽  
Infected Cells ◽  
Theoretical Results ◽  
Pathogenic Infection

This paper studies the global dynamics of a general pathogenic infection model with two ways of infections. The effect of antibody immune response is analyzed. We incorporate three discrete time delays and both latently infected cells and actively infected cells. The infection rate and production and clearance/death rates of the cells and pathogens are given by general functions. We determine two threshold parameters to investigate the global stability of three equilibria. We use Lyapunov method to establish the global stability. We support our theoretical results by numerical simulations.

A NOVEL STUDY PARADIGM FOR LONG-TERM PREVENTION TRIALS IN ALZHEIMER DISEASE: THE PLACEBO GROUP SIMULATION APPROACH (PGSA). APPLICATION TO MCI DATA FROM THE NACC DATABASE

2014 ◽  
pp. 1-11
Author(s):  
M. Berres ◽  
W.A. Kukull ◽  
A.R. Miserez ◽  
A.U. Monsch ◽  
S.E. Monsell ◽  
...  
Keyword(s):  
Placebo Group ◽  
Mixed Model ◽  
Ethical Issues ◽  
Neuropsychological Test ◽  
Simulated Data ◽  
Test Battery ◽  
Simulation Approach ◽  
Prevention Trials ◽  
Neuropsychological Outcomes

INTRODUCTION: The PGSA (Placebo Group Simulation Approach) aims at avoiding problems of sample representativeness and ethical issues typical of placebo-controlled secondary prevention trials with MCI patients. The PGSA uses mathematical modeling to forecast the distribution of quantified outcomes of MCI patient groups based on their own baseline data established at the outset of clinical trials. These forecasted distributions are then compared with the distribution of actual outcomes observed on candidate treatments, thus substituting for a concomitant placebo group. Here we investigate whether a PGSA algorithm that was developed from the MCI population of ADNI 1*, can reliably simulate the distribution of composite neuropsychological outcomes from a larger, independently selected MCI subject sample. Methods: Data available from the National Alzheimer's Coordinating Center (NACC) were used. We included 1523 patients with single or multiple domain amnestic mild cognitive impairment (aMCI) and at least two follow-ups after baseline. In order to strengthen the analysis and to verify whether there was a drift over time in the neuropsychological outcomes, the NACC subject sample was split into 3 subsamples of similar size. The previously described PGSA algorithm for the trajectory of a composite neuropsychological test battery (NTB) score was adapted to the test battery used in NACC. Nine demographic, clinical, biological and neuropsychological candidate predictors were included in a mixed model; this model and its error terms were used to simulate trajectories of the adapted NTB. Results The distributions of empirically observed and simulated data after 1, 2 and 3 years were very similar, with some over-estimation of decline in all 3 subgroups. The by far most important predictor of the NTB trajectories is the baseline NTB score. Other significant predictors are the MMSE baseline score and the interactions of time with ApoE4 and FAQ (functional abilities). These are essentially the same predictors as determined for the original NTB score. Conclusion: An algorithm comprising a small number of baseline variables, notably cognitive performance at baseline, forecasts the group trajectory of cognitive decline in subsequent years with high accuracy. The current analysis of 3 independent subgroups of aMCI patients from the NACC database supports the validity of the PGSA longitudinal algorithm for a NTB. Use of the PGSA in long-term secondary AD prevention trials deserves consideration.

scholarly journals Designing and testing a blockchain application for patient identity management in healthcare

JAMIA Open ◽  
2021 ◽  
Author(s):  
Anjum Khurshid ◽  
Cole Holan ◽  
Cody Cowley ◽  
Jeremiah Alexander ◽  
Daniel Toshio Harrell ◽  
...  
Keyword(s):  
Management System ◽  
Identity Management ◽  
Simulated Data ◽  
Great Promise ◽  
Data Errors ◽  
Blockchain Technology ◽  
Virtual Visits ◽  
Identity Management System ◽  
Study Participants ◽  
Patient Centric

Abstract Objective Healthcare systems suffer from a lack of interoperability that creates “data silos,” causing patient linkage and data sharing problems. Blockchain technology’s unique architecture provides individuals greater control over their information and may help address some of the problems related to health data. A multidisciplinary team designed and tested a blockchain application, MediLinker, as a patient-centric identity management system. Methods The study used simulated data of “avatars” representing different types of patients. Thirty study participants were enrolled to visit simulated clinics, and perform various activities using MediLinker. Evaluation was based on Bouras’ criteria for patient-centric identity management and on the number of errors in entry and sharing of data by participants. Results Twenty-nine of the 30 participants completed all study activities. MediLinker fulfilled all of Bouras’ criteria except for one which was not testable. A majority of data errors were due to user error, such as wrong formatting and misspellings. Generally, the number of errors decreased with time. Due to COVID-19, sprint 2 was completed using “virtual” clinic visits. The number of user errors were less in virtual visits than in personal visits. Discussion The evaluation of MediLinker provides some evidence of the potential of a patient-centric identity management system using blockchain technology. The results showed a working system where patients have greater control over their information and can also easily provide consent for use of their data. Conclusion Blockchain applications for identity management hold great promise for use in healthcare but further research is needed before real-world adoption.

scholarly journals Ethical considerations in Controlled Human Malaria Infection studies in low resource settings: Experiences and perceptions of study participants in a malaria Challenge study in Kenya

2018 ◽  
Vol 3 ◽  
pp. 39 ◽  
Author(s):  
Maureen Njue ◽  
Patricia Njuguna ◽  
Melissa C. Kapulu ◽  
Gladys Sanga ◽  
Philip Bejon ◽  
...  
Keyword(s):  
Ethical Issues ◽  
Human Infection ◽  
Screening Tests ◽  
Research Review ◽  
Infection Model ◽  
Technological Advancement ◽  
Lump Sum ◽  
Low Middle Income Countries ◽  
Study Team ◽  
Study Participants

Background: The range and amount of volunteer infection studies, known as Controlled Human Infection Model (CHMI) studies, in Low-Middle Income Countries (LMICs) is increasing with rapid technological advancement, world-class laboratory facilities and increasing capacity development initiatives. However, the ethical issues these studies present in LMICs have not been empirically studied. We present findings of a descriptive social science study nested within a malaria volunteer infection study, on-going at the time of writing, at the KEMRI-Wellcome Trust Research Programme (KWTRP) on the Kenyan Coast. Methods: The study included non-participant observations, five group discussions with more than half of the CHMI study participants, two in-depth interviews with study team members, and an exit questionnaire administered to the participants. Results: Participants understood the key elements of the study, including that they would be deliberately infected with malaria parasites and may get malaria as a result, there would be regular blood draws, and they would spend up to 24 days in a residence facility away from their homes. The greatest motivation for participation was the monetary compensation of 20 USD per overnight stay given as a lump-sum at the end of their residency stay. Also appreciated were the health screening tests prior to enrolment and the positive relations with the study team. Concerns raised included the amount and regularity of blood draws experienced, and concerns that this type of research may feed into on-going rumours about research generally. Conclusion: With the increasing range and number of CHMI studies being conducted in LMICs, current ethical guidance are inadequate. This study highlights some of the ethical issues that could emerge in these settings, emphasizing the heavy responsibility placed on research review and regulatory systems, researchers and funders, as well as the importance of carefully tailored community engagement and consent processes.

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