Spatial modeling of HIV cryptic viremia and 2-LTR formation during raltegravir intensification.

Combination Antiretroviral Therapy (cART) can suppress plasma HIV below the limit of detection in normal assays. Recently reported results suggest that viral replication may continue in some patients, despite undetectable levels in the blood. It has been suggested that the appearance of the circularized episomal HIV DNA artifact 2-LTR following treatment intensification with the integrase inhibitor raltegravir is a marker of ongoing viral replication. Other work has suggested that lymphoid organs may be a site of reduced antiviral penetration and increased viral production. In this study we model the hypothesis that this ongoing replication occurs in lymphoid follicle sanctuary sites and investigate the patterns of 2-LTR formation expected after raltegravir application. Experimental data is used to estimate the reaction and diffusion parameters in the model, and Monte-Carlo simulations are used to explore model behavior subject to variation in these rates. The results suggest that conditions for the formation of an observed transient peak in 2-LTR formation following raltegravir intensification include a sanctuary site diameter larger than 0.2mm, a viral basic reproductive ratio within the site larger than 1, and a total volume of active sanctuary sites above 20mL. Significant levels of uncontrolled replication can occur in the sanctuary sites without measurable changes in the plasma viral load. By contrast, subcritical replication (where the basic reproductive ratio of the virus is less than 1 in all sites) always results in monotonic increases of measured 2-LTR following raltegravir intensification, occurring at levels below the limit of detection.

Experimental investigation of brain contusion characteristics and dynamic response in low-age children using an animal model.

INTRODUCTION: Brain contusion is a prevalent traumatic brain injury (TBI) in low-age children, bearing the potential for coma and fatality. Hence, it is imperative to undertake comprehensive research in this field. METHODS: This study employed 4-week-old piglets as surrogates for children and introduced self-designed devices for both free-fall drop impact tests and drop-hammer impact tests. The study explored the characteristics of brain contusion and dynamic responses of brain under these distinct testing conditions. RESULTS: Brain contusions induced by free-fall and drop-hammer conditions both were categorized as the coup injury, except that slight difference in the contusion location was observed, with contusion occurring mainly in the surrounding regions beneath the impact location under free-fall condition and the region just right beneath the impact location under drop-hammer condition. Analysis of impact force and intracranial pressure (ICP) curves indicated similar trends in impact forces under both conditions, yet different trends in ICPs. Further examination of the peak impact forces and ICPs elucidated that, with increasing impact energy, the former followed a combined power and first-order polynomial function, while the latter adhered to a power function. The brain contusion was induced at the height (energy) of 2 m (17.2 J), but not at the heights of 0.4, 0.7, 1, 1.35 and 1.7 m, when the vertex of the piglet head collided with a rigid plate. In the case of a cylindrical rigid hammer (cross-sectional area constituting 40 % of the parietal bone) striking the head, the brain contusion was observed under the energy of 21.9 J, but not under energies of 8.1 J, 12.7 J and 20.3 J. Notably, the incidence of brain contusion was more pronounced under the free-fall condition. CONCLUSIONS: These findings not only facilitate a comprehensive understanding of brain contusion dynamics in pediatric TBIs, but also contribute to the validation of theories and finite element models for piglet heads, which are commonly employed as surrogates for children.

Modeling uncertainty in single-copy assays for HIV.

We present a simple computational model of measurement accuracy for single-copy sensitivity assays (SCA) of HIV RNA that was developed from first principles. The model shows that the SCA is significantly right-skewed. Measured virus concentrations of 1 and 10 virions/ml had overlapping 95% confidence intervals and were statistically indistinguishable.

Assessment of Surgical Outcomes in Children and Adult Ischemic Moyamoya Disease and Its Relationship with the Pre-infarction Cerebral Perfusion Status.

AIM: To clarify perfusion differences, and to determine whether children and adults respond similarly to surgical prevention and how brain perfusion stages before surgery predict outcomes in ischaemic moyamoya disease (MMD) in children and adults. MATERIAL AND METHODS: A total of 355 patients with ischaemic MMD, including 74 children and 281 adults, were enrolled in the study. Computerized tomography perfusion (CTP) scans were used to identify the perfusion status according to a novel staging system of the pre-infarction period. The perfusion status of each hemisphere between the children and adult groups was analysed. The modified Rankin scale was used during long-term follow-up as an indicator of clinical outcomes. RESULTS: The proportions of stages 0 and IV in adults were significantly higher than those in children (p=0.09 and p=0.003, respectively). Stage III was more common in the children's group (p=0.001). The stroke data showed an increasing tendency in the infarction rate from stages I to IV. Both groups in stage 0 and in the early stages had a similar highly improved ratio after surgery; the children, however, achieved significantly better clinical outcomes in stage III and late stages. CONCLUSION: There are differences in the perfusion status between child and adult patients with MMD. The pre-infarction staging system is associated with MMD-related stroke to some extent. Children have a greater chance for improvement than adults in stage III and later stages.

Controlling the Evolution of Resistance.

Evolution has long been understood as the driving force for many problems of medical interest. The evolution of drug resistance in HIV and bacterial infections is recognized as one of the most significant emerging problems in medicine. In cancer therapy, the evolution of resistance to chemotherapeutic agents is often the differentiating factor between effective therapy and disease progression or death. Interventions to manage the evolution of resistance have, up to this point, been based on steady-state analysis of mutation and selection models. In this paper, we review the mathematical methods applied to studying evolution of resistance in disease. We present a broad review of several classical applications of mathematical modeling of evolution, and review in depth two recent problems which demonstrate the potential for interventions which exploit the dynamic behavior of resistance evolution models. The first problem addresses the problem of sequential treatment failures in HIV; we present a review of our recent publications addressing this problem. The second problem addresses a novel approach to gene therapy for pancreatic cancer treatment, where selection is used to encourage optimal spread of susceptibility genes through a target tumor, which is then eradicated during a second treatment phase. We review the recent in Vitro laboratory work on this topic, present a new mathematical model to describe the treatment process, and show why model-based approaches will be necessary to successfully implement this novel and promising approach.

Measurement of Cortical Atrophy and Its Correlation to Memory Impairment in Patients With Asymptomatic Carotid Artery Stenosis Based on VBM-DARTEL.

OBJECTIVE: Severe carotid artery stenosis (CAS) can lead to atrophy of gray matter (GM) and memory impairment; however, the underlying mechanism is unknown. Thus, we aimed to identify memory impairment and GM atrophy and explore the possible correlation between them in patients with asymptomatic severe CAS. METHODS: Twenty-four patients with asymptomatic severe CAS and 10 healthy controls completed the mini-mental state examination (MMSE) and clinical memory scale (CMS) and underwent 7T magnetic resonance imaging (MRI) scan. Field intensity inhomogeneities were corrected. Images were processed using VBM8, and GM images were flipped. First, 11 flipped and 10 non-flipped images of patients with unilateral CAS and 5 flipped and 5 non-flipped images of controls were pre-processed using DARTEL algorithm and analyzed using an analysis of variance (ANOVA). Second, flipped and non-flipped images of unilateral patients were similarly pre-processed and analyzed using the paired t-test. Third, pre-processed non-flipped GM images and CMS scores of 24 patients were analyzed by multiple regression analysis. Nuisance variables were corrected accordingly. RESULTS: Basic information was well matched between patients and controls. MMSE scores of patients were in the normal range; however, memory function was significantly reduced (all P < 0.05). GM volumes of patients were significantly reduced in the anterior circulation regions. The stenosis-side hemispheres showed greater atrophy. GM volumes of the left pars opercularis, pars triangularis, and middle frontal gyrus were strongly positively correlated with the total scores of CMS (all r > 0.7, P = 0.001). Additionally, the left middle frontal gyrus was strongly positively correlated with associative memory (r = 0.853, P = 0.001). The left pars opercularis was moderately positively correlated with semantic memory (r = 0.695, P = 0.001). CONCLUSION: Patients with asymptomatic CAS suffer from memory impairment. Bilateral anterior circulation regions showed extensive atrophy. The hemisphere with stenosis showed severer atrophy. Memory impairment in patients may be related to atrophy of the left frontal gyrus and atrophy of different regions may result in different memory impairments.

A comprehensive study on the mechanical properties of different regions of 8-week-old pediatric porcine brain under tension, shear, and compression at various strain rates.

Young porcine brain is often used as a surrogate for studying the mechanical factors affecting traumatic brain injury in children. However, the mechanical properties of pediatric brain tissue derived from humans and piglets are very scarce, and this seriously detracts from the biofidelity of the developed finite element (FE) models of the pediatric head/brain. The present study addresses this issue by subjecting the cerebrum (white matter and gray matter), cerebellum, and brainstem specimens derived from 8-week-old piglets to tension and shear testing at strain rates of 0.01, 1, and 50/s. The experimental data are combined with the corresponding data derived from a previous study under compression to obtain comprehensive stress-strain curves of the pediatric porcine cerebrum, cerebellum, and brainstem tissue specimens. In general, the average stress level of the white matter is somewhat higher than that of the gray matter under the tension, shear and compression conditions, however, this difference does not reach a significant level. The stiffness of the cerebellum and the cerebrum does not differ significantly under tension and shear conditions, but the stiffness of the cerebellum is greater than that of the cerebrum under compression. The brainstem has significantly higher stiffness than the cerebrum and the cerebellum under all loading modes. In addition, the mechanical properties of brain tissue exhibit significant strain-rate dependences. With increasing strain rate from 0.01/s to 50/s, the average stress at a strain of 0.5 for all of the brain tissue increased by about 2.2 times under tension, about 2.4 times under shearing and about 2.2 times under compression. The variations in the stress as a function of the strain rate for brain tissue specimens were well characterized by exponential functions at strains of 0.25 and 0.5 under all three loading modes. The results of this study are useful for developing biofidelic FE models of the pediatric brain.

Results of Conservative Follow-up or Surgical Treatment of Moyamoya Patients Who Present without Hemorrhage, Transient Ischemic Attack, or Stroke.

OBJECTIVE: The epidemiology of asymptomatic moyamoya disease (MMD) is still unclear, and the best management remains controversial. The aim of this study is to evaluate the prognosis of these patients with different management, conservative follow-up, or surgical treatment. METHODS: This prospective cohort study screened a series of 696 consecutive MMD patients from 2009-2015. Patients with any episodes of hemorrhage and ischemic stroke or TIA were excluded. Finally, 61 patients who were followed up for at least 12 months were included, with 52 patients who underwent surgical treatment and 9 patients who underwent conservative follow-up. Patients were divided into 2 groups: surgical and conservative. Advert events including newly hemorrhage and ischemic stroke and death were compared between the groups. Relationships between disease progression and collaterals and cerebral blood flow were analyzed separately. RESULTS: The mean follow-up period was 56.32 months (range, 11.3-112.62 months). During the follow-up period, 3 patients had symptomatic progression in the conservative group, 1 suffered a hemorrhage, and 2 had TIAs. Among the patients in the surgical group, 6 of them experienced TIAs. Kaplan-Meier analysis showed that patients receiving surgeries had a longer symptom-free time compared with patients in the conservative group (P = 0.015). Decreased cerebral blood flow had no influence on disease progression in patients in both groups. Existence of extracranial to intracranial collaterals showed a better outcome for patients in the surgical group but not the conservative group. CONCLUSIONS: Surgical treatment may be a better choice for patients with asymptomatic MMD. And patients with better collateral circulations, especially extracranial to intracranial collateral arteries, may have a better prognosis.

Modelling HIV-1 2-LTR dynamics following raltegravir intensification.

A model of reservoir activation and viral replication is introduced accounting for the production of 2-LTR HIV-1 DNA circles following antiviral intensification with the HIV integrase inhibitor raltegravir, considering contributions of de novo infection events and exogenous sources of infected cells, including quiescent infected cell activation. The model shows that a monotonic increase in measured 2-LTR concentration post intensification is consistent with limited de novo infection primarily maintained by sources of infected cells unaffected by raltegravir, such as quiescent cell activation, while a transient increase in measured 2-LTR concentration is consistent with significant levels of efficient (R0 > 1) de novo infection. The model is validated against patient data from the INTEGRAL study and is shown to have a statistically significant fit relative to the null hypothesis of random measurement variation about a mean. We obtain estimates and confidence intervals for the model parameters, including 2-LTR half-life. Seven of the 13 patients with detectable 2-LTR concentrations from the INTEGRAL study have measured 2-LTR dynamics consistent with significant levels of efficient replication of the virus prior to treatment intensification.

HIV model parameter estimates from interruption trial data including drug efficacy and reservoir dynamics.

Mathematical models based on ordinary differential equations (ODE) have had significant impact on understanding HIV disease dynamics and optimizing patient treatment. A model that characterizes the essential disease dynamics can be used for prediction only if the model parameters are identifiable from clinical data. Most previous parameter identification studies for HIV have used sparsely sampled data from the decay phase following the introduction of therapy. In this paper, model parameters are identified from frequently sampled viral-load data taken from ten patients enrolled in the previously published AutoVac HAART interruption study, providing between 69 and 114 viral load measurements from 3-5 phases of viral decay and rebound for each patient. This dataset is considerably larger than those used in previously published parameter estimation studies. Furthermore, the measurements come from two separate experimental conditions, which allows for the direct estimation of drug efficacy and reservoir contribution rates, two parameters that cannot be identified from decay-phase data alone. A Markov-Chain Monte-Carlo method is used to estimate the model parameter values, with initial estimates obtained using nonlinear least-squares methods. The posterior distributions of the parameter estimates are reported and compared for all patients.

Quantitative analysis of viral persistence and transient viral load rebound from HIV clinical data.

Highly active antiretroviral therapy (HAART) suppresses HIV RNA viral load below the limit of detection for many patients. However, clinical data demonstrates that the HIV virus is not eradicated by HAART, even in patients who have had no detectable virus for 7 years [1]. One possible reason is that a stable resting latent reservoir with a long half-life exists in resting memory CD4(+)T cells [2]. In this paper, we propose a mathematical model with a constant contribution of a stable latent reservoir and identified this constant by using one patient's data from AutoVac HAART interruption study [3]. Many patients also have transient rebounds of plasma viral RNA (viral blips) under otherwise successful control of the virus by HAART. Activation of latently infected cells can explain these transient rebounds of viral load. Little quantitative analysis about the activation of reservoir has been done based on any clinical experiment data. Here, we model the activation dynamics of the reservoir by a time-independent activation rate and estimate this rate by using the clinical data from the AutoVac HAART interruption study [3].

Optimal antiviral switching to minimize resistance risk in HIV therapy.

The development of resistant strains of HIV is the most significant barrier to effective long-term treatment of HIV infection. The most common causes of resistance development are patient noncompliance and pre-existence of resistant strains. In this paper, methods of antiviral regimen switching are developed that minimize the risk of pre-existing resistant virus emerging during therapy switches necessitated by virological failure. Two distinct cases are considered; a single previous virological failure and multiple virological failures. These methods use optimal control approaches on experimentally verified mathematical models of HIV strain competition and statistical models of resistance risk. It is shown that, theoretically, order-of-magnitude reduction in risk can be achieved, and multiple previous virological failures enable greater success of these methods in reducing the risk of subsequent treatment failures.

Modeling-error robustness of a viral-load preconditioning strategy for HIV treatment switching.

In previous work, we have developed optimal-control based approaches that seek to minimize the risk of subsequent virological failure by "pre-conditioning" the viral load during therapy switches. In this paper, we use Monte-Carlo methods to evaluate the sensitivity of an open-loop implementation of these approaches to modeling errors. To account for hidden parameter dependencies, we use parameter distributions obtained from the convergence of Bayesian parameter estimation techniques applied to sets of clinical data obtained during serial therapy interruptions as the distribution from which the Monte-Carlo method samples.