Three-state Model Research Articles

Cost-effectiveness of pembrolizumab versus brentuximab vedotin for patients with relapsed or refractory classical Hodgkin’s lymphoma: a United States payer perspective

Aims: Patients with classical Hodgkin’s lymphoma (cHL) who have relapsed after or are ineligible for autologous stem cell transplantation (ASCT) have limited treatment options and generally a poor prognosis. Pembrolizumab was recently approved in the US for the treatment of such patients having demonstrated clinical benefit and tolerability in relapsed/refractory cHL; however, the cost-effectiveness of pembrolizumab in this population is currently unknown.Materials and methods: A three-state Markov model (progression-free [PF], progressed disease, and death) was developed to assess the cost-effectiveness of pembrolizumab (200 mg) vs brentuximab vedotin (BV; 1.8 mg/kg) in patients with relapsed/refractory cHL after ASCT who have not received BV post-ASCT over a 20-year time horizon from a US payer perspective. PF survival was modeled using a naïve indirect treatment comparison of data from KEYNOTE-087 and the SG035-003 trial. Post-progression survival was modeled using data from published literature. Costs (drug acquisition and administration, disease management, subsequent treatment, and adverse events) and outcomes were discounted at an annual rate of 3.0%. Uncertainty surrounding cost-effectiveness was assessed via probabilistic, deterministic, and scenario analyses.Results: In the base case, pembrolizumab was predicted to yield an additional 0.574 life-years (LYs) and 0.500 quality-adjusted life-years (QALYs) vs BV and cost savings of $63,278. Drug acquisition costs were the biggest driver of incremental costs between strategies. Pembrolizumab had a 99.6% probability of being cost-effective compared with BV at a willingness-to-pay threshold of $20,000/QALY and dominated BV in all scenarios tested.Limitations: The analysis was subject to potential bias due to the use of a naïve indirect treatment comparison and, given the current immaturity of OS in KEYNOTE-087, PPS was assumed equivalent across both treatments.Conclusion: Pembrolizumab is a cost-effective alternative to BV for patients with relapsed/refractory cHL after ASCT.

Energy analysis of the three-vertex Potts model ground state

An energy analysis of the ground state in the triangular lattice three-state Potts model is conducted with allowance for the contribution of the nearest and next-nearest neighbors having interaction values J1 and J2. The ranges of existence of ordered and disordered phases in the spin structures described by this model, with the interaction values J1 < 0, J2 < 0 and J1 > 0, J2 < 0, are inferred from the numerical experiment.

Immigration and Adherence to Cervical Cancer Screening: A Provincewide Longitudinal Matched Cohort Study Using Multistate Transitional Models.

Previous studies highlighting inequities in cancer screening between immigrants and non-immigrants have been methodologically limited. This longitudinal matched cohort study used a multistate modelling framework to examine associations between immigration status and cervical cancer screening adherence. A 1:1 matched cohort of women aged 25 and older from 1992-2014 who were residing in Ontario was examined. For each woman, the proportion of time spent being non-adherent was determined. Disparities in cervical screening adherence, and specifically the association between immigration status and the rate of becoming adherent, were investigated with a three-state transitional model. The model was adjusted for individual- and physician-level characteristics, which were updated annually and incorporated as time-varying covariates. The matched cohort consisted of 1156720 immigrant and non-immigrant women. The median proportion of time spent non-adherent was 38.9% for immigrants and 24.7% for non-immigrants. The rate of becoming adherent among immigrants was lower than that among non-immigrants, after accounting for individual- and physician-level characteristics (relative rate 0.933; 95% CI 0.928-0.937). Other characteristics such as socioeconomic status, immigrant region of origin, presence of primary physician, and physician's sex were found to be significantly associated with cervical screening adherence. This study assessed the association between immigration status and adherence to cervical cancer screening. The insights from this work can be used to target groups of women vulnerable to underscreening and to minimize their time spent non-adherent to cancer screening. The methodology serves as a useful framework for examining adherence to other types of cancer screening.

Energy efficient and delay aware ternary-state transceivers for aerial base stations

In recent times, Aerial Base Stations(AeBSs) are being investigated to provide wireless coverage to terrestrial radio terminals. There are many advantages of using aerial platforms to provide wireless coverage, including larger coverage in remote areas and better line-of-sight conditions, etc. Energy is a scarce resource for the AeBSs, hence the wise management of energy is quite beneficial for the aerial network. In this context, we study the means of reducing the total energy consumption by designing and implementing an energy efficient AeBSs as presented in this paper. Implementing the sleep mode in the Base Stations (BSs) has been proven to be a very good approach for improving the energy efficiency and we propose a novel strategy for further improving energy efficiency by considering ternary state transceivers for AeBSs. Using the three state model, we propose a Markov Decision Process (MDP) based algorithm, which intelligently switches among three states of the transceivers based on the offered traffic meanwhile maintaining a prescribed minimum channel rate per user. We define a reward function for the MDP, which helps us to get an optimal policy for selecting a particular mode for the transceivers of the AeBS. Considering an AeBS with transceivers whose states are changeable, we perform simulations to analyse the performance of the algorithm. Our results show that, compared with the always active model, around 40% gain in the energy efficiency is achieved by using our proposed MDP algorithm together with the three-state transceivers model. We also show the energy-delay tradeoff in order to design an efficient AeBS.

Singlet Fission in Perylenediimide Dimers

Singlet fission is a process in which one singlet exciton is converted to two triplets. By using transient absorption and time-resolved emission spectroscopy, recent experimental study (J. Am. Chem. Soc. 2017, 140, 814) investigated how different crystal packing of perylenediimide (PDI) molecules modulates their singlet fission rates and yields. It was observed that the rates vary between 0.33 and 4.3 ns–1. By employing a simple three-state kinetic model and restricted active-space configuration interaction method with double spin-flip, we study the electronic factors (excitation energies and coupling between relevant states) responsible for the variation of singlet fission rates in these PDI derivatives. Our approach reproduces the trends in singlet fission rates and provides explanations for the experimental findings. Our analysis reveals that the electronic energies and the coupling play significant roles in controlling the singlet fission rates. The wave function analysis of the adiabatic electronic states shows that in many model PDI structures, the multiexciton character is spread over several states, in contrast to previously studied systems. This different nature of the multiexciton state poses interesting mechanistic questions. By mapping the relation between the stacking geometries of PDIs and the rates of the singlet multiexciton formation and the binding energies, we suggest favorable PDI structures that should not lead to exciton trapping.

PCN139 - COST-EFFECTIVENESS ANALYSIS OF PEMBROLIZUMAB FOR PATIENTS WITH LOCALLY ADVANCED OR METASTATIC UROTHELIAL CANCER WHO ARE INELIGIBLE FOR CISPLATIN-CONTAINING CHEMOTHERAPY IN ENGLAND

To assess the cost-effectiveness of pembrolizumab versus carboplatin plus gemcitabine in patients with locally advanced or metastatic urothelial cancer, who are not eligible for cisplatin-containing chemotherapy. A three-state partition survival model was developed with a 20-year time horizon and a weekly cycle. KEYNOTE-052, phase II single arm clinical trial informed the clinical efficacy and adverse events parameters of pembrolizumab in the model. Overall survival (OS) was extrapolated using a piece-wise approach, utilising Kaplan-Meier data until week 32 and using a log-normal distribution for the remainder of the time horizon. A network meta-analysis, enabled through the use of a simulated treatment comparison (STC), provided comparative effectiveness estimates of pembrolizumab versus carboplatin plus gemcitabine as time-varying hazard ratios (HRs). Quality-adjusted life years (QALYs) were estimated using utilities derived from EQ-5D data collected in KEYNOTE-052. Resource use and unit costs were applied from a NHS perspective. Probabilistic-, deterministic-, and scenario- analyses were performed to assess model uncertainty. The model demonstrated that pembrolizumab increases the life expectancy of patients by 1.39 years, corresponding to 1.04 additional QALYs. The base case incremental cost-effectiveness ratio (ICER) is £35,016 (confidential discount included). Model results are sensitive to the following assumptions: comparative effectiveness HR for pembrolizumab vs. carboplatin plus gemcitabine, extrapolation of overall survival data, and the utility estimates used. The results of this cost-effectiveness analysis demonstrated that pembrolizumab is a cost-effective choice compared to carboplatin plus gemcitabine when considering a willingness to pay threshold of £50,000 per QALY, as per NICE end-of-life criteria.

UPF1-like helicase grip on nucleic acids dictates processivity

Helicases are molecular engines which translocate along nucleic acids (NA) to unwind double-strands or remodel NA–protein complexes. While they have an essential role in genome structure and expression, the rules dictating their processivity remain elusive. Here, we developed single-molecule methods to investigate helicase binding lifetime on DNA. We found that UPF1, a highly processive helicase central to nonsense-mediated mRNA decay (NMD), tightly holds onto NA, allowing long lasting action. Conversely, the structurally similar IGHMBP2 helicase has a short residence time. UPF1 mutants with variable grip on DNA show that grip tightness dictates helicase residence time and processivity. In addition, we discovered via functional studies that a decrease in UPF1 grip impairs NMD efficiency in vivo. Finally, we propose a three-state model with bound, sliding and unbound molecular clips, that can accurately predict the modulation of helicase processivity.

Investigation on the Control Strategy for Marine Selective Catalytic Reduction System

Selective catalytic reduction (SCR) system has been proven to be an effective technology for the removal of NOx emitted from marine diesel engines. In order to comply with stringent International Maritime Organization (IMO) Tier III NOx emission regulations, a number of engine manufacturers have developed their own SCR systems. This paper focuses on modeling of an SCR reactor and developing model-based urea dosing control strategy. A mathematical model of SCR reactors has been established. Model-based control strategy relies on the three-state and one-state reactor models established to accomplish urea dosing algorithm and is promising in limiting excessive NH3 slip. The SCR reactor model is further used in a simulation for the purpose of developing model-based urea dosing control strategies. The simulation results show that the NO sliding mode control requires a massive prestudy of the NOx reduction capability of the catalyst in order to set an appropriate control objective for each operating condition. However, this calibration work can be omitted in the optimal control and NH3 sliding mode control, which mitigates the workload of the controller design. The optimal control strategy presents a satisfied control performance in limiting NH3 slip during transient state engine operating conditions.

Working life expectancy in good and poor self-perceived health among Dutch workers aged 55–65 years with a chronic disease over the period 1992–2016

ObjectivesSeveral governments have taken measures to encourage prolonged working. It is therefore likely that older adults with a chronic disease are required to work longer in poor self-perceived health (SPH)...

Nonequilibrium uncertainty principle from information geometry

With a statistical measure of distance, we derive a classical uncertainty relation for processes traversing nonequilibrium states both transiently and irreversibly. The geometric uncertainty associated with dynamical histories that we define is an upper bound for the entropy production and flow rates, but it does not necessarily correlate with the shortest distance to equilibrium. For a model one-bit memory device, we find that expediting the erasure protocol increases the maximum dissipated heat and geometric uncertainty. A driven version of Onsager's three-state model shows that a set of dissipative, high-uncertainty initial conditions, some of which are near equilibrium, scar the state space.

Backstepping Nonlinear Control for Blood Glucose Based on Sliding Mode Meal Observer

Diabetes is one of the most critical diseases in the world which requires measuring the concentration of glucose also the injection of insulin to control the glucose rate in the body. The proposed controller is applied to the Bergman’s three-state minimal patient model, where the model is considered certain but with unknown meal. In the present work, a nonlinear controller is designed to control the concentration of glucose based on the Backstepping approached with a sliding mode for observing the disturbance meal. So will have estimated the meal and have canceled the effect that the glucose concentration has regulating to the basal level.
 The effectiveness of the proposed controller, which represent the insulin dose, is proved via simulating the Bergman’s model with designed controller via MATLAB Simulink software. The result clarify the ability and the robustness of the proposed controller.

Analysis of Effective Capacity and Throughput of Polling-Based Device-To-Device Networks

Next-generation wireless networks will give rise to heterogeneous networks by integrating multiple wireless access technologies to provide seamless mobility to mobile users with high-speed wireless connectivity. Device-to-device (D2D) communication has proven to be a promising technology that can increase the capacity and coverage of wireless networks. The D2D communication was first introduced in long-term evolution advanced (LTE-A) and has gained immense popularity for the offloading traffic using the licensed and unlicensed band. Challenges arise from resource allocation, provision of quality-of-service (QoS), and the quantification of capacity in an unlicensed band due to the distributed nature of Wi-Fi. In this paper, we propose an analytical performance model for the scalable MAC protocol (SC-MP) in which a resource allocation mechanism is based on the IEEE 802.11 point coordinated function to access the Wi-Fi channel for voice and video/multimedia traffic. In the SC-MP, D2D communication is applied to further offload the video/multimedia traffic. In particular, this paper establishes a three-state semi-Markovian model to derive a closed-form expression of effective capacity in terms of transmission rate and quality-of-service. Further, the SC-MP is analytically modeled using the four-state traditional Markov model to derive the saturation throughput. The analytical results are validated through simulations, hence, proving the appropriateness of the model.

Changes in working life expectancy with disability in the Netherlands, 1992-2016.

Objectives Like other western countries, the Netherlands has abolished early retirement schemes and is currently increasing the statutory retirement age. It is likely that also older workers with disabilities will be required to work longer. We examine the change in working life expectancy (WLE) with disability of older workers by comparing data from three periods: 1992-1996, 2002-2006 and 2012-2016. Methods Data are from the Longitudinal Aging Study Amsterdam (LASA). Respondents aged 55-65 with a paid job at baseline were included (N=1074). Disability was measured using the Global Activity Limitations Indicator (GALI). First, a continuous-time three-state survival model was created. Second, WLE with and without disability were estimated using MSM and ELECT in R. The modifying effects of gender and educational level were examined. Results Among those initially in paid employment, total WLE increased over 20 years. For example at age 58, total WLE increased from 3.7 to 5.5 years. WLE with disability at age 58 increased from 0.8 to 1.5 years. There was no difference in WLE with disability between male and female workers or low- and highly educated workers. Conclusions Between the 1990s and the 2010s, subsequent generations of older workers with disabilities have extended their working lives. The findings emphasize the importance of workplace interventions that facilitate older workers with disabilities to maintain well-being and work ability. In addition, the question arises whether current exit routes out of the workforce are still adequate.

Hidden three-state survival model for bivariate longitudinal count data

A model is presented that describes bivariate longitudinal count data by conditioning on a progressive illness-death process where the two living states are latent. The illness-death process is modelled in continuous time, and the count data are described by a bivariate extension of the binomial distribution. The bivariate distributions for the count data approach include the correlation between two responses even after conditioning on the state. An illustrative data analysis is discussed, where the bivariate data consist of scores on two cognitive tests, and the latent states represent two stages of underlying cognitive function. By including a death state, possible association between cognitive function and the risk of death is accounted for.

Localization-protected order in spin chains with non-Abelian discrete symmetries

We study the non-equilibrium phase structure of the three-state random quantum Potts model in one dimension. This spin chain is characterized by a non-Abelian $D_3$ symmetry recently argued to be incompatible with the existence of a symmetry-preserving many-body localized (MBL) phase. Using exact diagonalization and a finite-size scaling analysis, we find that the model supports two distinct broken-symmetry MBL phases at strong disorder that either break the ${\mathbb{Z}_3}$ clock symmetry or a ${\mathbb{Z}_2}$ chiral symmetry. In a dual formulation, our results indicate the existence of a stable finite-temperature topological phase with MBL-protected parafermionic end zero modes. While we find a thermal symmetry-preserving regime for weak disorder, scaling analysis at strong disorder points to an infinite-randomness critical point between two distinct broken-symmetry MBL phases.

Heat Capacity of DPPC/Cholesterol Mixtures: Comparison of Single Bilayers with Multibilayers and Simulations.

The excess heat capacity (Δ C p) of mixtures of dipalmitoylphosphatidylcholine (DPPC) and cholesterol (Chol) is examined in detail in large unilamellar vesicles (LUVs), both experimentally, using differential scanning calorimetry (DSC), and theoretically, using a three-state Ising model. The model postulates that DPPC can access three conformational states: gel, liquid-disordered (Ld), and liquid-ordered (Lo). The Lo state, however, is only available if coupled with interaction with an adjacent Chol. Δ C p was calculated using Monte Carlo simulations on a lattice and compared to experiment. The DSC results in LUVs are compared with literature data on multilamellar vesicles (MLVs). The enthalpy change of the complete phase transition from gel to Ld is identical in LUVs and MLVs, and the melting temperatures ( Tm) are similar. However, the DSC curves in LUVs are significantly broader, and the maxima of Δ C p are accordingly smaller. The parameters in the Ising model were chosen to match the DSC curves in LUVs and the nearest-neighbor recognition (NNR) data. The model reproduces the NNR data very well. It also reproduces the phase transition in DPPC, the freezing point depression induced by Chol, and the broad component of Δ C p in DPPC/Chol LUVs. However, there is a sharp component, between 5 and 15 mol % Chol, that the model does not reproduce. The broad component of Δ C p becomes dominant as Chol concentration increases, indicating that it involves melting of the Lo phase. Because the simulations reproduce this component, the conclusions regarding the nature of the phase transition at high Chol concentrations and the structure of the Lo phase are important: there is no true phase separation in DPPC/Chol LUVs. There are large domains of gel and Lo phase coexisting below Tm of DPPC, but above Tm the three states of DPPC are mixed with Chol, although clusters persist.

Identifying and Modulating Accidental Fermi Resonance: 2D IR and DFT Study of 4-Azido-l-phenylalanine.

Azido-modified aromatic amino acids have been used as powerful infrared probes for the site-specific detection of proteins because of their large transition dipole strengths. However, their complex absorption profiles hinder their wider application. The complicated absorption profile of 4-azido-l-phenylalanine (pN3Phe) in isopropanol was identified and attributed to accidental Fermi resonances (FRs) by means of linear absorption and two-dimensional (2D) IR spectroscopies. The 2D IR results of pN3Phe in H2O and D2O further demonstrate that the FRs are distinctively influenced by the hydrogen-bonding environment. Under the influence of FRs, the 2D IR shape is distorted, indicating that pN3Phe is not a good candidate in spectral diffusion studies. A three-state model and first-principles calculations were used to analyze unperturbed energy levels, unveiling the FRs between the azide asymmetric stretching band and two combination bands. Furthermore, the anharmonic frequency calculations suggest that changing the substitution position of the azide group from para to meta can effectively modulate the FRs by reducing the coupling strength. This work provides a deep understanding of the FRs in azido-modified aromatic amino acids and sheds light on the modification of azido-modified amino acids for wider utilization as vibrational probes.

Ground State of an Antiferromagnetic Three-State Potts Model on a Triangular Lattice with Competing Interactions

The ground state of the spin structures described by an antiferromagnetic three-state Potts model on a triangular lattice is studied with allowance for the next-nearest neighbors. The numerical data obtained by the Monte Carlo method are used to reveal the ranges of ordered and disordered phases in these structures.

A spin-1 representation for dual-funnel energy landscapes.

The interconversion between the left- and right-handed helical folds of a polypeptide defines a dual-funneled free energy landscape. In this context, the funnel minima are connected through a continuum of unfolded conformations, evocative of the classical helix-coil transition. Physical intuition and recent conjectures suggest that this landscape can be mapped by assigning a left- or right-handed helical state to each residue. We explore this possibility using all-atom replica exchange molecular dynamics and an Ising-like model, demonstrating that the energy landscape architecture is at odds with a two-state picture. A three-state model-left, right, and unstructured-can account for most key intermediates during chiral interconversion. Competing folds and excited conformational states still impose limitations on the scope of this approach. However, the improvement is stark: Moving from a two-state to a three-state model decreases the fit error from 1.6 kBT to 0.3 kBT along the left-to-right interconversion pathway.

Evaluation of potential impact of benzodiazepine consumption reduction on future of dementia burden

Introduction Primarily indicated for treating the symptoms of anxiety and sleep disorders over short periods, benzodiazepines are widely prescribed in developed countries. In France, 30% of people aged 65 years and over use benzodiazepines [1] . Some studies found an increased risk of dementia or cognitive impairment in benzodiazepines users [2] . Moreover, the aging of the population should lead to a sharp rise of the number of demented subjects. To reduce the burden of dementia, interventions targeting dementia risk factors could be proposed, but the association between most of these risk factors and mortality makes it difficult to anticipate the potential impact of such interventions. Assuming a causal effect of benzodiazepines on dementia risk, the main objective of this work is to evaluate consequences of benzodiazepine consumption reduction on various measures of dementia burden. Methods A three-state model called illness-death model was used to estimate the dementia incidence rate and the over-risk of death for demented subjects [3] . National demographic projections provided general mortality rates and population at 65 years. We assumed that a subject who used benzodiazepines for more than 6 months continuously after age 65 remained at higher risk of dementia until the end of his/her life. A Monte Carlo algorithm with a discrete time model was implemented to make projections for the life expectancies with and without dementia, the age at dementia onset, the lifelong probability of dementia and the prevalence of dementia. The methodology took into account the mortality trend over calendar time and age in both healthy and demented subjects. The method was used to provide projections for dementia in 2040 under two scenarios, either division by two or suppression of benzodiazepines use from 2020. Results We estimated that more than 2.8 million subjects will live with dementia in France in 2040. Dividing the benzodiazepine consumption by two from 2020 should led to 5.5% fewer demented cases in France in 2040. With the extreme scenario of suppression of benzodiazepine use from 2020, the number of cases would be reduced by 12.8%. Moreover, the life expectancy without dementia for 65-years-old women in 2040 was estimated at 21.85 years without intervention versus 22.47 years if benzodiazepine consumption was divided by two and 23.33 years with a removal of benzodiazepine use in 2020. In the same way, the lifelong probability of dementia was higher without intervention. For example, this estimated probability without intervention was 59.07% for non-demented men 65-years-old in 2040 versus 50.72% if benzodiazepine use was null from 2020. Conclusion Assuming a causal relationship, the proposed methodology showed that a decrease in benzodiazepine consumption could reduce dementia burden in the future. The method could be used for evaluating scenarios of change for other drugs or risk factors for any chronic diseases.