Single-cell multi-omic velocity infers dynamic and decoupled gene regulation

Single-cell multi-omic datasets, in which multiple molecular modalities are profiled within the same cell, provide a unique opportunity to discover the relationships between cellular epigenomic and transcriptomic changes. To realize this potential, we developed MultiVelo, a mechanistic model of gene expression that extends the RNA velocity framework to incorporate epigenomic data. MultiVelo uses a probabilistic latent variable model to estimate the switch time and rate parameters of chromatin accessibility and gene expression from single-cell data, providing a quantitative summary of the temporal relationship between epigenomic and transcriptomic changes. Incorporating chromatin accessibility data significantly improves the accuracy of cell fate prediction compared to velocity estimates from RNA only. Fitting MultiVelo on single-cell multi-omic datasets from brain, skin, and blood cells reveals two distinct classes of genes distinguished by whether chromatin closes before or after transcription ceases. Our model also identifies four types of cell states--two states in which epigenome and transcriptome are coupled and two distinct decoupled states. The parameters inferred by MultiVelo quantify the length of time for which genes occupy each of the four states, ranking genes by the degree of coupling between transcriptome and epigenome. Finally, we identify time lags between transcription factor expression and binding site accessibility and between disease-associated SNP accessibility and expression of the linked genes. We provide an open-source Python implementation of MultiVelo on PyPI and GitHub (https://github.com/welch-lab/MultiVelo).

Numerical Study on Heat Transfer Efficiency of Regenerative Thermal Oxidizers with Three Canisters

The heat transfer efficiency of a regenerative thermal oxidizer with three canisters used for volatile organic compounds treatment was studied using numerical simulation methods. A one-dimensional model that took into account the variation of physical parameters with temperature was built. The results show that the preheating temperature and outlet temperature tend to be stable as the operation time is increased. The heat transfer efficiency of equipment was mainly evaluated by heat recovery efficiency and energy recovery ratio under steady state conditions, which was affected by the inlet gas flow and temperature, valve switch time, combustion temperature, materials and porosity of the regenerative medium, and packing height. With the increase in packing cross-sectional area and packing height, the increase in heat transfer efficiency leads to an increase in equipment cost. Simultaneously, the shorter the valve switch time and the higher the density of the regenerative medium battery also help to improve the heat transfer efficiency without blocking equipment. Unless the removal efficiency of volatile organic compound treatment is reduced, it is recommended to reduce the inlet and combustion temperatures.

Adaptive Therapy for Metastatic Melanoma: Predictions from Patient Calibrated Mathematical Models

Adaptive therapy is an evolution-based treatment approach that aims to maintain tumor volume by employing minimum effective drug doses or timed drug holidays. For successful adaptive therapy outcomes, it is critical to find the optimal timing of treatment switch points in a patient-specific manner. Here we develop a combination of mathematical models that examine interactions between drug-sensitive and resistant cells to facilitate melanoma adaptive therapy dosing and switch time points. The first model assumes genetically fixed drug-sensitive and -resistant popul tions that compete for limited resources. The second model considers phenotypic switching between drug-sensitive and -resistant cells. We calibrated each model to fit melanoma patient biomarker changes over time and predicted patient-specific adaptive therapy schedules. Overall, the models predict that adaptive therapy would have delayed time to progression by 6–25 months compared to continuous therapy with dose rates of 6–74% relative to continuous therapy. We identified predictive factors driving the clinical time gained by adaptive therapy, such as the number of initial sensitive cells, competitive effect, switching rate from resistant to sensitive cells, and sensitive cell growth rate. This study highlights that there is a range of potential patient-specific benefits of adaptive therapy and identifies parameters that modulate this benefit.

Transposition of the great vessels and intact ventricular septum: is there an age limit for the arterial switch? Personal experience and review of the literature

Objective:Prognosis of the transposition of the great arteries has completely changed since the introduction of the arterial switch. Time limit to perform this intervention is still controversial. The aim of this study is to demonstrate the early and late outcome of primary arterial switch operation beyond the age of months.Methods:We included all patients with the diagnosis of transposition of the great arteries with intact ventricular septum beyond the age of 8 weeks who underwent primary arterial switch operation. The procedures were performed by the same surgeon, in two different institutes. Patients who had transposition of the great arteries and associated anomalies (except atrial septal defect and persistent arterial duct) were excluded. Ventricular shape, geometry, and mass were not considered during the decision on procedure type.Results:In the study, 11 patients with the diagnosis of simple d-transposition of the great arteries beyond 8 weeks were undergone primary arterial switch operation with a mean age of 90.63 days (60–137 days), and 7 patients had a Rashkind procedure. All patients had squashed left ventricle shape with preserved function. The sternum was left open in 10 patients. Extracorporeal membrane oxygenation support was necessary in 45.45% of cases. The mean mechanical ventilation time was 7.27 days (1–16 days). No mortality was recorded until now. Post-operatory left ventricular function was preserved in 90.9% of the patients. Only one patient had mild myocardial dysfunction at the time of discharge.Conclusions:Primary arterial switch procedure can still be the best surgical option in patients with the diagnosis of transposition of the great arteries with intact ventricular septum beyond 8 weeks of age, providing that mechanical circulatory support and an expert cardiac intensive care unit service are available.

Changes in mortality hazard of the Korean long-term dialysis population: The dependencies of time and modality switch

Background: Many studies have compared patient survival outcome between hemodialysis (HD) and peritoneal dialysis (PD); however, time-varying risks of dialysis modality have been rarely investigated. This study aimed to investigate dialysis modality switch and its association with the survival outcome in the Korean population. Methods: Data from the Korean Society of Nephrology were used. A total of 21,840 incident dialysis patients who started dialysis in or after 2000 were analyzed. For the survival analysis, both proportional and non-proportional hazard assumptions were applied. For the modality switch, time-varying covariate Cox regression was applied. Results: During the median follow-up of 8 years, PD group showed increased adjusted hazard ratio (HR) of 1.248 (95% CI 1.071–1.454, p = 0.004) for mortality. Interaction of PD status with female sex was significant with an HR of 1.080 (95% CI 1.000–1.165, p = 0.050). Dialysis modality switch was associated with increased HR of 1.094 (95% CI 1.015–1.180, p = 0.019), albeit switch from PD to HD did not show significant HR until 6 years. Interestingly, time-varying risk analysis showed a decreased HR of PD after 10 years in the non-switcher group, which was consistent in patients with high traditional risk factors (with diabetes, elderly). Conclusions: PD was associated with increased HR of mortality in the first 8 years, then it was associated with decreased HR of mortality after 10 years. Dialysis modality switch was associated with increased mortality risk, but switch from PD to HD within 6 years did not show significant hazard of mortality.

The Impact of Delayed Switch to Second-Line Antiretroviral Therapy on Mortality, Depending on Definition of Failure Time and CD4 Count at Failure

Little is known about the functional relationship of delaying second-line treatment initiation for human immunodeficiency virus–positive patients and mortality, given a patient’s immune status. We included 7,255 patients starting antiretroviral therapy during 2004–2017, from 9 South African cohorts, with virological failure and complete baseline data. We estimated the impact of switch time on the hazard of death using inverse probability of treatment weighting of marginal structural models. The nonlinear relationship between month of switch and the 5-year survival probability, stratified by CD4 count at failure, was estimated with targeted maximum likelihood estimation. We adjusted for measured time-varying confounding by CD4 count, viral load, and visit frequency. Five-year mortality was estimated to be 10.5% (95% CI: 2.2, 18.8) for immediate switch and to be 26.6% (95% CI: 20.9, 32.3) for no switch (51.1% if CD4 count was <100 cells/mm3). The hazard of death was estimated to be 0.37 (95% CI: 0.30, 0.46) times lower if everyone had been switched immediately compared with never. The shorter the delay in switching, the lower the hazard of death—delaying 30–59 days reduced the hazard by 0.53 (95% CI: 0.43, 0.65) times and 60–119 days by 0.58 (95% CI: 0.49, 0.69) times, compared with no switch. Early treatment switch is particularly important for patients with low CD4 counts at failure.

The impact of delayed switch to second-line antiretroviral therapy on mortality, depending on failure time definition and CD4 count at failure

ABSTRACTBackgroundLittle is known about the functional relationship of delaying second-line treatment initiation for HIV-positive patients and mortality, given a patient’s immune status.MethodsWe included 7255 patients starting antiretroviral therapy between 2004-2017, from 9 South African cohorts, with virological failure and complete baseline data. We estimated the impact of switch time on the hazard of death using inverse probability of treatment weighting (IPTW) of marginal structural models. The non-linear relationship between month of switch and the 5-year survival probability, stratified by CD4 count at failure, was estimated with targeted maximum likelihood estimation (TMLE). We adjusted for measured time-varying confounding by CD4 count, viral load and visit frequency.Results5-year mortality was estimated as 10.5% (2.2%; 18.8%) for immediate switch and as 26.6% (20.9%; 32.3%) for no switch (49.9% if CD4 count<100 cells/mm3). The hazard of death was estimated to be 0.40 (95%CI: 0.33-0.48) times lower if everyone had been switched immediately compared to never. The shorter the delay in switching, the lower the hazard of death, e.g. delaying 30-60 days reduced the hazard 0.52 (0.41-0.65) times, and 60-120 days 0.56 (0.47-0.66) times.ConclusionsEarly treatment switch is particularly important for patients with low CD4 counts at failure.