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Background Minimal aortic injury (MAI), a subtype of acute traumatic aortic injury, is being increasingly recognized with better imaging techniques. Given conservative management, the role of follow-up imaging albeit important yet has to be defined. Methods All trauma chest computed tomography angiographies (CTAs) at our center between January 2012 and January 2019 were retrospectively reviewed for presence of MAI. MAIs were generally reimaged at 24 to 72 hours and then at a 7- and 30-day interval. Follow-up CTAs were reviewed for stability, progression, or resolution of MAI, along with assessment of injury severity scores (ISS) and concomitant injuries, respectively. Results A total of 17,569 chest CTAs were performed over this period. Incidence of MAI on the initial chest CTA was 113 (0.65%), with 105 patients receiving follow-up CTAs. The first, second, third, and fourth follow-up CTAs were performed at a median of 2, 10, 28, and 261 days, respectively. Forty five (42.9%), 22 (21%), 5 (4.8%), and 1 (1%) of the MAIs were resolved by first, second, third, and fourth follow-up CTAs. Altogether, 21 patients showed stability (mean ISS of 16.6), and 11 demonstrated improvement (mean ISS 25.8) of MAIs. Eight patients had no follow-up CTA (mean ISS 21). No progression to higher-grade injury was observed. Advancing age decreased the odds of MAI resolution on follow-up. A possible trend (p-value 0.22) between increasing ISS and time to resolution of MAIs was noted. Conclusion In our series of acute traumatic MAIs diagnosed on CTA imaging, there was no progression of injuries with conservative management, questioning the necessity of sequential follow-up imaging.

This paper introduces a nonparametric regression approach for univariate and multivariate skewed responses using Bayesian additive regression trees (BART). Existing BART methods use ensembles of decision trees to model a mean function, and have become popular recently due to their high prediction accuracy and ease of use. The usual assumption of a univariate Gaussian error distribution, however, is restrictive in many biomedical applications. Motivated by an oral health study, we provide a useful extension of BART, the skewBART model, to address this problem. We then extend skewBART to allow for multivariate responses, with information shared across the decision trees associated with different responses within the same subject. The methodology accommodates within-subject association, and allows varying skewness parameters for the varying multivariate responses. We illustrate the benefits of our multivariate skewBART proposal over existing alternatives via simulation studies and application to the oral health dataset with bivariate highly skewed responses. Our methodology is implementable via the R package skewBART, available on GitHub.

The formation of virus-laden colloidal respiratory microdroplets - the sneeze or cough virulets and their evaporation driven miniaturization in the open air are found to have a significant impact on the community transmission of COVID-19 pandemic.We simulate the motions and trajectories of virulets by employing laminar fluid flow coupled with droplet tracing physics. A force field analysis has been included considering the gravity, drag, and inertial forces to unleash some of the finer features of virulet trajectories leading to the droplet and airborne transmissions of the virus. Furthermore, an analytical model corroborates temperature (T) and relative humidity (RH) controlled droplet miniaturization.The study elucidates that the tiny (1-50 µm) and intermediate (60-100 µm) size ranged virulets tend to form bioaerosol and facilitate an airborne transmission while the virulets of larger dimensions (300 to 500 µm) are more prone to gravity dominated droplet transmission. Subsequently, the mapping between the T and RH guided miniaturization of virulets with the COVID-19 cases for six different cities across the globe justifies the significant contribution of miniaturization-based bioaerosol formation for community transmission of the pandemic.

Cardiovascular disease is a leading contributor to mortality among childhood, adolescent and young adult (C-AYA) cancer survivors. While serial cardiovascular screening is recommended in this population, optimal screening strategies, including the use of echocardiography-based myocardial strain, are not fully defined. Our objective was to determine the relationship between longitudinal and circumferential strain (LS, CS) and fractional shortening (FS) among survivors. This single-center cohort study retrospectively measured LS and CS among C-AYAs treated with anthracycline/anthracenedione chemotherapy. The trajectory of LS and CS values over time were examined among two groups of survivors: those who experienced a reduction of >5 fractional shortening (FS) units from pre-treatment to the most recent echocardiogram, and those who did not. Using mixed modeling, LS and CS were used to estimate FS longitudinally. A receiver operator characteristic curve was generated to determine the ability of our model to correctly predict an FS ≤ 27%. A total of 189 survivors with a median age of 14 years at diagnosis were included. Among the two survivor groups, the trajectory of LS and CS differed approximately five years from cancer diagnosis. A statistically significant inverse relationship was demonstrated between FS and LS −0.129, p = 0.039, as well as FS and CS −0.413, p < 0.001. The area under the curve for an FS ≤ 27% was 91%. Among C-AYAs, myocardial strain measurements may improve the identification of individuals with cardiotoxicity, thereby allowing earlier intervention.

Supplementary Data from Chk1 Inhibition Potently Blocks STAT3 Tyrosine705 Phosphorylation, DNA-Binding Activity, and Activation of Downstream Targets in Human Multiple Myeloma Cells

Epigenetic regulators can modulate the effects of cancer therapeutics. To further these observations, we discovered that the bromodomain PHD finger transcription factor subunit (BPTF) of the nucleosome remodeling factor (NURF) promotes resistance to doxorubicin, etoposide, and paclitaxel in the 4T1 breast tumor cell line. BPTF functions in promoting resistance to doxorubicin and etoposide, but not paclitaxel, and may be selective to cancer cells, as a similar effect was not observed in embryonic stem cells. Sensitization to doxorubicin and etoposide with BPTF knockdown (KD) was associated with increased DNA damage, topoisomerase II (TOP2) crosslinking and autophagy; however, there was only a modest increase in apoptosis and no increase in senescence. Sensitization to doxorubicin was confirmed in vivo with the syngeneic 4T1 breast tumor model using both genetic and pharmacologic inhibition of BPTF. The effects of BPTF inhibition in vivo are autophagy dependent, based on genetic autophagy inhibition. Finally, treatment of 4T1, 66cl4, 4T07, MDA-MB-231, but not ER-positive 67NR and MCF7 breast cancer cells with the selective BPTF bromodomain inhibitor, AU1, recapitulates genetic BPTF inhibition, including in vitro sensitization to doxorubicin, increased TOP2-DNA crosslinks and DNA damage. Taken together, these studies demonstrate that BPTF provides resistance to the antitumor activity of TOP2 poisons, preventing the resolution of TOP2 crosslinking and associated autophagy. These studies suggest that BPTF can be targeted with small-molecule inhibitors to enhance the effectiveness of TOP2-targeted cancer chemotherapeutic drugs.Implications:These studies suggest NURF can be inhibited pharmacologically as a viable strategy to improve chemotherapy effectiveness.

Supplemental Figure 5. Selective BPTF Bromdomain Inhibitor AU1 Recapitulates Effects from BPTF KD in Human MDA-MB-231 and Mouse 66cl4 and 4T07 Cell Lines.

Supplemental Figure 2. NURF Selectively Suppresses Toxicity to Topoisomerase 2 Poisons and Improves their DNA Damaging Effects.

Supplemental Figure 4. Selective BPTF Bromdomain Inhibitor AU1 Recapitulates Effects from BPTF KD in 4T1 Cells and Tumors.

Supplemental Figure 3. Validation of Autophagy by Microscopy and ATG5 KD in 4T1 Cells.

Experimental investigations with high-speed imaging reveal that two unequal sized oppositely charged droplets suspended in an insulating oil can come in contact in an asymmetric manner under an electric field. The approaching poles of the droplets undergo asymmetric "cone-cone" to "cone-groove" deformations during noncoalescence under an electric field. Nonlinear three-dimensional simulations confirm the occurrence of a third "groove-groove" configuration at close proximity. A general linear stability analysis confirms the cone-cone to cone-groove transitions of the oil-water interfaces with decreasing thickness of the oil film. Experiments together with simulations confirm the bifurcation of the Taylor cone on the smaller droplet into a number of liquid "tentilla" bridges prior to contact with the bigger droplet. Simulations also predict that the length scales of the formation of such tentillar bridges from the initial Taylor cone match well with the predictions from the nonlinear bifurcation theory.

In clinical studies or trials comparing survival times between two treatment groups, the restricted mean lifetime (RML), defined as the expectation of the survival from time 0 to a prespecified time-point, is often the quantity of interest that is readily interpretable to clinicians without any modeling restrictions. It is well known that if the treatments are not randomized (as in observational studies), covariate adjustment is necessary to account for treatment imbalances due to confounding factors. In this article, we propose a simple doubly-robust pseudo-value approach to effectively estimate the difference in the RML between two groups (akin to a metric for estimating average causal effects), while accounting for confounders. The proposed method combines two general approaches: (a) group-specific regression models for the time-to-event and covariate information, and (b) inverse probability of treatment assignment weights, where the RMLs are replaced by the corresponding pseudo-observations for survival outcomes, thereby mitigating the estimation complexities in presence of censoring. The proposed estimator is double-robust, in the sense that it is consistent if at least one of the two working models remains correct. In addition, we explore the potential of available machine learning algorithms in causal inference to reduce possible bias of the causal estimates in presence of a complex association between the survival outcome and covariates. We conduct extensive simulation studies to assess the finite-sample performance of the pseudo-value causal effect estimators. Furthermore, we illustrate our methodology via application to a dataset from a breast cancer cohort study. The proposed method is implementable using the R package drRML, available in GitHub.

The relationship between the checkpoint kinase Chk1 and the STAT3 pathway was examined in multiple myeloma cells. Gene expression profiling of U266 cells exposed to low (nmol/L) Chk1 inhibitor [PF-477736 (PF)] concentrations revealed STAT3 pathway-related gene downregulation (e.g., BCL-XL, MCL-1, c-Myc), findings confirmed by RT-PCR. This was associated with marked inhibition of STAT3 Tyr705 (but not Ser727) phosphorylation, dimerization, nuclear localization, DNA binding, STAT3 promoter activity by chromatin immunoprecipitation assay, and downregulation of STAT-3-dependent proteins. Similar findings were obtained in other multiple myeloma cells and with alternative Chk1 inhibitors (e.g., prexasertib, CEP3891). While PF did not reduce GP130 expression or modify SOCS or PRL-3 phosphorylation, the phosphatase inhibitor pervanadate antagonized PF-mediated Tyr705 dephosphorylation. Significantly, PF attenuated Chk1-mediated STAT3 phosphorylation in in vitro assays. Surface plasmon resonance analysis suggested Chk1/STAT3 interactions and PF reduced Chk1/STAT3 co-immunoprecipitation. Chk1 CRISPR knockout or short hairpin RNA knockdown cells also displayed STAT3 inactivation and STAT3-dependent protein downregulation. Constitutively active STAT3 diminished PF-mediated STAT3 inactivation and downregulate STAT3-dependent proteins while significantly reducing PF-induced DNA damage (γH2A.X formation) and apoptosis. Exposure of cells with low basal phospho-STAT3 expression to IL6 or human stromal cell conditioned medium activated STAT3, an event attenuated by Chk1 inhibitors. PF also inactivated STAT3 in primary human CD138+ multiple myeloma cells and tumors extracted from an NSG multiple myeloma xenograft model while inhibiting tumor growth. Implications: These findings identify a heretofore unrecognized link between the Chk1 and STAT3 pathways and suggest that Chk1 pathway inhibitors warrant attention as novel and potent candidate STAT3 antagonists in myeloma.

In this work, we propose nonparametric two-sample tests for population-averaged transition and state occupation probabilities for continuous-time and finite state space processes with clustered, right-censored, and/or left-truncated data. We consider settings where the two groups under comparison are independent or dependent, with or without complete cluster structure. The proposed tests do not impose assumptions regarding the structure of the within-cluster dependence and are applicable to settings with informative cluster size and/or non-Markov processes. The asymptotic properties of the tests are rigorously established using empirical process theory. Simulation studies show that the proposed tests work well even with a small number of clusters, and that they can be substantially more powerful compared to the only, to the best of our knowledge, previously proposed test for this problem. The tests are illustrated using data from a multicenter randomized controlled trial on metastatic squamous-cell carcinoma of the head and neck.

We computationally explore the effects of pre-impact shape of an oil droplet on the spatiotemporal dynamics after the droplet impacts an air-water interface. Simulations reveal that the initial shape of the impacting oil-droplet alters the post-impact transient flow structures during the evolution. The spherical and oblate drop spreads over the crater to manifest interesting flow morphologies including the formation of oil-toroids and compound oil-droplets. However, the prolate drop impinges much deeper into the water pool after impact to create a few more exclusive flow features, such as, interface overturning, vortex shedding and formation of secondary droplets. The temporal variation of the crater depth shows distinct three stage dynamics, which can be explained by the generic energy analysis of the entire system. The combined theoretical and numerical energy analyses reveal the influences of the pre-impact drop shape and their effects on the subsequent energy conversion after the impact takes place. The analysis also reveals that the initial surface and kinetic energies are different for non-spherical droplets than for the spherical ones. The conversion of such excess surface energy due to the non-spherical curvature into kinetic energy dictates the impact and subsequently the crater dynamics of such systems. Such influences largely lead to the exclusive flow patterns demonstrated here. Concisely, this study presents a tri-phasic computational model, which is capable of analyzing the salient features of the impact and splash dynamics of the non-spherical droplets into a water continuum.

For large observational studies lacking a control group (unlike randomized controlled trials, RCT), propensity scores (PS) are often the method of choice to account for pre-treatment confounding in baseline characteristics, and thereby avoid substantial bias in treatment estimation. A vast majority of PS techniques focus on average treatment effect estimation, without any clear consensus on how to account for confounders, especially in a multiple treatment setting. Furthermore, for time-to event outcomes, the analytical framework is further complicated in presence of high censoring rates (sometimes, due to non-susceptibility of study units to a disease), imbalance between treatment groups, and clustered nature of the data (where, survival outcomes appear in groups). Motivated by a right-censored kidney transplantation dataset derived from the United Network of Organ Sharing (UNOS), we investigate and compare two recent promising PS procedures, (a) the generalized boosted model (GBM), and (b) the covariate-balancing propensity score (CBPS), in an attempt to decouple the causal effects of treatments (here, study subgroups, such as hepatitis C virus (HCV) positive/negative donors, and positive/negative recipients) on time to death of kidney recipients due to kidney failure, post transplantation. For estimation, we employ a 2-step procedure which addresses various complexities observed in the UNOS database within a unified paradigm. First, to adjust for the large number of confounders on the multiple sub-groups, we fit multinomial PS models via procedures (a) and (b). In the next stage, the estimated PS is incorporated into the likelihood of a semi-parametric cure rate Cox proportional hazard frailty model via inverse probability of treatment weighting, adjusted for multi-center clustering and excess censoring, Our data analysis reveals a more informative and superior performance of the full model in terms of treatment effect estimation, over sub-models that relaxes the various features of the event time dataset.

Purpose:The goal of this study was to characterize the activity of the covalent CDK7 inhibitor THZ1 in multiple myeloma models.Experimental Design:Multiple myeloma lines were exposed to varying THZ1 concentrations alone or with carfilzomib or ABT-199, after which apoptosis was monitored by flow cytometry, protein expression by Western blot analysis, mRNA by RT-PCR. Analogous studies were performed in cells ectopically expressing c-MYC, MCL-1, or BCL-XL, or CRISPER-Cas CDK7 sgRNA knockout. Primary multiple myeloma cells were exposed to THZ1 ± carfilzomib or ABT-199. In vivo effects of THZ1 were examined in a systemic U266 xenograft model.Results:THZ1 markedly diminished multiple myeloma cell proliferation and survival despite bortezomib or stromal cell resistance in association with G2–M arrest, inactivation of CTD RNA Pol II, dephosphorylation of CDKs 7 as well as 1, 2, and 9, and MCL-1, BCL-xL, and c-MYC mRNA or protein downregulation. Ectopic MCL-1, c-MYC, or BCL-XL expression significantly protected cells from THZ1 lethality. Both THZ1 and CRISPR-Cas CDK7 knockout sharply diminished multiple myeloma cell proliferation and significantly increased carfilzomib and ABT-199 lethality. Parallel effects and interactions were observed in primary CD138+ (N = 22) or primitive multiple myeloma cells (CD138−/CD19+/CD20+/CD27+; N = 16). THZ1 administration [10 mg/kg i.p. twice daily (BID), 5 days/week] significantly improved survival in a systemic multiple myeloma xenograft model with minimal toxicity and induced similar events observed in vitro, for example, MCL-1 and c-MYC downregulation.Conclusions:THZ1 potently reduces multiple myeloma cell proliferation through transcriptional downregulation of MCL-1, BCL-XL, and c-MYC in vitro and in vivo. It warrants further attention as a therapeutic agent in multiple myeloma.

Supplementary Data

The impact of an oil droplet on a water surface has been explored with the aid of computational fluid dynamics simulations. The study reveals the details of the spatiotemporal evolution of such a ternary system with a triplet of interfaces, e.g., air-water, oil-water, and oil-air, when the impact velocity of the oil droplet with the water surface is high. The oil droplet is found to flatten, spread, stretch, and eventually dewet on the water surface of the deep crater to show a host of interesting post-impact flow morphologies. Furthermore, at higher impact velocities, the formation of a biphasic oil-water crown is observed followed by the ejection of secondary water droplets from the crown tip due to capillary instability. The rapidly spreading oil film on the "crater" of the water surface is found to undergo Kelvin-Helmholtz instability before dewetting the same due to cohesion failure. Subsequently, the formation of an array of secondary oil droplets is observed during the process of dewetting. The dominant wavelength evaluated from the linear stability analysis of a representative flow system could faithfully predict the simulated spacing of dewetted oil droplets floating on the crater. Importantly, the variations in Laplace pressure around the curvatures of the undulatory interfaces along with sharp viscosity gradients across the three-phase contact line is found to engender interesting recirculation patterns, which eventually shed to form a coherent wake region in air near the crater. We also uncover the conditions under which the counter-rotating vortices shed along the oil-water interface resembling a von Kármán vortex street.

SummaryBeta distributions are commonly used to model proportion valued response variables, commonly encountered in longitudinal studies. In this article, we develop semi-parametric Beta regression models for proportion valued responses, where the aggregate covariate effect is summarized and flexibly modeled, using a interpretable monotone time-varying single index transform of a linear combination of the potential covariates. We utilize the potential of single index models, which are effective dimension reduction tools and accommodate link function misspecification in generalized linear mixed models. Our Bayesian methodology incorporates the missing-at-random feature of the proportion response, and utilize Hamiltonian Monte Carlo sampling to conduct inference. We explore finite-sample frequentist properties of our estimates, and assess the robustness via detailed simulation studies. Finally, we illustrate our methodology via application to a motivating longitudinal dataset on obesity research recording proportion body fat.

A single-step self-organized pathway is harnessed to generate large-area and high-density liquid-crystal (LC) microdroplets via rapid spreading of an LC-laden volatile liquid film on an aqueous surfactant bath. The surfactant loading on the water bath and LC loading in the solvent fluid help in tuning the size, periodicity, and ordering of LC microdroplets. Remarkably, the experiments reveal a transition from a spinodal to heterogeneous nucleation pathway of dewetting when the surfactant loading is modulated from below to beyond the critical micellar concentration in the aqueous phase. In the process, a host of unprecedented drop formation modes, such as dewetting and contact-line instability, random ejection, and "fire cracker" toroid splitting, have been uncovered. Subsequently, the LC microdroplets on the air-water interface are employed as photomasks suitable for soft-photolithography applications. Such masks help in the decoration of a host of mesoscale three-dimensional features on the films of photoresists when photons are guided through the LC droplets. In such a scenario, phase transition of LC droplets under solvent vapor annealing is employed to control the movement of photons through drops and subsequently modulate the light exposure on the photoresist surface. Such a simple soft-photolithography setup leads to an array of flattened droplets on a positive resist, while donut features are observed on the negative tone. Remarkably, the orientation of nematogens within 4-cyano-4'-pentylbiphenyl droplets and at the three-phase contact-line provides additional handles in controlling the transmission of photons, which facilitates such a unique pattern formation. A number of low-cost and simple strategies are also discussed to order such soft-photolithography patterns. Importantly, with a minor modification to the same experimental setup, we could also measure the variation in the order parameter of the LC droplet during its phase transitions from the nematic to isotropic state.

Purpose The role of neoadjuvant endocrine therapy in the treatment of patients with early-stage, hormone receptor-positive (HR +) breast cancer is not well defined. Tools to better determine which patients may benefit from neoadjuvant endocrine therapy versus chemotherapy or upfront surgery remain an unmet need. Methods We assessed the rate of clinical and pathologic complete response (cCR, pCR) among a pooled cohort of patients with early-stage HR + breast cancer who had been randomized to neoadjuvant endocrine therapy or neoadjuvant chemotherapy in two earlier studies to understand better how outcomes varied by Oncotype DX Breast Recurrence Score® assay. Results We observed that patients with intermediate RS results had no statistically significant differences in pathologic outcomes at the time of surgery based on whether they received neoadjuvant endocrine therapy or neoadjuvant chemotherapy, suggesting that a subgroup of women with a RS 0–25 may omit chemotherapy without compromising outcomes. Conclusion These data suggest that Recurrence Score® (RS) results may serve as a useful tool in treatment decision-making in the neoadjuvant setting.

We report the synthesis of gold nanotwins (Au NTs) on a solid and transparent glass substrate which in turn has been employed for the selective optoplasmonic detection of

The electric field induced motion of a charged water droplet suspended in a low-dielectric oil medium is exploited to evaluate the rheological properties of the suspending medium. The time-periodic electrophoretic motion of the droplet between the electrodes decorated in a polymeric micro-well is translated into a proof-of-concept microfluidic prototype, which can measure viscosities of the unknown fluid samples. The variations in the instantaneous velocities of the migrating droplet have been measured inside silicone oil of known physical properties at different electric field intensities. Subsequently, a balance between the electric field to the viscous force has been employed to evaluate the experimental charge density on the droplet surface. Thereafter, a comprehensive scaling law has been devised to find a correlation between the charge on the droplet to the dielectric permittivity of the surrounding medium, size of the water droplet, and the applied electric field intensity. Following this, the scaling law and force balance have been employed together to evaluate the unknown viscosity of an array of suspending mediums by simply analyzing the electrophoretic motion of water droplet. The model proposed is also found to be consistent when a solid amberlite microparticle has been employed as a probe instead of the water droplet. In such a scenario, minor changes in the exponents of the scaling law are found to be necessary to reproduce the results obtained using the water droplet. The method paves the way for the making of an economical and portable microfluidic rheometer with further finetuning and translational developments.