A lineage tree-based hidden Markov model quantifies cellular heterogeneity and plasticity.

Individual cells can assume a variety of molecular and phenotypic states and recent studies indicate that cells can rapidly adapt in response to therapeutic stress. Such phenotypic plasticity may confer resistance, but also presents opportunities to identify molecular programs that could be targeted for therapeutic benefit. Approaches to quantify tumor-drug responses typically focus on snapshot, population-level measurements. While informative, these methods lack lineage and temporal information, which are particularly critical for understanding dynamic processes such as cell state switching. As new technologies have become available to measure lineage relationships, modeling approaches will be needed to identify the forms of cell-to-cell heterogeneity present in these data. Here we apply a lineage tree-based adaptation of a hidden Markov model that employs single cell lineages as input to learn the characteristic patterns of phenotypic heterogeneity and state transitions. In benchmarking studies, we demonstrated that the model successfully classifies cells within experimentally-tractable dataset sizes. As an application, we analyzed experimental measurements in cancer and non-cancer cell populations under various treatments. We find evidence of multiple phenotypically distinct states, with considerable heterogeneity and unique drug responses. In total, this framework allows for the flexible modeling of single cell heterogeneity across lineages to quantify, understand, and control cell state switching.

Antiplatelets and Vascular Dementia: A Systematic Review.

Vascular dementia (VD) is a neurocognitive disorder whose precise definition is still up for debate. VD generally refers to dementia that is primarily caused by cerebrovascular disease or impaired cerebral blood flow. It is a subset of vascular cognitive impairment, a class of diseases that relate any cerebrovascular injury as a causal or correlating factor for cognitive decline, most commonly seen in the elderly. Patients who present with both cognitive impairment and clinical or radiologic indications of cerebrovascular pathology should have vascular risk factors, particularly hypertension, examined and treated. While these strategies may be more effective at avoiding dementia than at ameliorating it, there is a compelling case for intensive secondary stroke prevention in these patients. Repeated stroke is related to an increased chance of cognitive decline, and poststroke dementia is connected with an increased risk of death. In general, most physicians follow recommendations for secondary stroke prevention in patients with VD, which can be accomplished by the use of antithrombotic medicines such as antiplatelets (aspirin, clopidogrel, ticlopidine, cilostazol, etc.). In individuals with a high risk of atherosclerosis and those with documented symptomatic cerebrovascular illness, antiplatelets treatment lowers the risk of stroke. While this therapy strategy of prevention and rigorous risk management has a compelling justification, there is only limited and indirect data to support it. The following systematic review examines the role of antiplatelets in the management of vascular dementia in published clinical trials and studies and comments on the current evidence available to support their use and highlights the need for further study.

S.M.A.R.T. F.U.S: Surrogate Model of Attenuation and Refraction in Transcranial Focused Ultrasound.

Low-intensity focused ultrasound (LIFU) is an increasingly applied method for achieving non-invasive brain stimulation. However, transmission of ultrasound through the human skull can substantially affect focal point characteristics of LIFU, including dramatic attenuation in intensity and refraction of focal point location. These effects depend on a high-dimensional parameter space, making these effects difficult to estimate from previous work. Instead, focal point properties of LIFU experiments are often estimated using numerical simulation of LIFU sonication through skull. However, this procedure presents many entry barriers to even computationally savvy investigators and often requires expensive computational hardware, impeding LIFU research. We present a novel MATLAB toolbox (data: doi:10.5068/D1QD60; Matlab Scripts: https://doi.org/10.5281/zenodo.5811122) for rapidly estimating beam properties of LIFU transmitted through bone. Users provide specific values for frequency of LIFU, bone thickness, angle at which LIFU is applied, depth of the LIFU focal point, and diameter of the transducer used and receive an estimation of the degree of refraction/attenuation expected for the given parameters.

Current Trends in the Duration of Anticoagulant Therapy for Venous Thromboembolism: A Systematic Review.

Anticoagulation therapy is the first line and drug of choice for both the treatment and prophylaxis of venous thromboembolism (deep vein thrombosis and/or pulmonary embolism). Anticoagulation drugs, ranging from different preparations of heparin, warfarin, and newer direct oral drugs such as rivaroxaban and dabigatran, work mainly by inhibiting important factors and enzymes in the coagulation cascade by preventing fibrin formation, platelet aggregation, and clot assembly. With recurrent thrombosis and embolisms being a feared complication for many physicians treating such cases, anticoagulation is often extended beyond the initial three- to six-month acute phase after an incident of venous thromboembolism. For some groups of patients, anticoagulation needs to be offered indefinitely to decrease the risk of a recurrent thrombosis. However, this concomitantly increases obvious and dangerous adverse effects such as increased risk of hemorrhage, as the ability to clot is hindered. This tradeoff between recurrent venous thromboembolism and bleeding is what underscores the controversy of the clinical question: for how long should anticoagulation be administered for venous thromboembolism? This review analyzes the use of anticoagulants in different types of venous thromboembolism and remarks on current consensus and trends on the length of anticoagulation treatment. We are doing so while acknowledging that venous thromboembolism management is an active area of research that is rapidly evolving. A literature search was performed looking at recent studies on anticoagulant administration for the treatment of venous thromboembolism with a focus on varying durations and patient populations. Factors that affect clinical decisions of duration are also elucidated. The most clinically relevant anticoagulants were discussed and their effects on the risk of recurrent thrombosis and embolism, and the risk of bleeding in relation to other drugs were analyzed. Ultimately, this article discussed patterns of anticoagulant treatments duration and which patient groups are likely to benefit the most from certain durations, shedding light on the ambiguity in how physicians should approach administering anticoagulation therapy over time for a broad range of presentations of venous thromboembolism.

Real time and delayed effects of subcortical low intensity focused ultrasound.

Deep brain nuclei are integral components of large-scale circuits mediating important cognitive and sensorimotor functions. However, because they fall outside the domain of conventional non-invasive neuromodulatory techniques, their study has been primarily based on neuropsychological models, limiting the ability to fully characterize their role and to develop interventions in cases where they are damaged. To address this gap, we used the emerging technology of non-invasive low-intensity focused ultrasound (LIFU) to directly modulate left lateralized basal ganglia structures in healthy volunteers. During sonication, we observed local and distal decreases in blood oxygenation level dependent (BOLD) signal in the targeted left globus pallidus (GP) and in large-scale cortical networks. We also observed a generalized decrease in relative perfusion throughout the cerebrum following sonication. These results show, for the first time using functional MRI data, the ability to modulate deep-brain nuclei using LIFU while measuring its local and global consequences, opening the door for future applications of subcortical LIFU.