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A framework for inferring and analyzing pharmacotherapy treatment patterns

Background: To discover pharmacotherapy prescription patterns and their statistical associations with outcomes through a clinical pathway inference framework applied to real-world data. Methods: We apply machine learning steps in our framework using a 2006 to 2020 cohort of veterans with major depressive disorder (MDD). Outpatient antidepressant pharmacy fills, dispensed inpatient antidepressant medications, emergency department visits, self-harm, and all-cause mortality data were extracted from the Department of Veterans Affairs Corporate Data Warehouse. Results: Our MDD cohort consisted of 252,179 individuals. During the study period there were 98,417 emergency department visits, 1,016 cases of self-harm, and 1,507 deaths from all causes. The top ten prescription patterns accounted for 69.3% of the data for individuals starting antidepressants at the fluoxetine equivalent of 20-39 mg. Additionally, we found associations between outcomes and dosage change. Conclusions: For 252,179 Veterans who served in Iraq and Afghanistan with subsequent MDD noted in their electronic medical records, we documented and described the major pharmacotherapy prescription patterns implemented by Veterans Health Administration providers. Ten patterns accounted for almost 70% of the data. Associations between antidepressant usage and outcomes in observational data may be confounded. The low numbers of adverse events, especially those associated with all-cause mortality, make our calculations imprecise. Furthermore, our outcomes are also indications for both disease and treatment. Despite these limitations, we demonstrate the usefulness of our framework in providing operational insight into clinical practice, and our results underscore the need for increased monitoring during critical points of treatment.

60 APPLIED LIFE SCIENCES↗

Combining Machine Learning and Comparative Effectiveness Methodology to Study Primary Care Pharmacotherapy Pathways for Veterans With Depression

Our objective is to demonstrate an innovative method combining machine learning with comparative effectiveness research techniques and to investigate a hitherto unstudied question about the effectiveness of common prescribing patterns. For Operation Enduring Freedom/Operation Iraqi Freedom veterans with major depressive disorder, we generate pharmacotherapy pathways (of antidepressants) using process mining and machine learning. We select the medication episodes that were started at subtherapeutic doses by the first assigned primary care physician and observe the paths that those medication episodes follow. Using 2-stage least squares, we test the effectiveness of starting at a low dose and staying low for longer versus ramping up fast while balancing observable and unobservable characteristics of patients and providers through instrumental variables. We leverage predetermined provider practice patterns as instruments. We collected outpatient pharmacy data for selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors, patient and provider characteristics (as control variables), and the instruments for our cohort. All data were extracted for the period between 2006 and 2020. There is a statistically significant positive effect (0.68, 95% CI 0.11–1.25) of “ramping up fast” on engagement in care. When we examine the effect of “ramping up slow”, we see an insignificant negative impact on engagement in care (−0.82, 95% CI −1.89 to 0.25). As expected, the probability of drop-out also seems to have a negative effect on engagement in care (−0.39, 95% CI −0.94 to 0.17). We further validate these results by testing with medication possession ratios calculated periodically as an alternative engagement in care metric. Our findings contradict the “Start low, go slow” adage, indicating that ramping up the dose of an antidepressant faster has a significantly positive effect on engagement in care for our population.

60 APPLIED LIFE SCIENCES↗

Experimental gastric ulcers induced by immobilization and electric shock of rats and their pharmacotherapy

The mechanism of development of experimental gastric ulcers, induced in rats by combined immobilization and electric shock, was analyzed pharmacologically with peripheral neurotropic agents. It is concluded that: (1) The most marked preventive effect in the development of the experimentally induced gastric ulcers was displayed by agents capable of blocking the ascending activation system of the reticular formation. (2) Sympathetic fibers, which disrupt the trophism of the gastric wall, form the efferent portion of the reflex arc. (3) Gastric secretion does not appear to be the primary cause of ulceration.

Zabrodin, O. N.↗

CPViz: Visualizing clinical pathways represented in higher-order networks

To improve clinical care practice, it is important to understand the variability of clinical pathways executed in different contexts (e.g., pathways in different geographical locations, demographics, and phenotypic groups). A common way of representing clinical pathways is through network-based representations that capture trajectories of treatment steps. However, first-order networks, which are based on the Markovian property and the de facto standard model to represent transitions between steps, often fail to capture real trajectories. This paper introduces a visual analytic tool to explore and compare pathways represented in higher-order networks. Because each higher node in the network is a subtrajectory (i.e., partial or full history of treatment steps), the tool can display true sequences of treatment steps and compute the similarity of the two networks in a space of higher-order nodes. The tool also highlights areas in which the two networks are similar and dissimilar and how a certain subtrajectory is realized differently in different pathways. The paper demonstrates the tool's usefulness by applying it to multiple antidepressant pharmacotherapy pathways for veterans diagnosed with major depressive disorder and by illustrating heterogeneity in prescription patterns across pathways.

Chae, Junghoon↗

Changes in the status of the human tibia during antiorthostatic hypokinesia

Changes were studied in biomechanical properties of the human tibia during prolonged antiorthostatic hypokinesia with different modes of motor activity and pharmacotherapy and comparison of results obtained with parallel examinations using ultrasonic diagnosis and photon absorptiometry.

Tatarinov, A. M.↗

Effects of normal aging on visuo-motor plasticity

Normal aging is associated with declines in neurologic function. Uncompensated visual and vestibular problems may have dire consequences including dangerous falls. Visuo-motor plasticity is a form of behavioral neural plasticity, which is important in the process of adapting to visual or vestibular alteration, including those changes due to pathology, pharmacotherapy, surgery or even entry into microgravity or an underwater environment. To determine the effects of aging on visuo-motor plasticity, we chose the simple and easily measured paradigm of visual-motor rearrangement created by using visual displacement prisms while throwing small balls at a target. Subjects threw balls before, during and after wearing a set of prisms which displace the visual scene by twenty degrees to the right. Data obtained during adaptation were modeled using multilevel modeling techniques for 73 subjects, aged 20 to 80 years. We found no statistically significant difference in measures of visuo-motor plasticity with advancing age. Further studies are underway examining variable practice training as a potential mechanism for enhancing this form of behavioral neural plasticity.

Clinical Trial↗

Is skeletal muscle ready for long-term spaceflight and return to gravity?

It is now clear that prevention of muscle debilitation during spaceflight will require a broader approach than simple exercise aimed at strengthening of the muscle fibers. The levels of several hormones and receptors are altered by unloading and must be returned to homeostasis. Pharmacotherapy and gene transfer strategies to raise the relative level of structural proteins may minimize the problems faced by astronauts in readapting to Earth-gravity. Up to now, we have only minimally exploited microgravity for advancing our understanding of muscle biology. A research laboratory in the space station with a centrifuge facility (gravity control) is essential for conducting basic research in this field. Microgravity has proven an excellent tool for noninvasively perturbing the synthesis of muscle proteins in the search for molecular signals and gene regulatory factors influencing differentiation, growth, maintenance and atrophy of muscle. Understanding the relation between blood flow and interstitial edema and between workload and subsequent structural failure are but two important problems that require serious attention. The roles of hormones and growth factors in regulating gene expression and their microgravity-induced altered production are other urgent issues to pursue. These types of studies will yield information that advances basic knowledge of muscle biology and offers insights into countermeasure design. This knowledge is likely to assist rehabilitation of diseased or injured muscles in humans on Earth, especially individuals in the more vulnerable aging population and persons participating in strenuous sports. Will the skeletal muscle system be prepared for the increased exposure to microgravity and the return to gravity loading without injury when space station is operational? The answer depends in large part on continued access to space and funding of ground-based models and flight experiments. The previous two decades of spaceflight research have described the effects of microgravity on multiple systems. The next generation of experiments promises to be even more exciting as we are challenged to define the cellular and molecular mechanisms of microgravity-induced changes.

manned↗

Effects of Normal Aging on Visuo-Motor Plasticity

Normal aging is associated with declines in neurologic function. Uncompensated visual and vestibular problems may have dire consequences including dangerous falls. Visuomotor plasticity is a form of behavioral neural plasticity which is important in the process of adapting to visual or vestibular alteration, including those changes due to pathology, pharmacotherapy, surgery or even entry into a microgravity or underwater environment. In order to determine the effects of aging on visuomotor plasticity, we chose the simple and easily measured paradigm of visual-motor re-arrangement created by using visual displacement prisms while throwing small balls at a target. Subjects threw balls before, during and after wearing a set of prisms which displace the visual scene by twenty degrees to the right. Data obtained during adaptation were modeled using multilevel analyses for 73 subjects aged 20 to 80 years. We found no statistically significant difference in measures of visuomotor plasticity with advancing age. Further studies are underway examining variable practice training as a potential mechanism for enhancing this form of behavioral neural plasticity.

Roller, Carrie A.↗