Mathematical model for rod outer segment dynamics during retinal detachment.

Retinal detachment (RD) is the separation of the neural layer from the retinal pigmented epithelium thereby preventing the supply of nutrients to the cells within the neural layer of the retina. In vertebrates, primary photoreceptor cells consisting of rods and cones undergo daily renewal of their outer segment through the addition of disc-like structures and shedding of these discs at their distal end. When the retina detaches, the outer segment of these cells begins to degenerate and, if surgical procedures for reattachment are not done promptly, the cells can die and lead to blindness. The precise effect of RD on the renewal process is not well understood. Additionally, a time frame within which reattachment of the retina can restore proper photoreceptor cell function is not known. Focusing on rod cells, we propose a mathematical model to clarify the influence of retinal detachment on the renewal process. Our model simulation and analysis suggest that RD stops or significantly reduces the formation of new discs and that an alternative removal mechanism is needed to explain the observed degeneration during RD. Sensitivity analysis of our model parameters points to the disc removal rate as the key regulator of the critical time within which retinal reattachment can restore proper photoreceptor cell function.

"They Don't Have Time, But It Would Be Wonderful": Residents' Views of Their Relationships With Staff.

Resident-staff relationships is a component of person-centered care (PCC); positive relationships are associated with positive outcomes. The current article explores the finding that residents living in different types of long-term care assigned the lowest ratings of importance to the PCC domain "relationships with staff " (one of eight domains studied). Thematic analysis of spontaneous comments made by residents during interviews identified two themes, Relationship Preferences (for privacy, boundaries, engagement) and Lived Experience With Staff (staff busyness, staff interactions). Low ratings of relationship importance may reflect preferences for privacy and maintaining boundaries with staff. Ratings by some residents may be related to staff busyness, an overarching theme. Staff busyness was associated with lack of personal interaction with staff, including for those who expressed preferences for engagement and those who described positive interactions with staff. Some residents may reappraise their views about the importance of relationships to reduce cognitive dissonance. Improving job quality is necessary to assure quality time with residents. [Journal of Gerontological Nursing, 49(11), 8-14.].

BCMA CAR-T induces complete and durable remission in refractory plasmablastic lymphoma.

Plasmablastic lymphoma (PBL) is a rare subtype of aggressive large B-cell lymphoma, with a dismal prognosis despite aggressive therapies. New approaches are needed for those with refractory disease. PBL expresses antigens similar to multiple myeloma (MM), including B-cell maturation antigen (BCMA). Chimeric antigen receptor T-cell (CAR-T) therapy directed against BCMA has shown efficacy for the treatment of heavily pretreated MM with low rates of grades 3 and 4 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in a phase Ib/II trial (A Study of JNJ-68284528, a CAR-T Directed Against BCMA in Participants With Relapsed or Refractory Multiple Myeloma (CARTITUDE-1), NCT03548207). However, data for the use of BCMA CAR-T for treating PBL are lacking.We report a challenging case of multiple refractory PBL that emerged from B-cell acute lymphoblastic leukemia in an adolescent who failed to respond to an allogeneic hematopoietic cell transplant. The patient developed rapidly advancing disease despite withdrawal of immunosuppression, treatment with etoposide, ibrutinib, and daratumumab, prompting consideration of BCMA CAR-T (under emergency investigational new drug (eIND)). The patient achieved a complete remission (CR), without recurrent acute graft versus host disease (GVHD), CRS or ICANS after BCMA CAR-T therapy. BCMA CAR-T expansion was detected in vivo, peaking on day 15. The patient remains in CR for more than a year post CAR-T therapy, supporting consideration of immunotherapy for future patients with refractory PBL, a disease with few treatment options.

The Resident VIEW in Community-Based Care Residential Settings.

The Resident VIEW is a measure of person-centered care (PCC) from residents' perspectives and was previously studied in nursing homes. The current study presents descriptive data for the Resident VIEW in community-based care settings including assisted living, residential care (AL/RC), and adult foster homes (AFH). Using a two-stage sampling design, we recruited 31 AL/RC and 119 AFH in Oregon and completed face-to-face structured interviews with 227 and 195 residents, respectively. Residents provided ratings for both the importance of and their experience with 66 items that tapped into PCC practices in eight domains. Results are provided for each item, many of which are significantly associated with greater quality of life, better resident satisfaction, and fewer depressive symptoms, especially in the domains of personalized care and being treated like a person. Incongruence between importance and experience ratings indicate many residents experience unmet needs across multiple domains. The Resident VIEW performed well in different types of settings, providing an important tool for researchers and providers who wish to learn about the PCC experience from residents' points of view.

Modeling optimal reopening strategies for COVID-19 and its variants by keeping infections low and fixing testing capacity.

Since early March 2020, government agencies have utilized a wide variety of non-pharmaceutical interventions to mitigate the spread of COVID-19 and have struggled to determine when it is appropriate to return to in-person activities after an outbreak is detected. At many universities, fundamental issues related to understanding the spread of the disease (e.g. the transmission rate), the ability of administrators to respond quickly enough by closing when there is a sudden rise in cases, and how to make a decision on when to reopen remains a concern. Surveillance testing strategies have been implemented in some places, and those test outcomes have dictated whether to reopen, to simultaneously monitor community spread, and/or to isolate discovered cases. However, the question remains as to when it is safe to reopen and how much testing is required to remain safely open while keeping infection numbers low. Here, we propose an extension of the classic SIR model to investigate reopening strategies for a fixed testing strategy, based on feedback from testing results. Specifically, we close when a predefined proportion of the population becomes infected, and later reopen when that infected proportion decreases below a predefined threshold. A valuable outcome of our approach is that our reopening strategies are robust to variation in almost all model parameters, including transmission rates, which can be extremely difficult to determine as they typically differ between variants, location, vaccination status, etc. Thus, these strategies can be, in theory, translated over to new variants in different regions of the world. Examples of robust feedback strategies for high disease transmission and a fixed testing capacity include (1) a single long lock down followed by a single long in-person period, and (2) multiple shorter lock downs followed by multiple shorter in-person periods. The utility of this approach of having multiple strategies is that administrators of universities, schools, business, etc. can use a strategy that is best adapted for their own functionality.

Modeling microtubule dynamic instability: Microtubule growth, shortening and pause.

Microtubules (MTs) are protein polymers found in all eukaryotic cells. They are crucial for normal cell development, providing structural support for the cell and aiding in the transportation of proteins and organelles. In order to perform these functions, MTs go through periods of relatively slow polymerization (growth) and very fast depolymerization (shortening), where the switch from growth to shortening is called a catastrophe and the switch from shortening to growth is called a rescue. Although MT dynamic instability has traditionally been described solely in terms of growth and shortening, MTs have been shown to pause for extended periods of time, however the reason for pausing is not well understood. Here, we present a new mathematical model to describe MT dynamics in terms of growth, shortening, and pausing. Typically, MT dynamics are defined by four key parameters which include the MT growth rate, shortening rate, frequency of catastrophe, and the frequency of rescue. We derive a mathematical expression for the catastrophe frequency in the presence of pausing, as well as expressions to describe the total time that MTs spend in a state of growth and pause. In addition to exploring MT dynamics in a control-like setting, we explore the implicit effect of stabilizing MT associated proteins (MAPs) and stabilizing and destabilizing chemotherapeutic drugs that target MTs on MT dynamics through variations in model parameters.

A machine-learning approach to predict success of a biocontrol for invasive Eurasian watermilfoil reduction.

Myriophyllum spicatum, more commonly known as Eurasian watermilfoil (EWM), is one of the most invasive aquatic plants in North America, causing negative ecological and economic impacts in ecosystems where it proliferates. Many control strategies have been developed and implemented to mitigate EWM growth and spread, although the results are mixed and there is no consensus on lake-specific strategies. Here, we describe the development of a predictive model using a support vector technique, that predicts the success of biological pest control using Euhrychiopsis lecontei (the milfoil weevil), a milfoil specialist, to reduce EWM in lakes. Such a model is informed by lake characteristics (limnological and landscape) and augmentation strategies. To develop our predictive model, we performed a metadata analysis from 133 published peer-reviewed literature and professional reports of milfoil weevil augmentation field experiments that contained information on lake characteristics. The predictive model's algorithm uses a support vector machine (SMV) to learn patterns among lake characteristics, along with the recorded augmentation strategy and the reported success of each study, where success is a measure of EWM change over a season and is recorded in a variety of ways (e.g., EWM biomass change, EWM percent change, EWM visual change, etc.,). Overall, the model results suggests that shallower lakes, more frequent weevil augmentations, and larger weevil overwintering habitat are the most important predictors for EWM reduction success by weevil augmentation. Although watermilfoil weevil augmentation is a promising mitigation strategy, it may not work for all lakes. However, in terms of suggesting weevil augmentation, our model is a valuable tool for lake stakeholders and resource managers, who can use it to determine whether milfoil weevil augmentation, which can be very costly due to the difficulties in finding and raising milfoil weevils, will be a useful and sustainable approach to control EWM in their lake community.

Person-centered care practices in nursing homes: Staff perceptions and the organizational environment.

Person-centered care (PCC) is considered the standard to assure quality of care and quality of life in long-term care, benefiting both residents and staff. This study examines the associations between nursing home staff perceptions of person-centered care practices, the organizational system, and work-related attitudes in a sample of 340 nurses and direct care workers across 32 nursing homes in Oregon. Random-intercepts regression models were used to estimate within- and between-nursing home variation in staff perceptions of PCC practices as measured by the Staff Assessment of Person-Directed Care (SA-PDC), and identify characteristics associated with these perceptions. Staff in nursing homes that accept Medicaid reported lower SA-PDC scores, and higher scores were reported in nonprofit nursing homes. Staff perceptions varied extensively within nursing homes, suggesting a lack of staff cohesion regarding core aspects of PCC. Cultivating a supportive work environment is key to promoting person-centered care practices, increasing job satisfaction, elevating affective commitment, and reducing turnover intention.

The Resident VIEW in Nursing Homes.

This article presents the Resident VIEW (Voicing Importance, Experience, and Well-Being), a measure designed to learn directly from long-term care residents the extent to which they experience support that matters most to them. The Resident VIEW contains 63 items across eight domains developed through cognitive interviews with residents in different types of residential settings (e.g., nursing homes, assisted living, and adult foster care). Residents rate items on both importance and their experience. In total, 258 nursing home residents living in 32 Oregon nursing homes were selected through a two-stage random sampling design and participated in the study. Results demonstrate that what matters most to residents varies, emphasizing the value of asking residents directly about their preferences. The relationship between importance and experience differed by item. Residents who experienced support rated very important within some domains, reported better quality of life and reported lower levels of depressive symptoms than those who did not experience these things. The interaction between importance and experience, however, did not reach statistical significance, suggesting that positive experiences may provide benefit even in some areas that are not perceived as important by residents. Results underscore the value of incorporating the resident perspective into measure development in long-term care.

The Impact of Communication Impairments on the Social Relationships of Older Adults: Pathways to Psychological Well-Being.

Purpose Social contact is known to be vital for older adults' mental and physical health but, because communication impairments often co-occur with other types of disability, it is difficult to generalize about the relative impact of a communication impairment on the social relationships of older adults. Specific aims of the study were to examine whether the severity of a communication impairment was associated with a range of social measures and to examine the association between these characteristics and psychological well-being. Method Community-dwelling older adults ranging in age from 65 to 94 were recruited for the study of Communication, Health, Aging, Relationship Types and Support. The sample included 240 participants with communication disorders arising from a variety of etiologies including hearing impairment, voice disorders, head and neck cancer, and neurologic disease, as well as older adults without a communication disorder. Results Communication impairment was a significant independent predictor for key characteristics of social relationships, including the number of friends in the social network, two types of social support, the frequency of social participation, and social self-efficacy. Communication impairment was also a significant predictor for higher levels of loneliness and depression. In addition, two distinct pathways between communication impairment and psychological well-being were identified, with social self-efficacy and reassurance of worth as mediators. Conclusions Even after controlling for age, gender, health, and disability, communication impairment is a significant independent predictor for key aspects of the social function of older adults and demonstrates two distinct pathways to loneliness and depression. Supplemental Material https://doi.org/10.23641/asha.7250282.

A Growth-Fragmentation Approach for Modeling Microtubule Dynamic Instability.

Microtubules (MTs) are protein filaments found in all eukaryotic cells which are crucial for many cellular processes including cell movement, cell differentiation, and cell division. Due to their role in cell division, they are often used as targets for chemotherapy drugs used in cancer treatment. Experimental studies of MT dynamics have played an important role in the development and administration of many novel cancer drugs; however, a complete description of MT dynamics is lacking. Here, we propose a new mathematical model for MT dynamics, that can be used to study the effects of chemotherapy drugs on MT dynamics. Our model consists of a growth-fragmentation equation describing the dynamics of a length distribution of MTs, coupled with two ODEs that describe the dynamics of free GTP- and GDP-tubulin concentrations (the individual dimers that comprise of MTs). Here, we prove the well-posedness of our system and perform a numerical exploration of the influence of certain model parameters on the systems dynamics. In particular, we focus on a qualitative description for how a certain class of destabilizing drugs, the vinca alkaloids, alter MT dynamics. Through variation of certain model parameters which we know are altered by these drugs, we make comparisons between simulation results and what is observed in in vitro studies.

Methods for determining key components in a mathematical model for tumor-immune dynamics in multiple myeloma.

In this work, we analyze a mathematical model we introduced previously for the dynamics of multiple myeloma and the immune system. We focus on four main aspects: (1) obtaining and justifying ranges and values for all parameters in the model; (2) determining a subset of parameters to which the model is most sensitive; (3) determining which parameters in this subset can be uniquely estimated given certain types of data; and (4) exploring the model numerically. Using global sensitivity analysis techniques, we found that the model is most sensitive to certain growth, loss, and efficacy parameters. This analysis provides the foundation for a future application of the model: prediction of optimal combination regimens in patients with multiple myeloma.

Infusion hemolysis after pediatric major ABO-mismatched bone marrow transplant: Comparison of two red blood cell depletion techniques.

BACKGROUND: During major ABO-mismatched bone marrow transplant (BMT), the infusion of incompatible red blood cells (RBCs) that are present in the bone marrow graft can cause adverse events from hemolysis. RBC depletion of the bone marrow graft can decrease this risk, but the optimal method to prevent hemolysis is unclear. PROCEDURE: We conducted a retrospective cohort study of patients who underwent major ABO-mismatched BMT at a pediatric center and had RBC depletion with either hydroxyethyl starch (HES) sedimentation or Ficoll density gradient separation. Postinfusion hemoglobinuria and creatinine values were compared. RESULTS: Between 2002 and 2016, 37 patients received HES-treated and 16 patients received Ficoll-treated major ABO-mismatched bone marrow grafts. The median residual volume of RBCs was significantly greater with HES-treated grafts (HES 21.0 ml vs. Ficoll 1.4 ml, P < 0.0001). Patients who received HES-treated grafts had a higher prevalence of postinfusion hemoglobinuria (HES 57% vs. Ficoll 6%, P = 0.0009), but renal impairment was rare. Considering only HES-treated grafts, the volume of RBCs was not associated with either postinfusion hemoglobinuria or a creatinine increase. CONCLUSIONS: Ficoll density gradient separation achieves smaller RBC volumes and less postinfusion hemoglobinuria than HES sedimentation, but both can prevent significant hemolysis. Further studies are needed to determine the residual incompatible RBC volume threshold in major ABO-mismatched BMT.

Perceived Preparedness of Health Care Students for Providing Cardiovascular Disease Risk Assessment and Management.

Early assessment and management of risk factors is known to have significant impact in preventing cardiovascular disease (CVD) and its associated burden. Cardiovascular disease risk assessment and management (CVDRAM) is best approached by teamwork across health care professionals. This study aimed at assessing health care students' (HCSs) knowledge about the parameters needed for estimating CVD risk, their self-assessed preparedness/confidence and perceived barriers for the provision of CVDRAM services through a survey administered to third and fourth year pharmacy, medical, and nursing students in Qatar. Although all student cohorts achieved similar knowledge scores, less than half (n = 38, 47%) were able to identify all of the six main risk factors necessary to estimate absolute CVD risk, and a third (32%) were unable to identify total cholesterol as an independent risk factor necessary to estimate CVD risk. Training on the use of CVD risk assessment tools differed among the three student cohorts. All student cohorts also perceived similar levels of preparedness in CVDRAM. However, pharmacy students reported the highest preparedness/confidence with the use of the latest CVDRAM guidelines. The majority of statements listed under the barriers scale were perceived by the students as being moderate (median score = 3). Poor public acceptance or unawareness of importance of estimating CVD risk was the only barrier perceived as a major by nursing students. Future integration of interprofessional educational (IPE) activities in the CVDRAM curricula of HCSs may be a suitable strategy to minimize barriers and foster collaborative practice for the provision of CVDRAM services in Qatar.

Exploring the effect of end-binding proteins and microtubule targeting chemotherapy drugs on microtubule dynamic instability.

Microtubules (MTs) play a key role in normal cell development and are a primary target for many cancer chemotherapy MT targeting agents (MTAs). As such, understanding MT dynamics in the presence of such agents, as well as other proteins that alter MT dynamics, is extremely important. In general, MTs grow relatively slowly and shorten very fast (almost instantaneously), an event referred to as a catastrophe. These dynamics, referred to as dynamic instability, have been studied in both experimental and theoretical settings. In the presence of MTAs, it is well known that such agents work by suppressing MT dynamics, either by promoting MT polymerization or promoting MT depolymerization. However, recent in vitro experiments show that in the presence of end-binding proteins (EBs), low doses of MTAs can increase MT dynamic instability, rather than suppress it. Here, we develop a novel mathematical model, to describe MT and EB dynamics, something which has not been done in a theoretical setting. Our MT model is based on previous modeling efforts, and consists of a pair of partial differential equations to describe length distributions for growing and shortening MT populations, and an ordinary differential equation (ODE) system to describe the time evolution for concentrations of GTP- and GDP-bound tubulin. A new extension of our approach is the use of an integral term, rather than an advection term, to describe very fast MT shortening events. Further, we introduce an ODE system to describe the binding and unbinding of EBs with MTs. To compare simulation results with experiment, we define novel mathematical expressions for time- and distance-based catastrophe frequencies. These quantities help to define MT dynamics in in vivo and in vitro settings. Simulation results show that increasing concentrations of EBs work to increase time-based catastrophe while distance-based catastrophe is less affected by changes in EB concentration, a result that is consistent with experiment. We further describe how EBs and MTAs alter MT dynamics. In the context of this modeling framework, we show that it is likely that MTAs and EBs do not work independently from one another. Thus, we propose a mechanism for how EBs can work synergistically with MTAs to promote MT dynamic instability at low MTA dose.

Existence and uniqueness for a coupled PDE model for motor-induced microtubule organization.

Microtubules (MTs) are protein filaments that provide structure to the cytoskeleton of cells and a platform for the movement of intracellular substances. The spatial organization of MTs is crucial for a cell's form and function. MTs interact with a class of proteins called motor proteins that can transport and position individual filaments, thus contributing to overall organization. In this paper, we study the mathematical properties of a coupled partial differential equation (PDE) model, introduced by White et al. in 2015, that describes the motor-induced organization of MTs. The model consists of a nonlinear coupling of a hyperbolic PDE for bound motor proteins, a parabolic PDE for unbound motor proteins, and a transport equation for MT dynamics. We locally smooth the motor drift velocity in the equation for bound motor proteins. The mollification is not only critical for the analysis of the model, but also adds biological realism. We then use a Banach Fixed Point argument to show local existence and uniqueness of mild solutions. We highlight the applicability of the model by showing numerical simulations that are consistent with in vitro experiments.

Building a 3D Virtual Liver: Methods for Simulating Blood Flow and Hepatic Clearance on 3D Structures.

In this paper, we develop a spatio-temporal modeling approach to describe blood and drug flow, as well as drug uptake and elimination, on an approximation of the liver. Extending on previously developed computational approaches, we generate an approximation of a liver, which consists of a portal and hepatic vein vasculature structure, embedded in the surrounding liver tissue. The vasculature is generated via constrained constructive optimization, and then converted to a spatial grid of a selected grid size. Estimates for surrounding upscaled lobule tissue properties are then presented appropriate to the same grid size. Simulation of fluid flow and drug metabolism (hepatic clearance) are completed using discretized forms of the relevant convective-diffusive-reactive partial differential equations for these processes. This results in a single stage, uniformly consistent method to simulate equations for blood and drug flow, as well as drug metabolism, on a 3D structure representative of a liver.

Mathematical and computational modeling in biology at multiple scales.

A variety of topics are reviewed in the area of mathematical and computational modeling in biology, covering the range of scales from populations of organisms to electrons in atoms. The use of maximum entropy as an inference tool in the fields of biology and drug discovery is discussed. Mathematical and computational methods and models in the areas of epidemiology, cell physiology and cancer are surveyed. The technique of molecular dynamics is covered, with special attention to force fields for protein simulations and methods for the calculation of solvation free energies. The utility of quantum mechanical methods in biophysical and biochemical modeling is explored. The field of computational enzymology is examined.

Microtubule patterning in the presence of stationary motor distributions.

In this paper, we construct a novel nonlocal transport model that describes the evolution of microtubules (MTs) as they interact with stationary distributions of motor proteins. An advection term accounts for directed MT transport (sliding due to motor protein action), and an integral term accounts for reorientation of MTs due to their interactions with cross-linking motor proteins. Simulations of our model show how MT patterns depend on boundary constraints, as well as model parameters that represent motor speed, cross-linking capability (motor activity), and directionality. In large domains, and using motor parameter values consistent with experimentally-derived values, we find that patterns such as asters, vortices, and bundles are able to persist. In vivo, MTs take on aster patterns during interphase and they form bundles in neurons and polarized epithelial cells. Vortex patterns have not been observed in vivo, however, are found in in vitro experiments. In constrained domains, we find that similar patterns form (asters, bundles, and vortices). However, we also find that when two opposing motors are present, anti-parallel bundles are able to form, resembling the mitotic spindle during cell division. This model demonstrates how MT sliding and MT reorientation are sufficient to produce experimentally observed patterns.

Geometrical comparison of two protein structures using Wigner-D functions.

In this article, we develop a quantitative comparison method for two arbitrary protein structures. This method uses a root-mean-square deviation characterization and employs a series expansion of the protein's shape function in terms of the Wigner-D functions to define a new criterion, which is called a "similarity value." We further demonstrate that the expansion coefficients for the shape function obtained with the help of the Wigner-D functions correspond to structure factors. Our method addresses the common problem of comparing two proteins with different numbers of atoms. We illustrate it with a worked example.