Multi-hazard hospital evacuation planning during disease outbreaks using agent-based modeling.

As different types of hazards, including natural and man-made, can occur simultaneously, to implement an integrated and holistic risk management, a multi-hazard perspective on disaster risk management, including preparedness and planning, must be taken for a safer and more resilient society. Considering the emerging challenges that the COVID-19 pandemic has been introducing to regular hospital operations, there is a need to adapt emergency plans with the changing conditions, as well. Evacuation of patients with different mobility disabilities is a complicated process that needs planning, training, and efficient decision-making. These protocols need to be revisited for multi-hazard scenarios such as an ongoing disease outbreak during which additional infection control protocols might be in place to prevent transmission. Computational models can provide insights on optimal emergency evacuation strategies, such as the location of isolation units or alternative evacuation prioritization strategies. This study introduces a non-ICU patient classification framework developed based on available patient mobility data. An agent-based model was developed to simulate the evacuation of the emergency department at the Johns Hopkins Hospital during the COVID-19 pandemic due to a fire emergency. The results show a larger nursing team can reduce the median and upper bound of the 95% confidence interval of the evacuation time by 36% and 33%, respectively. A dedicated exit door for COVID-19 patients is relatively less effective in reducing the median time, while it can reduce the upper bound by more than 50%.

Author Correction: Nuclear lamin A/C harnesses the perinuclear apical actin cables to protect nuclear morphology.

In the original version of this Article, the affiliation details for Arghavan Louhghalam were incorrectly given as 'Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, 21218, USA', and it should have been given as 'Department of Civil and Environmental Engineering, University of Massachusetts Dartmouth, Dartmouth, MA 02747, USA'. Furthermore, an incorrect grant number, R1610512, was acknowledged. The correct grant number is NRF-2016R1C1B2015018. These errors have now been corrected in both the PDF and HTML versions of the Article.

Nuclear lamin A/C harnesses the perinuclear apical actin cables to protect nuclear morphology.

The distinct spatial architecture of the apical actin cables (or actin cap) facilitates rapid biophysical signaling between extracellular mechanical stimuli and intracellular responses, including nuclear shaping, cytoskeletal remodeling, and the mechanotransduction of external forces into biochemical signals. These functions are abrogated in lamin A/C-deficient mouse embryonic fibroblasts that recapitulate the defective nuclear organization of laminopathies, featuring disruption of the actin cap. However, how nuclear lamin A/C mediates the ability of the actin cap to regulate nuclear morphology remains unclear. Here, we show that lamin A/C expressing cells can form an actin cap to resist nuclear deformation in response to physiological mechanical stresses. This study reveals how the nuclear lamin A/C-mediated formation of the perinuclear apical actin cables protects the nuclear structural integrity from extracellular physical disturbances. Our findings highlight the role of the physical interactions between the cytoskeletal network and the nucleus in cellular mechanical homeostasis.

Affine and non-affine deformations quantified in cytoskeletal networks through three-dimensional form-finding model.

Actin filaments and cross-linkers are main components of cytoskeletal networks in eukaryotic cells, and they support bending moments and axial forces respectively. A three-dimensional form-finding model is proposed in this work to investigate affine and non-affine deformations in cytoskeletal networks. In recent studies, modeling of cytoskeletal networks turns out to be a key piece in the cell mechanics puzzle. We used form-finding analysis to compute and analyze cytoskeletal models. A three-dimensional model is much more flexible and contains more elements than a two-dimensional model, and non-linear finite element analysis is difficult to converge. Thus, vector form intrinsic finite element analysis is employed here for valid results. The three-dimensional model reveals new behaviors beyond earlier two-dimensional models and better aligns with available data. Relative density of actin filaments and height of the form-finding model both play important roles in determining cytoskeletal stiffness, positively and negatively, respectively. Real cytoskeletal networks are quite mixed in terms of affine and non-affine deformations, which are quantified by internal strain energy in actin filaments and cross-linkers. Results are also influenced by actin filament relative density and height of the model. The three-dimensional form-finding model does provide much more room for intensive studies on cytoskeletal networks. In our future study, microtubules, fluidics, viscoelastic-plastic cross-linkers and even the whole cell model may be taken into account gradually to improve the cytoskeletal form-finding model.

The susceptibility of the femoral neck to fracture: an assessment incorporating the effects of age-remodeling and stress reduction.

Age-related bone remodeling may cause fragility of the femoral neck, thereby increasing fracture risk in elderly populations. We investigated the effects of age-remodeling and stress-reduction on the femoral neck region using the Finite Strip Method (FSM). We verified the possibility that the femoral neck is likely to undergo fracture through two mechanisms: yielding and local buckling. We hypothesized that the femoral necks of young subjects are more prone to fracture by yielding, whereas those of elderly subjects are more susceptible to fracture initiated by local buckling. The slices from the CT-scans of 15 subjects corresponding to the lowest area moment of inertia were segregated into cortex and trabeculae. Geometric and material properties for each strip were obtained from the CT-scans. The FSM, proposed here as an approximation to the better-known Finite Element Method (FEM), was implemented on a model comprising both cortex and trabeculae. Finite strip (FS) analyses were performed on models that incorporated the effects of age-related bone remodeling, as well as a reduction in physiological stress on the bone (as a result of weight loss). Comparisons were made with similar FS analyses performed on only the cortical shell, in order to ascertain the contributions of the trabeculae to femoral neck strength. We observed that the femoral necks of simulated young subjects manifested a marked predisposition to undergo yielding, whereas the femoral neck models of simulated elderly subjects were more prone to buckling before yielding. The trabecular degradation and cortical thinning involved in aging render the femoral neck more susceptible to failure by buckling.

Assessing the susceptibility to local buckling at the femoral neck cortex to age-related bone loss.

Although it is known that long cortical bone structurally alter their area moment of inertia with age related bone loss maintaining their bending strength, the incidence of fragility fractures associated with cortical thinning still prevails. We hypothesize that cortical thinning with aging increases the local buckling susceptibility under abnormal or eccentric loads, and initiates fracture. The paper presents a series of 3D geometrical model derived from CT scans of a human femoral neck used to simulate age-related bone loss. The purpose of the model is to predict the susceptibility of local buckling at the femoral neck in falls by elderly folks. Geometric three-dimensional models of femoral neck cortices were developed from 7 human cadaver femurs (4 female, 3 male, 52-68 years). Three age related femoral neck models were simulated by either reducing (young age-related model) or increasing (old age-related model) the outer cortical surfaces in the radial-direction, by 1-mm. The control model was the middle-age related model. The inner cortex diameter was also adjusted to equilibrate the compressive stresses, based on the load-profile of a single-legged stance. Based on the old age related model, two additional "fragile" models were simulated by reducing the compressive load profile by 10 and 20% changing the inner cortex diameter, respectively. Using these models for each specimen, the consequence of a fall on the greater trochanter was evaluated. The Finite Strip Method (FSM) was used to investigate the association between local buckling at the femoral neck and the load to failure. Under constant loading, buckling progressively reduced the load to failure with aging, as seen in 2/7 of the middle age (by 9-15%) and 5/7 of the old age (by 7-32%) related models. In the fragile models, a 51% reduction in the load to failure was noted. Structural adaptation to age-related bone loss might preserves the bending strength under physiologic loads, but cortical thinning effects the buckling ratio reaching a critical threshold that would make the bone susceptible to local buckling at the femoral neck increasing the risk of fracture in a fall.

How actin crosslinking and bundling proteins cooperate to generate an enhanced cell mechanical response.

Actin-crosslinking proteins organize actin filaments into dynamic and complex subcellular scaffolds that orchestrate important mechanical functions, including cell motility and adhesion. Recent mutation studies have shown that individual crosslinking proteins often play seemingly non-essential roles, leading to the hypothesis that they have considerable redundancy in function. We report live-cell, in vitro, and theoretical studies testing the mechanical role of the two ubiquitous actin-crosslinking proteins, alpha-actinin and fascin, which co-localize to stress fibers and the basis of filopodia. Using live-cell particle tracking microrheology, we show that the addition of alpha-actinin and fascin elicits a cell mechanical response that is significantly greater than that originated by alpha-actinin or fascin alone. These live-cell measurements are supported by quantitative rheological measurements with reconstituted actin filament networks containing pure proteins that show that alpha-actinin and fascin can work in concert to generate enhanced cell stiffness. Computational simulations using finite element modeling qualitatively reproduce and explain the functional synergy of alpha-actinin and fascin. These findings highlight the cooperative activity of fascin and alpha-actinin and provide a strong rationale that an evolutionary advantage might be conferred by the cooperative action of multiple actin-crosslinking proteins with overlapping but non-identical biochemical properties. Thus the combination of structural proteins with similar function can provide the cell with unique properties that are required for biologically optimal responses.

Nuclear envelope breakdown requires overcoming the mechanical integrity of the nuclear lamina.

In prophase cells, lamin B1 is the major component of the nuclear lamina, a filamentous network underlying the nucleoplasmic side of the nuclear membrane, whereas lamin A/C is dissociated from the scaffold. In vivo fluorescence microscopy studies have shown that, during the G2/M transition, the first gap in the nuclear envelope (NE) appears before lamin B1 disassembly and is caused by early spindle microtubules impinging on the NE. This result suggests that the mechanical tearing of the NE by microtubules plays a central role to the progression of mitosis. To investigate whether this microtubule-induced NE deformation is sufficient for NE breakdown, we assess the mechanical resilience of a reconstituted lamin B1 network. Quantitative rheological methods demonstrate that human lamin B1 filaments form stiff networks that can resist much greater deformations than those caused by microtubules impinging on the NE. Moreover, lamin B1 networks possess an elastic stiffness, which increases under tension, and an exceptional resilience against shear deformations. These results demonstrate that both mechanical tearing of the lamina and biochemical modification of lamin B1 filaments are required for NE breakdown.

Functional synergy of actin filament cross-linking proteins.

The organization of filamentous actin (F-actin) in resilient networks is coordinated by various F-actin cross-linking proteins. The relative tolerance of cells to null mutations of genes that code for a single actin cross-linking protein suggests that the functions of those proteins are highly redundant. This apparent functional redundancy may, however, reflect the limited resolution of available assays in assessing the mechanical role of F-actin cross-linking/bundling proteins. Using reconstituted F-actin networks and rheological methods, we demonstrate how alpha-actinin and fascin, two F-actin cross-linking/bundling proteins that co-localize along stress fibers and in lamellipodia, could synergistically enhance the resilience of F-actin networks in vitro. These two proteins can generate microfilament arrays that "yield" at a strain amplitude that is much larger than each one of the proteins separately. F-actin/alpha-actinin/fascin networks display strain-induced hardening, whereby the network "stiffens" under shear deformations, a phenomenon that is non-existent in F-actin/fascin networks and much weaker in F-actin/alpha-actinin networks. Strain-hardening is further enhanced at high rates of deformation and high concentrations of actin cross-linking proteins. A simplified model suggests that the optimum results of the competition between the increased stiffness of bundles and their decreased density of cross-links. Our studies support a re-evaluation of the notion of functional redundancy among cytoskeletal regulatory proteins.