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To navigate complex terrains, insects use diverse tarsal structures (adhesive pads, claws, spines) to reliably attach to and locomote across substrates. This includes surfaces of variable roughness and inclination, which often require reliable transitions from ambulatory to scansorial locomotion. Using bioinspired physical models as a means for comparative research, our study specifically focused on the diversity of tarsal spines, which facilitate locomotion via frictional engagement and shear force generation. For spine designs, we took inspiration from ground beetles (Family Carabidae), which is a largely terrestrial group known for their quick locomotion. Evaluating four different species, we found that the hind legs host linear rows of rigid spines along the entire tarsus. By taking morphometric measurements of the spines, we highlighted parameters of interest (e.g., spine angle and aspect ratio) in order to test their relationship to shear forces sustained during terrain interactions. We systematically evaluated these parameters using spines cut from stainless steel shim attached to a small acrylic sled loaded with various weights. The sled was placed on 3D-printed models of rough terrain, randomly generated using fractal Brownian motion, while a motorized pulley system applied force to the spines. A force sensor measured the reaction force on the terrain, recording shear force before failure occurred. Initial shear tests highlighted the importance of spine angle, with bioinspired anisotropic designs producing higher shear forces. Using this data, we placed the best (50○ angle) and worst (90○ angle) performing spines on the legs of our insect-scale ambulatory robot physical model. We then tested the robot on various surfaces at 0, 10 and 20○ inclines, seeing similar success with the more bioinspired spines.

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Self-propelling organisms locomote via generation of patterns of self-deformation. Despite the diversity of body plans, internal actuation schemes and environments in limbless vertebrates and invertebrates, such organisms often use similar traveling waves of axial body bending for movement. Delineating how self-deformation parameters lead to locomotor performance (e.g. speed, energy, turning capabilities) remains challenging. We show that a geometric framework, replacing laborious calculation with a diagrammatic scheme, is well-suited to discovery and comparison of effective patterns of wave dynamics in diverse living systems. We focus on a regime of undulatory locomotion, that of highly damped environments, which is applicable not only to small organisms in viscous fluids, but also larger animals in frictional fluids (sand) and on frictional ground. We find that the traveling wave dynamics used by mm-scale nematode worms and cm-scale desert dwelling snakes and lizards can be described by time series of weights associated with two principal modes. The approximately circular closed path trajectories of mode weights in a self-deformation space enclose near-maximal surface integral (geometric phase) for organisms spanning two decades in body length. We hypothesize that such trajectories are targets of control (which we refer to as "serpenoid templates"). Further, the geometric approach reveals how seemingly complex behaviors such as turning in worms and sidewinding snakes can be described as modulations of templates. Thus, the use of differential geometry in the locomotion of living systems generates a common description of locomotion across taxa and provides hypotheses for neuromechanical control schemes at lower levels of organization.

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INTRODUCTION: People with HIV are at higher risk of lung cancer; however, there is limited research on attitudes, barriers, and facilitators to lung cancer screening in people with HIV. The objective of this study was to understand the perspectives on lung cancer screening among people with HIV and their providers. METHODS: Surveys of people with HIV and HIV-care providers were complemented by qualitative focus groups and interviews designed to understand the determinants of lung cancer screening in people with HIV. Participants were recruited through an academic HIV clinic in Seattle, WA. Qualitative guides were developed by integrating the Consolidated Framework for Implementation Research and the Tailored Implementation of Chronic Diseases checklist. Themes that emerged from thematic analyses of qualitative data were compared with surveys in joint displays. All study components were conducted between 2021 and 2022. RESULTS: Sixty-four people with HIV completed surveys, and 43 participated in focus groups. Eleven providers completed surveys, and 10 were interviewed for the study. Themes from joint displays show overall enthusiasm for lung cancer screening among people with HIV and their providers, particularly with a tailored and evidence-based approach. Facilitators in this population may include longstanding engagement with providers and health systems and an emphasis on survivorship through preventive healthcare interventions. People with HIV may also face barriers acknowledged by providers, including a high level of medical comorbidities and competing issues such as substance abuse, mental health concerns, and economic instability. CONCLUSIONS: This study reveals that people with HIV and their providers have overall enthusiasm toward screening. However, tailored interventions may be needed to overcome specific barriers, including complex decision making in the setting of medical comorbidity and patient competing issues.

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Purpose: We developed a model integrating multimodal quantitative imaging features from tumor and nontumor regions, qualitative features, and clinical data to improve the risk stratification of patients with resectable non-small cell lung cancer (NSCLC). Approach: We retrospectively analyzed 135 patients [mean age, 69 years (43 to 87, range); 100 male patients and 35 female patients] with NSCLC who underwent upfront surgical resection between 2008 and 2012. The tumor and peritumoral regions on both preoperative CT and FDG PET-CT and the vertebral bodies L3 to L5 on FDG PET were segmented to assess the tumor and bone marrow uptake, respectively. Radiomic features were extracted and combined with clinical and CT qualitative features. A random survival forest model was developed using the top-performing features to predict the time to recurrence/progression in the training cohort ( n = 101 ), validated in the testing cohort ( n = 34 ) using the concordance, and compared with a stage-only model. Patients were stratified into high- and low-risks of recurrence/progression using Kaplan-Meier analysis. Results: The model, consisting of stage, three wavelet texture features, and three wavelet first-order features, achieved a concordance of 0.78 and 0.76 in the training and testing cohorts, respectively, significantly outperforming the baseline stage-only model results of 0.67 ( p < 0.005 ) and 0.60 ( p = 0.008 ), respectively. Patients at high- and low-risks of recurrence/progression were significantly stratified in both the training ( p < 0.005 ) and the testing ( p = 0.03 ) cohorts. Conclusions: Our radiomic model, consisting of stage and tumor, peritumoral, and bone marrow features from CT and FDG PET-CT significantly stratified patients into low- and high-risk of recurrence/progression.

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Small cell lung cancer (SCLC) is an aggressive neuroendocrine neoplasm with poor survival outcomes and little change to treatment standards over decades. SCLC is associated with heavy tobacco exposure and a high rate of somatic mutations in tumor cells, leading to hope that immune checkpoint inhibitors would dramatically reshape the treatment landscape of SCLC. Instead, immune checkpoint inhibitors have led to real but modest gains in outcomes, with only a small minority of patients deriving more durable benefit. Furthermore, biomarkers of ICI efficacy that have succeeded in other tumor types have not been validated in SCLC. However, recent research advances have suggested that epigenetic heterogeneity and plasticity play especially key roles in SCLC biology. Leveraging this emerging perspective, a new slate of candidate biomarkers of immune checkpoint inhibitor benefit have been described, and the novel treatment strategies combining rational epigenetic perturbation with immune checkpoint inhibitors are being developed. Finally, other immunotherapy strategies targeting SCLC-specific mechanisms are being tested. Together, these developments may lead to a second generation of much more efficacious immunotherapies in SCLC.

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PURPOSE: Time from diagnosis to treatment has been associated with worse survival outcomes in non-small-cell lung cancer (NSCLC). However, little is known about the impact of delay in time to diagnosis. We aimed to evaluate the impact of time from radiographic suspicion to histologic diagnosis on survival outcomes using the US SEER-Medicare population database. METHODS: We identified patients from the SEER-Medicare data set diagnosed with any stage NSCLC between January 1, 2011, and December 31, 2015, who received stage-appropriate treatment and had a computed tomography scan within 1 year of diagnosis. Time to confirmation was determined as the interval between most recent computed tomography imaging and date of histologic diagnosis. Our primary outcome was overall survival (OS). RESULTS: In total, 10,824 eligible patients were identified. The median time to confirmation was 20 (range 0-363) days. Using multivariate Cox regression models, longer time to confirmation was associated with improved OS in all comers driven by stage IV patients after adjustment for age, sex, diagnosis year, histology, and comorbidity index. In a separate landmark analysis excluding patients deceased within 6 months of diagnosis, the association between time to diagnosis and survival was no longer evident. CONCLUSION: Time to confirmation of NSCLC was inversely associated with OS in this US SEER population study. This association was lost when patients deceased within 6 months of diagnosis were excluded, suggesting that retrospective registry-claims databases may not be the optimal data source to study time to diagnosis as a quality metric because of the unaccounted confounding effects of tumor behavior. Prospective evaluations of clinically enriched data sources may better serve this purpose.

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The transition from the lab to natural environments is an archetypal challenge in robotics. While larger robots can manage complex limb-ground interactions using sensing and control, such strategies are difficult to implement on small platforms where space and power are limited. The Harvard Ambulatory Microrobot (HAMR) is an insect-scale quadruped capable of effective open-loop running on featureless, hard substrates. Inspired by the predominantly feedforward strategy of rapidly-running cockroaches on uneven terrain (Sponberg, 2007), we used HAMR to explore open-loop running on two 3D printed heterogeneous terrains generated using fractional Brownian motion. The 'pocked' terrain had foot-scale features throughout while the 'jagged' terrain features increased in height in the direction of travel. We measured the performance of trot and pronk gaits while varying limb amplitude and stride frequency. The frequencies tested encompassed different dynamics regimes: body resonance (10-25 Hz) and kinematic running (30-40 Hz), with dynamics typical of biological running and walking, respectively, and limb-transmission resonance (45-60 Hz). On the featureless and pocked terrains, low mechanical cost-of-transport (mCoT) kinematic running combinations performed best without systematic differences between trot and pronk; indicating that if terrain features are not too tall, a robot can transition from homo-to heterogeneous environments in open-loop. Pronk bypassed taller features than trot on the jagged terrain, and higher mCoT, lower frequency running was more often effective. While increasing input power to the robot improved performance in general, lower frequency pronking on jagged terrain allowed the robot to bypass taller features compared with the same input power at higher frequencies. This was correlated with the increased variation in center-of-mass orientation occurring at frequencies near body resonance. This study established that appropriate choice of robot dynamics, as mediated by gait, frequency, and limb amplitude, can expand the terrains accessible to microrobots without the addition of sensing or closed-loop control.

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Objectives The change in tumor fluorodeoxyglucose (FDG) uptake by positron emission tomography (PET) scan after one cycle of platinum-based chemotherapy has been shown to predict progression-free and overall survival (PFS and OS) among advanced non-small cell lung cancer (NSCLC) patients. Using early FDG-PET response to determine subsequent chemotherapy, we aim to evaluate the role that adaptive chemotherapy regimens have on later CT response, PFS, and OS in patients with advanced NSCLC. Materials and Methods Chemotherapy-naïve patients with metastatic NSCLC received carboplatin and paclitaxel (CP) on day one and repeated FDG-PET on day 18. PET-responding patients continued CP chemotherapy for a total of four cycles. PET non-responders were switched to alternate docetaxel and gemcitabine (DG) for three additional cycles. The primary outcome was the CT Response Evaluation Criteria in Solid Tumors (RECIST 1.0) response. Secondary endpoints included PFS and OS. Results  Forty-six patients initiated treatment with chemotherapy on trial and were evaluable by PET/CT. Of these, 19 (41%) met the FDG-PET criteria for the response after a single cycle of CP. Only one non-responding patient had a CT response. Despite the lack of CT response in the DG arm, no trend for worse PFS or OS was seen between the two arms. Conclusions This work demonstrates that changing chemotherapy in the event of non-response by PET did not lead to improved CT RECIST response. However, non-responding patients who switched chemotherapy had similar PFS and OS to those who responded by PET and continued the same regimen.

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OBJECTIVES: Timely administration of postoperative radiation therapy (PORT) impacts oncologic outcomes in resected squamous cell carcinomas of the head and neck. Salivary gland cancers (SGCs) are uncommon, and timing of PORT has not been extensively explored. We aimed to determine if the interval between surgery and PORT impacts outcomes in SGCs. MATERIALS AND METHODS: This is a retrospective study of patients with SGCs who underwent curative intent surgical resection followed by adjuvant PORT. Locoregional recurrence free survival (LRFS), disease free survival (DFS), and overall survival (OS) were estimated using the Kaplan Meier method. A multivariate analysis explored the association between demographics, tumor characteristics, and PORT timing with oncologic outcomes using a stepwise Cox proportional hazards model. RESULTS: 180 eligible patients were identified. The median time to PORT start was 61 (range 8-121) days. 169 (93.5%) of patients received neutron radiation. With a median follow up of 8.2 years in surviving patients, the 10-year OS and LRFS estimates were 61% and 53%. In a multivariate analysis, nodal involvement, histologic grade, and age at diagnosis were associated with OS, while nodal involvement, tumor size, and age at diagnosis were associated with LRFS and DFS. Time to PORT start or completion was not statistically associated with survival outcomes. CONCLUSION: SGC patients who underwent surgery in our tertiary institution received PORT within a median of 61 days after surgery. With long term follow up, PORT timing in this retrospective series was not associated with worse oncologic outcomes, and support timely administration of PORT.

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PURPOSE: This study evaluated the ability of 18F-Fluorodeoxyglucose (FDG) and 18F-Fluorothymidine (FLT) imaging with positron emission tomography (PET) to measure early response to endocrine therapy from baseline to just prior to surgical resection in estrogen receptor positive (ER+) breast tumors. METHODS: In two separate studies, women with early stage ER+ breast cancer underwent either paired FDG-PET (n = 22) or FLT-PET (n = 27) scans prior to endocrine therapy and again in the pre-operative setting. Tissue samples for Ki-67 were taken for all patients both prior to treatment and at the time of surgery. RESULTS: FDG maximum standardized uptake value (SUVmax) declined in 19 of 22 lesions (mean 17% (range -45 to 28%)). FLT SUVmax declined in 24 of 27 lesions (mean 26% (range -77 to 7%)). The Ki-67 index declined in both studies, from pre-therapy (mean 23% (range 1 to 73%)) to surgery [mean 8% (range < 1 to 41%)]. Pre- and post-therapy PET measures showed strong rank-order agreement with Ki-67 percentages for both tracers; however, the percent change in FDG or FLT SUVmax did not demonstrate a strong correlation with Ki-67 index change or Ki-67 at time of surgery. CONCLUSIONS: A window-of-opportunity approach using PET imaging to assess early response of breast cancer therapy is feasible. FDG and FLT-PET imaging following a short course of neoadjuvant endocrine therapy demonstrated measurable changes in SUVmax in early stage ER+ positive breast cancers. The percentage change in FDG and FLT-PET uptake did not correlate with changes in Ki-67; post-therapy SUVmax for both tracers was significantly associated with post-therapy Ki-67, an established predictor of endocrine therapy response.

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Terrestrial organisms that use traveling waves to locomote must leverage heterogeneities to overcome drag on the elongate body. While previous studies illuminated how habitat generalist snakes self-deform to use rigid obstacles in the surroundings, control strategies for multi-component terrain are largely unknown. We compared the sand-specialist Chionactis occipitalis to a habitat generalist, Pantherophis guttatus, navigating a model terrestrial terrain-rigid post arrays on a low-friction substrate. We found the waveshapes used by the generalist were more variable than the specialist. Principal component analysis revealed that while the specialized sand-swimming waveform was always present on C. occipitalis, the generalist did not have a similarly pervasive low-dimensional waveshape. We expected the generalist to thus outperform the specialist in the arrays, but body slip of both species was comparable on level ground and in all trials the snakes successfully traversed the arena. When we further challenged the snakes to ascend an inclined lattice, the sand-specialist had difficulty maintaining contact with the obstacles and was unable to progress up the steepest inclines in the largest lattice spacings. Our results suggest that species adapted to different habitats use different control modalities-the specialist is primarily controlling its kinematics to achieve a target shape while, consistent with previous research, the generalist is using force control and self-deforms in response to terrain contacts. While both strategies allowed progress on the uninclined low-friction terrain with posts, the more variable waveshapes of the generalist may be necessary when faced with more challenging locomotor tasks like climbing inclines.

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While terrestrial locomotors often contend with permanently deformable substrates like sand, soil, and mud, principles of motion on such materials are lacking. We study the desert-specialist shovel-nosed snake traversing a model sand and find body inertia is negligible despite rapid transit and speed dependent granular reaction forces. New surface resistive force theory (RFT) calculation reveals how wave shape in these snakes minimizes material memory effects and optimizes escape performance given physiological power limitations. RFT explains the morphology and waveform-dependent performance of a diversity of non-sand-specialist snakes but overestimates the capability of those snakes which suffer high lateral slipping of the body. Robophysical experiments recapitulate aspects of these failure-prone snakes and elucidate how re-encountering previously deformed material hinders performance. This study reveals how memory effects stymied the locomotion of a diversity of snakes in our previous studies (Marvi et al., 2014) and indicates avenues to improve all-terrain robots.

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Animals moving on and in fluids and solids move their bodies in diverse ways to generate propulsion and lift forces. In fluids, animals can wiggle, stroke, paddle or slap, whereas on hard frictional terrain, animals largely engage their appendages with the substrate to avoid slip. Granular substrates, such as desert sand, can display complex responses to animal interactions. This complexity has led to locomotor strategies that make use of fluid-like or solid-like features of this substrate, or combinations of the two. Here, we use examples from our work to demonstrate the diverse array of methods used and insights gained in the study of both surface and subsurface limbless locomotion in these habitats. Counterintuitively, these seemingly complex granular environments offer certain experimental, theoretical, robotic and computational advantages for studying terrestrial movement, with the potential for providing broad insights into morphology and locomotor control in fluids and solids, including neuromechanical control templates and morphological and behavioral evolution. In particular, granular media provide an excellent testbed for a locomotion framework called geometric mechanics, which was introduced by particle physicists and control engineers in the last century, and which allows quantitative analysis of alternative locomotor patterns and morphology to test for control templates, optimality and evolutionary alternatives. Thus, we posit that insights gained from movement in granular environments can be translated into principles that have broader applications across taxa, habitats and movement patterns, including those at microscopic scales.

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The analysis of games and sports as complex systems can give insights into the dynamics of human competition and has been proven useful in soccer, basketball, and other professional sports. In this paper, we present a model for dodgeball, a popular sport in U.S. schools, and analyze it using an ordinary differential equation (ODE) compartmental model and stochastic agent-based game simulations. The ODE model reveals a rich landscape with different game dynamics occurring depending on the strategies used by the teams, which can in some cases be mapped to scenarios in competitive species models. Stochastic agent-based game simulations confirm and complement the predictions of the deterministic ODE models. In some scenarios, game victory can be interpreted as a noise-driven escape from the basin of attraction of a stable fixed point, resulting in extremely long games when the number of players is large. Using the ODE and agent-based models, we construct a strategy to increase the probability of winning.

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Natural and artificial self-propelled systems must manage environmental interactions during movement. In complex environments, these interactions include active collisions, in which propulsive forces create persistent contacts with heterogeneities. Due to the driven and dissipative nature of these systems, such collisions are fundamentally different from those typically studied in classical physics. Here we experimentally and numerically study the effects of active collisions on a laterally undulating sensory-deprived robophysical model, whose dynamics are relevant to self-propelled systems across length scales and environments. Interactions with a single rigid post scatter the robot, and this deflection is dominated by head-post contact. These results motivate a model which reduces the snake to a circular particle with two key features: The collision dynamics are set by internal driving subject to the geometric constraints of the post, and the particle has an effective length equal to the wavelength of the snake. Interactions with a single row of evenly spaced posts (with interpost spacing d) produce distributions reminiscent of far-field diffraction patterns: As d decreases, distinct secondary peaks emerge as large deflections become more likely. Surprisingly, we find that the presence of multiple posts does not change the nature of individual collisions; instead, multimodal scattering patterns arise from multiple posts altering the likelihood of individual collisions to occur. As d decreases, collisions near the leading edges of the posts become more probable, and we find that these interactions are associated with larger deflections. Our results, which highlight the surprising dynamics that can occur during active collisions of self-propelled systems, can inform control principles for locomotors in complex terrain and facilitate design of task-capable active matter.

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Limbless animals like snakes inhabit most terrestrial environments, generating thrust to overcome drag on the elongate body via contacts with heterogeneities. The complex body postures of some snakes and the unknown physics of most terrestrial materials frustrates understanding of strategies for effective locomotion. As a result, little is known about how limbless animals contend with unplanned obstacle contacts. We studied a desert snake, Chionactis occipitalis, which uses a stereotyped head-to-tail traveling wave to move quickly on homogeneous sand. In laboratory experiments, we challenged snakes to move across a uniform substrate and through a regular array of force-sensitive posts. The snakes were reoriented by the array in a manner reminiscent of the matter-wave diffraction of subatomic particles. Force patterns indicated the animals did not change their self-deformation pattern to avoid or grab the posts. A model using open-loop control incorporating previously described snake muscle activation patterns and body-buckling dynamics reproduced the observed patterns, suggesting a similar control strategy may be used by the animals. Our results reveal how passive dynamics can benefit limbless locomotors by allowing robust transit in heterogeneous environments with minimal sensing.

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BACKGROUND: Neoadjuvant chemotherapy is effective in improving survival of resectable NSCLC. Based on findings in the adjuvant and metastatic setting, FDG positron emission tomography (PET) scans may offer early prognostic or predictive value after one cycle of induction chemotherapy. METHODS: In this phase II non-randomized trial, patients with AJCC version 6 stage IB to IIIB operable NSCLC were treated with 3 cycles of cisplatin and pemetrexed neoadjuvant chemotherapy. Patients underwent FDG-PET scanning prior to and 18 to 21 days after the first cycle of chemotherapy. Investigators caring for patients were blinded to results, unless the scans showed evidence of disease progression. FDG-PET response was defined prospectively as a ≥ 20% decrease in the SUV of the primary lesion. RESULTS: Between October 2005 and February 2010, 25 patients enrolled. Fifty two percent were female, 88% white, and median age was 62 years. Histology was divided into adenocarcinoma 66%, not otherwise specified (NOS) 16%, squamous cell 12%, and large cell 4%. Stage distribution was: 16% IB, 4% IIB, and 79% IIIA. Treatment was well tolerated and only one patient had a grade 4 toxicity. The median follow up was 95 months. The 5 year progression free survival (PFS) and overall survival (OS) for the entire population were 54 and 67%, respectively. Eighteen patients had a baseline FDG-PET scan and a repeat scan at day 18-21 available for comparison. Ten patients (56%) were considered metabolic responders on the day 18-21 FDG-PET scan. Responders had a 5 year PFS and OS of 60 and 70%, respectively, while the percentage for non-responders was 63 and 75% (p = 0.96 and 0.85). CONCLUSIONS: This phase II trial did not demonstrate that a PET scan after one cycle of chemotherapy can predict survival outcomes of patients with NSCLC treated with neoadjuvant chemotherapy. TRIAL REGISTRATION: NCT00227539 registered September 28th, 2005.

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INTRODUCTION: Chronic inflammation has been implicated in carcinogenesis, with increasing evidence of its role in lung cancer. We aimed to evaluate the role of genetic polymorphisms in inflammation-related genes in the risk for development of lung cancer. METHODS: A nested case-control study design was used, and 625 cases and 625 well-matched controls were selected from participants in the ß-Carotene and Retinol Efficacy Trial, which is a large, prospective lung cancer chemoprevention trial. The association between lung cancer incidence and survival and 23 polymorphisms descriptive of 11 inflammation-related genes (interferon gamma gene [IFNG], interleukin 10 gene [IL10], interleukin 1 alpha gene [IL1A], interleukin 1 beta gene [IL1B], interleukin 2 gene [IL2], interleukin 4 receptor gene [IL4R], interleukin 4 gene [IL4], interleukin 6 gene [IL6], prostaglandin-endoperoxide synthase 2 gene [PTGS2] (also known as COX2), transforming growth factor beta 1 gene [TGFB1], and tumor necrosis factor alpha gene [TNFA]) was evaluated. RESULTS: Of the 23 polymorphisms, two were associated with risk for lung cancer. Compared with individuals with the wild-type (CC) variant, individuals carrying the minor allele variants of the IL-1ß-511C>T promoter polymorphism (rs16944) (CT and TT) had decreased odds of lung cancer (OR = 0.74, [95% confidence interval (CI): 0.58-0.94] and OR = 0.71 [95% CI: 0.50-1.01], respectively, p = 0.03). Similar results were observed for the IL-1ß-1464 C>G promoter polymorphism (rs1143623), with presence of the minor variants CG and CC having decreased odds of lung cancer (OR = 0.75 [95% CI: 0.59-0.95] and OR = 0.69 [95% CI: 0.46-1.03], respectively, p = 0.03). Survival was not influenced by genotype. CONCLUSIONS: This study provides further evidence that IL1B promoter polymorphisms may modulate the risk for development of lung cancer.

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