NSF DARE-transforming modeling in neurorehabilitation: perspectives and opportunities from US funding agencies.

In recognition of the importance and timeliness of computational models for accelerating progress in neurorehabilitation, the U.S. National Science Foundation (NSF) and the National Institutes of Health (NIH) sponsored a conference in March 2023 at the University of Southern California that drew global participation from engineers, scientists, clinicians, and trainees. This commentary highlights promising applications of computational models to understand neurorehabilitation ("Using computational models to understand complex mechanisms in neurorehabilitation" section), improve rehabilitation care in the context of digital twin frameworks ("Using computational models to improve delivery and implementation of rehabilitation care" section), and empower future interdisciplinary workforces to deliver higher-quality clinical care using computational models ("Using computational models in neurorehabilitation requires an interdisciplinary workforce" section). The authors describe near-term gaps and opportunities, all of which encourage interdisciplinary team science. Four major opportunities were identified including (1) deciphering the relationship between engineering figures of merit-a term commonly used by engineers to objectively quantify the performance of a device, system, method, or material relative to existing state of the art-and clinical outcome measures, (2) validating computational models from engineering and patient perspectives, (3) creating and curating datasets that are made publicly accessible, and (4) developing new transdisciplinary frameworks, theories, and models that incorporate the complexities of the nervous and musculoskeletal systems. This commentary summarizes U.S. funding opportunities by two Federal agencies that support computational research in neurorehabilitation. The NSF has funding programs that support high-risk/high-reward research proposals on computational methods in neurorehabilitation informed by theory- and data-driven approaches. The NIH supports the development of new interventions and therapies for a wide range of nervous system injuries and impairments informed by the field of computational modeling. The conference materials can be found at https://dare2023.usc.edu/ .

Systematic Review of Active Travel to School Surveillance in the United States and Canada.

Active travel to school is one way youths can incorporate physical activity into their daily schedule. It is unclear the extent to which active travel to school is systematically monitored at local, state, or national levels. To determine the scope of active travel to school surveillance in the US and Canada and catalog the types of measures captured, we conducted a systematic review of peer-reviewed literature documenting active travel to school surveillance published from 2004 to February 2018. A study was included if it addressed children's school travel mode across two or more time periods in the US or Canada. Criteria were applied to determine whether a data source was considered an active travel to school surveillance system. We identified 15 unique data sources; 4 of these met our surveillance system criteria. One system is conducted in the US, is nationally representative, and occurs every 5-8 years. Three are conducted in Canada, are limited geographically to regions and provinces, and are administered with greater frequency (e.g., 2-year cycles). School travel mode was the primary measure assessed, most commonly through parent report. None of the systems collected data on school policies or program supports related to active travel to school. We concluded that incorporating questions related to active travel to school behaviors into existing surveillance systems, as well as maintaining them over time, would enable more consistent monitoring. Concurrently capturing behavioral information along with related environmental, policy, and program supports may inform efforts to promote active travel to school.

Improving active travel to school and its surveillance: an overlooked opportunity in health promotion and chronic disease prevention.

Increasing active travel to school (ATS) could reduce the deficit in youth physical activity participation; however, surveillance of ATS is limited. Given that ATS contributes to our understanding of children's physical activity patterns nationwide, is influenced by local contexts and state laws, and occurs within communities, surveillance could be informative at the national, state, and local levels. Following a National Collaborative on Childhood Obesity Research workshop, this commentary offers insights into strengthening surveillance and data collection of ATS behavior as well as ATS environmental, policy, and program supports.

Towards a multi-scale computer modeling workflow for simulation of pulmonary ventilation in advanced COVID-19.

Physics-based multi-scale in silico models offer an excellent opportunity to study the effects of heterogeneous tissue damage on airflow and pressure distributions in COVID-19-afflicted lungs. The main objective of this study is to develop a computational modeling workflow, coupling airflow and tissue mechanics as the first step towards a virtual hypothesis-testing platform for studying injury mechanics of COVID-19-afflicted lungs. We developed a CT-based modeling approach to simulate the regional changes in lung dynamics associated with heterogeneous subject-specific COVID-19-induced damage patterns in the parenchyma. Furthermore, we investigated the effect of various levels of inflammation in a meso-scale acinar mechanics model on global lung dynamics. Our simulation results showed that as the severity of damage in the patient's right lower, left lower, and to some extent in the right upper lobe increased, ventilation was redistributed to the least injured right middle and left upper lobes. Furthermore, our multi-scale model reasonably simulated a decrease in overall tidal volume as the level of tissue injury and surfactant loss in the meso-scale acinar mechanics model was increased. This study presents a major step towards multi-scale computational modeling workflows capable of simulating the effect of subject-specific heterogenous COVID-19-induced lung damage on ventilation dynamics.

The Relationship Between Perceived Confidence, Gender, and Writing in a Biomedical Engineering Research Experience for Undergraduates Site.

Women frequently feel alienated in science, technology, engineering, and mathematics (STEM) environments due to gender biases, ultimately leading them to feel less competent or leave the field altogether. This study utilizes personal statements from a subset of participants from a National Science Foundation (NSF) funded Research Experiences for Undergraduates (REU) Site: Biomedical Engineering in Simulations, Imaging, and Modeling (BME-SIM) to investigate how confidence is shown by participants and how confidence is perceived by faculty reviewers in personal statements. This study compares feedback from faculty reviewers to perceived and self-reported confidence using lexical (i.e., word choices and use) and syntactic (i.e., structures of language segments such as sentences, phrases, and organization of words) features of these personal statements. Women received more negative feedback related to confidence compared to their male counterparts, notably in relation to modesty. Few differences were found between writing styles of genders in their pre- and post-program statements. Overall, writing styles did not seem to correlate with the genders' perceived or self-reported confidence; however, perception of confidence suggested a relationship between genders' pre- and post-program statements when examined by noun and adjective variation. A similar relationship was found between self-reported confidence and noun variation in men and women participants. Findings suggest that writing style perceptions and practices may be influenced by gender norms; however, without looking at the specific diction and content of personal statements, these conclusions cannot be fully established.

Novel Application of Nutritional Biomarkers From a Controlled Feeding Study and an Observational Study to Characterization of Dietary Patterns in Postmenopausal Women.

Dietary guidance emphasizes healthy dietary patterns, but supporting evidence comes from self-reported dietary data, which are prone to measurement error. We explored whether nutritional biomarkers from the Women's Health Initiative Nutrition and Physical Activity Assessment Study Feeding Study (NPAAS-FS) (n = 153; 2010-2014) and the Women's Health Initiative Nutrition and Physical Activity Assessment Study Observational Study (NPAAS-OS) (n = 450; 2006-2009) could identify biomarker signatures of dietary patterns for development of corresponding regression calibration equations to help mitigate measurement error. Fasting blood samples were assayed for a specific panel of vitamins, carotenoids, and phospholipid fatty acids; 24-hour urine samples were assayed for nitrogen, sodium, and potassium levels. Intake records from the NPAAS-FS were used to calculate Healthy Eating Index 2010 (HEI-2010), Alternative Healthy Eating Index 2010 (AHEI-2010), alternative Mediterranean diet (aMED), and Dietary Approaches to Stop Hypertension (DASH) scores. Scores were regressed on blood and urine nutritional measures for discovery of dietary pattern biomarkers using a cross-validated model R2 ≥ 36% criterion (stage 1). Next, stepwise models (P ≤ 0.10 for entry/removal) using NPAAS-OS data were used to regress stage 1 dietary pattern biomarkers on NPAAS-OS self-reported dietary pattern scores using a food frequency questionnaire, a 4-day food record, and a 24-hour recall (stage 2). HEI-2010 and aMED analyses met the cross-validated R2 ≥ 36% criterion in stage 1, while AHEI-2010 and DASH analyses did not. The R2 values for HEI-2010 stage 2 calibration equations were as follows: food frequency questionnaire, 63.5%; 4-day food record, 83.1%; and 24-hour recall, 77.8%. Stage 2 aMED R2 values were 34.9%-46.8%. Dietary pattern biomarkers have potential for calibrating self-reports to enhance studies of diet-disease associations.

The immune response is a critical regulator of zebrafish retinal pigment epithelium regeneration.

Loss of the retinal pigment epithelium (RPE) because of dysfunction or disease can lead to blindness in humans. Harnessing the intrinsic ability of the RPE to self-repair is an attractive therapeutic strategy; however, mammalian RPE is limited in its regenerative capacity. Zebrafish possess tremendous intrinsic regenerative potential in ocular tissues, including the RPE, but little is known about the mechanisms driving RPE regeneration. Here, utilizing transgenic and mutant zebrafish lines, pharmacological manipulations, transcriptomics, and imaging analyses, we identified elements of the immune response as critical mediators of intrinsic RPE regeneration. After genetic ablation, the RPE express immune-related genes, including leukocyte recruitment factors such as interleukin 34 We demonstrate that macrophage/microglia cells are responsive to RPE damage and that their function is required for the timely progression of the regenerative response. These data identify the molecular and cellular underpinnings of RPE regeneration and hold significant potential for translational approaches aimed toward promoting a pro-regenerative environment in mammalian RPE.

Self-reported symptoms of arm lymphedema and health-related quality of life among female breast cancer survivors.

We examined cross-sectional associations between arm lymphedema symptoms and health-related quality of life (HRQoL) in the Health, Eating, Activity and Lifestyle (HEAL) Study. 499 women diagnosed with localized or regional breast cancer at ages 35-64 years completed a survey, on average 40 months after diagnosis, querying presence of lymphedema, nine lymphedema-related symptoms, e.g., tension, burning pain, mobility loss, and warmth/redness, and HRQoL. Analysis of covariance models were used to assess HRQoL scores in relation to presence of lymphedema and lymphedema-related symptoms. Lymphedema was self-reported by 137 women, of whom 98 were experiencing lymphedema at the time of the assessment. The most common symptoms were heaviness (52%), numbness (47%), and tightness (45%). Perceived physical health was worse for women reporting past or current lymphedema than those reporting no lymphedema (P-value < 0.0001). No difference was observed for perceived mental health (P-value = 0.31). Perceived physical health, stress, and lymphedema-specific HRQoL scores worsened as number of symptoms increased (P-values ≤ 0.01). Women reporting tension in the arm had lower physical health (P-value = 0.01), and those experiencing burning pain, tension, heaviness, or warmth/redness in the arm had lower lymphedema-specific HRQoL (P-values < 0.05). Treatment targeting specific lymphedema-related symptoms in addition to size/volume reduction may improve some aspects of HRQoL among affected women.

The retinal pigment epithelium: Development, injury responses, and regenerative potential in mammalian and non-mammalian systems.

Diseases that result in retinal pigment epithelium (RPE) degeneration, such as age-related macular degeneration (AMD), are among the leading causes of blindness worldwide. Atrophic (dry) AMD is the most prevalent form of AMD and there are currently no effective therapies to prevent RPE cell death or restore RPE cells lost from AMD. An intriguing approach to treat AMD and other RPE degenerative diseases is to develop therapies focused on stimulating endogenous RPE regeneration. For this to become feasible, a deeper understanding of the mechanisms underlying RPE development, injury responses and regenerative potential is needed. In mammals, RPE regeneration is extremely limited; small lesions can be repaired by the expansion of adjacent RPE cells, but large lesions cannot be repaired as remaining RPE cells are unable to functionally replace lost RPE tissue. In some injury paradigms, RPE cells proliferate but do not regenerate a morphologically normal monolayer, while in others, proliferation is pathogenic and results in further disruption to the retina. This is in contrast to non-mammalian vertebrates, which possess tremendous RPE regenerative potential. Here, we discuss what is known about RPE formation during development in mammalian and non-mammalian vertebrates, we detail the processes by which RPE cells respond to injury, and we describe examples of RPE-to-retina and RPE-to-RPE regeneration in non-mammalian vertebrates. Finally, we outline barriers to RPE-dependent regeneration in mammals that could potentially be overcome to stimulate a regenerative response from the RPE.

Systematic Review of Active Travel to School Surveillance in the United States and Canada.

Active travel to school is one way youths can incorporate physical activity into their daily schedule. It is unclear the extent to which active travel to school is systematically monitored at local, state, or national levels. To determine the scope of active travel to school surveillance in the US and Canada and catalog the types of measures captured, we conducted a systematic review of peer-reviewed literature documenting active travel to school surveillance published from 2004 to February 2018. A study was included if it addressed children's school travel mode across two or more time periods in the US or Canada. Criteria were applied to determine whether a data source was considered an active travel to school surveillance system. We identified 15 unique data sources; 4 of these met our surveillance system criteria. One system is conducted in the US, is nationally representative, and occurs every 5-8 years. Three are conducted in Canada, are limited geographically to regions and provinces, and are administered with greater frequency (e.g., 2-year cycles). School travel mode was the primary measure assessed, most commonly through parent report. None of the systems collected data on school policies or program supports related to active travel to school. We concluded that incorporating questions related to active travel to school behaviors into existing surveillance systems, as well as maintaining them over time, would enable more consistent monitoring. Concurrently capturing behavioral information along with related environmental, policy, and program supports may inform efforts to promote active travel to school.

Alignment of Dietary Patterns With the Dietary Guidelines for Americans 2015-2020 and Risk of All-Cause and Cause-Specific Mortality in the Women's Health Initiative Observational Study.

Poor diet quality is a leading risk factor for death in the United States. We examined the association between Healthy Eating Index-2015 (HEI-2015) scores and death from all causes, cardiovascular disease (CVD), cancer, Alzheimer disease, and dementia not otherwise specified (NOS) among postmenopausal women in the Women's Health Initiative Observational Study (1993-2017). This analysis included 59,388 participants who completed a food frequency questionnaire and were free of cancer, CVD, and diabetes at enrollment. Stratified Cox proportional hazards models were fit using person-years from enrollment as the underlying time metric. We estimated multivariable adjusted hazard ratios and 95% confidence intervals for risk of death associated with HEI-2015 quintiles, with higher scores reflecting more optimal diet quality. Over a median of 18.2 years, 9,679 total deaths 3,303 cancer deaths, 2,362 CVD deaths, and 488 deaths from Alzheimer disease and dementia NOS occurred. Compared with those with lower scores, women with higher HEI-2015 scores had an 18% lower risk of all-cause death and 21% lower risk of cancer death. HEI-2015 scores were not associated with death due to CVD, Alzheimer disease, and dementia NOS. Consuming a diet aligned with 2015-2020 US dietary guidelines may have beneficial impacts for preventing overall causes of death and death from cancer.

Mitf-family transcription factor function is required within cranial neural crest cells to promote choroid fissure closure.

A crucial step in eye development is the closure of the choroid fissure (CF), a transient structure in the ventral optic cup through which vasculature enters the eye and ganglion cell axons exit. Although many factors have been identified that function during CF closure, the molecular and cellular mechanisms mediating this process remain poorly understood. Failure of CF closure results in colobomas. Recently, MITF was shown to be mutated in a subset of individuals with colobomas, but how MITF functions during CF closure is unknown. To address this issue, zebrafish with mutations in mitfa and tfec, two members of the Mitf family of transcription factors, were analyzed and their functions during CF closure determined. mitfa;tfec mutants possess severe colobomas and our data demonstrate that Mitf activity is required within cranial neural crest cells (cNCCs) during CF closure. In the absence of Mitf function, cNCC migration and localization in the optic cup are perturbed. These data shed light on the cellular mechanisms underlying colobomas in individuals with MITF mutations and identify a novel role for Mitf function in cNCCs during CF closure.

A Six-Year Review of the Biomedical Engineering in Simulations, Imaging, and Modeling Undergraduate Research Experience.

Undergraduate research continues to serve as an effective strategy for mitigating the effects of a leaky pipeline. Significant funding from institutions and government agencies has increased the number of students participating in undergraduate research. In this paper, we report on the six-year experience of a National Science Foundation funded Research Experiences for Undergraduates (REU) Site: Biomedical Engineering in Simulations, Imaging, and Modeling (BME-SIM). The operation and evaluation of the program are both described. We report on the results from 55 students over six summers from 2014 to 2019. Our program was successful in attracting a diverse group of participants including 46% under-represented minority students and 53% women. Based on evaluation results, students reported significant gains in technical skills, communication skills, and knowledge of graduate school. Our findings indicate baseline gender differences for several learning outcomes, where women and nonbinary students report lower levels of mastery. These gaps are closed by the end of the program except for confidence in skills, which is still significantly lower than those reported by male counterparts. The impact of the experience on ultimate career path is difficult to determine due to underlying biases and other motivating factors; however, 67.6% of graduates have entered graduate programs. Finally, we have provided lessons learned for those who are interested in building a summer research program. In conclusion, we have described the successful implementation of an REU site and the positive learning outcomes of the student participants.

Essential Ingredients and Innovations in the Design and Analysis of Group-Randomized Trials.

This article reviews the essential ingredients and innovations in the design and analysis of group-randomized trials. The methods literature for these trials has grown steadily since they were introduced to the biomedical research community in the late 1970s, and we summarize those developments. We review, in addition to the group-randomized trial, methods for two closely related designs, the individually randomized group treatment trial and the stepped-wedge group-randomized trial. After describing the essential ingredients for these designs, we review the most important developments in the evolution of their methods using a new bibliometric tool developed at the National Institutes of Health. We then discuss the questions to be considered when selecting from among these designs or selecting the traditional randomized controlled trial. We close with a review of current methods for the analysis of data from these designs, a case study to illustrate each design, and a brief summary.

American College of Sports Medicine Roundtable Report on Physical Activity, Sedentary Behavior, and Cancer Prevention and Control.

INTRODUCTION: The American College of Sports Medicine convened an International Multidisciplinary Roundtable on Exercise and Cancer in March 2018 to evaluate and translate the evidence linking physical activity and cancer prevention, treatment, and control. This article discusses findings from the Roundtable in relation to the biologic and epidemiologic evidence for the role of physical activity in cancer prevention and survival. RESULTS: The evidence supports that there are a number of biologically plausible mechanisms, whereby physical activity can influence cancer risk, and that physical activity is beneficial for the prevention of several types of cancer including breast, colon, endometrial, kidney, bladder, esophageal, and stomach. Minimizing time spent in sedentary behavior may also lower risk of endometrial, colon and lung cancers. Conversely, physical activity is associated with higher risk of melanoma, a serious form of skin cancer. Further, physical activity before and after a cancer diagnosis is also likely to be relevant for improved survival for those diagnosed with breast and colon cancer; with data suggesting that postdiagnosis physical activity provides greater mortality benefits than prediagnosis physical activity. CONCLUSIONS: Collectively, there is consistent, compelling evidence that physical activity plays a role in preventing many types of cancer and for improving longevity among cancer survivors, although the evidence related to higher risk of melanoma demonstrates the importance of sun safe practices while being physically active. Together, these findings underscore the importance of physical activity in cancer prevention and control. Fitness and public health professionals and health care providers worldwide are encouraged to spread the message to the general population and cancer survivors to be physically active as their age, abilities, and cancer status will allow.

Physical Activity to Prevent and Treat Hypertension: A Systematic Review.

PURPOSE: This systematic umbrella review examines and updates the evidence on the relationship between physical activity (PA) and blood pressure (BP) presented in the 2008 Physical Activity Guidelines Advisory Committee Scientific Report. METHODS: We performed a systematic review to identify systematic reviews and meta-analyses involving adults with normal BP, prehypertension, and hypertension published from 2006 to February 2018. RESULTS: In total, 17 meta-analyses and one systematic review with 594,129 adults ≥18 yr qualified. Strong evidence demonstrates: 1) an inverse dose-response relationship between PA and incident hypertension among adults with normal BP; 2) PA reduces the risk of cardiovascular disease (CVD) progression among adults with hypertension; 3) PA reduces BP among adults with normal BP, prehypertension, and hypertension; and 4) the magnitude of the BP response to PA varies by resting BP, with greater benefits among adults with prehypertension than normal BP. Moderate evidence indicates the relationship between resting BP and the magnitude of benefit does not vary by PA type among adults with normal BP, prehypertension, and hypertension. Limited evidence suggests the magnitude of the BP response to PA varies by resting BP among adults with hypertension. Insufficient evidence is available to determine if factors such as sex, age, race/ethnicity, socioeconomic status, and weight status or the frequency, intensity, time, and duration of PA influence the associations between PA and BP. CONCLUSIONS: Future research is needed that adheres to standard BP measurement protocols and classification schemes to better understand the influence of PA on the risk of comorbid conditions, health-related quality of life, and CVD progression and mortality; the interactive effects between PA and antihypertensive medication use; and the immediate BP-lowering benefits of PA.

Effects of Physical Activity in Knee and Hip Osteoarthritis: A Systematic Umbrella Review.

INTRODUCTION: We conducted a systematic umbrella review to evaluate the literature relating to effects of physical activity on pain, physical function, health-related quality of life, comorbid conditions and osteoarthritis (OA) structural disease progression in individuals with lower-extremity OA. METHODS: Our primary search encompassed 2011 to February 2018 for existing systematic reviews (SR), meta-analyses (MA) and pooled analyses dealing with physical activity including exercise (not mixed with any other intervention and compared to a no-activity control group). A supplementary search encompassed 2006 to February 2018 for original research related to physical activity (including exercise) and lower limb OA progression. Study characteristics were abstracted, and risk of bias was assessed. RESULTS: Physical activity decreased pain and improved physical function (strong evidence) and improved health-related quality of life (moderate evidence) among people with hip or knee OA relative to less active adults with OA. There was no evidence to suggest accelerated OA progression for physical activity below 10,000 steps per day. Both physical activity equivalent to the 2008 Physical Activity Guidelines for Americans (150 min·wk of moderate-intensity exercise in bouts ≥10 min) and lower levels of physical activity (at least 45 total minutes per week of moderate-intensity) were associated with improved or sustained high function. No SR/MA addressing comorbid conditions in OA were found. Measurable benefits of physical activity appeared to persist for periods of up to 6 months following cessation of a defined program. CONCLUSIONS: People with lower-extremity OA should be encouraged to engage in achievable amounts of physical activity, of even modest intensities. They can choose to accrue minutes of physical activity throughout the entire day, irrespective of bout duration, and be confident in gaining some health and arthritis-related benefits.

Physical Activity in Cancer Prevention and Survival: A Systematic Review.

PURPOSE: This article reviews and updates the evidence on the associations between physical activity and risk for cancer, and for mortality in persons with cancer, as presented in the 2018 Physical Activity Guidelines Advisory Committee Scientific Report. METHODS: Systematic reviews of meta-analyses, systematic reviews, and pooled analyses were conducted through December 2016. An updated systematic review of such reports plus original research through February 2018 was conducted. This article also identifies future research needs. RESULTS: In reviewing 45 reports comprising hundreds of epidemiologic studies with several million study participants, the report found strong evidence for an association between highest versus lowest physical activity levels and reduced risks of bladder, breast, colon, endometrial, esophageal adenocarcinoma, renal, and gastric cancers. Relative risk reductions ranged from approximately 10% to 20%. Based on 18 systematic reviews and meta-analyses, the report also found moderate or limited associations between greater amounts of physical activity and decreased all-cause and cancer-specific mortality in individuals with a diagnosis of breast, colorectal, or prostate cancer, with relative risk reductions ranging almost up to 40% to 50%. The updated search, with five meta-analyses and 25 source articles reviewed, confirmed these findings. CONCLUSIONS: Levels of physical activity recommended in the 2018 Guidelines are associated with reduced risk and improved survival for several cancers. More research is needed to determine the associations between physical activity and incidence for less common cancers and associations with survival for other cancers. Future studies of cancer incidence and mortality should consider these associations for population subgroups, to determine dose-response relationships between physical activity and cancer risk and prognosis, and to establish mechanisms to explain these associations.