Comparing finite viscoelastic constitutive relations and variational principles in modeling gastrointestinal soft tissue deformation.

The mechanical attributes of soft tissues within the gastrointestinal (GI) tract are crucial for the effective operation of the GI system, and alterations in these properties may play a role in motility-related disorders. Various constitutive modeling approaches have been suggested to comprehend the response of soft tissues to diverse loading conditions. Among these, hyperelastic constitutive models based on finite elasticity have gained popularity. However, these models fall short in capturing rate- and time-dependent tissue properties. In contrast, finite viscoelastic models offer a solution to overcome these limitations. Nevertheless, the development of a suitable finite viscoelastic model, coupled with a variational formulation for efficient finite element (FE) implementation, remains an ongoing challenge. This study aims to address this gap by developing diverse finite viscoelastic constitutive relations and applying them to characterize soft tissue. Furthermore, the research explores the creation of compressible, nearly incompressible, and incompressible versions of viscoelastic constitutive relations, along with their variational formulation, to facilitate efficient FE implementation. The proposed model demonstrates remarkable accuracy in replicating experimental results, achieving an R2 value exceeding 0.99.

Higher temperature accelerates the aging-dependent weakening of the melanization immune response in mosquitoes.

The body temperature of mosquitoes, like most insects, is dictated by the environmental temperature. Climate change is increasing the body temperature of insects and thereby altering physiological processes such as immune proficiency. Aging also alters insect physiology, resulting in the weakening of the immune system in a process called senescence. Although both temperature and aging independently affect the immune system, it is unknown whether temperature alters the rate of immune senescence. Here, we evaluated the independent and combined effects of temperature (27°C, 30°C and 32°C) and aging (1, 5, 10 and 15 days old) on the melanization immune response of the adult female mosquito, Anopheles gambiae. Using a spectrophotometric assay that measures phenoloxidase activity (a rate limiting enzyme) in hemolymph, and therefore, the melanization potential of the mosquito, we discovered that the strength of melanization decreases with higher temperature, aging, and infection. Moreover, when the temperature is higher, the aging-dependent decline in melanization begins at a younger age. Using an optical assay that measures melanin deposition on the abdominal wall and in the periostial regions of the heart, we found that melanin is deposited after infection, that this deposition decreases with aging, and that this aging-dependent decline is accelerated by higher temperature. This study demonstrates that higher temperature accelerates immune senescence in mosquitoes, with higher temperature uncoupling physiological age from chronological age. These findings highlight the importance of investigating the consequences of climate change on how disease transmission by mosquitoes is affected by aging.

Mosquito larvae exposed to a sublethal dose of photosensitive insecticides have altered juvenile development but unaffected adult life history traits.

BACKGROUND: Larvicides are critical for the control of mosquito-borne diseases. However, even sublethal exposure to a larvicide can alter development and life history traits, which can then affect population density and disease transmission dynamics. Photosensitive insecticides (PSIs) are a promising class of larvicide that are toxic when ingested and activated by light. We investigated whether the time of day when exposure occurs, or the process of pupation, affects larval susceptibility to PSI phototoxicity in the mosquito Anopheles gambiae, and whether sublethal exposure to PSIs alters life history traits. METHODS: Larvae were treated with lethal concentrations of the PSIs methylene blue (MB) and rose bengal (RB), and larval survival was measured at various times of day. Additionally, larvae were exposed to two concentrations of each PSI that resulted in low and medium mortality, and the life history traits of the surviving larvae were measured. RESULTS: Pupation, which predominantly occurs in the evening, protected larvae from PSI toxicity, but the toxicity of PSIs against larvae that had yet to pupate was unaffected by time of day. Larval exposure to a sublethal concentration of MB, but not RB, shortened the time to pupation. However, larval exposure to a sublethal concentration of RB, but not MB, increased pupal mortality. Neither PSI had a meaningful effect on the time to eclosion, adult longevity, or adult melanization potential. CONCLUSIONS: PSIs are lethal larvicides. Sublethal PSI exposure alters mosquito development, but does not affect adult life history traits.

Quantifying Fitness Costs in Transgenic Aedes aegypti Mosquitoes.

Transgenic mosquitoes often display fitness costs compared to their wild-type counterparts. In this regard, fitness cost studies involve collecting life parameter data from genetically modified mosquitoes and comparing them to mosquitoes lacking transgenes from the same genetic background. This manuscript illustrates how to measure common life history traits in the mosquito Aedes aegypti, including fecundity, wing size and shape, fertility, sex ratio, viability, development times, male contribution, and adult longevity. These parameters were chosen because they reflect reproductive success, are simple to measure, and are commonly reported in the literature. The representative results quantify fitness costs associated with either a gene knock-out or a single insertion of a gene drive element. Standardizing how life parameter data are collected is important because such data may be used to compare the health of transgenic mosquitoes generated across studies or to model the transgene fixation rate in a simulated wild-type mosquito population. Although this protocol is specific for transgenic Aedes aegypti, the protocol may also be used for other mosquito species or other experimental treatment conditions, with the caveat that certain biological contexts may require special adaptations.

Establishment of a Private Foundation-Academic Partnership to Promote Careers of Early-Stage Investigators Examining the Influence of Sex and Gender on Health and Health Care.

Biological sex and gender-based constructs contribute significantly to the diversity of disease outcomes and treatment responses across the life course. To promote research considering sex and gender, the National Institutes of Health (NIH) Office of Research on Women's Health (ORWH) launched the Specialized Centers of Research Excellence (SCORE) on sex differences program. The Career Enhancement Core (CEC) of the Johns Hopkins SCORE on Sex and Age Differences in Immunity to Influenza (SADII) partnered with the Foundation for Gender-Specific Medicine, which matched NIH funding to support seed grants. Over 3 years we awarded 12 (10 were women faculty) seed grants to early-stage investigators. One year after the award, the seed grant awardees highlighted their progress, including publications, grant applications, and abstracts. All awardees noted challenges with their progress related to the COVID-19 pandemic and supply chain delays and shared suggestions for improving the programming of the CEC. They also highlighted the multiple ways the awards had helped them gain pilot data toward larger grants, build collaborative relationships, and present at the annual SCORE symposium. We describe a model and evidence supporting a private-academic collaboration to support the careers of early-stage investigators conducting research related to sex and gender.

Associations between sleep health and obesity and weight change in adults: The Daily24 Multisite Cohort Study.

OBJECTIVES: To examine cross-sectional and longitudinal associations of individual sleep domains and multidimensional sleep health with current overweight or obesity and 5-year weight change in adults. METHODS: We estimated sleep regularity, quality, timing, onset latency, sleep interruptions, duration, and napping using validated questionnaires. We calculated multidimensional sleep health using a composite score (total number of "good" sleep health indicators) and sleep phenotypes derived from latent class analysis. Logistic regression was used to examine associations between sleep and overweight or obesity. Multinomial regression was used to examine associations between sleep and weight change (gain, loss, or maintenance) over a median of 1.66 years. RESULTS: The sample included 1016 participants with a median age of 52 (IQR = 37-65), who primarily identified as female (78%), White (79%), and college-educated (74%). We identified 3 phenotypes: good, moderate, and poor sleep. More regularity of sleep, sleep quality, and shorter sleep onset latency were associated with 37%, 38%, and 45% lower odds of overweight or obesity, respectively. The addition of each good sleep health dimension was associated with 16% lower adjusted odds of having overweight or obesity. The adjusted odds of overweight or obesity were similar between sleep phenotypes. Sleep, individual or multidimensional sleep health, was not associated with weight change. CONCLUSIONS: Multidimensional sleep health showed cross-sectional, but not longitudinal, associations with overweight or obesity. Future research should advance our understanding of how to assess multidimensional sleep health to understand the relationship between all aspects of sleep health and weight over time.

Association of Eating and Sleeping Intervals With Weight Change Over Time: The Daily24 Cohort.

Background We aim to evaluate the association between meal intervals and weight trajectory among adults from a clinical cohort. Methods and Results This is a multisite prospective cohort study of adults recruited from 3 health systems. Over the 6-month study period, 547 participants downloaded and used a mobile application to record the timing of meals and sleep for at least 1 day. We obtained information on weight and comorbidities at each outpatient visit from electronic health records for up to 10 years before until 10 months after baseline. We used mixed linear regression to model weight trajectories. Mean age was 51.1 (SD 15.0) years, and body mass index was 30.8 (SD 7.8) kg/m2; 77.9% were women, and 77.5% reported White race. Mean interval from first to last meal was 11.5 (2.3) hours and was not associated with weight change. The number of meals per day was positively associated with weight change. The average difference in annual weight change (95% CI) associated with an increase of 1 daily meal was 0.28 kg (0.02-0.53). Conclusions Number of daily meals was positively associated with weight change over 6 years. Our findings did not support the use of time-restricted eating as a strategy for long-term weight loss in a general medical population.

Electronic Health Record-Based Recruitment and Retention and Mobile Health App Usage: Multisite Cohort Study.

BACKGROUND: To address the obesity epidemic, there is a need for novel paradigms, including those that address the timing of eating and sleep in relation to circadian rhythms. Electronic health records (EHRs) are an efficient way to identify potentially eligible participants for health research studies. Mobile health (mHealth) apps offer available and convenient data collection of health behaviors, such as timing of eating and sleep. OBJECTIVE: The aim of this descriptive analysis was to report on recruitment, retention, and app use from a 6-month cohort study using a mobile app called Daily24. METHODS: Using an EHR query, adult patients from three health care systems in the PaTH clinical research network were identified as potentially eligible, invited electronically to participate, and instructed to download and use the Daily24 mobile app, which focuses on eating and sleep timing. Online surveys were completed at baseline and 4 months. We described app use and identified predictors of app use, defined as 1 or more days of use, versus nonuse and usage categories (ie, immediate, consistent, and sustained) using multivariate regression analyses. RESULTS: Of 70,661 patients who were sent research invitations, 1021 (1.44%) completed electronic consent forms and online baseline surveys; 4 withdrew, leaving a total of 1017 participants in the analytic sample. A total of 53.79% (n=547) of the participants were app users and, of those, 75.3% (n=412), 50.1% (n=274), and 25.4% (n=139) were immediate, consistent, and sustained users, respectively. Median app use was 28 (IQR 7-75) days over 6 months. Younger age, White race, higher educational level, higher income, having no children younger than 18 years, and having used 1 to 5 health apps significantly predicted app use (vs nonuse) in adjusted models. Older age and lower BMI predicted early, consistent, and sustained use. About half (532/1017, 52.31%) of the participants completed the 4-month online surveys. A total of 33.5% (183/547), 29.3% (157/536), and 27.1% (143/527) of app users were still using the app for at least 2 days per month during months 4, 5, and 6 of the study, respectively. CONCLUSIONS: EHR recruitment offers an efficient (ie, high reach, low touch, and minimal participant burden) approach to recruiting participants from health care settings into mHealth research. Efforts to recruit and retain less engaged subgroups are needed to collect more generalizable data. Additionally, future app iterations should include more evidence-based features to increase participant use.

How does the Nature of an Excipient and an Atheroma Influence Drug-Coated Balloon Therapy?

The advent of drug-eluting stents and drug-coated balloons have significantly improved the clinical outcome of patients with vascular occlusions. However, ischemic vascular disease remains the most common cause of death worldwide. Improving the current treatment modalities demands a better understanding of the processes which govern drug uptake and retention in blood vessels. In this study, we evaluated the influence of urea and butyryl-trihexyl citrate, as excipients, on the efficacy of drug-coated balloon therapy. An integrated approach, utilizing both in-vitro and in-silico methods, was used to quantify the tracking loss, vessel adhesion, drug release, uptake, and distribution associated with the treatment. Moreover, a parametric study was used to evaluate the potential influence of different types of lesions on drug-coated balloon therapy. Despite the significantly higher tracking loss (urea: 35.5% vs. butyryl-trihexyl citrate: 8.13%) observed in the urea-based balloons, the drug uptake was almost two times greater than with its hydrophobic counterpart. Non-calcified lesions were found to delay the transmural propagation of sirolimus while calcification was shown to limit the retentive potential of lesions. Ultimately this study helps to elucidate how different excipients and types of lesions may influence the efficacy of drug-coated balloon therapy.

Night eating, weight, and health behaviors in adults participating in the Daily24 study.

BACKGROUND: Night eating syndrome (NES) is associated with adverse health outcomes. This study evaluated the relationship between night eating severity, weight, and health behaviors. METHODS: Participants (N = 1017; 77.6% female, mean Body Mass Index (BMI) = 30.5, SD = 7.8 kg/m2, age = 51.1, SD = 15.0 years) were recruited from three health systems. Participants completed the Night Eating Questionnaire (NEQ) and questionnaires assessing sleep, chronotype, physical activity, diet, weight, and napping. RESULTS: In the overall sample, higher NEQ scores were associated with higher BMI (p < .001) and consumption of sugar-sweetened beverages (p < .001), as well as lower fruit/vegetable consumption (p = .001). Higher NEQ scores were associated with increased odds of having overweight/obesity (p < .001), eating fast food (p < .001), moderate-vigorous physical activity (p = .005), and smoking (p = .004). Participants who exceeded the screening threshold for NES (n = 48, 4.7%) reported elevated BMI (p = .014), an increased likelihood of overweight/obesity (p = .004), greater sugar-sweetened beverages consumption (p < .001), napping less than twice per week (p = .029), shorter sleep duration (p = .012), and a later chronotype (M = 4:55, SD = 2:45). CONCLUSION: Night eating severity was associated with obesity and intake of fast food and sugar-sweetened beverages. Interventions to address night eating and associated behaviors may enhance the efficacy of weight management interventions and promote engagement in positive health behaviors.

Enterocyte-innate lymphoid cell crosstalk drives early IFN-γ-mediated control of Cryptosporidium.

The intestinal parasite, Cryptosporidium, is a major contributor to global child mortality and causes opportunistic infection in immune deficient individuals. Innate resistance to Cryptosporidium, which specifically invades enterocytes, is dependent on the production of IFN-γ, yet whether enterocytes contribute to parasite control is poorly understood. In this study, utilizing a mouse-adapted strain of C. parvum, we show that epithelial-derived IL-18 synergized with IL-12 to stimulate innate lymphoid cell (ILC) production of IFN-γ required for early parasite control. The loss of IFN-γ-mediated STAT1 signaling in enterocytes, but not dendritic cells or macrophages, antagonized early parasite control. Transcriptional profiling of enterocytes from infected mice identified an IFN-γ signature and enrichment of the anti-microbial effectors IDO, GBP, and IRG. Deletion experiments identified a role for Irgm1/m3 in parasite control. Thus, enterocytes promote ILC production of IFN-γ that acts on enterocytes to restrict the growth of Cryptosporidium.

Healthy for Two/Healthy for You: Design and methods for a pragmatic randomized clinical trial to limit gestational weight gain and prevent obesity in the prenatal care setting.

OBJECTIVE: To compare the effect of Healthy for Two/Healthy for You (H42/H4U), a health coaching program, in prenatal care clinics that serve a racially and economically diverse population, on total gestational weight gain (GWG) (vs. usual care). We hypothesize that compared to usual prenatal care, intervention participants will have lower GWG and lower rates of gestational diabetes mellitus (GDM). METHODS: We report the rationale and design of a pragmatic, parallel arm randomized clinical trial with 380 pregnant patients ≤15 weeks gestation with overweight or obesity from one of 6 academic and community-based obstetrics practices, randomized to either H42/H4U or usual prenatal care in a 1:1 ratio. The study duration is early pregnancy to 6 months postpartum. The primary outcome is total GWG, calculated as the difference between first clinic-assessed pregnancy weight and the weight at 37 weeks gestation. Key maternal and infant secondary outcomes include GDM incidence, weight retention at 6 months postpartum, infant weight, maternal health behaviors and wellness. CONCLUSIONS: This pragmatic clinical trial embeds a pregnancy health coaching program into prenatal care to allow parallel testing compared to usual prenatal care on the outcome of total GWG. The real-world design provides an approach to enhance its sustainability beyond the trial to ultimately improve maternal/child health outcomes and reduce future obesity. TRIAL REGISTRATION: The study was first registered at clinicaltrials.gov on 1/26/21 (NCT04724330).

Development of a Mobile App for Ecological Momentary Assessment of Circadian Data: Design Considerations and Usability Testing.

BACKGROUND: Collecting data on daily habits across a population of individuals is challenging. Mobile-based circadian ecological momentary assessment (cEMA) is a powerful frame for observing the impact of daily living on long-term health. OBJECTIVE: In this paper, we (1) describe the design, testing, and rationale for specifications of a mobile-based cEMA app to collect timing of eating and sleeping data and (2) compare cEMA and survey data collected as part of a 6-month observational cohort study. The ultimate goal of this paper is to summarize our experience and lessons learned with the Daily24 mobile app and to highlight the pros and cons of this data collection modality. METHODS: Design specifications for the Daily24 app were drafted by the study team based on the research questions and target audience for the cohort study. The associated backend was optimized to provide real-time data to the study team for participant monitoring and engagement. An external 8-member advisory board was consulted throughout the development process, and additional test users recruited as part of a qualitative study provided feedback through in-depth interviews. RESULTS: After ≥4 days of at-home use, 37 qualitative study participants provided feedback on the app. The app generally received positive feedback from test users for being fast and easy to use. Test users identified several bugs and areas where modifications were necessary to in-app text and instructions and also provided feedback on the engagement strategy. Data collected through the mobile app captured more variability in eating windows than data collected through a one-time survey, though at a significant cost. CONCLUSIONS: Researchers should consider the potential uses of a mobile app beyond the initial data collection when deciding whether the time and monetary expenditure are advisable for their situation and goals.

Immediate Reactions After the First Dose of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Messenger RNA Vaccines Do Not Preclude Second-Dose Administration.

Addressing coronavirus disease 2019 (COVID-19) vaccine hesitancy and minimizing potential vaccine contraindications are critical to combatting the pandemic. We describe a practical approach to immediate adverse events after the first dose of messenger RNA vaccines for severe acute respiratory syndrome coronavirus 2, focusing on diagnosis and management of allergic reactions.

Assessing the influence of atherosclerosis on drug coated balloon therapy using computational modelling.

Interventional therapies such as drug-eluting stents (DES) and drug-coated balloons (DCB) have significantly improved the clinical outcomes of patients with coronary occlusions in recent years. Despite this marked improvement, ischemic cardiovascular disease remains the most common cause of death worldwide. To address this, research efforts are focused on improving the safety and efficacy of the next generation of these devices. However, current experimental methods are unable to account for the influence of atherosclerotic lesions on drug uptake and retention. Therefore, in this study, we used an integrated approach utilizing both in vitro and in silico methods to assess the performance of DCB therapy. This approach was validated against existing in vivo results before being used to numerically estimate the effect of the atheroma. A bolus release of sirolimus was observed with our coating matrix. This, coupled with the rapid saturation of specific and non-specific binding sites observed in our study, indicated that increasing the therapeutic dose coated onto the balloons might not necessarily result in greater uptake and/or retention. Additionally, our findings alluded to an optimal exposure time, dependent on the coating matrix, for the DCBs to be expanded against the vessel. Moreover, our findings suggest that a biphasic drug release profile might be beneficial for establishing and maintaining the saturation of bindings sites within severely occluded vessels. Ultimately, we have demonstrated that computational methods may be capable of assessing the efficacy of DCB therapy as well as predict the influence of atherosclerotic lesions on said efficacy.

What influences the "when" of eating and sleeping?A qualitative interview study.

Timing of eating relative to sleep and endogenous circadian rhythm impacts weight and cardiometabolic health. We used qualitative methods to explore what influences the "when" of eating and sleeping. We conducted 37 one-on-one semi-structured interviews among participants with a body mass index (BMI) ≥ 25 kg/m2 recruited from three internal medicine clinics affiliated with an urban academic hospital. Participants (70.3% Female; 51.4% White; Age range: 21-83 years old) completed measures of social jetlag, physical activity, eating habits, and mobile application use and participated in interviews following a guide developed by the study team. Responses were recorded, transcribed and coded sequentially by two trained researchers using editing-style analysis to identify themes. We identified two main themes, each with subthemes: 1) influences on the "when" of eating and sleeping, with subthemes including social jetlag and being overscheduled, and 2) contextualizing beliefs and perceptions about the "when" of eating and sleeping, with subthemes including perceived recommendations for timing of eating and sleeping, and alignment of behaviors with perceived recommendations. Many participants noted being more flexible in their eating and sleeping times on work-free vs work days. The themes this study identified should be considered when designing interventions that influence the timing of eating and sleeping for weight management.

Biomechanics of Human Fetal Hearts with Critical Aortic Stenosis.

Critical aortic stenosis (AS) of the fetal heart causes a drastic change in the cardiac biomechanical environment. Consequently, a substantial proportion of such cases will lead to a single-ventricular birth outcome. However, the biomechanics of the disease is not well understood. To address this, we performed Finite Element (FE) modelling of the healthy fetal left ventricle (LV) based on patient-specific 4D ultrasound imaging, and simulated various disease features observed in clinical fetal AS to understand their biomechanical impact. These features included aortic stenosis, mitral regurgitation (MR) and LV hypertrophy, reduced contractility, and increased myocardial stiffness. AS was found to elevate LV pressures and myocardial stresses, and depending on severity, can drastically decrease stroke volume and myocardial strains. These effects are moderated by MR. AS alone did not lead to MR velocities above 3 m/s unless LV hypertrophy was included, suggesting that hypertrophy may be involved in clinical cases with high MR velocities. LV hypertrophy substantially elevated LV pressure, valve flow velocities and stroke volume, while reducing LV contractility resulted in diminished LV pressure, stroke volume and wall strains. Typical extent of hypertrophy during fetal AS in the clinic, however, led to excessive LV pressure and valve velocity in the FE model, suggesting that reduced contractility is typically associated with hypertrophy. Increased LV passive stiffness, which might represent fibroelastosis, was found to have minimal impact on LV pressures, stroke volume, and wall strain. This suggested that fibroelastosis could be a by-product of the disease progression and does not significantly impede cardiac function. Our study demonstrates that FE modelling is a valuable tool for elucidating the biomechanics of congenital heart disease and can calculate parameters which are difficult to measure, such as intraventricular pressure and myocardial stresses.

Perspectives of pregnant and postpartum women and obstetric providers to promote healthy lifestyle in pregnancy and after delivery: a qualitative in-depth interview study.

BACKGROUND: Pregnancy provides an opportunity to promote healthy lifestyle behaviors. This study's aim was to explore the perspectives of pregnant and postpartum women and obstetric providers around behavioral lifestyle changes in pregnancy and postpartum. METHODS: We conducted a qualitative study with pregnant and postpartum patients recruited from 2 prenatal care clinics at an urban, academic hospital in the United States. In-depth interviews with 23 pregnant or postpartum women and 11 obstetric providers were completed between October 2015-April 2016. Interviews were audio-recorded and transcribed verbatim. We coded transcripts for thematic content and applied the PRECEDE-PROCEED framework for results to directly inform program development. RESULTS: Six themes highlighted the predisposing, enabling and reinforcing factors that enable and sustain health behavior changes in pregnancy and postpartum: 1) "Motivation to have a healthy baby" during pregnancy and to "have my body back" after delivery, 2) Pre-pregnancy knowledge and experiences about pregnancy and the postpartum period, 3) Prioritizing wellness during pregnancy and postpartum, 4) The power of social support, 5) Accountability, 6) Integration with technology to reinforce behavior change. CONCLUSIONS: In this qualitative study, pregnant and postpartum women and obstetric providers described themes that are aimed at encouraging lifestyle changes to promote healthy weight gain in pregnancy and can directly inform the development of a behavioral weight management intervention for pregnant and postpartum women that is patient-centered and tailored to their needs.

A viscoelastic framework for inflation testing of gastrointestinal tissue.

Gastrointestinal (GI) diseases are often associated with hypertrophy of the layers of the GI wall, along with dilatation and a denervation of smooth muscle cells which alters the biomechanical properties of the tissue. 'Balloon distension' is a specialised experimental protocol performed on hollow organs to investigate their biomechanical properties. A balloon is inserted and pressurized during this procedure and the change in external diameter is monitored as a function of the applied pressure. A hyperelastic framework is often used in this context to evaluate the stresses in the wall after inflation. However, this only gives an idea about the final equilibrium state of the tissue, whereas the intermediate states of deformations are overlooked. GI soft tissues are viscoelastic, thus, the stress values during inflation are loading rate dependent and are higher than the equilibrium state values. Therefore, it is necessary to consider the time- and rate-dependent material properties during a balloon distension test. The aim of this work was to develop a viscoelastic framework for interpreting balloon distension experiments under finite deformation. To demonstrate the efficacy of the framework, it was used to recreate experimental results from intestinal and colonic tissue segments. In all cases, the simulation results were well matched (R2>0.9) with the experimental data.