Biomimetic Non-ergodic Aging by Dynamic-to-covalent Transitions in Physical Hydrogels.

Hydrogels are soft materials engineered to suit a multitude of applications that exploit their tunable mechanochemical properties. Dynamic hydrogels employing noncovalent, physically cross-linked networks dominated by either enthalpic or entropic interactions enable unique rheological and stimuli-responsive characteristics. In contrast to enthalpy-driven interactions that soften with increasing temperature, entropic interactions result in largely temperature-independent mechanical properties. By engineering interfacial polymer-particle interactions, we can induce a dynamic-to-covalent transition in entropic hydrogels that leads to biomimetic non-ergodic aging in the microstructure without altering the network mesh size. This transition is tuned by varying temperature and formulation conditions such as pH, which allows for multivalent tunability in properties. These hydrogels can thus be designed to exhibit either temperature-independent metastable dynamic cross-linking or time-dependent stiffening based on formulation and storage conditions, all while maintaining structural features critical for controlling mass transport, akin to many biological tissues. Such robust materials with versatile and adaptable properties can be utilized in applications such as wildfire suppression, surgical adhesives, and depot-forming injectable drug delivery systems.

Implementing a Quality Intervention to Improve Confidence in Outpatient Venous Thromboembolism Management.

INTRODUCTION: Guidelines recommend that patients with acute venous thromboembolism (VTE) represented by low-risk deep vein thrombosis (DVT) and pulmonary embolism (PE) receive initial treatment at home versus at the hospital, but a large percentage of these patients are not managed at home. This study assessed the effectiveness of a quality intervention on provider knowledge and confidence in evaluating outpatient treatment for patients with VTE in the emergency department (ED). METHODS: A pilot program to overcome obstacles to outpatient VTE treatment in appropriate patients was initiated at Baylor Scott & White Health Temple ED. Subsequently, a formalized quality intervention with a targeted educational program was developed and delivered to ED providers. Provider surveys were administered pre- and post-quality intervention in order to assess clinical knowledge, confidence levels, and perceived barriers. Patient discharge information was extracted from electronic health records. RESULTS: Twenty-five ED providers completed the pre- and post-surveys; 690 and 356 patients with VTE were included in the pre- and post-pilot and pre- and post-quality intervention periods, respectively. Many ED providers reported that a major barrier to discharging patients to outpatient care was the lack of available and adequate patient follow-up appointments. Notably, after the quality intervention, an increase in provider clinical knowledge and confidence scores was observed. Discharge rates for patients with VTE increased from 25.6% to 27.5% after the pilot intervention and increased from 28.5% to 29.9% after the quality intervention, but these differences were not statistically significant. Despite instantaneous uptick in discharge rates after the interventions, there was not a long-lasting effect. CONCLUSION: Although the quality intervention led to improvements in provider clinical knowledge and confidence and identified barriers to discharging patients with VTE, discharge rates remained stable, underscoring the need for additional endeavors.

When patients develop blood clots in their veins or have blood clots travel to their lungs, they may seek treatment at the hospital emergency department. As a best practice, most people can treat blood clots with medicines at home; however, many patients are treated at the hospital. This study looked at how an education program for doctors in the hospital could help more patients be treated at home. The education program improved doctors' knowledge and confidence when evaluating patients with blood clots who could be treated at home. However, this study found that the number of patients treated at home was the same before and after the doctors participated in the education program. Two major problems that prevented patients from being treated at home were not having follow-up appointments readily available and patients taking their medicine as needed. More and different types of programs may help doctors understand the best ways to treat patients with blood clots in the emergency department.

Mechanisms of Exercise Intolerance Across the Breast Cancer Continuum: A Pooled Analysis of Individual Patient Data.

PURPOSE: The purpose of this study is to evaluate the prevalence of abnormal cardiopulmonary responses to exercise and pathophysiological mechanism(s) underpinning exercise intolerance across the continuum of breast cancer (BC) care from diagnosis to metastatic disease. METHODS: Individual participant data from four randomized trials spanning the BC continuum ([1] prechemotherapy [n = 146], [2] immediately postchemotherapy [n = 48], [3] survivorship [n = 138], and [4] metastatic [n = 47]) were pooled and compared with women at high-risk of BC (BC risk; n = 64). Identical treadmill-based peak cardiopulmonary exercise testing protocols evaluated exercise intolerance (peak oxygen consumption; V̇O2peak) and other resting, submaximal, and peak cardiopulmonary responses. The prevalence of 12 abnormal exercise responses was evaluated. Graphical plots of exercise responses were used to identify oxygen delivery and/or uptake mechanisms contributing to exercise intolerance. Unsupervised, hierarchical cluster analysis was conducted to explore exercise response phenogroups. RESULTS: Mean V̇O2peak was 2.78 ml O2.kg-1·min-1 (95% confidence interval [CI], -3.94, -1.62 mL O2.kg-1·min-1; P < 0.001) lower in the pooled BC cohort (52 ± 11 yr) than BC risk (55 ± 10 yr). Compared with BC risk, the pooled BC cohort had a 2.5-fold increased risk of any abnormal cardiopulmonary response (odds ratio, 2.5; 95% confidence interval, 1.2, 5.3; P = 0.014). Distinct exercise responses in BC reflected impaired oxygen delivery and uptake relative to control, although considerable inter-individual heterogeneity within cohorts was observed. In unsupervised, hierarchical cluster analysis, six phenogroups were identified with marked differences in cardiopulmonary response patterns and unique clinical characteristics. CONCLUSIONS: Abnormal cardiopulmonary response to exercise is common in BC and is related to impairments in oxygen delivery and uptake. The identification of exercise response phenogroups could help improve cardiovascular risk stratification and guide investigation of targeted exercise interventions.

Cost-Effectiveness Evaluation of Oral CGRP Antagonists, Atogepant and Rimegepant, for the Preventative Treatment of Episodic Migraine: Results from a US Societal Perspective Model.

BACKGROUND AND OBJECTIVES: Two oral calcitonin gene-related peptide (CGRP) antagonists, atogepant and rimegepant, were approved in 2021 for the preventive treatment of episodic migraine (EM), yet no formal cost-effectiveness analysis has been published. The objective of this study was to evaluate the cost-effectiveness of atogepant 60 mg and rimegepant 75 mg compared with placebo. METHODS: A decision tree model was constructed over a 1-year time horizon from a US societal perspective. Patient cohorts were simulated using baseline and change from baseline monthly migraine days (MMDs) reported in the trials to incorporate responder rates and within patient response into the model. Due to heterogeneity between the trial populations, each medication was compared with its respective trial's placebo group. Direct healthcare resource costs, productivity costs, acute medication costs, and quality-of-life values were obtained from the literature. RESULTS: The atogepant cohort experienced an incremental increase in healthcare plus productivity costs of $11,978 when compared with placebo, with a gain of 0.026 quality-adjusted life-years (QALYs). This yielded an incremental cost-effectiveness ratio (ICER) of more than $450,000/QALY. The rimegepant cohort experienced an incremental increase of $21,692 when compared with placebo, with a gain of 0.024 QALYs. This yields an ICER of more than $890,000/QALY when comparing rimegepant with placebo. Cost savings between atogepant and atogepant placebo were greatest with respect to acute medication costs at $735 of savings over 1 year, followed by savings of $135 for healthcare resource utilization and $34 for productivity costs. A similar relationship was seen between rimegepant and rimegepant placebo. One-way deterministic sensitivity analysis found that monthly acquisition costs of atogepant and rimegepant had the largest impact on the ICER, respectively. CONCLUSIONS: Atogepant and rimegepant were both unable to meet generally accepted cost-effectiveness thresholds < 150,0000/QALY. Additional studies are needed to better guide decision making regarding oral CGRPs' place in therapy.

Characterization of Regolith And Trace Economic Resources (CRATER): An Orbitrap-based laser desorption mass spectrometry instrument for in situ exploration of the Moon.

RATIONALE: Characterization of Regolith And Trace Economic Resources (CRATER), an Orbitrap™-based laser desorption mass spectrometry instrument designed to conduct high-precision, spatially resolved analyses of planetary materials, is capable of answering outstanding science questions about the Moon's formation and the subsequent processes that have modified its (sub)surface. METHODS: Here, we describe the baseline design of the CRATER flight model, which requires <20 000 cm3  volume, <10 kg mass, and <60 W peak power. The analytical capabilities and performance metrics of a prototype that meets the full functionality of the flight model are demonstrated. RESULTS: The instrument comprises a high-power, solid-state, pulsed ultraviolet (213 nm) laser source to ablate the surface of the lunar sample, a custom ion optical interface to accelerate and collimate the ions produced at the ablation site, and an Orbitrap mass analyzer capable of discriminating competing isobars via ultrahigh mass resolution and high mass accuracy. The CRATER instrument can measure elemental and isotopic abundances and characterize the organic content of lunar surface samples, as well as identify economically valuable resources for future exploration. CONCLUSION: An engineering test unit of the flight model is currently in development to serve as a pathfinder for near-term mission opportunities.

Space-qualifying silicon photonic modulators and circuits.

Reducing the form factor while retaining the radiation hardness and performance matrix is the goal of avionics. While a compromise between a transistor's size and its radiation hardness has reached consensus in microelectronics, the size-performance balance for their optical counterparts has not been quested but eventually will limit the spaceborne photonic instruments' capacity to weight ratio. Here, we performed space experiments of photonic integrated circuits (PICs), revealing the critical roles of energetic charged particles. The year-long cosmic radiation exposure does not change carrier mobility but reduces free carrier lifetime, resulting in unchanged electro-optic modulation efficiency and well-expanded optoelectronic bandwidth. The diversity and statistics of the tested PIC modulator indicate the minimal requirement of shielding for PIC transmitters with small footprint modulators and complexed routing waveguides toward lightweight space terminals for terabits communications and intersatellite ranging.

Exploring factors related to clinically advanced fibrosis in patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis.

OBJECTIVES: To describe the clinical profile of nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) patients in a Texas integrated delivery network (IDN) and elucidate the local relationship between patient factors and the risk of advanced fibrosis. METHODS: This observational, retrospective, cross-sectional study utilized existing data from the electronic health record at a large Texas IDN. Data was collected during the study period from 1 January 2019, to 1 March 2023. Patient characteristics, comorbidities, labs, and medication orders were collected from the most recent encounter in which a Fibrosis-4 (FIB-4) score could be calculated. Chi square tests and analysis of variance (ANOVA) tests were conducted to evaluate differences among the three fibrosis risk categories. Ordinal logistic regression was utilized to assess associations between select variables and a higher risk of advanced fibrosis. RESULTS: A total of 56,253 patients were included in the study. 34,839 (61.9%) were Low-Risk 15,578 (27.7%) were Intermediate-Risk, and 5,836 (10.4%) were High-Risk of advanced fibrosis. Results showed that up to 70.4% of patients within a risk group were obese. Only 49.5% of patients in the High-Risk group had at least one gastroenterologist or hepatologist visit. Males, Medicare patients, former smokers, and those with hypertension, type 2 diabetes, and chronic kidney disease were associated with a higher risk of advanced fibrosis. CONCLUSION: This study highlights the need for early screening and proactive management of metabolic risk factors for patients with NAFLD/NASH. The findings indicate a notable prevalence of obesity in the study population, a need for specialist referral for those at High-Risk of advanced fibrosis, and the importance of routine labs to evaluate metabolic factors. Primary care providers may be ideal providers to target these interventions and address this care need.

Nomogram for Predicting Risk of Cancer Therapy-Related Cardiac Dysfunction in Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.

BACKGROUND: Cancer therapy-related cardiac dysfunction (CTRCD) is an important treatment-limiting toxicity for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer that adversely affects cancer and cardiovascular outcomes. Easy-to-use tools that incorporate readily accessible clinical variables for individual estimation of CTRCD risk are needed. METHODS AND RESULTS: From 2004 to 2013, 1440 patients with stage I to III HER2-positive breast cancer treated with trastuzumab-based therapy were identified. A multivariable Cox proportional hazards model was constructed to identify risk factors for CTRCD and included the 1377 patients in whom data were complete. Nine clinical variables, including age, race, body mass index, left ventricular ejection fraction, systolic blood pressure, coronary artery disease, diabetes, arrhythmia, and anthracycline exposure were built into a nomogram estimating risk of CTRCD at 1 year. The nomogram was validated for calibration and discrimination using bootstrap resampling. A total of 177 CTRCD events occurred within 1 year of HER2-targeted treatment. The nomogram for prediction of 1-year CTRCD probability demonstrated good discrimination, with a concordance index of 0.687. The predicted and observed probabilities of CTRCD were similar, demonstrating good model calibration. CONCLUSIONS: A nomogram composed of 9 readily accessible clinical variables provides an individualized 1-year risk estimate of CTRCD among women with HER2-positive breast cancer receiving HER2-targeted therapy. This nomogram represents a simple-to-use tool for clinicians and patients that can inform clinical decision-making on breast cancer treatment options, optimal frequency of cardiac surveillance, and role of cardioprotective strategies.

Regional nodal irradiation for breast cancer using volumetric modulated arc therapy: Echocardiographic functional outcomes.

Introduction: Regional nodal irradiation (RNI) for breast cancer yields improvements in disease outcomes, yet comprehensive target coverage often increases cardiac radiation (RT) dose. Volumetric modulated arc therapy (VMAT) may mitigate high-dose cardiac exposure, although often increases the volume of low-dose exposure. The cardiac implications of this dosimetric configuration (in contrast to historic 3D conformal techniques) remains uncertain. Methods: Eligible patients receiving adjuvant RNI using VMAT for locoregional breast cancer were prospectively enrolled on an IRB-approved study. Echocardiograms were performed prior to RT, at the conclusion of RT, and 6-months following RT. Echocardiographic parameters were measured by a single reader (AY) and measures were compared pre- and post-RT via the Wilcoxon rank sum test. Changes in echocardiographic parameters over time were compared to mean and max heart doses via the Spearman correlation test. Results: Among 19 evaluable patients (median age 38), 89% (n=17) received doxorubicin and 37% (n=7) received trastuzumab/pertuzumab combination therapy. All patients received VMAT-based whole-breast/chest-wall and regional nodal irradiation. Average mean heart dose was 456cGy (range 187-697cGy) and average max heart dose was 3001cGy (1560-4793cGy). Among salient echocardiographic parameters, no significant decrement in cardiac function was observed when comparing pre-RT to 6-months post-RT: mean left ventricular ejection fraction (LVEF) was 61.8 (SD 4.4) pre-RT and 62.7 (SD 3.8) 6-months post-RT (p=0.493); mean global longitudinal strain (GLS) was -19.3 (SD 2.2) pre-RT and -19.6 (SD 1.8) 6-months post-RT (p=0.627). No individual patient exhibited reduced LVEF or sustained decrement in GLS. No correlations were observed for changes in LVEF or GLS when compared to mean or maximum heart doses (p>0.1 for all). Conclusions: VMAT for left-sided RNI yielded no significant early decrement in echocardiographic parameters of cardiac function, including LVEF and GLS. No patient exhibited significant LVEF changes, and none exhibited sustained decrements in GLS. VMAT may be a reasonable approach to cardiac avoidance in patients requiring RNI, including those receiving anthracyclines and HER2-directed therapy. Larger cohorts with longer follow-up will be needed to validate these findings.

Hospital outcomes and costs for prostate cancer patients with comorbid heart failure by age group: An analysis of the US Nationwide Inpatient Sample.

RATIONALE, AIMS, AND OBJECTIVES: The prevalence of patients hospitalized with comorbid prostate cancer (PC) and heart failure (HF) has been steadily increasing. Both diseases share a set of common risk factors, with the most prominent being age. This study aimed to examine the outcomes and costs for patients with comorbid PC and HF, stratified by age. METHODS: We analyzed 41,340 hospitalization events of patients with PC using the US National Inpatient Sample from 2015 to 2018. Associations of HF with in-hospital mortality, length of stay (LOS), and hospital costs per hospitalization were measured using multivariable logistic regression, negative binomial regression, and generalized linear regression with log-link and gamma distribution, respectively, controlling for covariates. Subgroup analyses were performed for age groups <65 and ≥65. RESULTS: Visits of comorbid HF patients made up 2.3% (n = 952) of the PC study sample. Compared with PC patients without HF, those with HF had higher in-hospital mortality rates (odds ratio = 1.33, 95% confidence interval [CI] = 0.96-1.84, p = 0.085), longer hospital stays (incidence rate ratio = 1.32, 95% CI = 1.21-1.44, p < 0.001), and higher hospital costs (cost ratio = 1.17, 95% CI = 1.07-1.27, p = 0.001), controlling for covariates. On average, this amounted to a higher in-hospital mortality rate of 2.10%, an increased LOS of 1.73 days, and higher hospital costs of $2110 per patient. While in-hospital mortality did not differ significantly in patients aged <65 (p = 0.900), patients aged ≥65 had a 41% increased risk of in-hospital mortality compared with those without HF (p = 0.047). CONCLUSIONS: In comparison to those without HF, PC patients with comorbid HF showed higher rates of in-hospital mortality, LOS, and hospital costs, with mortality showing a significant difference exclusively in the ≥65 population. Effective management of older patients with PC is needed to improve outcomes and decrease costs.

Association of Circulating Cardiomyocyte Cell-Free DNA With Cancer Therapy-Related Cardiac Dysfunction in Patients Undergoing Treatment for ERBB2-Positive Breast Cancer.

Importance: Cancer therapy-related cardiac dysfunction (CTRCD) is a potentially serious cardiotoxicity of treatments for ERBB2-positive breast cancer (formerly HER2). Identifying early biomarkers of cardiotoxicity could facilitate an individualized approach to cardiac surveillance and early pharmacologic intervention. Circulating cell-free DNA (cfDNA) of cardiomyocyte origin is present during acute cardiac injury but has not been established as a biomarker of CTRCD. Objective: To determine whether circulating cardiomyocyte cfDNA is associated with CTRCD in patients with ERBB2-positive breast cancer treated with anthracyclines and ERBB2-targeted therapy. Design, Setting, and Participants: A prospective cohort of 80 patients with ERBB2-positive breast cancer enrolled at an academic cancer center between July 2014 and April 2016 underwent echocardiography and blood collection at baseline, after receiving anthracyclines, and at 3 months and 6 months of ERBB2-targeted therapy. Participants were treated with doxorubicin-based chemotherapy followed by trastuzumab (+/- pertuzumab). The current biomarker study includes participants with sufficient biospecimen available for analysis after anthracycline therapy. Circulating cardiomyocyte-specific cfDNA was quantified by a methylation-specific droplet digital polymerase chain reaction assay. Data for this biomarker study were collected and analyzed from June 2021 through April 2022. Main Outcomes and Measures: The outcome of interest was 1-year CTRCD, defined by symptomatic heart failure or an asymptomatic decline in left ventricular ejection fraction (≥10% from baseline to less than lower limit of normal or ≥16%). Values for cardiomyocyte cfDNA and high-sensitivity cardiac troponin I (hs-cTnI) measured after patients completed treatment with anthracyclines were compared between patients who later developed CTRCD vs patients who did not using the Wilcoxon rank sum test, and the association of post-anthracycline cardiomyocyte cfDNA level with CTRCD was estimated using logistic regression. Results: Of 71 patients included in this study, median (IQR) age was 50 (44-58) years, all were treated with dose-dense doxorubicin, and 48 patients underwent breast radiotherapy. Ten of 71 patients (14%) in this analysis developed CTRCD. The level of cardiomyocyte cfDNA at the post-anthracycline time point was higher in patients who subsequently developed CTRCD (median, 30.5 copies/mL; IQR, 24-46) than those who did not (median, 7 copies/mL; IQR, 2-22; P = .004). Higher cardiomyocyte cfDNA level after completion of anthracycline chemotherapy was associated with risk of CTRCD (hazard ratio, 1.02 per 1-copy/mL increase; 95% CI, 1.00-1.03; P = .046). Conclusions and Relevance: This study found that higher cardiomyocyte cfDNA level after completion of anthracycline chemotherapy was associated with risk of CTRCD. Cardiomyocyte cfDNA quantification shows promise as a predictive biomarker to refine risk stratification for CTRCD among patients with breast cancer receiving cardiotoxic cancer therapy, and its use warrants further validation. Trial Registration: ClinicalTrials.gov Identifier: NCT02177175.

pH-responsive ratiometric photoacoustic imaging of polyaniline nanoparticle-coated needle for targeted cancer biopsy.

Cancer microenvironment exhibits lower pH compared to healthy tissues, a characteristic which can be exploited using a pH-responsive needle to increase the accuracy of cancer biopsy. A needle, coated with pH-responsive polyaniline (PANI) nanoparticles (PANI-needle), is developed for the minimally invasive and quantitative pH analysis of tissue based on ratiometric photoacoustic (PA) imaging. The ratiometric PA signal from the PANI-needle within the 850-700 nm wavelength range shows a linear response as pH changes from 7.5 to 6.5. Owing to the high surface area of nanostructured PANI, the PA signal of PANI-needle exhibits a fast and reversible response of less than a few seconds. In a tissue-mimicking hydrogel phantom composed of two regions with different pH, PA ratios of PANI-needle successfully differentiate the local pH. The PANI-needle coupled with ultrasound-guided PA imaging is a promising technology for detection of malignant tissue through quantitative pH analysis during needle biopsy.

Impact of specialty pharmacy collaboration with rheumatology clinics to improve the achievement of treat-to-target goals in patients with rheumatoid arthritis: a pilot study.

In rheumatoid arthritis, the use of Routine Assessment of Patient Index Data 3 (RAPID3) assessments to meet treat-to-target goals is endorsed by the 2021 American College of Rheumatology guidelines. In November 2020, the Baylor Scott & White specialty pharmacy implemented a new service that included more frequent collection of RAPID3 scores and standardized provider communication for patients co-managed by a Baylor Scott & White rheumatology clinic. The objective was to evaluate the impact of this new service on rheumatoid arthritis disease activity. Before the new service started, patients followed a protocol of RAPID3 assessments that occurred every 6 months; once the service began, patients were followed using an algorithm in which patients with higher disease activity were contacted more frequently. Eighty-six percent of patients in the pre-intervention group (n = 7) compared with 100% of patients in the post-intervention group (n = 10) had high to moderate disease activity at baseline. Within a 6-month follow-up period in both groups, the percentage of high to moderate disease activity patients decreased by 30% in the post-intervention group and remained the same in the pre-intervention group. These results support the positive impact increased specialty pharmacy services may have on clinical outcomes; therefore, the continued expansion of these services should be considered.

Rationale and design of a cardiac safety study for reduced cardiotoxicity surveillance during HER2-targeted therapy.

BACKGROUND: Echocardiograms are recommended every 3 months in patients receiving human epidermal growth factor 2 (HER2)-targeted therapy for surveillance of left ventricular ejection fraction (LVEF). Efforts to tailor treatment for HER2-positive breast cancer have led to greater use of non-anthracycline regimens that are associated with lower cardiotoxicity risk, raising into question the need for frequent cardiotoxicity surveillance for these patients. This study seeks to evaluate whether less frequent cardiotoxicity surveillance (every 6 months) is safe for patients receiving a non-anthracycline HER2-targeted treatment regimen. METHODS/DESIGN: We will enroll 190 women with histologically confirmed HER2-positive breast cancer scheduled to receive a non-anthracycline HER2-targeted treatment regimen for a minimum of 12 months. All participants will undergo echocardiograms before and 6-, 12-, and 18-months after initiation of HER2-targeted treatment. The primary composite outcome is symptomatic heart failure (New York Heart Association class III or IV) or death from cardiovascular causes. Secondary outcomes include: 1) echocardiographic indices of left ventricular systolic function; 2) incidence of cardiotoxicity, defined by a ≥ 10% absolute reduction in left ventricular ejection fraction (LVEF) from baseline to < 53%; and 3) incidence of early interruption of HER2-targeted therapy. CONCLUSIONS: To our knowledge, this will be the first prospective study of a risk-based approach to cardiotoxicity surveillance. We expect findings from this study will inform the development of updated clinical practice guidelines to improve cardiotoxicity surveillance practices during HER2-positive breast cancer treatment. TRIAL REGISTRATION: The trial was registered in the ClinicalTrials.gov registry (identifier NCT03983382) on June 12, 2019.

Characterizing a photoacoustic and fluorescence imaging platform for preclinical murine longitudinal studies.

Significance: To effectively study preclinical animal models, medical imaging technology must be developed with a high enough resolution and sensitivity to perform anatomical, functional, and molecular assessments. Photoacoustic (PA) tomography provides high resolution and specificity, and fluorescence (FL) molecular tomography provides high sensitivity; the combination of these imaging modes will enable a wide range of research applications to be studied in small animals. Aim: We introduce and characterize a dual-modality PA and FL imaging platform using in vivo and phantom experiments. Approach: The imaging platform's detection limits were characterized through phantom studies that determined the PA spatial resolution, PA sensitivity, optical spatial resolution, and FL sensitivity. Results: The system characterization yielded a PA spatial resolution of 173 ± 17 µ m in the transverse plane and 640 ± 120 µ m in the longitudinal axis, a PA sensitivity detection limit not less than that of a sample with absorption coefficient µ a = 0.258 cm - 1 , an optical spatial resolution of 70 µ m in the vertical axis and 112 µ m in the horizontal axis, and a FL sensitivity detection limit not < 0.9 µ M concentration of IR-800. The scanned animals displayed in three-dimensional renders showed high-resolution anatomical detail of organs. Conclusions: The combined PA and FL imaging system has been characterized and has demonstrated its ability to image mice in vivo, proving its suitability for biomedical imaging research applications.

Timing of exercise therapy when initiating adjuvant chemotherapy for breast cancer: a randomized trial.

AIMS: The most appropriate timing of exercise therapy to improve cardiorespiratory fitness (CRF) among patients initiating chemotherapy is not known. The effects of exercise therapy administered during, following, or during and following chemotherapy were examined in patients with breast cancer. METHODS AND RESULTS: Using a parallel-group randomized trial design, 158 inactive women with breast cancer initiating (neo)adjuvant chemotherapy were allocated to receive (1:1 ratio): usual care or one of three exercise regimens-concurrent (during chemotherapy only), sequential (after chemotherapy only), or concurrent and sequential (continuous) (n = 39/40 per group). Exercise consisted of treadmill walking three sessions/week, 20-50 min at 55%-100% of peak oxygen consumption (VO2peak) for ≈16 (concurrent, sequential) or ≈32 (continuous) consecutive weeks. VO2peak was evaluated at baseline (pre-treatment), immediately post-chemotherapy, and ≈16 weeks after chemotherapy. In intention-to-treat analysis, there was no difference in the primary endpoint of VO2peak change between concurrent exercise and usual care during chemotherapy vs. VO2peak change between sequential exercise and usual care after chemotherapy [overall difference, -0.88 mL O2·kg-1·min-1; 95% confidence interval (CI): -3.36, 1.59, P = 0.48]. In secondary analysis, continuous exercise, approximately equal to twice the length of the other regimens, was well-tolerated and the only strategy associated with significant improvements in VO2peak from baseline to post-intervention (1.74 mL O2·kg-1·min-1, P < 0.001). CONCLUSION: There was no statistical difference in CRF improvement between concurrent vs. sequential exercise therapy relative to usual care in women with primary breast cancer. The promising tolerability and CRF benefit of ≈32 weeks of continuous exercise therapy warrant further evaluation in larger trials.

Subcutaneous delivery of an antibody against SARS-CoV-2 from a supramolecular hydrogel depot.

Prolonged maintenance of therapeutically-relevant levels of broadly neutralizing antibodies (bnAbs) is necessary to enable passive immunization against infectious disease. Unfortunately, protection only lasts for as long as these bnAbs remain present at a sufficiently high concentration in the body. Poor pharmacokinetics and burdensome administration are two challenges that need to be addressed in order to make pre- and post-exposure prophylaxis with bnAbs feasible and effective. In this work, we develop a supramolecular hydrogel as an injectable, subcutaneous depot to encapsulate and deliver antibody drug cargo. This polymer-nanoparticle (PNP) hydrogel exhibits shear-thinning and self-healing properties that are required for an injectable drug delivery vehicle. In vitro drug release assays and diffusion measurements indicate that the PNP hydrogels prevent burst release and slow the release of encapsulated antibodies. Delivery of bnAbs against SARS-CoV-2 from PNP hydrogels is compared to standard routes of administration in a preclinical mouse model. We develop a multi-compartment model to understand the ability of these subcutaneous depot materials to modulate the pharmacokinetics of released antibodies; the model is extrapolated to explore the requirements needed for novel materials to successfully deliver relevant antibody therapeutics with different pharmacokinetic characteristics.

Association of cardiac calcium burden with overall survival after radiotherapy for non-small cell lung cancer.

Background and purpose: Coronary calcifications are associated with coronary artery disease in patients undergoing radiotherapy (RT) for non-small cell lung cancer (NSCLC). We quantified calcifications in the coronary arteries and aorta and investigated their relationship with overall survival (OS) in patients treated with definitive RT (Def-RT) or post-operative RT (PORT). Materials and methods: We analyzed 263 NSCLC patients treated from 2004 to 2017. Calcium burden was ascertained with a Hounsfield unit (HU) cutoff of > 130 in addition to a deep learning (DL) plaque estimator. The HU cutoff volumes were defined for coronary arteries (PlaqueCoro) and coronary arteries and aorta combined (PlaqueCoro+Ao), while the DL estimator ranged from 0 (no plaque) to 3 (high plaque). Patient and treatment characteristics were explored for association with OS. Results: The median PlaqueCoro and PlaqueCoro+Ao was 0.75 cm3 and 0.87 cm3 in the Def-RT group and 0.03 cm3 and 0.52 cm3 in the PORT group. The median DL estimator was 2 in both cohorts. In Def-RT, large PlaqueCoro (HR:1.11 (95%CI:1.04-1.19); p = 0.008), and PlaqueCoro+Ao (HR:1.06 (95%CI:1.02-1.11); p = 0.03), and poor Karnofsky Performance Status (HR: 0.97 (95%CI: 0.94-0.99); p = 0.03) were associated with worse OS. No relationship was identified between the plaque volumes and OS in PORT, or between the DL plaque estimator and OS in either Def-RT or PORT. Conclusions: Coronary artery calcification assessed from RT planning CT scans was significantly associated with OS in patients who underwent Def-RT for NSCLC. This HU thresholding method can be straightforwardly implemented such that the role of calcifications can be further explored.

Bridging the Cervicothoracic Junction During Multi-Level Posterior Cervical Decompression and Fusion: A Systematic Review and Meta-Analysis.

STUDY DESIGN: Systematic review and Meta-analysis. OBJECTIVE: This systematic review seeks to compare fusion, reoperation and complication rates, estimated blood loss (EBL), and surgical time between multi-level instrumented fusions with LIVs (lowest instrumented vertebra) in the cervical spine and those that extend into the thoracic spine. SUMMARY OF BACKGROUND DATA: Several studies address the question of whether to extend a long-segment, posterior cervical fusions, performed for degenerative disease, into the upper thoracic spine. Recommendations for appropriate LIV continue to vary. METHODS: A comprehensive computerized literature search through multiple electronic databases without date limits up until April 3rd, 2020 using combinations of key search terms and sets of inclusion/exclusion criteria was performed. RESULTS: Our comprehensive literature search yielded 3852 studies. Of these, 8 articles consisting of 1162 patients were included in the meta-analysis. In 61.2% of the patients, the fusion did not cross the cervicothoracic junction (CTJ) (cervical LIV, CLV). In the remaining 38.8%, the fusion extended into the upper thoracic spine (thoracic LIV, TLV). Overall, mean patient age was 62.5 years (range: 58.8-66.1 years). Our direct analysis showed that odds of fusion were not statistically different between the CLV and TLV groups (OR: .648, 95% CI: .336-1.252, P = .197). Similarly, odds of reoperation (OR: 0.726, 95% CI: 0.493-1.068, P = .104) and complication rates were similar between the 2 groups (OR: 1.214, 95% CI: 0.0.750-1.965, P = .430). Standardized mean difference (SMD) for the blood loss (SMD: .728, 95% CI: 0.554-.901, P = .000) and operative (SMD: 0.653, 95% CI: .479-.826, P = .000) differed significantly between the 2 groups. The indirect analysis showed similar fusion (Effect Size (ES)TLV: .892, 95% CI: .840-.928 vs ESCLV:0.894, 95% CI:0.849-.926); reoperation rate (ESTLV:0.112, 95% CI: 0.075-.164 vs ESCLV: .125, 95% CI: .071-.211) and complication rates (ESTLV: .108, 95% CI: .074-.154 vs ESCLV:0.081, 95% CI: .040-.156). CONCLUSIONS: Our meta-analysis showed that fusion, complication, and reoperation rates did not differ significantly between patients in whom multi-level posterior fusions ended in the cervical spine vs those of which was extended into the thoracic spine. The mean blood loss, operative time and length of stay were significantly lower in patients with CLV at C6 or C7, compared to their counterparts. These data suggest that, absent focal, C7-T1 pathology, extension of long, posterior cervical fusions into the thoracic spine may not be necessary.

Innate immune signaling drives late cardiac toxicity following DNA-damaging cancer therapies.

Late cardiac toxicity is a potentially lethal complication of cancer therapy, yet the pathogenic mechanism remains largely unknown, and few treatment options exist. Here we report DNA-damaging agents such as radiation and anthracycline chemotherapies inducing delayed cardiac inflammation following therapy due to activation of cGAS- and STING-dependent type I interferon signaling. Genetic ablation of cGAS-STING signaling in mice inhibits DNA damage-induced cardiac inflammation, rescues late cardiac functional decline, and prevents death from cardiac events. Treatment with a STING antagonist suppresses cardiac interferon signaling following DNA-damaging therapies and effectively mitigates cardiac toxicity. These results identify a therapeutically targetable, pathogenic mechanism for one of the most vexing treatment-related toxicities in cancer survivors.