Intravascular delivery of an MK2 inhibitory peptide to prevent restenosis after angioplasty.

Peripheral artery disease is commonly treated with balloon angioplasty, a procedure involving minimally invasive, transluminal insertion of a catheter to the site of stenosis, where a balloon is inflated to open the blockage, restoring blood flow. However, peripheral angioplasty has a high rate of restenosis, limiting long-term patency. Therefore, angioplasty is sometimes paired with delivery of cytotoxic drugs like paclitaxel to reduce neointimal tissue formation. We pursue intravascular drug delivery strategies that target the underlying cause of restenosis - intimal hyperplasia resulting from stress-induced vascular smooth muscle cell switching from the healthy contractile into a pathological synthetic phenotype. We have established MAPKAP kinase 2 (MK2) as a driver of this phenotype switch and seek to establish convective and contact transfer (coated balloon) methods for MK2 inhibitory peptide delivery to sites of angioplasty. Using a flow loop bioreactor, we showed MK2 inhibition in ex vivo arteries suppresses smooth muscle cell phenotype switching while preserving vessel contractility. A rat carotid artery balloon injury model demonstrated inhibition of intimal hyperplasia following MK2i coated balloon treatment in vivo. These studies establish both convective and drug coated balloon strategies as promising approaches for intravascular delivery of MK2 inhibitory formulations to improve efficacy of balloon angioplasty.

Evaluating the potential impact of lifestyle-based behavior change interventions delivered at the time of colorectal cancer screening.

PURPOSE: To analyze interventions implemented at the time of colorectal cancer (CRC) screening, or among individuals who have previously undergone investigation for CRC, focused on reducing CRC risk through promotion of lifestyle behavior change. Additionally, this review evaluated to what extent such interventions apply behavior change techniques (BCTs) to achieve their objectives. METHODS: Five databases were systematically searched to identify randomized control trials seeking to reduce CRC risk through behavior change. Outcomes were changes in health-related lifestyle behaviors associated with CRC risk, including changes in dietary habits, body mass index, smoking behaviors, alcohol consumption, and physical activity. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using random effects models. BCT's were coded from a published taxonomy of 93 techniques. RESULTS: Ten RCT's met the inclusion criteria. Greater increase in fruit/vegetable consumption in the intervention group were observed with respect to the control (SMD 0.13, 95% CI 0.08 to 0.18; p < 0.001). Across fiber, alcohol, fat, red meat, and multivitamin consumption, and smoking behaviors, similar positive outcomes were observed (SMD 0.09-0.57 for all, p < 0.01). However, among physical activity and body mass index, no difference between the intervention groups compared with controls were observed. A median of 7.5 BCTs were applied across included interventions. CONCLUSION: While magnitude of the observed effect sizes varied, they correspond to potentially important changes in lifestyle behaviors when considered on a population scale. Future interventions should identify avenues to maximize long-term engagement to promote sustained lifestyle behavior change.

Albumin-binding RNAi Conjugate for Carrier Free Treatment of Arthritis.

Osteoarthritis (OA) and rheumatoid arthritis (RA) are joint diseases that are associated with pain and lost quality of life. No disease modifying OA drugs are currently available. RA treatments are better established but are not always effective and can cause immune suppression. Here, an MMP13-selective siRNA conjugate was developed that, when delivered intravenously, docks onto endogenous albumin and promotes preferential accumulation in articular cartilage and synovia of OA and RA joints. MMP13 expression was diminished upon intravenous delivery of MMP13 siRNA conjugates, consequently decreasing multiple histological and molecular markers of disease severity, while also reducing clinical manifestations such as swelling (RA) and joint pressure sensitivity (RA and OA). Importantly, MMP13 silencing provided more comprehensive OA treatment efficacy than standard of care (steroids) or experimental MMP inhibitors. These data demonstrate the utility of albumin 'hitchhiking' for drug delivery to arthritic joints, and establish the therapeutic utility of systemically delivered anti-MMP13 siRNA conjugates in OA and RA. Editorial summary: Lipophilic siRNA conjugates optimized for albumin binding and "hitchhiking" can be leveraged to achieve preferential delivery to and gene silencing activity within arthritic joints. Chemical stabilization of the lipophilic siRNA enables intravenous siRNA delivery without lipid or polymer encapsulation. Using siRNA sequences targeting MMP13, a key driver of arthritis-related inflammation, albumin hitchhiking siRNA diminished MMP13, inflammation, and manifestations of osteoarthritis and rheumatoid arthritis at molecular, histological, and clinical levels, consistently outperforming clinical standards of care and small molecule MMP antagonists.

Medial Patellofemoral Ligament Reconstruction Using Allografts in Skeletally Immature Patients.

BACKGROUND: Patellar instability has the highest incidence in adolescents aged between 14 and 18 years. The unique relationship between the medial patellofemoral ligament (MPFL) and the distal femoral physis in skeletally immature patients warrants precisely positioned MPFL graft insertion. A paucity of data are available evaluating the results of MPFL reconstruction using allograft tendon before skeletal maturity. PURPOSES: (1) To assess the results of MPFL reconstruction using allograft tendon in skeletally immature patients by analyzing redislocation and reoperation rates, radiological outcomes, and patient-reported outcomes and (2) to determine whether epidemiological, intraoperative, or radiographic factors influence recurrent instability and clinical outcomes. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Prospectively collected data were retrospectively analyzed for 69 skeletally immature patients who experienced a first-time or recurrent lateral patellar dislocation and were treated with anatomic MPFL reconstruction. Inclusion criteria were MPFL reconstruction using allograft and the availability of preoperative magnetic resonance imaging scans in the presence of open or partially open physes. Patients with <2 years of follow-up and patients with previous surgeries on the same knee were excluded from the study. Preoperative radiographic imaging was reviewed and analyzed. Trochlear dysplasia, tibial tubercle-trochlear groove distance, and patellar height were evaluated. Descriptive data, concomitant injuries, surgical procedure details, complications, and postoperative history were assessed via review of medical records and patient charts. Validated patient-reported and surgeon-measured outcomes were collected pre- and postoperatively, including Kujala score, Lysholm score, and Tegner activity score. Return-to-sports rate was assessed. The influence of epidemiological, intraoperative, and radiographic parameters on the redislocation rates and clinical outcomes was assessed using a multiple linear regression model. RESULTS: A total of 79 physeal-sparing MPFL reconstructions (69 patients) met the inclusion criteria. The mean age of the patient cohort was 14.7 ± 1.8 years (range, 8.5-16.9 years). Within the mean follow-up time of 37.9 ± 12.1 months (range, 24-85 months after surgery, there were 12 patients with clinical failures resulting in reoperation. Eleven patients experienced a redislocation of the patella, and 1 patient sustained a transverse noncontact patellar fracture 6 months after index surgery that required operative fixation. No injuries to the distal femoral physes were clinically observed. At the final follow-up, patients had a mean Lysholm score (1-100) of 96.5 ± 6.7, a mean Kujala score (1-100) of 96.5 ± 7.4, and a mean Tegner Activity Scale score (1-10) of 4.9 ± 1.3. Patellar height and trochlear dysplasia did not influence redislocation or clinical scores. In total, 57 of the 63 patients (90.5%) who were engaged in sports before injury returned to the same or higher level of competition. In a subgroup analysis of patients who underwent isolated MPFL reconstruction (n = 44) without concomitant procedures, 9 patients (20.5%) experienced failure and had a redislocation. A univariate analysis of hazards for failure based on patient-specific variables was carried out. A body mass index ≥30 conveyed a hazard ratio of 2.51 (95% CI, 0.63-10.1; P = .19), and the tibial tubercle-trochlear groove distance by increments of 1 mm was associated with a hazard ratio of 2.02 (95% CI, 0.51-8.11; P = .32). CONCLUSION: Physeal-sparing anatomic reconstruction of the MPFL using an allograft tendon in skeletally immature patients was a safe and effective treatment for patellar instability, regardless of patellar height and trochlear dysplasia. Failure rates decreased when the MPFL reconstruction was performed concomitantly with a tibial tubercle osteotomy.

Acceptability of risk stratification within population-based cancer screening from the perspective of the general public: A mixed-methods systematic review.

INTRODUCTION: Risk-stratified cancer screening has the potential to improve resource allocation and the balance of harms and benefits by targeting those most likely to benefit. Public acceptability has implications for engagement, uptake and the success of such a programme. Therefore, this review seeks to understand whether risk stratification of population-based cancer screening programmes is acceptable to the general public and in what context. METHODS: Four electronic databases were searched from January 2010 to November 2021. Qualitative, quantitative and mixed-methods papers were eligible for inclusion. The Joanna Briggs Institute convergent integrated approach was used to synthesize the findings and the quality of included literature was assessed using the Mixed Methods Appraisal Tool. The Theoretical Framework of Acceptability was used as a coding frame for thematic analysis. PROSPERO record 2021 CRD42021286667. RESULTS: The search returned 12,039 citations, 22 of which were eligible for inclusion. The majority of studies related to breast cancer screening; other cancer types included ovarian, kidney, colorectal and prostate cancer. Risk stratification was generally acceptable to the public, who considered it to be logical and of wider benefit than existing screening practices. We identified 10 priorities for implementation across four key areas: addressing public information needs; understanding communication preferences for risk estimates; mitigating barriers to accessibility to avoid exacerbating inequalities; and the role of healthcare professionals in relation to supporting reduced screening for low-risk individuals. CONCLUSION: The public generally find risk stratification of population-based cancer screening programmes to be acceptable; however, we have identified areas that would improve implementation and require further consideration. PATIENT OR PUBLIC CONTRIBUTION: This paper is a systematic review and did not formally involve patients or the public; however, three patient and public involvement members were consulted on the topic and scope before the review commenced.

Assessing the Clinical Robustness of Digital Health Startups: Cross-sectional Observational Analysis.

BACKGROUND: The digital health sector has experienced rapid growth over the past decade. However, health care technology stakeholders lack a comprehensive understanding of clinical robustness and claims across the industry. OBJECTIVE: This analysis aimed to examine the clinical robustness and public claims made by digital health companies. METHODS: A cross-sectional observational analysis was conducted using company data from the Rock Health Digital Health Venture Funding Database, the US Food and Drug Administration, and the US National Library of Medicine. Companies were included if they sell products targeting the prevention, diagnosis, or treatment phases of the care continuum. Clinical robustness was defined using regulatory filings and clinical trials completed by each company. Public claims data included clinical, economic, and engagement claims regarding product outcomes made by each company on its website. RESULTS: A total of 224 digital health companies with an average age of 7.7 years were included in our cohort. Average clinical robustness was 2.5 (1.8 clinical trials and 0.8 regulatory filings) with a median score of 1. Ninety-eight (44%) companies had a clinical robustness score of 0, while 45 (20%) companies had a clinical robustness score of 5 or more. The average number of public claims was 1.3 (0.5 clinical, 0.4 economic, and 0.4 engagement); the median number of claims was 1. No correlation was observed between clinical robustness and number of clinical claims (r2=0.02), clinical robustness and total funding (r2=0.08), or clinical robustness and company age (r2=0.18). CONCLUSIONS: Many digital health companies have a low level of clinical robustness and do not make many claims as measured by regulatory filings, clinical trials, and public data shared online. Companies and customers may benefit from investing in greater clinical validation efforts.

Willingness of Black and White Adults to Accept Vaccines in Development: An Exploratory Study Using National Survey Data.

PURPOSE: Explore acceptability of vaccines in development: cancer, Type II diabetes, Alzheimer's disease, Lyme disease, Ebola, and obesity. Research questions: To what extent does acceptability vary by vaccine type? To what extent does acceptability of vaccines in development vary by race and other key demographics? To what extent are general vaccine hesitancy and key demographics associated with acceptability of vaccines in development? DESIGN: Cross-sectional online survey administered through GfK's KnowledgePanel in 2015. Analysis completed in 2020. SUBJECTS: Nationally representative sample of Black and White American adults (n = 1,643). MEASURES: Willingness to accept a novel vaccine was measured on a 4-point Likert scale. Independent variables included demographics (e.g. age, race, gender) and measures of vaccine hesitancy, trust, and the "Three C's" of vaccine confidence, complacency, and convenience. ANALYSIS: Exploratory analysis including descriptive statistics and regression modeling. RESULTS: Acceptability varied from 77% for a cancer vaccine to 55% for an obesity vaccine. White race, male gender, older age, having a chronic health condition, and higher socioeconomic status were associated with higher acceptability. Higher vaccine confidence and lower vaccine hesitancy were predictors for acceptability. CONCLUSION: The success of a vaccine depends on widespread public acceptance. Vaccine hesitancy may hinder acceptance of future vaccines, with significant differences by demographics. Future social science research is necessary to better understand and address vaccine hesitancy.

The prevalence of altered body image in patients with primary brain tumors: an understudied population.

PURPOSE: Body image (BI) is an important issue for cancer patients, as patients with BI concerns are susceptible to depression, anxiety, difficulty coping, and poor quality of life (QoL). While this concern has been documented in patients with other malignancies, no data exists of this QoL issue in patients with primary brain tumors (PBT). METHODS: A cross-sectional survey of 100 PBT patients was conducted on an IRB approved prospective protocol using structured questionnaires. Participants completed the body image scale (BIS), Appearance Scheme Inventory Revised (ASI-R), MD Anderson Symptom Inventory Brain Tumor (MDASI-BT), and Patient-Reported Outcomes Measurement Information System (PROMIS) Depression, Anxiety, and Psychosocial Impact Positive measures. RESULTS: The prevalence of clinically significant body image dissatisfaction (BIS ≥ 10) was 28% (95% CI 19-37%), median BIS score was 5 (range 0-27). The median ASI-R composite score was 2.9 (range 1.5-4.7). BIS was significantly correlated with the ASI-R (r = 0.53, 95% CI 0.37 to 0.65). The mean PROMIS Depression score was 48.4 (SD = 8.9), PROMIS Anxiety score was 49.4 (SD = 9.9), and PROMIS Psychosocial Illness Impact Positive score was 48.9 (SD = 9.7). BIS was significantly correlated with age, and trended with BMI and sex. The PROMIS Psychosocial Illness Impact Positive and PROMIS Anxiety scores were the most strongly related to BIS. CONCLUSIONS: This study, the first to explore altered body image in PBT patients, revealed clinically significant body image dissatisfaction in nearly 1/3 of patients, similar to other malignancies. These findings underscore the potential contribution of disease and treatment-related body image concerns on psychosocial wellbeing in patients with PBT.

Needs and Challenges for Radiation Oncology in the Era of Precision Medicine.

Modern medicine, including the care of the cancer patient, has significantly advanced, with the evidence-based medicine paradigm serving to guide clinical care decisions. Yet we now also recognize the tremendous heterogeneity not only of disease states but of the patient and his or her environment as it influences treatment outcomes and toxicities. These reasons and many others have led to a reevaluation of the generalizability of randomized trials and growing interest in accounting for this heterogeneity under the rubric of precision medicine as it relates to personalizing clinical care predictions, decisions, and therapy for the disease state. For the cancer patient treated with radiation therapy, characterizing the spatial treatment heterogeneity has been a fundamental tenet of routine clinical care facilitated by established database and imaging platforms. Leveraging these platforms to further characterize and collate all clinically relevant sources of heterogeneity that affect the longitudinal health outcomes of the irradiated cancer patient provides an opportunity to generate a critical informatics infrastructure on which precision radiation therapy may be realized. In doing so, data science-driven insight discoveries, personalized clinical decisions, and the potential to accelerate translational efforts may be realized ideally within a network of institutions with locally developed yet coordinated informatics infrastructures. The path toward realizing these goals has many needs and challenges, which we summarize, with many still to be realized and understood. Early efforts by our group have identified the feasibility of this approach using routine clinical data sets and offer promise that this transformation can be successfully realized in radiation oncology.

Data integrity systems for organ contours in radiation therapy planning.

The purpose of this research is to develop effective data integrity models for contoured anatomy in a radiotherapy workflow for both real-time and retrospective analysis. Within this study, two classes of contour integrity models were developed: data driven models and contiguousness models. The data driven models aim to highlight contours which deviate from a gross set of contours from similar disease sites and encompass the following regions of interest (ROI): bladder, femoral heads, spinal cord, and rectum. The contiguousness models, which individually analyze the geometry of contours to detect possible errors, are applied across many different ROI's and are divided into two metrics: Extent and Region Growing over volume. After analysis, we found that 70% of detected bladder contours were verified as suspicious. The spinal cord and rectum models verified that 73% and 80% of contours were suspicious respectively. The contiguousness models were the most accurate models and the Region Growing model was the most accurate submodel. 100% of the detected noncontiguous contours were verified as suspicious, but in the cases of spinal cord, femoral heads, bladder, and rectum, the Region Growing model detected additional two to five suspicious contours that the Extent model failed to detect. When conducting a blind review to detect false negatives, it was found that all the data driven models failed to detect all suspicious contours. The Region Growing contiguousness model produced zero false negatives in all regions of interest other than prostate. With regards to runtime, the contiguousness via extent model took an average of 0.2 s per contour. On the other hand, the region growing method had a longer runtime which was dependent on the number of voxels in the contour. Both contiguousness models have potential for real-time use in clinical radiotherapy while the data driven models are better suited for retrospective use.

Using Big Data Analytics to Advance Precision Radiation Oncology.

Big clinical data analytics as a primary component of precision medicine is discussed, identifying where these emerging tools fit in the spectrum of genomics and radiomics research. A learning health system (LHS) is conceptualized that uses clinically acquired data with machine learning to advance the initiatives of precision medicine. The LHS is comprehensive and can be used for clinical decision support, discovery, and hypothesis derivation. These developing uses can positively impact the ultimate management and therapeutic course for patients. The conceptual model for each use of clinical data, however, is different, and an overview of the implications is discussed. With advancements in technologies and culture to improve the efficiency, accuracy, and breadth of measurements of the patient condition, the concept of an LHS may be realized in precision radiation therapy.