Ultrasound controlled mechanophore activation in hydrogels for cancer therapy.

Mechanophores are molecular motifs that respond to mechanical perturbance with targeted chemical reactions toward desirable changes in material properties. A large variety of mechanophores have been investigated, with applications focusing on functional materials, such as strain/stress sensors, nanolithography, and self-healing polymers, among others. The responses of engineered mechanophores, such as light emittance, change in fluorescence, and generation of free radicals (FRs), have potential for bioimaging and therapy. However, the biomedical applications of mechanophores are not well explored. Herein, we report an in vitro demonstration of an FR-generating mechanophore embedded in biocompatible hydrogels for noninvasive cancer therapy. Controlled by high-intensity focused ultrasound (HIFU), a clinically proven therapeutic technique, mechanophores were activated with spatiotemporal precision to generate FRs that converted to reactive oxygen species (ROS) to effectively kill tumor cells. The mechanophore hydrogels exhibited no cytotoxicity under physiological conditions. Upon activation with HIFU sonication, the therapeutic efficacies in killing in vitro murine melanoma and breast cancer tumor cells were comparable with lethal doses of H2O2 This process demonstrated the potential for mechanophore-integrated HIFU combination as a noninvasive cancer treatment platform, named "mechanochemical dynamic therapy" (MDT). MDT has two distinct advantages over other noninvasive cancer treatments, such as photodynamic therapy (PDT) and sonodynamic therapy (SDT). 1) MDT is ultrasound based, with larger penetration depth than PDT. 2) MDT does not rely on sonosensitizers or the acoustic cavitation effect, both of which are necessary for SDT. Taking advantage of the strengths of mechanophores and HIFU, MDT can provide noninvasive treatments for diverse cancer types.

Remote monitoring of patients with rheumatoid arthritis: a mixed methods evaluation across six hospitals in London, UK.

OBJECTIVES: This study evaluated the scale-up of a remote monitoring (RM) service, capturing monthly Rheumatoid Arthritis Impact of Disease scores and patient-generated text messages, for patients with rheumatoid arthritis (RA; in remission or with low disease activity) attending routine outpatient clinics across six hospitals. We explored patients and staff experiences and implementation outcomes. METHODS: A pragmatic, mixed methods approach was used, with active patient involvement throughout. We undertook a rapid review, analysed service-level data, and conducted a patient survey and patient and staff interviews, informed by the Capability, Opportunity, Motivation, Behaviour (COM-B) and Exploration, Preparation, Implementation, Sustainment (EPIS) theoretical frameworks. RESULTS: The review included 37 articles, covering themes of patient and clinician acceptability, engagement, feasibility and clinical impact. Service-level data (n = 202) showed high levels of patient engagement with the service. The patient survey (n = 155) showed patients felt the service was easy to use, had confidence in it and felt it improved access to care. Patient interview (n = 22) findings mirrored those of the survey. Motivating factors included increased responsiveness and ease of contact with clinical teams. Views from staff interviews (n = 16) were more mixed. Some implementation barriers were specific to roll-out sites. Prioritisation of staff needs was emphasised. CONCLUSION: Patients were positive about the service and engagement was high. Staff views and engagement were more mixed. Results suggest that equal levels of patient and staff engagement are required for sustainability. These findings further our understanding of the implementation challenges to scaling RM interventions for patients with RA in routine care settings.

Representation of aided AAC in contemporary young adult fiction.

The current study explored both the extent to which representation of augmentative and alternative communication (AAC) exists in young adult literature, as well as qualitative characteristics of that representation. A systematic search of multiple databases was conducted using standardized keywords and inclusion criteria. Descriptive statistics and literary content analysis were employed in order to analyze quantitative and qualitative information about each of the 32 novels that fit inclusion criteria. Results indicated that, while representation of AAC in young adult fiction largely aligned with existing statistics regarding types of AAC devices used, stories often differed from current information about the most common etiologies of AAC users. Analyses of character development revealed most featured AAC-using characters were multidimensional and expressed positive attitudes regarding their devices, although some characters also expressed frustration. These results indicated that representation of AAC in young adult literature was sparse. However, the representation that did exist at least partially reflected reality and may represent a positive portrayal of AAC use and users.

Tumour necrosis factor alpha, interleukin 1 beta and interferon gamma have detrimental effects on equine tenocytes that cannot be rescued by IL-1RA or mesenchymal stromal cell-derived factors.

Tendon injuries occur commonly in both human and equine athletes, and poor tendon regeneration leads to functionally deficient scar tissue and an increased frequency of re-injury. Despite evidence suggesting inadequate resolution of inflammation leads to fibrotic healing, our understanding of the inflammatory pathways implicated in tendinopathy remains poorly understood, meaning successful targeted treatments are lacking. Here, we demonstrate IL-1ß, TNFα and IFN-γ work synergistically to induce greater detrimental consequences for equine tenocytes than when used individually. This includes altering tendon associated and matrix metalloproteinase gene expression and impairing the cells' ability to contract a 3-D collagen gel, a culture technique which more closely resembles the in vivo environment. Moreover, these adverse effects cannot be rescued by direct suppression of IL-1ß using IL-1RA or factors produced by BM-MSCs. Furthermore, we provide evidence that NF-κB, but not JNK, P38 MAPK or STAT 1, is translocated to the nucleus and able to bind to DNA in tenocytes following TNFα and IL-1ß stimulation, suggesting this signalling cascade may be responsible for the adverse downstream consequences of these inflammatory cytokines. We suggest a superior approach for treatment of tendinopathy may therefore be to target specific signalling pathways such as NF-κB.

Differentiating radiation necrosis from tumor recurrence: a systematic review and diagnostic meta-analysis comparing imaging modalities.

PURPSOSE: Cerebral radiation necrosis (RN) is often a delayed phenomenon occurring several months to years after the completion of radiation treatment. Differentiating RN from tumor recurrence presents a diagnostic challenge on standard MRI. To date, no evidence-based guidelines exist regarding imaging modalities best suited for this purpose. We aim to review the current literature and perform a diagnostic meta-analysis comparing various imaging modalities that have been studied to differentiate tumor recurrence and RN. METHODS: A systematic search adherent to PRISMA guidelines was performed using Scopus, PubMed/MEDLINE, and Embase. Pooled sensitivities and specificities were determined using a random-effects or fixed-effects proportional meta-analysis based on heterogeneity. Using diagnostic odds ratios, a diagnostic frequentist random-effects network meta-analysis was performed, and studies were ranked using P-score hierarchical ranking. RESULTS: The analysis included 127 studies with a total of 220 imaging datasets, including the following imaging modalities: MRI (n = 10), MR Spectroscopy (MRS) (n = 28), dynamic contrast-enhanced MRI (n = 7), dynamic susceptibility contrast MRI (n = 36), MR arterial spin labeling (n = 5), diffusion-weighted imaging (n = 13), diffusion tensor imaging (DTI) (n = 2), PET (n = 89), and single photon emission computed tomography (SPECT) (n = 30). MRS had the highest pooled sensitivity (90.7%). DTI had the highest pooled specificity (90.5%). Our hierarchical ranking ranked SPECT and MRS as most preferable, and MRI was ranked as least preferable. CONCLUSION: These findings suggest SPECT and MRS carry greater utility than standard MRI in distinguishing RN from tumor recurrence.

Robotic external ventricular drain placement for acute neurosurgical care in low-resource settings: feasibility considerations and a prototype design.

OBJECTIVE: Emergency neurosurgical care in lower-middle-income countries faces pronounced shortages in neurosurgical personnel and infrastructure. In instances of traumatic brain injury (TBI), hydrocephalus, and subarachnoid hemorrhage, the timely placement of external ventricular drains (EVDs) strongly dictates prognosis and can provide necessary stabilization before transfer to a higher-level center of care that has access to neurosurgery. Accordingly, the authors have developed an inexpensive and portable robotic navigation tool to allow surgeons who do not have explicit neurosurgical training to place EVDs. In this article, the authors aimed to highlight income disparities in neurosurgical care, evaluate access to CT imaging around the world, and introduce a novel, inexpensive robotic navigation tool for EVD placement. METHODS: By combining the worldwide distribution of neurosurgeons, CT scanners, and gross domestic product with the incidence of TBI, meningitis, and hydrocephalus, the authors identified regions and countries where development of an inexpensive, passive robotic navigation system would be most beneficial and feasible. A prototype of the robotic navigation system was constructed using encoders, 3D-printed components, machined parts, and a printed circuit board. RESULTS: Global analysis showed Montenegro, Antigua and Barbuda, and Seychelles to be primary candidates for implementation and feasibility testing of the novel robotic navigation system. To validate the feasibility of the system for further development, its performance was analyzed through an accuracy study resulting in accuracy and repeatability within 1.53 ± 2.50 mm (mean ± 2 × SD, 95% CI). CONCLUSIONS: By considering regions of the world that have a shortage of neurosurgeons and a high incidence of EVD placement, the authors were able to provide an analysis of where to prioritize the development of a robotic navigation system. Subsequently, a proof-of-principle prototype has been provided, with sufficient accuracy to target the ventricles for EVD placement.

Military self-stigma as a mediator of the link between military identity and suicide risk.

US military Veterans are at greater risk for suicide than those who have never served in the US military. Recent federal calls include the need to investigate military-specific suicide risk and protective factors among military-affiliated populations. To date, no study has examined the link between military identity, self-stigma, and suicide risk. The current study used a nationally representative sample of post-Vietnam US military Veterans (N = 1,461) in order to determine relationships between military identity, self-stigma, and suicide risk. Idealism (OR = 0.86) with less odds of elevated suicide risk, whereas individualism (OR = 1.15) and military self-stigma (OR = 1.39) were associated with increased odds of elevated suicide risk. Military self-stigma was found to mediate the relationship between military identity components and suicide risk. Implications for conceptualization of military Veteran identity, suicide prevention, and future research are discussed.

Networks, space, and residents' perception of cohesion.

Community scholars increasingly focus on the linkage between residents' sense of cohesion with the neighborhood and their own social networks in the neighborhood. A challenge is that whereas some research only focuses on residents' social ties with fellow neighbors, such an approach misses out on the larger constellation of individuals' relationships and the spatial distribution of those relationships. Using data from the Twin Communities Network Study, the current project is one of the first studies to examine the actual spatial distribution of respondents' networks for a variety of relationships and the consequences of these for neighborhood and city cohesion. We also examine how a perceived structural measure of cohesion-triangle degree-impacts their perceptions of neighborhood and city cohesion. Our findings suggest that perceptions of cohesion within the neighborhood and the city depend on the number of neighborhood safety contacts as well as on the types of people with which they discuss important matters. On the other hand, kin and social friendship ties do not impact cohesion. A key finding is that residents who report more spatially dispersed networks for certain types of ties report lower levels of neighborhood and city cohesion. Residents with higher triangle degree within their neighborhood safety networks perceived more neighborhood cohesion.

Equine Embryonic Stem Cell-Derived Tenocytes are Insensitive to a Combination of Inflammatory Cytokines and Have Distinct Molecular Responses Compared to Primary Tenocytes.

Tissue fibrosis following tendon injury is a major clinical problem due to the increased risk of re-injury and limited treatment options; however, its mechanism remains unclear. Evidence suggests that insufficient resolution of inflammation contributes to fibrotic healing by disrupting tenocyte activity, with the NF-κB pathway being identified as a potential mediator. Equine embryonic stem cell (ESC) derived tenocytes may offer a potential cell-based therapy to improve tendon regeneration, but how they respond to an inflammatory environment is largely unknown. Our findings reveal for the first time that, unlike adult tenocytes, ESC-tenocytes are unaffected by IFN-γ, TNFα, and IL-1ß stimulation; producing minimal changes to tendon-associated gene expression and generating 3-D collagen gel constructs indistinguishable from unstimulated controls. Inflammatory pathway analysis found these inflammatory cytokines failed to activate NF-κB in the ESC-tenocytes. However, NF-κB could be activated to induce changes in gene expression following stimulation with NF-κB pharmaceutical activators. Transcriptomic analysis revealed differences between cytokine and NF-κB signalling components between adult and ESC-tenocytes, which may contribute to the mechanism by which ESC-tenocytes escape inflammatory stimuli. Further investigation of these molecular mechanisms will help guide novel therapies to reduce fibrosis and encourage superior tendon healing.

Adult neuro-oncology trials in the United States over 5 decades: Analysis of trials completion rate to guide the path forward.

Background: Clinical trials are important to close the gap between therapeutic unmet needs and scientific advances in neuro-oncology. This study analyzes the landscape of neuro-oncology trials to identify completion rates and guide strategies for the path forward. Methods: US-registered adult neuro-oncology clinical trials were extracted from www.clinicaltrials.gov (1966-2019), including funding source, trial type, scope, phase, and subjects' demographics. Completed trials defined as those that had completed participants' examinations or intervention administration for the purpose of the final collection of data for the primary outcome were dichotomized against those that failed to reach completion. Univariate and multivariate analyses were used to detect differences across factors comparing the last 2 decades (2000-2009, 2010-2019). Results: Our search yielded 4522 trials, of which 1257 are eligible for this study. In 25 US states, neuro-oncology trial availability is <0.85/100,000 population. Comparing the past 2 decades, trial completion rate decreased from 88% to 64% (P < .001) and National Institutes of Health funding decreased from 47% to 24% (P < .001). Inclusion of subjects >65-year-old and women increased, while inclusion of Hispanic subjects decreased (P < .001). The top 2 reasons for lack of completion included accrual and operational difficulties. A larger proportion of women, non-Hispanic subjects, and older adults were enrolled in completed trials than in those that failed completion. Conclusions: Our study is the first report on the neuro-oncology clinical trial landscape in the United States and supports the development of strategies to further improve access to these trials. Additionally, attention is needed to identify and modify other factors contributing to lack of completion.

Health Disparities in Young Adults: A Direct Comparison of Distress and Unmet Needs Across Cancer Centers.

PURPOSE: Information on concerns that young adults (YAs) with cancer face when receiving care outside of specialized treatment centers is needed to increase equitable care to YAs at greater risk of marginalization by the health care system. The current study compared distress and unmet needs at the time of clinic visit between YAs receiving care from three different cancer clinics: (1) a National Cancer Institute-designated center, (2) a community-based clinic, and (3) a county hospital outpatient clinic. METHODS: The Adolescent and Young Adult Psycho-Oncology Screening Tool (AYA-POST) was administered to measure distress and cancer-related concerns of YAs in active treatment. A one-way analysis of variance (ANOVA) compared distress scores by treatment site. A Fisher's exact test compared the number of participants endorsing each item on the Needs Assessment Checklist from each site. A simple linear regression determined the association between distress and number of items endorsed on the Needs Assessment Checklist. RESULTS: Ninety-seven participants completed the AYA-POST, endorsing, on average, 11 concerns. Fisher's exact test showed significant differences between sites in the proportion of participants endorsing eight items: boredom (P < .001), eating/appetite (P < .001), nausea/vomiting (P < .001), financial concern (P = .002), hopelessness/helplessness (P = .03), confidentiality (P = .04), sibling concern (P = .04), and insurance (P = .05). The simple linear regression model was significant (F(1, 94) = 39.772, P < .001, R2 = 0.297), indicating the number of unmet needs accounted for almost 30% of the variance in distress. The one-way ANOVA was not significant (F(2, 93) = 1.34, P = .267). CONCLUSION: Social determinants of health can influence the number and type of unmet needs experienced, affecting distress and other outcomes and underscoring the importance of timely, effective, age-appropriate screening and intervention for distress and unmet needs in YAs with cancer.

Differential Distribution of the DNA-PKcs Inhibitor Peposertib Selectively Radiosensitizes Patient-derived Melanoma Brain Metastasis Xenografts.

Radioresistance of melanoma brain metastases limits the clinical utility of conventionally fractionated brain radiation in this disease, and strategies to improve radiation response could have significant clinical impact. The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is critical for repair of radiation-induced DNA damage, and inhibitors of this kinase can have potent effects on radiation sensitivity. In this study, the radiosensitizing effects of the DNA-PKcs inhibitor peposertib were evaluated in patient-derived xenografts of melanoma brain metastases (M12, M15, M27). In clonogenic survival assays, peposertib augmented radiation-induced killing of M12 cells at concentrations ≥100 nmol/L, and a minimum of 16 hours exposure allowed maximal sensitization. This information was integrated with pharmacokinetic modeling to define an optimal dosing regimen for peposertib of 125 mpk dosed just prior to and 7 hours after irradiation. Using this drug dosing regimen in combination with 2.5 Gy × 5 fractions of radiation, significant prolongation in median survival was observed in M12-eGFP (104%; P = 0.0015) and M15 (50%; P = 0.03), while more limited effects were seen in M27 (16%, P = 0.04). These data support the concept of developing peposertib as a radiosensitizer for brain metastases and provide a paradigm for integrating in vitro and pharmacokinetic data to define an optimal radiosensitizing regimen for potent DNA repair inhibitors.

The State of Machine Learning in Outcomes Prediction of Transsphenoidal Surgery: A Systematic Review.

The purpose of this analysis is to assess the use of machine learning (ML) algorithms in the prediction of postoperative outcomes, including complications, recurrence, and death in transsphenoidal surgery. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically reviewed all papers that used at least one ML algorithm to predict outcomes after transsphenoidal surgery. We searched Scopus, PubMed, and Web of Science databases for studies published prior to May 12, 2021. We identified 13 studies enrolling 5,048 patients. We extracted the general characteristics of each study; the sensitivity, specificity, area under the curve (AUC) of the ML models developed as well as the features identified as important by the ML models. We identified 12 studies with 5,048 patients that included ML algorithms for adenomas, three with 1807 patients specifically for acromegaly, and five with 2105 patients specifically for Cushing's disease. Nearly all were single-institution studies. The studies used a heterogeneous mix of ML algorithms and features to build predictive models. All papers reported an AUC greater than 0.7, which indicates clinical utility. ML algorithms have the potential to predict postoperative outcomes of transsphenoidal surgery and can improve patient care. Ensemble algorithms and neural networks were often top performers when compared with other ML algorithms. Biochemical and preoperative features were most likely to be selected as important by ML models. Inexplicability remains a challenge, but algorithms such as local interpretable model-agnostic explanation or Shapley value can increase explainability of ML algorithms. Our analysis shows that ML algorithms have the potential to greatly assist surgeons in clinical decision making.

Analysis of Rural Disparities in Ultrasound Access.

Purpose This work aims to conduct a geospatial analysis of recent ultrasound access and usage within the United States, with a particular focus on disparities between rural and urban areas. Methods/Materials Multiple public datasets were merged on a county level, including US Department of Agriculture economic metrics and Centers for Medicare Services data using the most recent years available (2015-2019). From these databases, 39 total variables encompassing the socioeconomic, health, and ultrasound characteristics of each county were obtained. Current Procedural Terminology (CPT) codes incorporated included ultrasound-guided procedures and diagnostic exams. Three thousand eleven counties were included. The combined dataset was then exported to GeoDa for network-based analysis and to produce map visualizations. To identify statistically significant (p < 0.05) hotspots and coldspots in point-of-care ultrasound (POCUS) prevalence, Moran's I was used. Choropleth maps were created for visualization. ANOVA was run across the four Moran's I groups for each of 39 variables of interest. Results A total of 30,135,085 ultrasound-related CPT codes were billed to Medicare over 2015-2019, with 26.55% of codes being ultrasound-guided procedures and 73.45% being diagnostic exams. 38.84% of rural counties had access to POC ultrasound compared to 88.56% of metropolitan counties and 74.19% of counties overall. Hotspots of POCUS were in Southern California and the Eastern US (average of 1,441 per 10,000 Medicare members per year). Coldspot areas were seen in the Great Plains and Midwest (average of 7.43 per 10k Medicare members per year). Hotspot clusters, when compared to coldspot clusters, were significantly (p < 0.001) more dense (703.6 to 14.9 people per square mile), more urbanized (3.5 to 7.1 Rural-Urban Continuum (RUC)), more college-educated (25.1% to 20.0%), more likely to have an Emergency Department (ED) visit (725.8 to 616.9 visits per 1,000 Medicare members), more likely to be obese (19.0% to 12.9%), less likely to be uninsured (10.1% to 13.0%), had more Black representation (8.5% to 3.4%), and less Hispanic representation (2.6% to 5.5%). Conclusions Ultrasound access and usage demonstrate significant geospatial trends across the United States. Hotspot and coldspot counties differ on several key sociodemographic and economic variables.

Comparison of fluorescein sodium, 5-ALA, and intraoperative MRI for resection of high-grade gliomas: A systematic review and network meta-analysis.

High grade gliomas (HGGs) are aggressive brain tumors associated with poor prognosis despite advances in surgical treatment and therapy. Navigated tumor resection has yielded improved outcomes for patients. We compare 5-ALA, fluorescein sodium (FS), and intraoperative MRI (IMRI) with no image guidance to determine the best intraoperative navigation method to maximize rates of gross total resection (GTR) and outcomes. A frequentist network meta-analysis was performed following standard PRISMA guidelines (PROSPERO registration CRD42021268659). Surface-under-the-cumulative ranking (SUCRA) analysis was executed to hierarchically rank modalities by the outcomes of interest. Heterogeneity was measured by the I2 statistic. Publication bias was assessed by funnel plots and the use of Egger's test. Statistical significance was determined by p < 0.05. Twenty-three studies were included for analysis with a total of 2,643 patients. Network meta-analysis comparing 5-ALA, IMRI, and FS was performed. The primary outcome assessed was the rate of GTR. Analysis revealed the superiority of all intraoperative navigation to control (no navigation). SUCRA analysis revealed the superiority of IMRI + 5-ALA, IMRI alone, followed by FS, and 5-ALA. Overall survival (OS) and progression free survival (PFS) were also examined. FS (vs. control) was associated with improved OS, while IMRI was associated with improved PFS (vs. control, FS, and 5-ALA). Intraoperative navigation using IMRI, FS, and 5-ALA lead to greater rates of GTR in HGGs. FS and 5-ALA also yielded improvement in OS and PFS. Further studies are needed to evaluate differences in survival benefit, operative duration, and cost.

Geospatial evaluation of disparities in neurosurgical access in the United States.

When neurosurgical care is needed, the distance to a facility staffed with a neurosurgeon is critical. This work utilizes geospatial analysis to analyze access to neurosurgery in the Medicare population and relevant socioeconomic factors. Medicare billing and demographic data from 2015 to 2019 were combined with national National Provider Identifier (NPI) registry data to identify the average travel distance to reach a neurosurgeon as well as the number of neurosurgeons in each county. This was merged with U.S. Census data to capture 23 socioeconomic attributes. Moran's I statistic was calculated across counties. Socioeconomic variables were compared using ANOVA. Hotspots with the highest neurosurgeon access were predominantly located in the Mid-Atlantic region, central Texas, and southern Montana. Coldspots were found in the Great Plains, Midwest, and Southern Texas. There were statistically significant differences (p < 0.05) between high- and low-access counties, including: stroke prevalence, poverty, median household income, and total population density. There were no statistically significant differences in most races or ethnicities. Overall, there exist statistically significant clusters of decreased neurosurgery access within the United States, with varying sociodemographic characteristics between access hotspots and coldspots.

Fluorescein-Guided Resection of High Grade Gliomas: A Meta-Analysis.

BACKGROUND: High-grade gliomas (HGGs) have a poor prognosis despite current standard of care of surgery, chemotherapy, and radiation therapy. Achieving gross total resection (GTR) has been found to prolong survival in these patients. Intraoperative fluorescent agents are often used to aid in the resection of HGGs. One commonly used fluorescent agent is fluorescein sodium, which is U.S. Food and Drug Administration-approved for ocular surgeries and has a better side effect profile and is less costly than 5-aminolevulinic acid (5-ALA). In this meta-analysis, we provide statistical evidence of the efficacy in using fluorescein for HGG resection. METHODS: Following the PRISMA framework, we assessed 119 reports from PubMed, Medline (Ovid), and BIOSIS Citation Index and found 21 eligible studies for meta-analysis, assessing the rates of GTR with fluorescein-guided resection of HGGs. RESULTS: A pooled cohort of 336 patients underwent fluorescein-guided HGG resection with a GTR rate of 81% (95% confidence interval 73%-89%; P < 0.001). Ten case-controlled studies were analyzed, showing a 29.5% increase in GTR rate in the fluorescein group compared with non-fluorescein-guided surgeries. CONCLUSIONS: This meta-analysis shows that fluorescein-guided surgery improves GTR rates of HGGs when compared with non-fluorescence guided surgery and has similar GTR rates when compared with reported 5-ALA-guided resection rates.

Physical Activity after Cardiac EventS (PACES): a group education programme with subsequent text message support designed to increase physical activity in individuals with diagnosed coronary heart disease: a randomised controlled trial.

AIM: To assess the effectiveness of a low-cost pragmatic intervention (structured education and ongoing text message support) to increase daily physical activity in participants 12-48 months after a coronary heart disease cardiac event (myocardial infarction, angina or acute coronary syndrome) diagnosis. METHODS: A single-centre randomised controlled trial of 291 adults randomised to a structured education programme (n=145) or usual care (n=146). The programme consisted of two 2.5 hour sessions delivered 2 weeks apart, followed by supplementary text message support. The GENEActiv accelerometer assessed the primary outcome at 12 months (change in overall physical activity (expressed in milli gravitational (mg) units) from baseline). Secondary outcomes included anthropometric, physical function, cardiovascular, biochemical and patient-reported outcome measures. Linear regression was used to compare outcome measures between groups on a modified intention-to-treat basis. RESULTS: Participants' mean age was 66.5±9.7 years, 84.5% males, 82.5% white British and 15.5% south Asian. At 12 months, there was no difference between the groups in terms of change in overall physical activity (-0.23 mg (95% CI -1.22 to 0.75), p=0.64) and the programme was well accepted (88% attendance). Exploratory analyses showed that average moderate to vigorous physical activity (MVPA) levels increased in individuals not meeting physical activity guidelines (≥150 min per week) on enrolment compared with those who did, by 8 minutes per day (8.04 (95% CI 0.99 to 15.10), p=0.03). CONCLUSION: The programme was well attended but showed no change in physical activity levels. Results show high baseline MVPA levels and suggest that Physical Activity after Cardiac EventS education may benefit cardiac patients not currently meeting activity guidelines. TRIAL REGISTRATION NUMBER: ISRCTN91163727.

Imaging and Dosimetry Study of Inter-fraction Setup Error in a Murine Xenograft Flank Tumor Radiation Model.

Modern small animal irradiation platforms provide for accurate delivery of radiation under 3D image guidance. However, leveraging these improvements currently comes at the cost of lower-throughput experimentation. Herein, we characterized setup accuracy and dosimetric robustness for mock/sham irradiation of a murine xenograft flank tumor model using the X-RAD SmART+ with the vendor-supplied Monte Carlo (MC) treatment planning system (SmART ATP). The chosen beam arrangement was parallel-opposing using a 20 mm square collimator, aligned off-axis for ipsilateral lung sparing. Using a cohort of five mice imaged with cone beam computed tomography (CBCT) over five consecutive mock-irradiation fractions, we compared inter-fraction setup variability resulting from a vendor-supplied multi-purpose bed with anesthesia nose cone with a more complicated immobilization solution with an integrated bite block with nose cone and Styrofoam platform. A hypothetical "high-throughput" image-guidance scenario was investigated, wherein the day 1 stage coordinates (resulting from CBCT guidance) were applied on days 2-5. Daily inter-fraction setup errors were evaluated per specimen (days 2-5) using CBCT-derived offsets from day 1 stage coordinates. Using the CBCT images and Monte Carlo dose calculation, 3D dosimetric plan robustness was evaluated for the vendor-supplied immobilization solution, for both the high-throughput guidance scenario as well as for use of daily CBCT-based alignment. Inter-fraction setup offset magnitude was 3.6 (±1.5) mm for the vendor-supplied immobilization compared to 3.3 (±1.8) mm for the more complicated solution. For the vendor-supplied immobilization, we found that daily CBCT was needed to adequately cover the flank tumors dosimetrically, given our chosen treatment approach.

PARP Inhibitors for Sensitization of Alkylation Chemotherapy in Glioblastoma: Impact of Blood-Brain Barrier and Molecular Heterogeneity.

Prognosis of patients with glioblastoma (GBM) remains dismal despite maximal surgical resection followed by aggressive chemo-radiation therapy. Almost every GBM, regardless of genotype, relapses as aggressive recurrent disease. Sensitization of GBM cells to chemo-radiation is expected to extend survival of patients with GBM by enhancing treatment efficacy. The PARP family of enzymes has a pleiotropic role in DNA repair and metabolism and has emerged as an attractive target for sensitization of cancer cells to genotoxic therapies. However, despite promising results from a number of preclinical studies, progress of clinical trials involving PARP inhibitors (PARPI) has been slower in GBM as compared to other malignancies. Preclinical in vivo studies have uncovered limitations of PARPI-mediated targeting of base excision repair, considered to be the likely mechanism of sensitization for temozolomide (TMZ)-resistant GBM. Nevertheless, PARPI remain a promising sensitizing approach for at least a subset of GBM tumors that are inherently sensitive to TMZ. Our PDX preclinical trial has helped delineate MGMT promoter hyper-methylation as a biomarker of the PARPI veliparib-mediated sensitization. In clinical trials, MGMT promoter hyper-methylation now is being studied as a potential predictive biomarker not only for response to TMZ therapy alone, but also PARPI-mediated sensitization of TMZ therapy. Besides the combination approach being investigated, IDH1/2 mutant gliomas associated with 2-hydroxygluterate (2HG)-mediated homologous recombination (HR) defect may potentially benefit from PARPI monotherapy. In this article, we discuss existing results and provide additional data in support of potential alternative mechanisms of sensitization that would help identify potential biomarkers for PARPI-based therapeutic approaches to GBM.