Metastatic breast cancer is a major cause of death among women worldwide; therefore efficient therapeutic strategies are extremely needed. In this work we have developed a gene therapy- and ...bacteria-based combined neoadjuvant approach and evaluated its antitumor effect in a clinically relevant animal model of metastatic breast cancer.
2×10(8) particles of a Semliki Forest virus vector expressing interleukin-12 (SFV-IL-12) and/or 2×10(7) units of an aroC (-) Samonella Typhimurium strain (LVR01) were injected into 4T1 tumor nodules orthotopically implanted in mice. Tumors were surgically resected and long-term survival was determined. IL-12 and interferon-γ were quantified by Enzyme-Linked ImmunoSorbent Assay, bacteria was visualized by inmunohistochemistry and the number of lung metastasis was calculated with a clonogenic assay.
SFV-IL-12 and LVR01 timely inoculated and followed by surgical resection of tumors succeeded in complete inhibition of lethal lung metastasis and long-term survival in 90% of treated mice. The combined therapy was markedly synergistic compared to each treatment alone, since SFV-IL-12 monotherapy showed a potent antiangiogenic effect, being able to inhibit tumor growth and extend survival, but could not prevent establishment of distant metastasis and death of tumor-excised animals. On the other hand, LVR01 alone also showed a significant, although limited, antitumor potential, despite its ability to invade breast cancer cells and induce granulocyte recruitment. The efficacy of the combined therapy depended on the order in which both factors were administered; inasmuch the therapeutic effect was only observed when SFV-IL-12 was administered previous to LVR01, whereas administration of LVR01 before SFV-IL-12 had negligible antitumor activity. Moreover, pre-treatment with LVR01 seemed to suppress SFV-IL-12 antiangiogenic effects associated to lower IL-12 expression in this group. Re-challenged mice were unable to reject a second 4T1 tumor; however 100% of them could be totally cured by applying the same neoadjuvant combined regimen. To our knowledge, these are the most encouraging results obtained to date in a post-operatory setting using the highly aggressive 4T1 animal model.
SFV-IL-12-based gene therapy combined with Salmonella LVR01 neoadjuvant administration has a synergic antitumor effect and may be a promising therapeutic option to prevent and/or eradicate pre-operatory metastasis in locally advanced breast cancer.
Direct observation of clinical task performance plays a pivotal role in competency-based medical education. Although formal guidelines require supervisors to engage in direct observations, research ...demonstrates that trainees are infrequently observed. Supervisors may not only experience practical and socio-cultural barriers to direct observations in healthcare settings, they may also question usefulness or have low perceived self-efficacy in performing direct observations. A better understanding of how these multiple factors interact to influence supervisors' intention to perform direct observations may help us to more effectively implement the aforementioned guidelines and increase the frequency of direct observations.
We conducted an exploratory quantitative study, using the Theory of Planned Behaviour (TPB) as our theoretical framework. In applying the TPB, we transfer a psychological theory to medical education to get insight in the influence of cognitive and emotional processes on intentions to use direct observations in workplace based learning and assessment. We developed an instrument to investigate supervisors intention to perform direct observations. The relationships between the TPB measures of our questionnaire were explored by computing bivariate correlations using Pearson's R tests. Hierarchical regression analysis was performed in order to assess the impact of the respective TPB measures as predictors on the intention to perform direct observations.
In our study 82 GP supervisors completed our TPB questionnaire. We found that supervisors had a positive attitude towards direct observations. Our TPB model explained 45% of the variance in supervisors' intentions to perform them. Normative beliefs and past behaviour were significant determinants of this intention.
Our study suggests that supervisors use their past experiences to form intentions to perform direct observations in a careful, thoughtful manner and, in doing so, also take the preferences of the learner and other stakeholders potentially engaged in direct observations into consideration. These findings have potential implications for research into work-based assessments and the development of training interventions to foster a shared mental model on the use of direct observations.
In recent years, the subspecialty of neuropalliative care has emerged with the goal of improving the quality of life of patients suffering from neurological disease, though gaps remain in ...neuropalliative care education and training. E-learning has been described as a way to deliver interactive and facilitated lower-cost learning to address global gaps in medical care. We describe here the development of a novel, international, hybrid, and asynchronous curriculum with both self-paced modules and class-based lectures on neuropalliative care topics designed for the neurologist interested in palliative care, the palliative care physician interested in caring for neurological patients, and any other physician or advanced care providers interested in neuropalliative care.
The course consisted of 12 modules, one per every four weeks, beginning July 2022. Each module is based on a case and relevant topics. Course content was divided into three streams (Neurology Basics, Palliative Care Basics, and Neuropalliative Care Essentials) of which two were optional and one was mandatory, and consisted of classroom sessions, webinars, and an in-person skills session. Evaluation of learners consisted of multiple choice questions and written assignments for each module. Evaluation of the course was based on semi-structured qualitative interviews conducted with both educator and learner, the latter of which will be published separately. Audio files were transcribed and underwent thematic analysis. For the discussion of the results, Khan's e-learning framework was used.
Ten of the 12 participating educators were interviewed. Of the educators, three identified as mid-career and seven as senior faculty, ranging from six to 33 years of experience. Nine of ten reported an academic affiliation and all reported association with a teaching hospital. Themes identified from the educators' evaluations were: bridging the global gap, getting everybody on board, defining the educational scope, investing extensive hours of voluntary time and resources, benefiting within and beyond the curriculum, understanding the learner's experience, creating a community of shared learning, adapting future teaching and learning strategies, and envisioning long term sustainability.
The first year of a novel, international, hybrid, and asynchronous neuropalliative care curriculum has been completed, and its educators have described both successes and avenues for improvement. Further research is planned to assess this curriculum from the learner perspective.
Following new and innovative concepts of energy recovery which use micro-hydro impulse turbines in drinking water systems, more sophisticated turbine designs become essential to improve energy ...recovery efficiency. In the case of implementing a hydraulic impulse turbine with tailwater depression in such systems, one major challenge to optimising overall efficiency is the reduction of the turbine's air demand. Firstly, a lower air demand would reduce the required dimensions of the ventilation system and therefore increase energy efficiency. Secondly, a minimised air demand would considerably reduce negative effects downstream of the turbine casing, such as a reduced transport capacity and corrosion. To achieve a minimised air demand, detailed experimental investigations are conducted, during which different casing inserts are tested in a micro-hydro Pelton machine. A specially constructed turbine test-bed, featuring two separately installed measuring units, allows for the partitioning and measurement of dissolved and undissolved air. In the case of the used Pelton machine, the results clearly identify different air detrainment processes. The undissolved air demand strongly depends on the particular casing insert and can be reduced by 90% through optimal flow condition using flow straighteners as insert. In contrast, the amount of dissolved air demand cannot be controlled by additional casing inserts. This can be explained due its different entrainment processes. The analysis of the dependency of the measurement results on scale shows that a direct transfer to a prototype application will underestimate the air demand. Nevertheless, the presented research findings show an effective way, also relevant to turbine manufacturers, to reduce air demand and improve overall efficiency of impulse turbines in counter pressure operation.
•Experimental air demand measurements of a counter pressure Pelton turbine.•Undissolved air demand strongly depends on the particular casing setup.•Reduction of undissolved air demand by more than 90% due to flow straighteners.•Dissolved air demand can barely be reduced through casing installations due its different intrusion processes.
ABSTRACT
We present the discovery of FRB 20210410D with the MeerKAT radio interferometer in South Africa, as part of the MeerTRAP commensal project. FRB 20210410D has a dispersion measure DM ...= 578.78 ± 2 ${\rm pc \, cm^{-3}}$ and was localized to subarcsec precision in the 2 s images made from the correlation data products. The localization enabled the association of the FRB with an optical galaxy at z = 0.1415, which when combined with the DM places it above the 3σ scatter of the Macquart relation. We attribute the excess DM to the host galaxy after accounting for contributions from the Milky Way’s interstellar medium and halo, and the combined effects of the intergalactic medium and intervening galaxies. This is the first FRB that is not associated with a dwarf galaxy to exhibit a likely large host galaxy DM contribution. We do not detect any continuum radio emission at the FRB position or from the host galaxy down to a 3σ rms of 14.4 $\mu$Jy beam−1. The FRB has a scattering delay of $29.4^{+2.8}_{-2.7}$ ms at 1 GHz, and exhibits candidate subpulses in the spectrum, which hint at the possibility of it being a repeating FRB. Although not constraining, we note that this FRB has not been seen to repeat in 7.28 h at 1.3 GHz with MeerKAT, 3 h at 2.4 GHz with Murriyang, and 5.7 h at simultaneous 2.3 GHz and 8.4 GHz observations with the Deep Space Network. We encourage further follow-up to establish a possible repeating nature.
Abstract Mental retardation (MR) is a highly diverse group of cognitive disorders. Gene defects account for about half of all patients and mutations causative for impaired cognition have been ...identified in more than 400 genes. While there are numerous genetic defects underlying MR, a more limited number of pathways is emerging whose disruption appears to be shared by groups of MR genes. One of these common pathways is composed of MR genes that encode regulators of chromatin structure and of chromatin-mediated transcription regulation. Already more than 20 “epigenetic MR genes” have been identified and this number is likely to increase in the coming years when deep sequencing of exomes and genomes will become commonplace. Prominent examples of epigenetic MR genes include the methyl CpG-binding protein MECP2 and the CREB binding protein, CBP. Interestingly, several epigenetic MR proteins have been found to interact directly with one another or act together in complexes that regulate the local chromatin structure at target genes. Thus, it appears that the functions of individual epigenetic MR proteins converge onto similar biological processes that are crucial to neuronal processes. The next challenge will be to gain more insight into patterns of altered DNA methylation and histone modifications that are caused by epigenetic gene mutations and how these will disrupt the brain-specific expression of target genes. Such research may reveal that a wide variety of mutations in the genetic code result in a more limited number of disruptions to the epigenetic code. If so, this will provide a rationale for therapeutic strategies.
Abstract Objectives The aim of this study was to describe associations of the presence of lipid-rich necrotic core (LRNC) in the proximal superficial femoral artery (SFA) with lower extremity ...peripheral artery disease (PAD) event rates and systemic cardiovascular event rates. Background LRNC in the coronary and carotid arteries is associated with adverse outcomes but has not been studied previously in lower extremity arteries. Methods Participants with ankle-brachial index (ABI) values <1.00 were identified from Chicago medical centers and followed annually. Magnetic resonance imaging was used to characterize SFA atherosclerotic plaque at baseline. Medical records for hospitalizations and procedures after baseline were adjudicated for lower extremity revascularization, amputation, and critical limb ischemia and also for new coronary events, ischemic stroke, and mortality. Results Of 254 participants with PAD, 62 (24%) had LRNC and 149 (59%) had calcium in the SFA at baseline. Cox regression analyses were adjusted for age, sex, race, comorbidities, baseline ABI, and other confounders. SFA LRNC was associated with an increased incidence of the combined outcome of lower extremity amputation, critical limb ischemia, ABI decline >0.15, and revascularization at 47-month follow-up (hazard ratio: 2.18; 95% confidence interval: 1.27 to 3.75; p = 0.005). The association of SFA LRNC with PAD events was maintained even when this combined outcome excluded lower extremity revascularization (hazard ratio: 2.58; 95% confidence interval: 1.25 to 5.33; p = 0.01). LRNC in the SFA was not associated with all-cause mortality, acute coronary events, or stroke. Conclusions Among patients with PAD, LRNC in the SFA was associated with higher rates of clinical PAD events, and this association was independent of ABI. Further study is needed to determine whether interventions that reduce SFA LRNC prevent PAD events.
Roughly 40% of those with intellectual/developmental disabilities (IDD) have mental health needs, twice the national average. Unfortunately, outpatient mental health services are often inaccessible, ...increasing reliance on hospital-based services. While telemental health services hold potential to address this gap, little is known about the effectiveness of telemental health for the diversity of persons with IDD, especially as it relates to crisis prevention and intervention services. Accordingly, the aims of this study are to: (1) compare telemental health versus in-person crisis prevention and intervention services among people with IDD; and (2) understand if outcomes vary across subpopulations, in order to identify potential disparities.
This study will take place within START (Systemic, Therapeutic, Assessment, Resources, and Treatment), a national evidence-based model of mental health crisis prevention and intervention for people with IDD. A total of 500 youth and adults, located across nine states, will be randomized 1:1 to telemental health vs. in-person. Participant inclusion criteria are ages 12-45 years, living in a family setting, and newly enrolled (within 90 days) to START. Outcomes will be assessed, using a non-inferiority design, for up to 1 year or until discharge. The intervention is comprised of four components: (1) outreach; (2) consultation/coping skills; (3) intake/assessment; and, (4) 24-hour crisis response. The in-person condition will deliver all components in-person. The telemental health condition will deliver components 1 & 2, via telephonic or other communication technology, and components 3 & 4 in-person. Outcomes include mental health crisis contacts, mental health symptoms, emergency psychiatric service use, perceived quality of mental healthcare, and time to discharge.
To our knowledge, this will be the first trial of a telemental health crisis program for the IDD population. The study will be executed by an interdisciplinary team of experts that includes persons with lived experience of disability. Understanding the benefits of specific telemental health methods has important implications to the design of interventions. This telemental health study offers promise to address disparities in access to mental health care for people with IDD across diverse racial, ethnic, linguistic, and cultural groups.
Clinicaltrials.gov ( #NCT05336955 ; Registration Date: 4/20/2022).
In our recent clinical trial, increased peripheral concentrations of pro-inflammatory molecular mediators were determined in complex regional pain syndrome (CRPS) patients. After 3 months adjunctive ...unilateral, selective L4 dorsal root ganglion stimulation (L4-DRG
), significantly decreased serum IL-10 and increased saliva oxytocin levels were assessed along with an improved pain and functional state. The current study extended molecular profiling towards gene expression analysis of genes known to be involved in the gonadotropin releasing hormone receptor and neuroinflammatory (cytokines/chemokines) signaling pathways.
Blood samples were collected from 12 CRPS patients for whole-transcriptome profiling in order to assay 18,845 inflammation-associated genes from frozen blood at baseline and after 3 months L4-DRG
using PANTHER™ pathway enrichment analysis tool.
Pathway enrichment analyses tools (GOrilla™ and PANTHER™) showed predominant involvement of inflammation mediated by chemokines/cytokines and gonadotropin releasing hormone receptor pathways. Further, screening of differentially regulated genes showed changes in innate immune response related genes. Transcriptomic analysis showed that 21 genes (predominantly immunoinflammatory) were significantly changed after L4-DRG
. Seven genes including TLR1, FFAR2, IL1RAP, ILRN, C5, PKB and IL18 were down regulated and fourteen genes including CXCL2, CCL11, IL36G, CRP, SCGB1A1, IL-17F, TNFRSF4, PLA2G2A, CREB3L3, ADAMTS12, IL1F10, NOX1, CHIA and BDKRB1 were upregulated.
In our sub-group analysis of L4-DRG
treated CRPS patients, we found either upregulated or downregulated genes involved in immunoinflammatory circuits relevant for the pathophysiology of CRPS indicating a possible relation. However, large biobank-based approaches are recommended to establish genetic phenotyping as a quantitative outcome measure in CRPS patients. Trial registration The study protocol was registered at the 15.11.2016 on German Register for Clinical Trials (DRKS ID 00011267). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011267.
Cardiac magnetic resonance (CMR) provides a unique approach to the characterization of hypertensive heart disease (HHD), enabling the measurement of left ventricular mass and expansion of ...extracellular volume (ECV). Combining plasma biomarkers with CMR could provide potential insights into the pathophysiological mechanisms in ventricular remodelling.
In this study, we estimated correlations between plasma biomarkers and CMR parameters of HHD. Patients with a history of hypertension with or without left ventricular hypertrophy (LVH) and healthy volunteers (17 hypertensive non-LVH, 13 hypertensive LVH and 11 controls) underwent CMR on a Siemens 1.5T Avanto. T1 mapping was performed before (native T1) and serially after injection of 0.15 mmol/kg gadolinium-DTPA. Mean ECV and left ventricular mass index (LVMI) were determined. Blood samples were obtained and analysed using the Olink CVD 92-plex biomarker panel.
Individual groups were compared on the basis of 91 plasma biomarkers using partial least squares discriminant analysis (PLS-DA). ECV and LVMI were correlated with the 91 distinct plasma biomarkers via orthogonal projection to latent structures by partial least square (OPLS) analysis. A two-dimensional PLS-DA explained 49% of the differences between the three groups. OPLS analysis showed that four plasma biomarkers were significantly correlated to both ECV and LVMI, eight were significantly correlated with LVMI only and 11 were significantly correlated to ECV only.
ECV and LVMI correlate differentially in plasma biomarker patterns. Top predictors of ECV consisted of well established biomarkers of systemic inflammation and metabolic function.
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