Novel Use of Fractal Analysis for Quantifying Polymethylmethacrylate Distribution Patterns in Osteoporotic and Malignant Vertebral Compression Fractures Following Vertebroplasty.

Purpose: Fractal analysis is a mathematical tool which allows the evaluation of complex microstructural features within materials that cannot be expressed in traditional geometric terms. The purpose of this study is to quantify the differences in polymethylmethacrylate intravertebral cement spatial distribution patterns following vertebroplasty using fractal analysis through the examination of osteoporotic and malignant compression fractures. Methods: Frontal and lateral post-vertebroplasty radiographs were evaluated from 29 patients with osteoporotic and malignant compression fractures who underwent vertebroplasty. The individually treated vertebra were divided into osteoporotic (n = 35) and malignant groups (n = 41). Images underwent segmentation, thresholding, and binarization prior to fractal analysis. Fractal dimension and lacunarity values were derived from the region of interest in treated vertebrae using the "box-counting" and "gliding-box" techniques respectively using ImageJ. The mean values of both parameters were compared between the 2 groups. Results: The mean fractal dimension was significantly higher in the malignant vertebral compression fracture group (1.53 ± 0.08) compared to the osteoporotic group (1.34 ± 0.17; P < .001). Similarly, mean lacunarity values were significantly higher in the malignant fracture group (0.50 ± 0.09) compared to the osteoporotic group (0.37 ± 0.10; P < .001). Conclusions: Fractal dimension and lacunarity values of cement spatial distribution patterns obtained from the post-vertebroplasty radiographs can differentiate between benign osteoporotic and malignant vertebral compression fractures. This novel technique may be useful for evaluating cement spatial distribution patterns in spine augmentation procedures, although further research is warranted in this area.

Feasibility of [18F]fluoropivalate hybrid PET/MRI for imaging lower and higher grade glioma: a prospective first-in-patient pilot study.

PURPOSE: MRI and PET are used in neuro-oncology for the detection and characterisation of lesions for malignancy to target surgical biopsy and to plan surgical resections or stereotactic radiosurgery. The critical role of short-chain fatty acids (SCFAs) in brain tumour biology has come to the forefront. The non-metabolised SCFA radiotracer, [18F]fluoropivalate (FPIA), shows low background signal in most tissues except eliminating organs and has appropriate human dosimetry. Tumour uptake of the radiotracer is, however, unknown. We investigated the uptake characteristics of FPIA in this pilot PET/MRI study. METHODS: Ten adult glioma subjects were identified based on radiological features using standard-of-care MRI prior to any surgical intervention, with subsequent histopathological confirmation of glioma subtype and grade (lower-grade - LGG - and higher-grade - HGG - patients). FPIA was injected as an intravenous bolus injection (range 342-368 MBq), and dynamic PET and MRI data were acquired simultaneously over 66 min. RESULTS: All patients tolerated the PET/MRI protocol. Three patients were reclassified following resection and histology. Tumour maximum standardised uptake value (SUVmax,60) increased in the order LGG (WHO grade 2) < HGG (WHO grade 3) < HGG (WHO grade 4). The net irreversible solute transfer, Ki, and influx rate constant, K1, were significantly higher in HGG (p < 0.05). Of the MRI variables studied, DCE-MRI-derived extravascular-and-extracellular volume fraction (ve) was high in tumours of WHO grade 4 compared with other grades (p < 0.05). SLC25A20 protein expression was higher in HGG compared with LGG. CONCLUSION: Tumoural FPIA PET uptake is higher in HGG compared to LGG. This study supports further investigation of FPIA PET/MRI for brain tumour imaging in a larger patient population. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT04097535.

Changes in interoception after alcohol administration correlate with expectancies and subjective effects.

Interoceptive signals give rise to subjective feeling states that can drive motivational and behavioural responses. In the context of alcohol use behaviours, interoceptive signals may shape subjective alcohol experiences and thereby support biobehavioural mechanisms of drinking behaviour change. This study examined the acute effects of alcohol on participants' interoceptive abilities and determined whether pharmacologically induced changes in heart beat detection correlate with subjective alcohol effects, craving and expectancies. Participants completed a two-session, double-blind placebo controlled experiment (n = 27). Participants consumed a beverage containing 0.4 g/kg of alcohol or a placebo. They also completed measurements of alcohol expectancies at baseline, and alcohol-induced changes in mood, craving and light-headedness. Interoceptive ability was measured using the heartbeat discrimination task prior to and following beverage administration, yielding indices of interoceptive accuracy, confidence and meta-cognition. Alcohol administration increased interoceptive accuracy compared with baseline and placebo; and those changes in interoception negatively correlated with negative alcohol expectancies. Further, changes in interoception positively correlated with perceived light-headedness and positive mood after alcohol administration, whereas null effects were found for craving. In the placebo condition, null results were obtained. Alcohol is well established to change bodily states, and here, we find that the extent to which alcohol increases participants' sensitivity to bodily states correlates with their subjective drinking experiences. This was observed in relation to mood, light-headedness and prospective alcohol expectancies. We posit that over successive alcohol experiences, changes in bodily states may feed into the development of alcohol expectancies that could in turn predict future drinking behaviours.

Understanding the Impact of Schwartz Rounds on Pediatric Clinicians' Well-Being Using the Positive Emotion, Engagement, Relationships, Meaning, and Accomplishment (PERMA) Model for Flourishing: A Qualitative Analysis.

Objective Schwartz Rounds (SR) is an interdisciplinary, case-based forum that augments compassionate care at the bedside and promotes discussion of the psycho-emotional aspects of patient care. This pilot study analyzed the perspectives of pediatric SR attendees through the lens of human flourishing, as defined by "PERMA" (positive emotion, engagement, relationships, meaning, and accomplishment). Methods This qualitative study was conducted at our Children's Hospital from September 2023 to October 2023. Focus group questions were developed from the Secure Flourishing Index and Community Workplace Flourishing validated tools. Clinicians who attended at least one SR in our Children's Hospital from January 2019 through September 2021 were recruited to participate in focus groups. Transcripts were analyzed using a direct content analysis based on the PERMA framework. Coded content from participants who attended >2 SR since 2019 was considered frequent (FR), whereas that of participants who attended ≤2 SR since 2019 was considered non-frequent (NFR). Results Sixteen clinicians (14 pediatric and two non-pediatric) participated in focus groups, including seven FR and nine NFR participants. There were nine emerging themes, eight of which were characterized among frequent SR attendees: SR serves as a safe and trusted space, promotes validation and support, facilitates introspective thinking, stimulates perspective shifts, augments compassion, reaffirms purpose, positively impacts one's professional identity, and no impact on resilience. In comparison, five of these themes and another theme (humanizes medicine) were identified among non-frequent attendees. All themes reflected one or more PERMA categories. Conclusion SR has the potential to augment human flourishing and holds a vital role in promoting a supportive environment in the workplace. SR thereby offers institutions an effective interventional tool to promote elevated well-being in the workforce.

Stem cells in cancer: instigators and propagators?

There is growing realization that many - if not all - cancer-cell populations contain a subpopulation of self-renewing stem cells known as cancer stem cells (CSCs). Unlike normal adult stem cells that remain constant in number, CSCs can increase in number as tumours grow, and give rise to progeny that can be both locally invasive and colonise distant sites - the two hallmarks of malignancy. Immunodeficient mouse models in which human tumours can be xenografted provide persuasive evidence that CSCs are present in human leukaemias and many types of solid tumour. In addition, many studies have found similar subpopulations in mouse tumours that show enhanced tumorigenic properties when they are transplanted into histocompatible mice. In this Commentary, we refer to CSCs as tumour-propagating cells (TPCs), a term that reflects the assays that are currently employed to identify them. We first discuss evidence that cancer can originate from normal stem cells or closely related descendants. We then outline the attributes of TPCs and review studies in which they have been identified in various cancers. Finally, we discuss the implications of these findings for successful cancer therapies.

Data for evaluating mine roof stability via acoustic impact.

The stability of underground mine roofs is critical to the safety of miners. They often assess the condition of the roof by striking it with a long bar and then interpret the sound of the impact as either "tight" (safe) or "drummy" (unsafe). This paper presents a dataset of a 3309 acoustic recordings of such impacts, labelled as by an expert miner as either drummy or tight. Data was recorded from a number of sites within 5 different underground mines, all potash mines in the Canadian province of Saskatchewan.

Cardiovascular mechanisms of interoceptive awareness: Effects of resonance breathing.

Interoception, the ability to perceive internal bodily sensations, and heart rate variability (HRV) share common physiological pathways, including the baroreflex feedback loop. The baroreflex can be activated by resonance breathing, wherein respiration is paced at 6 times per minute (0.1 Hz), eliciting immediate physiological changes and longer-term therapeutic responses. This registered report characterizes baroreflex functioning as a cardiac mechanism of interoception in a two-session study (n = 67). The heartbeat discrimination task was used to obtain indices of interoceptive accuracy, sensibility and metacognition. Baroreflex functioning was measured as HRV at 0.1 Hz and baroreflex sensitivity (BRS); high frequency (HF) HRV was calculated as a control. Cardiovascular indices were measured at baseline and during active and control paced breathing after which changes in interoception were measured. The first hypothesis was that baseline baroreflex functioning would predict individual differences in interoceptive awareness. The second hypothesis was that resonance breathing would increase participants' ability to detect their own heartbeats, and that this effect would be mediated by increases in 0.1 Hz HRV and BRS. Data were collected upon in principle acceptance of the manuscript. We found a negative relationship of interoceptive accuracy with baseline HF HRV and BRS, and a positive relationship between metacognitive interoception and 0.1HZ HRV, BRS and HF HRV. We found that changes in 0.1 Hz HRV and BRS during resonance breathing positively correlate with increases in interoceptive accuracy. Our results show that the extent to which breathing recruits the resonant properties of the cardiovascular system can facilitate the conscious perception of participants' heartbeats. We interpret this as an increase in vagal afferent signaling and baroreflex functioning following resonance breathing. We put forward an alternative explanation that HRV modulation can reduce interoceptive prediction errors, facilitating the conscious perception of interoceptive signals, and consider the role of resonance breathing on mental health from an interoceptive inference perspective.

Locating the stem cell niche and tracing hepatocyte lineages in human liver.

UNLABELLED: We have used immunohistochemical and histochemical techniques to identify patches of hepatocytes deficient in the enzyme cytochrome c oxidase, a component of the electron transport chain and encoded by mitochondrial DNA (mtDNA). These patches invariably abutted the portal tracts and expanded laterally as they spread toward the hepatic veins. Here we investigate, using mtDNA mutations as a marker of clonal expansion, the clonality of these patches. Negative hepatocytes were laser-capture microdissected and mutations identified by polymerase chain reaction sequencing of the entire mtDNA genome. Patches of cytochrome c oxidase-deficient hepatocytes were clonal, suggesting an origin from a long-lived cell, presumably a stem cell. Immunohistochemical analysis of function and proliferation suggested that these mutations in cytochrome c oxidase-deficient hepatocytes were nonpathogenic. CONCLUSION: These data show, for the first time, that clonal proliferative units exist in the human liver, an origin from a periportal niche is most likely, and that the trajectory of the units is compatible with a migration of cells from the periportal regions to the hepatic veins.

A methodological approach to tracing cell lineage in human epithelial tissues.

Methods for lineage tracing of stem cell progeny in human tissues are currently not available. We describe a technique for detecting the expansion of a single cell's progeny that contain clonal mitochondrial DNA (mtDNA) mutations affecting the expression of mtDNA-encoded cytochrome c oxidase (COX). Because such mutations take up to 40 years to become phenotypically apparent, we believe these clonal patches originate in stem cells. Dual-color enzyme histochemistry was used to identify COX-deficient cells, and mutations were confirmed by microdissection of single cells with polymerase chain reaction sequencing of the entire mtDNA genome. These techniques have been applied to human intestine, liver, pancreas, and skin. Our results suggest that the stem cell niche is located at the base of colonic crypts and above the Paneth cell region in the small intestine, in accord with dynamic cell kinetic studies in animals. In the pancreas, exocrine tissue progenitors appeared to be located in or close to interlobular ducts, and, in the liver, we propose that stem cells are located in the periportal region. In the skin, the origin of a basal cell carcinoma appeared to be from the outer root sheath of the hair follicle. We propose that this is a general method for detecting clonal cell populations from which the location of the niche can be inferred, also affording the generation of cell fate maps, all in human tissues. In addition, the technique allows analysis of the origin of human tumors from specific tissue sites.

Number crunching in the cancer stem cell market.

Like their normal counterparts, many tumours are thought to have a hierarchical organization, albeit a disorganized one. Accordingly, the concept of cancer stem cells has emerged, and that these cells are responsible for perpetuating tumour existence. Operationally, cancer stem cells are regarded as prospectively purified cells that are the most effective at tumour initiation in an in vivo assay, usually after xenotransplantation to NOD/SCID mice. The conventional wisdom is that such tumour-initiating cells are rare based upon having to xenotransplant large numbers of human tumour cells into immunodeficient mice to propagate the tumour, but new evidence indicates that perhaps these cells are not so rare, at least in malignant melanoma, if a supportive soil is provided for the transplanted cells along with further restriction of the murine host's immune response.

Metabolic activity of primary uveal melanoma on PET/CT scan and its relationship with monosomy 3 and other prognostic factors.

PURPOSE: To correlate the metabolic activity of primary uveal melanoma on positron emission tomography (PET)/CT scan with known clinical and pathological prognostic factors. METHODS: A retrospective cohort analysis of eyes enucleated for uveal melanoma that underwent preoperative imaging with a PET/CT scan was performed. Tumour dimensions were recorded and classified using Collaborative Ocular Melanoma Study (COMS) and American Joint Committee on Cancer (AJCC) Tumour - Nodes - Metastases (TNM) criteria. Metabolic activity was determined by measurement of the maximal standardised uptake value (SUVmax) on PET/CT scans. SUVmax of >2.5 and >4 was also used as cut-off value for metabolic positivity. Chromosome 3 and 8 status was determined using fluorescence in situ hybridisation analysis. Pearson correlation, χ(2) test and non-parametric tests were used. p<0.05 was considered statistically significant. RESULTS: Seventy-six uveal melanomas were imaged preoperatively with a PET/CT scan. Overall 92% of tumours had a SUVmax >2.5 and 67% had a SUVmax >4. Monosomy 3 was found in 35 melanomas, of which 94% had an SUVmax >2.5 and 80% had an SUVmax >4. Only 57% of disomy 3 melanomas had an SUVmax >4. SUVmax was significantly increased in tumours with monosomy 3 (p=0.043) but not in tumours with chromosome 8 gain (p=0.49). SUVmax and increasing tumour size were positively correlated (p<0.05). Using the AJCC criteria, there was a significant difference in SUVmax among prognostic groups (p=0.024). There was no correlation with histopathological cell type (p=0.923). CONCLUSIONS: Metabolic activity of uveal melanoma on PET/CT scan is positively correlated with monosomy 3, increasing tumour size and TNM prognostic groups. No association with chromosome 8 gain or histopathology cell type was noted. SUVmax >4 is a relative but not an absolute indicator of monosomy 3 status.

Stem cells and lung cancer: future therapeutic targets?

In both the UK and USA more people die of lung cancer than any other type of cancer. Lung cancer's high mortality rate is also reflected on a global scale, with lung cancer accounting for more than 1 million deaths per year. In tissues with ordered structure such a lung epithelia, it is likely that the cancers have their origins in normal adult stem cells, and then the tumours themselves are maintained by a population of malignant stem cells - so-called cancer stem cells. This review examines both these postulates in animal models and in the clinical setting, noting that stem cell niches appear to foster tumour development, and that drug resistance can often be attributed to malignant cells with stem cell properties.

Cell therapy for liver disease.

The clinical demand for whole organ transplantation for the treatment of end-stage liver disease far outstrips supply. As a result, research efforts have focused on hepatocyte therapies to support this scarce clinical resource, including the investigation of alternative cell sources, in particular bone marrow cells (BMCs). In animal models of metabolic liver disease, adopting strategies that provide a selective advantage for transplanted hepatocytes have proved to be highly effective in repopulating recipient livers, and the current relatively poor success rate of hepatocyte transplants in humans can be attributed to the lack of a clinically applicable procedure to induce a similar repopulation of the human liver. Autologous BMCs have been transplanted in a number of clinical trials involving patients with liver cirrhosis; modest improvements in liver health have been reported, but the mechanisms responsible for these effects are currently unknown. Transplanted hepatocytes can effectively repopulate a metabolically deficient liver, provided that a selective advantage exists for the donor cells. Some reports suggest that BMCs can differentiate into hepatocytes, but for the treatment of cirrhosis, the primary goal is to render the ingressing cells capable of degrading the excessive collagen associated with the disease. This review presents the progress and discusses some of the problems that need to be overcome in the field of cell transplantation for the treatment of metabolic and fibrogenic liver diseases.