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The potential use of lasers to vaporise atherosclerotic plaque obstructions is rapidly becoming recognised. The properties of laser light are unique in that it is coherent, monochromatic and collimated. It can be focused into tiny, flexible optical fibre made of silica which can be inserted into a blood vessel and passed intravascularly to an area of obstruction. The ease of plaque penetration is largely dependent upon the absorptive characteristics of the plaque's substances (i.e., lipid, hyaline or calcium), beam focus, power intensity and duration of laser exposure. Laser radiation of fibrous areas and especially calcified areas causes remnants of charred debris in the irradiated pathway, whereas no debris is found when exposure is focused over a primarily fatty plaque. The laser can also be utilised to canalise the organised thrombus. Since blood clots are comprised of red blood cells which contain haemoglobin pigments, the red clot is readily absorbed and thus vaporised by argon laser energies. Potential complications of recanalising coronary obstructions include perforation, aneurysm formation and red cell damage. Improvements in intravascular laser delivery systems are required before clinical application. The fibre-optic catheter to view and target obstructed sites and the use of the laser cautery cap to vaporise the plaque or thrombus will be helpful in this regard. [ABSTRACT FROM PUBLISHER]

In the course of preparing experiments withHf, optical isotope shifts for the stable Hf isotopes and forHf were measured. For the rms nuclear charge radii we obtain 〈r〉 -(r)=−0.242(16) fm. [ABSTRACT FROM AUTHOR]

Cytosine DNA methylation is essential in brain development and is implicated in various neurological disorders. Understanding DNA methylation diversity across the entire brain in a spatial context is fundamental for a complete molecular atlas of brain cell types and their gene regulatory landscapes. Here we used single-nucleus methylome sequencing (snmC-seq3) and multi-omic sequencing (snm3C-seq) 1 technologies to generate 301,626 methylomes and 176,003 chromatin conformation-methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell taxonomy with 4,673 cell groups and 274 cross-modality-annotated subclasses. We identified 2.6 million differentially methylated regions across the genome that represent potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide spatial transcriptomics data validated the association of spatial epigenetic diversity with transcription and improved the anatomical mapping of our epigenetic datasets. Furthermore, chromatin conformation diversities occurred in important neuronal genes and were highly associated with DNA methylation and transcription changes. Brain-wide cell-type comparisons enabled the construction of regulatory networks that incorporate transcription factors, regulatory elements and their potential downstream gene targets. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a whole-brain SMART-seq 2 dataset. Our study establishes a brain-wide, single-cell DNA methylome and 3D multi-omic atlas and provides a valuable resource for comprehending the cellular-spatial and regulatory genome diversity of the mouse brain., (© 2023. The Author(s).)

Single-cell analyses parse the brain's billions of neurons into thousands of 'cell-type' clusters residing in different brain structures 1 . Many cell types mediate their functions through targeted long-distance projections allowing interactions between specific cell types. Here we used epi-retro-seq 2 to link single-cell epigenomes and cell types to long-distance projections for 33,034 neurons dissected from 32 different regions projecting to 24 different targets (225 source-to-target combinations) across the whole mouse brain. We highlight uses of these data for interrogating principles relating projection types to transcriptomics and epigenomics, and for addressing hypotheses about cell types and connections related to genetics. We provide an overall synthesis with 926 statistical comparisons of discriminability of neurons projecting to each target for every source. We integrate this dataset into the larger BRAIN Initiative Cell Census Network atlas, composed of millions of neurons, to link projection cell types to consensus clusters. Integration with spatial transcriptomics further assigns projection-enriched clusters to smaller source regions than the original dissections. We exemplify this by presenting in-depth analyses of projection neurons from the hypothalamus, thalamus, hindbrain, amygdala and midbrain to provide insights into properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription-factor-binding motifs, and neurotransmitter use., (© 2023. The Author(s).)

Delineating the gene-regulatory programs underlying complex cell types is fundamental for understanding brain function in health and disease. Here, we comprehensively examined human brain cell epigenomes by probing DNA methylation and chromatin conformation at single-cell resolution in 517 thousand cells (399 thousand neurons and 118 thousand non-neurons) from 46 regions of three adult male brains. We identified 188 cell types and characterized their molecular signatures. Integrative analyses revealed concordant changes in DNA methylation, chromatin accessibility, chromatin organization, and gene expression across cell types, cortical areas, and basal ganglia structures. We further developed single-cell methylation barcodes that reliably predict brain cell types using the methylation status of select genomic sites. This multimodal epigenomic brain cell atlas provides new insights into the complexity of cell-type-specific gene regulation in adult human brains.

Objectives: The goal of this study is to demonstrate the performance of radiomics and CNN-based classifiers in determining the primary origin of gastrointestinal liver metastases for visually indistinguishable lesions., Methods: In this retrospective, IRB-approved study, 31 pancreatic cancer patients with 861 lesions (median age [IQR]: 65.39 [56.87, 75.08], 48.4% male) and 47 colorectal cancer patients with 435 lesions (median age [IQR]: 65.79 [56.99, 74.62], 63.8% male) were enrolled. A pretrained nnU-Net performed automated segmentation of 1296 liver lesions. Radiomics features for each lesion were extracted using pyradiomics. The performance of several radiomics-based machine-learning classifiers was investigated for the lesions and compared to an image-based deep-learning approach using a DenseNet-121. The performance was evaluated by AUC/ROC analysis., Results: The radiomics-based K-nearest neighbor classifier showed the best performance on an independent test set with AUC values of 0.87 and an accuracy of 0.67. In comparison, the image-based DenseNet-121-classifier reached an AUC of 0.80 and an accuracy of 0.83., Conclusions: CT-based radiomics and deep learning can distinguish the etiology of liver metastases from gastrointestinal primary tumors. Compared to deep learning, radiomics based models showed a varying generalizability in distinguishing liver metastases from colorectal cancer and pancreatic adenocarcinoma., (© 2023. International Cancer Imaging Society (ICIS).)

Objectives: Abbreviated breast MRI (AB-MRI) was introduced to reduce both examination and image reading times and to improve cost-effectiveness of breast cancer screening. The aim of this model-based economic study was to analyze the cost-effectiveness of full protocol breast MRI (FB-MRI) vs. AB-MRI in screening women with dense breast tissue for breast cancer., Methods: Decision analysis and a Markov model were designed to model the cumulative costs and effects of biennial screening in terms of quality-adjusted life years (QALYs) from a US healthcare system perspective. Model input parameters for a cohort of women with dense breast tissue were adopted from recent literature. The impact of varying AB-MRI costs per examination as well as specificity on the resulting cost-effectiveness was modeled within deterministic sensitivity analyses., Results: At an assumed cost per examination of $ 263 for AB-MRI (84% of the cost of a FB-MRI examination), the discounted cumulative costs of both MR-based strategies accounted comparably. Reducing the costs of AB-MRI below $ 259 (82% of the cost of a FB-MRI examination, respectively), the incremental cost-effectiveness ratio of FB-MRI exceeded the willingness to pay threshold and the AB-MRI-strategy should be considered preferable in terms of cost-effectiveness., Conclusions: Our preliminary findings indicate that AB-MRI may be considered cost-effective compared to FB-MRI for screening women with dense breast tissue for breast cancer, as long as the costs per examination do not exceed 82% of the cost of a FB-MRI examination., Key Points: • Cost-effectiveness of abbreviated breast MRI is affected by reductions in specificity and resulting false positive findings and increased recall rates. • Abbreviated breast MRI may be cost-effective up to a cost per examination of 82% of the cost of a full protocol examination. • Abbreviated breast MRI could be an economically preferable alternative to full protocol breast MRI in screening women with dense breast tissue., (© 2022. The Author(s).)

Background: For patients with solid renal masses, a precise differentiation between malignant and benign tumors is crucial for forward treatment management. Even though MRI and CT are often deemed as the gold standard in the diagnosis of solid renal masses, CEUS may also offer very high sensitivity in detection. The aim of this study therefore was to evaluate the effectiveness of CEUS from an economical point of view., Methods: A decision-making model based on a Markov model assessed expenses and utilities (in QALYs) associated with CEUS, MRI and CT. The utilized parameters were acquired from published research. Further, a Monte Carlo simulation-based deterministic sensitivity analysis of utilized variables with 30,000 repetitions was executed. The willingness-to-pay (WTP) is at USD 100,000/QALY., Results: In the baseline, CT caused overall expenses of USD 10,285.58 and an efficacy of 11.95 QALYs, whereas MRI caused overall expenses of USD 7407.70 and an efficacy of 12.25. Further, CEUS caused overall expenses of USD 5539.78, with an efficacy of 12.44. Consequently, CT and MRI were dominated by CEUS, and CEUS remained cost-effective in the sensitivity analyses., Conclusions: CEUS should be considered as a cost-effective imaging strategy for the initial diagnostic workup and assessment of solid renal masses compared to CT and MRI.

Objective: Pancreatic cancer is portrayed to become the second leading cause of cancer-related death within the next years. Potentially complicating surgical resection emphasizes the importance of an accurate TNM classification. In particular, the failure to detect features for non-resectability has profound consequences on patient outcomes and economic costs due to incorrect indication for resection. In the detection of liver metastases, contrast-enhanced MRI showed high sensitivity and specificity; however, the cost-effectiveness compared to the standard of care imaging remains unclear. The aim of this study was to analyze whether additional MRI of the liver is a cost-effective approach compared to routinely acquired contrast-enhanced computed tomography (CE-CT) in the initial staging of pancreatic cancer., Methods: A decision model based on Markov simulation was developed to estimate the quality-adjusted life-years (QALYs) and lifetime costs of the diagnostic modalities. Model input parameters were assessed based on evidence from recent literature. The willingness-to-pay (WTP) was set to $100,000/QALY. To evaluate model uncertainty, deterministic and probabilistic sensitivity analyses were performed., Results: In the base-case analysis, the model yielded a total cost of $185,597 and an effectiveness of 2.347 QALYs for CE-MR/CT and $187,601 and 2.337 QALYs for CE-CT respectively. With a net monetary benefit (NMB) of $49,133, CE-MR/CT is shown to be dominant over CE-CT with a NMB of $46,117. Deterministic and probabilistic survival analysis showed model robustness for varying input parameters., Conclusion: Based on our results, combined CE-MR/CT can be regarded as a cost-effective imaging strategy for the staging of pancreatic cancer., Key Points: • Additional MRI of the liver for initial staging of pancreatic cancer results in lower total costs and higher effectiveness. • The economic model showed high robustness for varying input parameters., (© 2021. The Author(s).)

(1) Background: Tumoral heterogeneity (TH) is a major challenge in the treatment of metastatic colorectal cancer (mCRC) and is associated with inferior response. Therefore, the identification of TH would be beneficial for treatment planning. TH can be assessed by identifying genetic alterations. In this work, a radiomics-based approach for assessment of TH in colorectal liver metastases (CRLM) in CT scans is demonstrated. (2) Methods: In this retrospective study, CRLM of mCRC were segmented and radiomics features extracted using pyradiomics. Unsupervised k-means clustering was applied to features and lesions. Feature redundancy was evaluated by principal component analysis and reduced by Pearson correlation coefficient cutoff. Feature selection was conducted by LASSO regression and visual analysis of the clusters by radiologists. (3) Results: A total of 47 patients’ (36% female, median age 64) CTs with 261 lesions were included. Five clusters were identified, and the categories small disseminated (n = 31), heterogeneous (n = 105), homogeneous (n = 64), mixed (n = 59), and very large type (n = 2) were assigned based on visual characteristics. Further statistical analysis showed correlation (p < 0.01) of clusters with sex, primary location, T- and N-status, and mutational status. Feature reduction and selection resulted in the identification of four features as a final set for cluster definition. (4) Conclusions: Radiomics features can characterize TH in liver metastases of mCRC in CT scans, and may be suitable for a better pretherapeutic classification of liver lesion phenotypes.

Objectives: To evaluate the cost-effectiveness of MR-mammography (MRM) vs. x-ray based mammography (XM) in two-yearly screening women of intermediate risk for breast cancer in the light of recent literature., Methods: Decision analysis and Markov modelling were used to compare cumulative costs (in US-$) and outcomes (in QALYs) of MRM vs. XM over the model runtime of 20 years. The perspective of the U.S. healthcare system was selected. Incremental cost-effectiveness ratios (ICER) were calculated and related to a willingness to pay-threshold of $ 100,000 per QALY in order to evaluate the cost-effectiveness. Deterministic and probabilistic sensitivity analyses were conducted to test the impact of variations of the input parameters. In particular, variations of the rate of false positive findings beyond the first screening round and their impact on cost-effectiveness were assessed., Results: Breast cancer screening with MRM resulted in increased costs and superior effectiveness. Cumulative average costs of $ 6,081 per woman and cumulative effects of 15.12 QALYs were determined for MRM, whereas screening with XM resulted in costs of $ 5,810 and 15.10 QALYs, resulting in an ICER of $ 13,493 per QALY gained. When the specificity of MRM in the second and subsequent screening rounds was varied from 92% to 99%, the ICER resulted in a range from $ 38,849 to $ 5,062 per QALY., Conclusions: Based on most recent data on the diagnostic performance beyond the first screening round, MRM may remain the economically preferable alternative in screening women of intermediate risk for breast cancer due to their dense breast tissue., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tollens, Baltzer, Dietzel, Schnitzer, Kunz, Rink, Rübenthaler, Froelich and Kaiser.)

Background ApoAI (apolipoproteins AI) and apoAII (apolipoprotein AII) are structural and functional proteins of high-density lipoproteins (HDL) which undergo post-translational modifications at specific residues, creating distinct proteoforms. While specific post-translational modifications have been reported to alter apolipoprotein function, the full spectrum of apoAI and apoAII proteoforms and their associations with cardiometabolic phenotype remains unknown. Herein, we comprehensively characterize apoAI and apoAII proteoforms detectable in serum and their post-translational modifications and quantify their associations with cardiometabolic health indices. Methods and Results Using top-down proteomics (mass-spectrometric analysis of intact proteins), we analyzed paired serum samples from 150 CARDIA (Coronary Artery Risk Development in Young Adults) study participants from year 20 and 25 exams. Measuring 15 apoAI and 9 apoAII proteoforms, 6 of which carried novel post-translational modifications, we quantified associations between percent proteoform abundance and key cardiometabolic indices. Canonical (unmodified) apoAI had inverse associations with HDL cholesterol and HDL-cholesterol efflux, and positive associations with obesity indices (body mass index, waist circumference), and triglycerides, whereas glycated apoAI showed positive associations with serum glucose and diabetes mellitus. Fatty-acid‒modified ApoAI proteoforms had positive associations with HDL cholesterol and efflux, and inverse associations with obesity indices and triglycerides. Truncated and dimerized proteoforms of apoAII were associated with HDL cholesterol (positively) and obesity indices (inversely). Several proteoforms had no significant associations with phenotype. Conclusions Associations between apoAI and AII and cardiometabolic indices are proteoform-specific. These results provide "proof-of-concept" that precise chemical characterization of human apolipoproteins will yield improved insights into the complex pathways through which proteins signify and mediate health and disease.

The enzyme, 2'-3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) has been known for over fifty years. Nevertheless, the roles this membrane-bound enzyme play have yet to be described completely. Recently, there has been renewed interest in the study of this enzyme due to studies that suggest that CNPase plays a role in the mediation of cellular inflammatory responses in renal and nervous system tissues. Also, this enzyme, found in oligodendrocytes of the nervous system, has been reported to participate in significant regulatory changes associated with age which may be involved in age-related CNS degeneration. Consequently, development of CNPase inhibitors is of interest and should aid in the study of this, as yet, poorly understood enzyme. In this work we utilized a spectrophotometric enzyme assay to determine the effect a panel of organo-vanadium complexes had on isolated hamster myelin CNPase activity. Our group has now identified several potent in vitro CNPase inhibitors that could prove useful in clarifying the important roles of this enzyme.

Background: Both post-traumatic stress disorder (PTSD) and complex post-traumatic stress disorder (CPTSD) have been included in the 11th edition of the International Classification of Diseases (ICD-11). Although the validity of CPTSD has been controversial, a growing number of studies support the distinction between PTSD and CPTSD. However, the majority of this research has originated in high-income countries (HICs), whereas the prevalence of trauma experience associated with PTSD/CPTSD diagnosis is significantly higher in low- and middle-income countries (LMICs). Objective: This study assessed whether a sample from an LMIC setting produced distinct classes that reflect ICD-11 criteria for PTSD and CPTSD. Furthermore, this study investigated whether childhood trauma distinguished between PTSD and CPTSD. Method: International Trauma Questionnaire responses from a sample of South African university undergraduates were used as indicator variables in a latent class analysis (LCA). Chi-squared tests of independence and Kruskal-Wallis H tests were used to assess between-class differences. Results: The LCA identified four distinct classes: a PTSD class with elevated symptoms of PTSD, but low endorsement of disturbances in self-organization (DSO; symptoms that are specific to CPTSD); a CPTSD class with elevated symptoms of PTSD and DSO; a DSO class with low symptoms of PTSD, but elevated symptoms of DSO; and a Low class with low endorsements on all symptoms. Regarding childhood trauma, participants in the CPTSD class had more severe childhood abuse and neglect, specifically emotional abuse and neglect, than participants in the PTSD class. Conclusions: Findings were consistent with the distinction between PTSD and CPTSD symptom profiles in the ICD-11. Our findings support a similar qualitative distinction between PTSD and CPTSD in our LMIC context, as previously reported in HICs. This distinction is especially relevant in LMICs because of the significant number of individuals vulnerable to these disorders., Competing Interests: No potential conflict of interest was reported by the authors., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Objective: To investigate the effect of phase polarity and charge balance of spinal cord stimulation (SCS) waveforms on pain behavior and gene expression in a neuropathic pain rodent model. We hypothesized that differing waveforms will result in diverse behavioral and transcriptomics expression due to unique mechanisms of action., Materials and Methods: Rats were implanted with a four-contact cylindrical mini-lead and randomly assigned to two control (no-pain and pain model) and five test groups featuring monophasic, as well as charge-unbalanced and charge-balanced biphasic SCS waveforms. Mechanical and cold allodynia were assessed to measure efficacy. The ipsilateral dorsal quadrant of spinal cord adjacent to the lead was harvested post-stimulation and processed to determine gene expression via real-time reverse-transcriptase polymerase chain reaction (RT-PCR). Gene expression, SCS intensity (mA), and behavioral score as percent of baseline (BSPB) were statistically analyzed and used to generate correlograms using R-Studio. Statistical analysis was performed using SPSS22.0, and p < 0.05 was considered significant., Results: As expected, BSPB was significantly lower for the pain model group compared to the no-pain group. BSPB was significantly improved post-stim compared to pre-stim using cathodic, anodic, symmetric biphasic, or asymmetric biphasic 1:2 waveforms; however, BSPB was not restored to Sham levels. RT-PCR analysis showed that eight genes demonstrated a significant difference between the pain model and SCS waveforms and between waveforms. Correlograms reveal a linear correlation between regulation of expression of a given gene in relation to mA, BSPB, or other genes., Conclusions: Our results exhibit that specific SCS waveforms differentially modulate several key transcriptional pathways that are relevant in chronic pain conditions. These results have significant implications for SCS: whether to move beyond traditional paradigm of neuronal activation to focus also on modulating immune-driven processes., (© 2019 International Neuromodulation Society.)

Background: British National guidelines (NICE) recommend bariatric surgery for patients with a body mass index (BMI) > 40 kg/m2, or BMI > 35 kg/m2 with any comorbidities of the metabolic syndrome. Intra-gastric balloons (IGB) can be used in super obese patients as a first step, before definitive surgery., Aims: Quantify weight loss 6 months after IGB placement, measure progression to definitive surgery and identify complications., Methods: Data collected retrospectively on 50 patients. Forty-six proposed for definitive bariatric surgery, four patients excluded. Analysis performed using SPSS v23.0., Results: Median weight decreased from 165.5 to 155 kg (range 78 to 212, p < 0.01), BMI from 57.4 to 52.15 (range 32.9 to 70.5, p < 0.01), percentage excess weight loss (%EWL) was 12.9% (range - 3.3 to 64.66%, p < 0.01) and BMI reduction was 4.25 kg/m2 (range - 1.3 to 13.9, p < 0.01). Twenty-nine out of 46 patients (63%) progressed to definitive bariatric surgery. Ten out of 46 patients (21.7%) had complications requiring readmission. Seven of these patients required early balloon removal and six failed to progress to definitive surgery. Six patients had a second balloon placement, their actual weight loss was less successful, with some regaining weight., Discussion: IGB is useful to aid weight loss prior to definitive bariatric surgery. Results from first balloon placement are encouraging and comparable with other studies "as reported by Genco et al. (Int J of Obes 30:129-133, 2006)." Readmission due to nausea, vomiting, dehydration and poor compliance may be associated with poor weight loss and failure to progress to definitive surgery. Second balloon placements were less successful., Conclusion: IGB as bridging therapy is a safe and useful adjunct. Sequential IGBs do not seem to provide additional benefit.

Previous studies have shown that T cell receptor (TCR) and CD28 coreceptor stimulation involves rapid ATP release, autocrine purinergic feedback via P2X receptors, and mitochondrial ATP synthesis that promote T cell activation. Here, we show that ADP formation and autocrine stimulation of P2Y1 receptors are also involved in these purinergic signaling mechanisms. Primary human CD4 T cells and the human Jurkat CD4 T cell line express P2Y1 receptors. The expression of this receptor increases following T cell stimulation. Inhibition of P2Y1 receptors impairs the activation of mitochondria, as assessed by mitochondrial Ca 2+ uptake, and reduces cytosolic Ca 2+ signaling in response to TCR/CD28 stimulation. We found that the addition of exogenous ADP or overexpression of P2Y1 receptors significantly increased IL-2 mRNA transcription in response to TCR/CD28 stimulation. Conversely, antagonists or silencing of P2Y1 receptors reduced IL-2 mRNA transcription and attenuated T cell functions. We conclude that P2Y1 and P2X receptors have non-redundant, synergistic functions in the regulation of T cell activation. P2Y1 receptors may represent potential therapeutic targets to modulate T cell function in inflammation and host defense.

Fluorescence microscopy is a key driver of discoveries in the life sciences, with observable phenomena being limited by the optics of the microscope, the chemistry of the fluorophores, and the maximum photon exposure tolerated by the sample. These limits necessitate trade-offs between imaging speed, spatial resolution, light exposure, and imaging depth. In this work we show how content-aware image restoration based on deep learning extends the range of biological phenomena observable by microscopy. We demonstrate on eight concrete examples how microscopy images can be restored even if 60-fold fewer photons are used during acquisition, how near isotropic resolution can be achieved with up to tenfold under-sampling along the axial direction, and how tubular and granular structures smaller than the diffraction limit can be resolved at 20-times-higher frame rates compared to state-of-the-art methods. All developed image restoration methods are freely available as open source software in Python, FIJI, and KNIME.

Planarians are on the rise as a model system for regeneration and stem cell dynamics. Almost in parallel the interest in planarian field biology has declined. Besides representing an independent research discipline in its own right, understanding of the natural habitat is also directly relevant to optimizing culture conditions in the laboratory. Moreover, the current laboratory models are but few of hundreds of planarian species worldwide. Their adaptation to a wide range of ecological niches has resulted in a fascinating diversity of regenerative abilities, body size, reproduction strategies, and life expectancy, to name just a few. With the currently ongoing establishment of large planarian species collections, such phenotypic diversity becomes accessible to comparative mechanistic analysis in the laboratory. Overall, we hope that this chapter inspires an integral view of the planarian model system that not only includes the molecular and cellular processes under investigation but also the evolutionary forces that shaped them in the first place.