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Whole person (holistic) health deals with the mind-body-spirit connection as a unified domain. Balancing the whole person's health makes it possible for cells, tissues, and fluids that are out of balance in disease to come back into balance as the person heals from illness. The Automatic Pattern Recognition and Interruption system can facilitate rapid change in people, once they are freed up from subconscious mind constraints. The goal of the modern, transformed health-care system should be to combine the best of conventional care and whole person health to produce the best health care on the planet.

Fluorine 18–labeled sodium fluoride PET/MRI characteristics were associated with the culprit atherosclerotic plaques in the carotid circulation of study participants with acute neurovascular syndrome; PET/MRI was also usable in the assessment of carotid stenosis, high-risk plaque features, and plaque biologic activity.BackgroundMRI and fluorine 18–labeled sodium fluoride (18F-NaF) PET can be used to identify features of plaque instability, rupture, and disease activity, but large studies have not been performed.PurposeTo evaluate the association between 18F-NaF activity and culprit carotid plaque in acute neurovascular syndrome.Materials and MethodsIn this prospective observational cohort study (October 2017 to January 2020), participants underwent 18F-NaF PET/MRI. An experienced clinician determined the culprit carotid artery based on symptoms and record review. 18F-NaF uptake was quantified using standardized uptake values and tissue-to-background ratios. Statistical significance was assessed with the Welch, χ2, Wilcoxon, or Fisher test. Multivariable models were used to evaluate the relationship between the imaging markers and the culprit versus nonculprit vessel.ResultsA total of 110 participants were evaluated (mean age, 68 years ± 10 [SD]; 70 men and 40 women). Of the 110, 34 (32%) had prior cerebrovascular disease, and 26 (24%) presented with amaurosis fugax, 54 (49%) with transient ischemic attack, and 30 (27%) with stroke. Compared with nonculprit carotids, culprit carotids had greater stenoses (≥50% stenosis: 30% vs 15% [P = .02]; ≥70% stenosis: 25% vs 4.5% [P < .001]) and had increased prevalence of MRI-derived adverse plaque features, including intraplaque hemorrhage (42% vs 23%; P = .004), necrotic core (36% vs 18%; P = .004), thrombus (7.3% vs 0%; P = .01), ulceration (18% vs 3.6%; P = .001), and higher 18F-NaF uptake (maximum tissue-to-background ratio, 1.38 [IQR, 1.12–1.82] vs 1.26 [IQR, 0.99–1.66], respectively; P = .04). Higher 18F-NaF uptake was positively associated with necrosis, intraplaque hemorrhage, ulceration, and calcification and inversely associated with fibrosis (P = .04 to P < .001). In multivariable analysis, carotid stenosis at or over 70% (odds ratio, 5.72 [95% CI: 2.2, 18]) and MRI-derived adverse plaque characteristics (odds ratio, 2.16 [95% CI: 1.2, 3.9]) were both associated with the culprit versus nonculprit carotid vessel.ConclusionFluorine 18–labeled sodium fluoride PET/MRI characteristics were associated with the culprit carotid vessel in study participants with acute neurovascular syndrome.Clinical trial registration no. NCT03215550 and NCT03215563

The endocannabinoid system is located throughout the central and peripheral nervous systems, endocrine system, gastrointestinal system, and within inflammatory cells. The use of medical cannabinoids has been gaining traction as a viable treatment option for varying illnesses in recent years. Research is ongoing looking at the effect of cannabinoids for treatment of common otolaryngologic pathologies. This article identifies common otolaryngologic pathologies where cannabinoids may have benefit, discusses potential drawbacks to cannabinoid use, and suggests future directions for research in the application of medical cannabinoids.

Myocarditis is defined as a non-ischemic inflammatory disease of the myocardium. It remains a challenge to diagnose given non-specific symptoms and lack of specific blood biomarkers. Cardiac imaging plays an important role in the evaluation of myocarditis with unique strengths and limitations of different imaging modalities, including cardiac magnetic resonance imaging, echocardiography, cardiac computed tomography, and positron emission tomography. The purpose of this review is to discuss the strengths and limitations of various cardiac imaging techniques in the evaluation of myocarditis, review imaging findings in specific causes of myocarditis including COVID-19 and after vaccination, evaluate the role of imaging in differentiating myocarditis from potential mimics and differential considerations, identify current gaps in knowledge, and propose future directions.

In vivo phosphoproteome

Supplementary Figures and Methods

Fanconi anemia (FA) is a genome instability syndrome that has been associated with both cancer predisposition and bone marrow failure. FA proteins are involved in cellular response to replication stress in which they coordinate DNA repair with DNA replication and cell-cycle progression. One regulator of the replication stress response is the ATP-dependent DNA translocase FANCM, which we have shown to be hyperphosphorylated in response to various genotoxic agents. However, the significance of this phosphorylation remained unclear. Here, we show that genotoxic stress–induced FANCM phosphorylation is ATR-dependent and that this modification is highly significant for the cellular response to replication stress. We identified serine (S1045) residue of FANCM that is phosphorylated in response to genotoxic stress and this effect is ATR-dependent. We show that S1045 is required for FANCM functions including its role in FA pathway integrity, recruiting FANCM to the site of interstrand cross links, preventing the cells from entering mitosis prematurely, and efficient activation of the CHK1 and G2–M checkpoints. Overall, our data suggest that an ATR-FANCM feedback loop is present in the FA and replication stress response pathways and that it is required for both efficient ATR/CHK1 checkpoint activation and FANCM function. Cancer Res; 73(14); 4300–10. ©2013 AACR.

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PDF file - 407K, DNA-damage-induced phosphorylation of FANCM is ATR dependent (S1); Peptides released from FANCM protein were analyzed for putative phosphorylation sites by mass spectrometry (S2); Immunoblot showing that antibody raised against phosphorylated S1045 specifically recognizes the ectopically expressed wildtype, but not S1045A mutant, form of FANCM (S3); UV mediated DNA-damage-induced phosphorylation of FANCM at S1045 (S4); Phosphorylation at S1045 is not required for FANCM binding to the FA core complex but for FANCD2 monoubiquitination (S5); MMC-induced chromatin association of the FA-core complex is impaired in S1045A-expressing cells (S6); Recruitment of FANCM to ICL site is ATR dependent (S7); S1045A mutant-expressing cells do not show any gross change in cell-cycle distribution (S8); Expression of FLAG tagged FANCMK117R in the context of knockdown of the endogenous protein (S9).

Machine learning has seen slow but steady uptake in diagnostic pathology over the past decade to assess digital whole slide images. Machine learning tools have incredible potential to standardize, and likely even improve, histopathologic diagnoses, but they are not yet widely used in clinical practice. We describe here the principles of these tools and technologies and some successful pre-clinical and pre-translational efforts in cardiovascular pathology, as well as a roadmap for moving forward. In animal models, one proof-of-principle application is in rodent progressive cardiomyopathy, of particular significance to drug toxicity studies. Basic science successes include screening the quality of differentiated stem cells and characterizing cardiomyocyte developmental stages, with potential applications for research and toxicology/drug safety screening using derived or native human pluripotent stem cells differentiated into cardiomyocytes. Translational studies of particular note include those with success in diagnosing the various forms of heart allograft rejection. In fully realizing the value of these tools in clinical cardiovascular pathology, we have identified three essential challenges. First is image quality standardization to ensure that algorithms can be developed and implemented on robust, consistent data. The second is consensus diagnosis; experts don't always agree, and thus "truth" may be difficult to establish, but the algorithms themselves may provide a solution. The third is the need for large enough data sets to facilitate robust algorithm development, necessitating large, cross-institutional, shared image databases. The power of histopathology-based machine learning technologies is tremendous; we outline here the next steps needed to capitalize on this power.

A patient with vascular Behçet’s syndrome (BS), a subtype of BS with mainly venous/arterial manifestations, presented with a left main aneurysm/thrombus and cardiogenic shock. The clinical diagnosis of BS includes mucocutaneous, vascular, and neurologic criteria. It is important to consider vascular BS as a nonatherosclerotic cause of coronary aneurysms. (Level of Difficulty: Intermediate.), Central Illustration

The use of complementary and integrative medicine has increased . It is estimated that one-third of the population of the United States uses some form of alternative medicine. Physicians should consider integrative medicine therapies . Alternative medical therapies for the common cold and influenza include herbal supplements, dietary supplements, diet, and other adjunct therapies. However, it is important to research and study these therapies. Therefore, communication with patients and other health care providers is important. This will ensure effective and positive patient care experiences. Further randomized clinical trials are necessary to further establish the role of various alternative options.

To compare pathological and hemodynamic modes of failure and operative outcomes between explanted porcine and bovine pericardial bioprosthetic valves.Patients who underwent explantation of their bioprosthetic valves at Toronto General Hospital from 2007-2019 were identified. Retrospective chart review was conducted to attain demographic information, operative outcomes, and echocardiography and pathology reports.A total of 278 patients underwent explantation of their porcine (n=183) or bovine pericardial (n=95) valves. A greater proportion of the porcine group had severe regurgitation, compared to the bovine group (45.3% vs. 19.8%, p0.001). Porcine valves had higher rates of cusp flail (19.4% vs. 3.3%, p0.001). The rates of moderate or worse stenosis were higher among bovine pericardial valves (37.9% vs. 15.8%, p0.001). On pathologic examination, the porcine valves exhibited more cusp tears (67.6% vs. 50.5%, p=0.006), while higher incidences of calcification were found in the bovine group (p0.001). Rate of stroke was higher during the explantation procedure of the bovine valves (5.3% vs. 0.5%, p=0.040).The primary mode of failure was regurgitation in porcine valves due to cusp tears and stenosis in bovine valves due to calcification. Establishing a clear understanding of failure modes based on valve material may improve design and guide valve selection at the time of surgery.

To evaluate the utility of intracochlear electrocochleography (ECochG) monitoring during cochlear implant (CI) surgery on postoperative hearing preservation.Prospective, randomized clinical trial.Ten high-volume, tertiary care CI centers.Adult patients with sensorineural hearing loss meeting the CI criteria who selected an Advanced Bionics CI.Patients were randomized to CI surgery either with audible ECochG monitoring available to the surgeon during electrode insertion or without ECochG monitoring. Hearing preservation was determined by comparing preoperative unaided low-frequency (125-, 250-, and 500-Hz) pure-tone average (LF-PTA) to postoperative LF-PTA at CI activation. Pre- and post-CI computed tomography was used to determine electrode scalar location and electrode translocation.Eighty-five adult CI candidates were enrolled. The mean (standard deviation [SD]) unaided preoperative LF-PTA across the sample was 54 (17) dB HL. For the whole sample, hearing preservation was "good" (i.e., LF-PTA change 0-15 dB) in 34.5%, "fair" (i.e., LF-PTA change15-29 dB) in 22.5%, and "poor" (i.e., LF-PTA change ≥30 dB) in 43%. For patients randomized to ECochG "on," mean (SD) LF-PTA change was 27 (20) dB compared with 27 (23) dB for patients randomized to ECochG "off" ( p = 0.89). Seven percent of patients, all of whom were randomized to ECochG off, showed electrode translocation from the scala tympani into the scala vestibuli.Although intracochlear ECochG during CI surgery has important prognostic utility, our data did not show significantly better hearing preservation in patients randomized to ECochG "on" compared with ECochG "off."

Myocarditis is an established but rare adverse event following administration of messenger RNA-based coronavirus disease 2019 (COVID-19) vaccines and is most common in male adolescents and young adults. Symptoms typically develop within a few days of vaccine administration. Most patients have mild abnormalities on cardiac imaging with rapid clinical improvement with standard treatment. However, longer term follow-up is needed to determine whether imaging abnormalities persist, to evaluate for adverse outcomes, and to understand the risk associated with subsequent vaccination. The purpose of the review is to evaluate the current literature related to myocarditis following COVID-19 vaccination, including the incidence, risk factors, clinical course, imaging findings, and proposed pathophysiologic mechanisms.

Background: Patients with thoracic aortopathy are at increased risk of catastrophic aortic dissection, carrying with it substantial mortality and morbidity. Although granular medial calcinosis (medial microcalcification) has been associated with thoracic aortopathy, its relationship to disease severity has yet to be established. Methods: One hundred one thoracic aortic specimens were collected from 57 patients with thoracic aortopathy and 18 control subjects. Standardized histopathologic scores, immunohistochemistry, and nanoindentation (tissue elastic modulus) were compared with the extent of microcalcification on von Kossa histology and 18F-sodium fluoride autoradiography. Results: Microcalcification content was higher in thoracic aortopathy samples with mild (n=28; 6.17 [2.71–10.39]; P ≤0.00010) or moderate histopathologic degeneration (n=30; 3.74 [0.87–11.80]; P P =0.0019) and OPN (osteopontin; n=26; P =0.0045) staining were increased in tissue with early aortopathy. Increasingly severe histopathologic degeneration was related to reduced microcalcification (n=82; Spearman ρ, −0.51; P P P =0.026). 18 F-sodium fluoride autoradiography demonstrated good correlation with histologically quantified microcalcification (n=66; r=0.76; P Conclusions: Medial microcalcification is a marker of aortopathy, although progression to severe aortopathy is associated with loss of both elastin fibers and microcalcification. 18 F-sodium fluoride positron emission tomography quantifies medial microcalcification and is a feasible noninvasive imaging modality for identifying aortic wall disruption with major translational promise.

Sumoylation is an important enhancer of responses to DNA replication stress and the SUMO-targeted ubiquitin E3 ligase RNF4 regulates these responses by ubiquitylation of sumoylated DNA damage response factors. The specific targets and functional consequences of RNF4 regulation in response to replication stress, however, have not been fully characterized. Here we demonstrated that RNF4 is required for the restart of DNA replication following prolonged hydroxyurea (HU)-induced replication stress. Contrary to its role in repair of γ-irradiation-induced DNA double-strand breaks (DSBs), our analysis revealed that RNF4 does not significantly impact recognition or repair of replication stress-associated DSBs. Rather, using DNA fiber assays, we found that the firing of new DNA replication origins, which is required for replication restart following prolonged stress, was inhibited in cells depleted of RNF4. We also provided evidence that RNF4 recognizes and ubiquitylates sumoylated Bloom syndrome DNA helicase BLM and thereby promotes its proteosome-mediated turnover at damaged DNA replication forks. Consistent with it being a functionally important RNF4 substrate, co-depletion of BLM rescued defects in the firing of new replication origins observed in cells depleted of RNF4 alone. We concluded that RNF4 acts to remove sumoylated BLM from collapsed DNA replication forks, which is required to facilitate normal resumption of DNA synthesis after prolonged replication fork stalling and collapse.

Supplemental Digital Content is available in the text., Background: Major uncertainties remain regarding disease activity within the retained native aortic valve, and regarding bioprosthetic valve durability, after transcatheter aortic valve implantation (TAVI). We aimed to assess native aortic valve disease activity and bioprosthetic valve durability in patients with TAVI in comparison with subjects with bioprosthetic surgical aortic valve replacement (SAVR). Methods: In a multicenter cross-sectional observational cohort study, patients with TAVI or bioprosthetic SAVR underwent baseline echocardiography, computed tomography angiography, and 18F-sodium fluoride (18F-NaF) positron emission tomography. Participants (n=47) were imaged once with 18F-NaF positron emission tomography/computed tomography either at 1 month (n=9, 19%), 2 years (n=22, 47%), or 5 years (16, 34%) after valve implantation. Patients subsequently underwent serial echocardiography to assess for changes in valve hemodynamic performance (change in peak aortic velocity) and evidence of structural valve dysfunction. Comparisons were made with matched patients with bioprosthetic SAVR (n=51) who had undergone the same imaging protocol. Results: In patients with TAVI, native aortic valves demonstrated 18F-NaF uptake around the outside of the bioprostheses that showed a modest correlation with the time from TAVI (r=0.36, P=0.023). 18F-NaF uptake in the bioprosthetic leaflets was comparable between the SAVR and TAVI groups (target-to-background ratio, 1.3 [1.2–1.7] versus 1.3 [1.2–1.5], respectively; P=0.27). The frequencies of imaging evidence of bioprosthetic valve degeneration at baseline were similar on echocardiography (6% versus 8%, respectively; P=0.78), computed tomography (15% versus 14%, respectively; P=0.87), and positron emission tomography (15% versus 29%, respectively; P=0.09). Baseline 18F-NaF uptake was associated with a subsequent change in peak aortic velocity for both TAVI (r=0.7, P

The authors report a 27-year-old woman with a remote left femoral osteosarcoma and amputation above the left knee who presented with a large right ventricular mass. Initial evaluation with thoracic CT was inconclusive regarding thrombus versus tumor, but metastatic osteosarcoma was suggested by findings at transthoracic echocardiography, cardiac CT, and cardiac MRI. The patient underwent tumor debulking, and osteosarcoma was confirmed with pathologic examination. She responded to chemotherapy, which resulted in reduction in size of the residual right ventricular tumor and of a few pulmonary metastases. Following induction chemotherapy, patient remains well undergoing maintenance therapy with an oral tyrosine kinase inhibitor. Keywords: CT, Echocardiography, MR Imaging, Intraoperative, Cardiac, Heart, Right Ventricle, Imaging Sequences, Metastases, Oncology Supplemental material is available for this article. © RSNA, 2021

Background Multiple system atrophy (MSA) is a neurodegenerative condition characterized by variable combinations of parkinsonism, autonomic failure, cerebellar ataxia and pyramidal features. Although the distribution of synucleinopathy correlates with the predominant clinical features, the burden of pathology does not fully explain observed differences in clinical presentation and rate of disease progression. We hypothesized that the clinical heterogeneity in MSA is a consequence of variability in the seeding activity of α-synuclein both between different patients and between different brain regions. Methods The reliable detection of α-synuclein seeding activity derived from MSA using cell-free amplification assays remains challenging. Therefore, we conducted a systematic evaluation of 168 different reaction buffers, using an array of pH and salts, seeded with fully characterized brain homogenates from one MSA and one PD patient. We then validated the two conditions that conferred the optimal ability to discriminate between PD- and MSA-derived samples in a larger cohort of 40 neuropathologically confirmed cases, including 15 MSA. Finally, in a subset of brains, we conducted the first multi-region analysis of seeding behaviour in MSA. Results Using our novel buffer conditions, we show that the physicochemical factors that govern the in vitro amplification of α-synuclein can be tailored to generate strain-specific reaction buffers that can be used to reliably study the seeding capacity from MSA-derived α-synuclein. Using this novel approach, we were able to sub-categorize the 15 MSA brains into 3 groups: high, intermediate and low seeders. To further demonstrate heterogeneity in α-synuclein seeding in MSA, we conducted a comprehensive multi-regional evaluation of α-synuclein seeding in 13 different regions from 2 high seeders, 2 intermediate seeders and 2 low seeders. Conclusions We have identified unexpected differences in seed-competent α-synuclein across a cohort of neuropathologically comparable MSA brains. Furthermore, our work has revealed a substantial heterogeneity in seeding activity, driven by the PBS-soluble α-synuclein, between different brain regions of a given individual that goes beyond immunohistochemical observations. Our observations pave the way for future subclassification of MSA, which exceeds conventional clinical and neuropathological phenotyping and considers the structural and biochemical heterogeneity of α-synuclein present. Finally, our methods provide an experimental framework for the development of vitally needed, rapid and sensitive diagnostic assays for MSA.

Telomere dysfunction-induced foci (TIF) can be measured by immunofluorescence, combined with telomere-fluorescent