Spatial Atlas for Mapping Vascular Microcalcification Using 18F-NaF PET/CT: Application in Hyperphosphatemic Familial Tumoral Calcinosis.

BACKGROUND: Vascular calcification causes significant morbidity and occurs frequently in diseases of calcium/phosphate imbalance. Radiolabeled sodium fluoride positron emission tomography/computed tomography has emerged as a sensitive and specific method for detecting and quantifying active microcalcifications. We developed a novel technique to quantify and map total vasculature microcalcification to a common space, allowing simultaneous assessment of global disease burden and precise tracking of site-specific microcalcifications across time and individuals. METHODS: To develop this technique, 4 patients with hyperphosphatemic familial tumoral calcinosis, a monogenic disorder of FGF23 (fibroblast growth factor-23) deficiency with a high prevalence of vascular calcification, underwent radiolabeled sodium fluoride positron emission tomography/computed tomography imaging. One patient received serial imaging 1 year after treatment with an IL-1 (interleukin-1) antagonist. A radiolabeled sodium fluoride-based microcalcification score, as well as calcification volume, was computed at all perpendicular slices, which were then mapped onto a standardized vascular atlas. Segment-wise mCSmean and mCSmax were computed to compare microcalcification score levels at predefined vascular segments within subjects. RESULTS: Patients with hyperphosphatemic familial tumoral calcinosis had notable peaks in microcalcification score near the aortic bifurcation and distal femoral arteries, compared with a control subject who had uniform distribution of vascular radiolabeled sodium fluoride uptake. This technique also identified microcalcification in a 17-year-old patient, who had no computed tomography-defined calcification. This technique could not only detect a decrease in microcalcification score throughout the patient treated with an IL-1 antagonist but it also identified anatomic areas that had increased responsiveness while there was no change in computed tomography-defined macrocalcification after treatment. CONCLUSIONS: This technique affords the ability to visualize spatial patterns of the active microcalcification process in the peripheral vasculature. Further, this technique affords the ability to track microcalcifications at precise locations not only across time but also across subjects. This technique is readily adaptable to other diseases of vascular calcification and may represent a significant advance in the field of vascular biology.

Unpacking overuse of androgen deprivation therapy for prostate cancer to inform de-implementation strategies.

BACKGROUND: Many men with prostate cancer will be exposed to androgen deprivation therapy (ADT). While evidence-based ADT use is common, ADT is also used in cases with no or limited evidence resulting in more harm than benefit, i.e., overuse. Since there are risks of ADT (e.g., diabetes, osteoporosis), it is important to understand the behaviors facilitating overuse to inform de-implementation strategies. For these reasons, we conducted a theory-informed survey study, including a discrete choice experiment (DCE), to better understand ADT overuse and provider preferences for mitigating overuse. METHODS: Our survey used the Action, Actor, Context, Target, Time (AACTT) framework, the Theoretical Domains Framework (TDF), the Capability, Opportunity, Motivation-Behavior (COM-B) Model, and a DCE to elicit provider de-implementation strategy preferences. We surveyed the Society of Government Service Urologists listserv in December 2020. We stratified respondents based on the likelihood of stopping overuse as ADT monotherapy for localized prostate cancer ("yes"/"probably yes," "probably no"/"no"), and characterized corresponding Likert scale responses to seven COM-B statements. We used multivariable regression to identify associations between stopping ADT overuse and COM-B responses. RESULTS: Our survey was completed by 84 respondents (13% response rate), with 27% indicating "probably no"/"no" to stopping ADT overuse. We found differences across respondents who said they would and would not stop ADT overuse in demographics and COM-B statements. Our model identified 2 COM-B domains (Opportunity-Social, Motivation-Reflective) significantly associated with a lower likelihood of stopping ADT overuse. Our DCE demonstrated in-person communication, multidisciplinary review, and medical record documentation may be effective in reducing ADT overuse. CONCLUSIONS: Our study used a behavioral theory-informed survey, including a DCE, to identify behaviors and context underpinning ADT overuse. Specifying behaviors supporting and gathering provider preferences in addressing ADT overuse requires a stepwise, stakeholder-engaged approach to support evidence-based cancer care. From this work, we are pursuing targeted improvement strategies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03579680.

Ninety-day toxicity and genotoxic effects of synthetically derived fully saturated forms of anacardic acid in mice.

Organically synthesized fully saturated form of Anacardic acid (AA) has previously shown to be effective in the treatment of inflammatory autoimmune disease. In this study, organically synthesized fully saturated form of AA was orally administered to male and female Swiss albino mice for 90 consecutive days at doses of 25, 50 and 100 mg/kg BW (n = 20 per sex/group). Administration of AA was well tolerated at all dose levels. The treated animals did not show a dose-response toxicity in their hematology, liver, or metabolic profile. Minimally significant changes in serum biochemistry and hematology parameters were noted, but these were not considered to be of biological or toxicological importance and were not outside the known accepted ranges. Sporadic differences in organ weights were observed between groups, but all were minimal (<10%) and unlikely to indicate toxicity. The incidence of histopathological lesions was comparable between treated and control groups across all tested organs. Based upon these findings, the no-observed-adverse-effect level was determined to be ≥ 100 mg/kg BW, which was the highest dose tested. There were no genotoxic (mutagenic and clastogenic) effects seen in In-vivo micronucleus test, In-vitro chromosomal aberration test and Bacterial reverse mutation test. These results support, no genotoxicity and no toxicity associated with oral consumption of AA in mice as a dietary supplement for beverages and food.

Emerging Role of 18F-NaF PET/Computed Tomographic Imaging in Osteoporosis: A Potential Upgrade to the Osteoporosis Toolbox.

Osteoporosis is a metabolic bone disorder that leads to a decline in bone microarchitecture, predisposing individuals to catastrophic fractures. The current standard of care relies on detecting bone structural change; however, these methods largely miss the complex biologic forces that drive these structural changes and response to treatment. This review introduces sodium fluoride (18F-NaF) positron emission tomography/computed tomography (PET/CT) as a powerful tool to quantify bone metabolism. Here, we discuss the methods of 18F-NaF PET/CT, with a special focus on dynamic scans to quantify parameters relevant to bone health, and how these markers are relevant to osteoporosis.

Accurate modeling of replication rates in genome-wide association studies by accounting for Winner's Curse and study-specific heterogeneity.

Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with complex human traits, but only a fraction of variants identified in discovery studies achieve significance in replication studies. Replication in genome-wide association studies has been well-studied in the context of Winner's Curse, which is the inflation of effect size estimates for significant variants due to statistical chance. However, Winner's Curse is often not sufficient to explain lack of replication. Another reason why studies fail to replicate is that there are fundamental differences between the discovery and replication studies. A confounding factor can create the appearance of a significant finding while actually being an artifact that will not replicate in future studies. We propose a statistical framework that utilizes genome-wide association studies and replication studies to jointly model Winner's Curse and study-specific heterogeneity due to confounding factors. We apply this framework to 100 genome-wide association studies from the Human Genome-Wide Association Studies Catalog and observe that there is a large range in the level of estimated confounding. We demonstrate how this framework can be used to distinguish when studies fail to replicate due to statistical noise and when they fail due to confounding.

Hyperadhesive von Willebrand Factor Promotes Extracellular Vesicle-Induced Angiogenesis: Implication for LVAD-Induced Bleeding.

Bleeding associated with left ventricular assist device (LVAD) implantation has been attributed to the loss of large von Willebrand factor (VWF) multimers to excessive cleavage by ADAMTS-13, but this mechanism is not fully supported by the current evidence. We analyzed VWF reactivity in longitudinal samples from LVAD patients and studied normal VWF and platelets exposed to high shear stress to show that VWF became hyperadhesive in LVAD patients to induce platelet microvesiculation. Platelet microvesicles activated endothelial cells, induced vascular permeability, and promoted angiogenesis in a VWF-dependent manner. Our findings suggest that LVAD-driven high shear stress primarily activates VWF, rather than inducing cleavage in the majority of patients.

Chronic kidney disease in Ecuador: An epidemiological and health system analysis of an emerging public health crisis.

The absence of a chronic kidney disease (CKD) registry in Ecuador makes it difficult to assess the burden of disease, but there is an anticipated increase in the incidence of CKD along with increasing diabetes, hypertension and population age. From 2012, augmented funding for renal replacement therapy expanded dialysis clinics and patient coverage. We conducted 73 in-depth sociological interviews with healthcare providers in eight provinces and collected quantitative epidemiological data on patients with CKD diagnoses from six national-level databases between 2015 and 2018. Datasets show a total of 17,484 dialysis patients in 2018, or 567 patients per million population (pmp), with an annual cost exceeding 11% of Ecuador's public health budget. Each year, there were 139-162 pmp new dialysis patients, while doctors reported waiting lists. The number of patients on peritoneal dialysis was static; those on hemodialysis increased over time. Only 13 of 24 provinces were found to have dialysis services, and nephrologists were clustered in major cities, which limits access, delays medical attention, and adds a travel burden on patients. Prevention and screening programs are scarce, while hospitalization is an important reality for CKD patients. CKD is an emerging public health crisis that has increased dramatically over the last decade in Ecuador and is expected to continue, making coverage for all patients impossible and the current structure, unsustainable. A patient registry would help health policymakers and administrators estimate the demand and progression of patients with consideration for comorbidities, disease stage, requirements and costs, mortality and follow-up. This should be used to help identify where to focus prevention and improved treatment efforts. Organized monitoring of CKD patients would benefit from improvements in patient referral. Community-based education and prevention programs, the strengthening of primary healthcare capacity (including basic routine tests) and improved nephrology services are also urgently needed.

Left Ventricular Assist Device Support and Longitudinal Sleeve Gastrectomy Combined With Diet in Bridge to Heart Transplant.

Combining left ventricular assist device (LVAD) implantation and longitudinal sleeve gastrectomy may enable patients with morbid obesity to lose enough weight for heart transplant eligibility. In a retrospective study, we evaluated long-term outcomes of patients with body mass indexes ≥35 who underwent LVAD implantation and longitudinal sleeve gastrectomy during the same hospitalization (from January 2013 through July 2018) and then adhered to a dietary protocol. We included 22 patients (mean age, 49.9 ± 12.5 yr; mean preoperative body mass index, 43.3 ± 6.2). Eighteen months after gastrectomy, all 22 patients were alive, and 16 (73%) achieved a body mass index of less than 35. Myocardial recovery in 2 patients enabled LVAD removal. As of October 2020, 10 patients (45.5%) had undergone heart transplantation, 5 (22.3%) were waitlisted, 5 (22.3%) still had a body mass index ≥35, and 2 (9%) had died. With LVAD support, longitudinal sleeve gastrectomy, and dietary protocols, most of our patients with morbid obesity and advanced heart failure lost enough weight for transplant eligibility. Support from physicians and dietitians can maximize positive results in these patients.

Applications of Artificial Intelligence in 18F-Sodium Fluoride Positron Emission Tomography/Computed Tomography:: Current State and Future Directions.

This review discusses the current state of artificial intelligence (AI) in 18F-NaF-PET/CT imaging and the potential applications to come in diagnosis, prognostication, and improvement of care in patients with bone diseases, with emphasis on the role of AI algorithms in CT bone segmentation, relying on their prevalence in medical imaging and utility in the extraction of spatial information in combined PET/CT studies.

Artificial Intelligence in Lymphoma PET Imaging:: A Scoping Review (Current Trends and Future Directions).

Malignant lymphomas are a family of heterogenous disorders caused by clonal proliferation of lymphocytes. 18F-FDG-PET has proven to provide essential information for accurate quantification of disease burden, treatment response evaluation, and prognostication. However, manual delineation of hypermetabolic lesions is often a time-consuming and impractical task. Applications of artificial intelligence (AI) may provide solutions to overcome this challenge. Beyond segmentation and detection of lesions, AI could enhance tumor characterization and heterogeneity quantification, as well as treatment response prediction and recurrence risk stratification. In this scoping review, we have systematically mapped and discussed the current applications of AI (such as detection, classification, segmentation as well as the prediction and prognostication) in lymphoma PET.

Artificial Intelligence in Vascular-PET:: Translational and Clinical Applications.

Positron emission tomography (PET) offers an incredible wealth of diverse research applications in vascular disease, providing a depth of molecular, functional, structural, and spatial information. Despite this, vascular PET imaging has not yet assumed the same clinical use as vascular ultrasound, CT, and MR imaging which provides information about late-onset, structural tissue changes. The current clinical utility of PET relies heavily on visual inspection and suboptimal parameters such as SUVmax; emerging applications have begun to harness the tool of whole-body PET to better understand the disease. Even still, without automation, this is a time-consuming and variable process. This review summarizes PET applications in vascular disorders, highlights emerging AI methods, and discusses the unlocked potential of AI in the clinical space.

Quantitative Craniofacial Analysis and Generation of Human Induced Pluripotent Stem Cells for Muenke Syndrome: A Case Report.

In this case report, we focus on Muenke syndrome (MS), a disease caused by the p.Pro250Arg variant in fibroblast growth factor receptor 3 (FGFR3) and characterized by uni- or bilateral coronal suture synostosis, macrocephaly without craniosynostosis, dysmorphic craniofacial features, and dental malocclusion. The clinical findings of MS are further complicated by variable expression of phenotypic traits and incomplete penetrance. As such, unraveling the mechanisms behind MS will require a comprehensive and systematic way of phenotyping patients to precisely identify the impact of the mutation variant on craniofacial development. To establish this framework, we quantitatively delineated the craniofacial phenotype of an individual with MS and compared this to his unaffected parents using three-dimensional cephalometric analysis of cone beam computed tomography scans and geometric morphometric analysis, in addition to an extensive clinical evaluation. Secondly, given the utility of human induced pluripotent stem cells (hiPSCs) as a patient-specific investigative tool, we also generated the first hiPSCs derived from a family trio, the proband and his unaffected parents as controls, with detailed characterization of all cell lines. This report provides a starting point for evaluating the mechanistic underpinning of the craniofacial development in MS with the goal of linking specific clinical manifestations to molecular insights gained from hiPSC-based disease modeling.

Disinfection and Electrostatic Recovery of N95 Respirators by Corona Discharge for Safe Reuse.

With the COVID-19 pandemic surging, the demand for masks is challenging, especially in less-developed areas across the world. Billions of used masks are threatening the environment as a new source of plastic pollution. In this paper, corona discharge (CD) was explored as a safe and reliable method for mask reuse to alleviate the situation. CD can disinfect masks and simultaneously restore electrostatic charges to prevent filtration efficiency deterioration. Electric field, ions, and reactive species generated by CD cause DNA damage and protein denaturation to effectively disinfect N95 respirators. Log reduction of 2-3 against Escherichia coli can be easily reached within 7.5 min. Log reduction of up to 6 can be reached after three cycles of treatment with optimized parameters. CD disinfection is a broad spectrum with log reduction >1 against yeast and >2.5 against spores. N95 respirators can be recharged within 30 s of treatment and the charges can be retained at a higher level than brand-new masks for at least 5 days. The filtration efficiency of masks was maintained at ∼95% after 15 cycles of treatment. CD can provide at least 10 cycles of safe reuse with benefits of high safety, affordability, accessibility, and device scalability/portability.

Selective Inhibition of the Second Bromodomain of BET Family Proteins Results in Robust Antitumor Activity in Preclinical Models of Acute Myeloid Leukemia.

Dual bromodomain BET inhibitors that bind with similar affinities to the first and second bromodomains across BRD2, BRD3, BRD4, and BRDT have displayed modest activity as monotherapy in clinical trials. Thrombocytopenia, closely followed by symptoms characteristic of gastrointestinal toxicity, have presented as dose-limiting adverse events that may have prevented escalation to higher dose levels required for more robust efficacy. ABBV-744 is a highly selective inhibitor for the second bromodomain of the four BET family proteins. In contrast to the broad antiproliferative activities observed with dual bromodomain BET inhibitors, ABBV-744 displayed significant antiproliferative activities largely although not exclusively in cancer cell lines derived from acute myeloid leukemia and androgen receptor positive prostate cancer. Studies in acute myeloid leukemia xenograft models demonstrated antitumor efficacy for ABBV-744 that was comparable with the pan-BET inhibitor ABBV-075 but with an improved therapeutic index. Enhanced antitumor efficacy was also observed with the combination of ABBV-744 and the BCL-2 inhibitor, venetoclax compared with monotherapies of either agent alone. These results collectively support the clinical evaluation of ABBV-744 in AML (Clinical Trials.gov identifier: NCT03360006).

Regression of severe heart failure after combined left ventricular assist device placement and sleeve gastrectomy.

Patients who suffer morbid obesity and heart failure (HF) present unique challenges. Two cases are described where concomitant use of laparoscopic sleeve gastrectomy (LSG) and left ventricular assist device (LVAD) placement enabled myocardial recovery and weight loss resulting in explantation. A 29-year-old male patient with a body mass index (BMI) of 59 kg/m2 and severe HF with a left ventricular ejection fraction (LVEF) of 20-25% underwent concomitant LSG and LVAD placement. Sixteen months after surgery, his BMI was reduced to 34 kg/m2 and his LVEF improved to 50-55%. A second 41-year-old male patient with a BMI of 44.8 kg/m2 with severe HF underwent the same procedures. Twenty-four months later, his BMI was 31.1 kg/m2 and his LVEF was 50-55%. In both cases, the LVAD was successfully explanted and patients remain asymptomatic. HF teams should consult and collaborate with bariatric experts to determine if LSG may improve the outcomes of their HF patients.

A physical phantom for amine chemical exchange saturation transfer (CEST) MRI.

OBJECTIVE: To develop a robust amine chemical exchange saturation transfer (CEST) physical phantom, validate the temporal stability, and create a supporting software for automatic image processing and quality assurance. MATERIALS AND METHODS: The phantom was designed as an assembled laser-cut acrylic rack and 18 vials of phantom solutions, prepared with different pHs, glycine concentrations, and gadolinium concentrations. We evaluated glycine concentrations using ultraviolet absorbance for 70 days and measured the pH, relaxation rates, and CEST contrast for 94 days after preparation. We used Spearman's correlation to determine if glycine degraded over time. Linear regression and Bland-Altman analysis were performed between baseline and follow-up measurements of pH and MRI properties. RESULTS: No degradation of glycine was observed (p > 0.05). The pH and MRI measurements stayed stable for 3 months and showed high consistency across time points (R2 = 1.00 for pH, R1, R2, and CEST contrast), which was further validated by the Bland-Altman plots. Examples of automatically generated reports are provided. DISCUSSION: We designed a physical phantom for amine CEST-MRI, which is easy to assemble and transfer, holds 18 different solutions, and has excellent short-term chemical and MRI stability. We believe this robust phantom will facilitate the development of novel sequences and cross-scanners validations.

Spoligotype Diversity of Mycobacterium tuberculosis over Two Decades from Tiruvallur, South India.

Geographically, most tuberculosis (TB) cases in 2018 were reported from India. This TB burden is compounded by MDR-TB and XDR-TB. The strategies for the management and control of TB in the community depend on an understanding of the mode of spread of the different strains of TB isolates in the community. To determine the distribution and trends of M. tb strains over the time period in the community due to treatment, we carried out the present study on changes over two decades. Design/Methods. A total of 1218 M. tb isolates (year: 2001-2018) from Tiruvallur, India, were genotyped by spoligotyping after DNA extraction and subjected to anti-TB drug susceptibility testing for the first-line anti-TB drugs. Results. On analysis with the SpolDB4 database, majority (2001-2003: 53.32% and 2015-2018: 46.3%) of the isolates belonged to East African Indian (EAI) lineage, and the orphans designated in comparison to SpolDB4 stood 33% among 2001-2003 strain collection and 46.3% among 2015-2018 strain collection. 10.2% (2001-2003) and 9.26% (2015 to 2018) of isolates were monoresistant to isoniazid (H). MDR strains were less common among EAI strains (3.2%) compared to non-EAI strains (10.32%). Conclusions. EAI is the most predominant lineage in Tiruvallur, despite the presence of highly transmissible lineages like Beijing for the last two decades. The prevalence of MDR-TB is below the national average of 2-3% among the new TB cases in the last two decades. The reason can be attributed to the well-established nature of the locally circulating strains in this region which are not associated with drug resistance.

Induction of Ced9 mediated anti-apoptosis in commercial banana cultivar Rasthali for stable resistance against Fusarium wilt.

Anti-apoptotic gene Ced-9 enhanced resistance against Fusarium oxysporum f. sp. cubense (Foc) in the susceptible banana cultivar Rasthali by arresting tissue necrosis. The embryogenic cell suspension of banana cultivar Rasthali was stably transformed with Ced-9 gene and transformed lines were regenerated independently. The putative transgenic lines were analyzed with PCR using gene primers and further subjected to Southern blot to estimate copy number. The root-challenge bioassay with Foc showed 17-51% Vascular Discoloration Index in independent transformants compared to untransformed banana cv Rasthali (98% VDI). Four transgenic events showed a higher level of resistance over a period of 6 months. Overcoming tissue necrosis is the most ideal method to avoid Fusarium multiplication and spread in banana. Oxidative stress-induced cell necrosis is prevented by the activation of antiapoptotic pathways by Ced-9 and is proving to be an effective method to control this dreaded disease. This is the first report from India on the generation of transgenic banana cultivar Rasthali expressing antiapoptotic Ced-9 gene for resistance to Fusarium wilt.