Human pulmonary microvascular endothelial cells respond to DAMPs from injured renal tubular cells.

Acute kidney injury (AKI) causes distant organ dysfunction through yet unknown mechanisms, leading to multiorgan failure and death. The lungs are one of the most common extrarenal organs affected by AKI, and combined lung and kidney injury has a mortality as high as 60%-80%. One mechanism that has been implicated in lung injury after AKI involves molecules released from injured kidney cells (DAMPs, or damage-associated molecular patterns) that promote a noninfectious inflammatory response by binding to pattern recognition receptors (PRRs) constitutively expressed on the pulmonary endothelium. To date there are limited data investigating the role of PRRs and DAMPs in the pulmonary endothelial response to AKI. Understanding these mechanisms holds great promise for therapeutics aimed at ameliorating the devastating effects of AKI. In this study, we stimulate primary human microvascular endothelial cells with DAMPs derived from injured primary renal tubular epithelial cells (RTECs) as an ex-vivo model of lung injury following AKI. We show that DAMPs derived from injured RTECs cause activation of Toll-Like Receptor and NOD-Like Receptor signaling pathways as well as increase human primary pulmonary microvascular endothelial cell (HMVEC) cytokine production, cell signaling activation, and permeability. We further show that cytokine production in HMVECs in response to DAMPs derived from RTECs is reduced by the inhibition of NOD1 and NOD2, which may have implications for future therapeutics. This paper adds to our understanding of PRR expression and function in pulmonary HMVECs and provides a foundation for future work aimed at developing therapeutic strategies to prevent lung injury following AKI.

ACR Appropriateness Criteria® Imaging of Invasive Breast Cancer.

As the proportion of women diagnosed with invasive breast cancer increases, the role of imaging for staging and surveillance purposes should be determined based on evidence-based guidelines. It is important to understand the indications for extent of disease evaluation and staging, as unnecessary imaging can delay care and even result in adverse outcomes. In asymptomatic patients that received treatment for curative intent, there is no role for imaging to screen for distant recurrence. Routine surveillance with an annual 2-D mammogram and/or tomosynthesis is recommended to detect an in-breast recurrence or a new primary breast cancer in women with a history of breast cancer, and MRI is increasingly used as an additional screening tool in this population, especially in women with dense breasts. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Diet modulates the gut microbiome, metabolism, and mammary gland inflammation to influence breast cancer risk.

Several studies have indicated a strong link between obesity and the risk of breast cancer. Obesity decreases gut microbial biodiversity and modulates Bacteroidetes-to-Firmicutes proportional abundance, suggesting that increased energy-harvesting capacity from indigestible dietary fibers and elevated lipopolysaccharide bioavailability may promote inflammation. To address the limited evidence linking diet-mediated changes in the gut microbiota to breast cancer risk, we aimed to determine how diet affects the microbiome and breast cancer risk. Female 3-week-old BALB/c mice were fed six different diets (control, high-sugar, lard, coconut oil, lard+flaxseed oil, and lard+safflower oil) for 10 weeks. Fecal 16s sequencing was performed for each group. Diet shifted fecal microbiome populations and modulated mammary gland macrophage infiltration. Fecal conditioned media shifted macrophage polarity and inflammation. In our DMBA-induced breast cancer model, diet differentially modulated tumor and mammary gland metabolism. We demonstrated how dietary patterns change metabolic outcomes, and gut microbiota, which may contribute to breast tumor risk. Furthermore, we showed the influence of diet on metabolism, inflammation, and macrophage polarity. This study suggests that dietary-microbiome interactions are key mediators of breast cancer risk.

Breast Density: Where Are We Now?

Breast density refers to the amount of fibroglandular tissue relative to fat on mammography and is determined either qualitatively through visual assessment or quantitatively. It is a heritable and dynamic trait associated with age, race/ethnicity, body mass index, and hormonal factors. Increased breast density has important clinical implications including the potential to mask malignancy and as an independent risk factor for the development of breast cancer. Breast density has been incorporated into breast cancer risk models. Given the impact of dense breasts on the interpretation of mammography, supplemental screening may be indicated.

Identifying Factors Associated with Bullying Roles Using the interRAI Child and Youth Mental Health (ChYMH) Suite of Instruments.

Bullying is a common problem amongst school-aged children and youth and is a significant concern for caregivers and teachers. interRAI is an international not-for-profit network of roughly 150 researchers and clinicians from over 35 countries. The main goal of interRAI is to develop and support standardized assessment systems for vulnerable individuals to support care planning, evidence-based clinical decision making, outcome measurement and quality assurance. This study aimed to examine factors associated with bullying roles in a large clinical sample (n = 26,069) using interRAI Child and Youth Mental Health assessments. Findings revealed children who both bullied peers and were victims of bullying (compared to those who were solely bullies, victims, or neither) were more likely to experience interpersonal traumas including witnessing domestic violence, physical and sexual assault; increased risk of self-harm and suicide, depression; more behavioural/externalizing problems; conflict within the school and home contexts; and higher levels of financial, familial, and living instability. The potential causes and implications of these distinctions are discussed. Findings can aid professionals in tailoring preventive measures that could more effectively minimize the incidence and effect of bullying.

Problem-solving Breast MRI.

Breast MRI has high sensitivity and negative predictive value, making it well suited to problem solving when other imaging modalities or physical examinations yield results that are inconclusive for the presence of breast cancer. Indications for problem-solving MRI include equivocal or uncertain imaging findings at mammography and/or US; suspicious nipple discharge or skin changes suspected to represent an abnormality when conventional imaging results are negative for cancer; lesions categorized as Breast Imaging Reporting and Data System 4, which are not amenable to biopsy; and discordant radiologic-pathologic findings after biopsy. MRI should not precede or replace careful diagnostic workup with mammography and US and should not be used when a biopsy can be safely performed. The role of MRI in characterizing calcifications is controversial, and management of calcifications should depend on their mammographic appearance because ductal carcinoma in situ may not appear enhancing on MR images. In addition, ductal carcinoma in situ detected solely with MRI is not associated with a higher likelihood of an upgrade to invasive cancer compared with ductal carcinoma in situ detected with other modalities. MRI for triage of high-risk lesions is a subject of ongoing investigation, with a possible future role for MRI in decreasing excisional biopsies. The accuracy of MRI is likely to increase with the use of advanced techniques such as deep learning, which will likely expand the indications for problem-solving MRI. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material.

Multiple Stool Sampling and Specific Parasitological Technique are Crucial to Diagnose Strongyloidiasis in Alcoholic Patients.

PURPOSE: Chronic alcoholism is a well-known risk factor for strongyloidiasis, in these patients the disease is potentially more severe, probably due to the breakdown of local protective barriers and immunosuppression caused by alcohol, which can lead to autoinfection and dissemination. The aim of this study was to evaluate multiple stool sampling and a specific parasitological assay agar plate culture (APC) for the diagnosis of Strongyloides stercoralis in alcoholics. METHODS: APC was compared to sedimentation technique (HPJ; Hoffman, Pons and Janer), as parasitological methods to detect S. stercoralis infection in alcoholic individuals. Three stool samples from 60 alcoholic and 60 non-alcoholic individuals were analyzed. RESULTS: S. stercoralis larvae were observed in 11 (18.3%) alcoholic individuals and 1 (1.7%) nonalcoholic individual (P = 0.0042). In view of the combined results, sensitivity for the APC method was 63.6% (CI 31.6-87.6%) with the first sample reaching 100% (CI 67.8-100%) after analyzing three fecal samples. The HPJ sensitivity was 36.4% (CI 12.4-68.4) in the first sample, reaching 72.7% (CI 39.3-92.7) after three samples analyzed. CONCLUSION: The present results suggest that in alcoholic patients, it is important to repeat stool sampling with specific techniques, especially using the APC method, to avoid misdiagnosis in cases that could evolve to disseminated strongyloidiasis.

BAITING AND BANDING: EXPERT OPINION ON HOW BAIT TRAPPING MAY INFLUENCE THE OCCURRENCE OF HIGHLY PATHOGENIC AVIAN INFLUENZA (HPAI) AMONG DABBLING DUCKS.

A Eurasian lineage highly pathogenic avian influenza virus (HPAIV) of the clade 2.3.4.4b (Goose/Guangdong lineage) was detected in migratory bird populations in North America in December 2021, and it, along with its reassortants, have since caused wild and domestic bird outbreaks across the continent. Relative to previous outbreaks, HPAIV cases among wild birds in 2022 exhibited wider geographic extent within North America and higher levels of mortality, suggesting the potential for population-level impacts. Given the possible conservation implications of HPAIV in wild birds, natural resource managers have sought guidance on actions that may mitigate negative effects of disease among North American bird populations, including modification of existing management practices. Banding of waterfowl is a critical tool for population management for several harvested species in North America, but some banding techniques, such as bait trapping, can lead to increased congregation of waterfowl, potentially altering HPAIV transmission. We used an expert opinion exercise to assess how bait trapping of dabbling ducks in Canada may influence HPAIV transmission and wild bird health. The expert group found that it is moderately likely that bait trapping of dabbling ducks in wetlands will significantly increase the transmission of HPAIV among individual ducks, but there is a low probability that this will result in significant population-level effects on North American dabbling ducks. Considering the lack of empirical work studying how capture and handling methods may change transmission of HPAIV among waterfowl, as well as the importance of bait trapping for waterfowl management in North America, future work should focus on filling knowledge gaps pertaining to the influence of baiting on HPAIV occurrence to better inform banding procedures and management decision making.

The initial steps toward the formation of somatic tissue banks and cell cultures derived from captive Antillean manatee (Trichechus manatus manatus) skin biopsies.

The declining population of the Antillean manatee caused by ecosystem degradation and rising pollution has prompted interest in developing conservation strategies for this species. Given this scenario, somatic tissue banks are important tools for acquiring knowledge about the species, as well as for obtaining somatic cells for biotechnological and ecotoxicological applications. Therefore, we aimed to assess the effects of slow freezing (SF) and solid-surface vitrification (SSV) of the dermis of captive Antillean manatees on the histology and ultrastructure of the tissue and cell viability in culture. While the SSV did not change the dermis thickness, the SF maintained the tissue proliferative potential, assessed by the nucleolar organizer region area, similar to noncryopreserved tissues. Moreover, both techniques reduced the number of fibroblasts and increased the percentage of collagen fibers. Nevertheless, only tissues cryopreserved with SF and noncryopreserved tissues were able to produce cells after in vitro culture. Although SF did not alter cell viability and proliferative activity, cells derived from cryopreserved tissues showed decreased metabolism, altered apoptosis, increased levels of reactive oxygen species, and mitochondrial membrane potential compared to cells from noncryopreserved tissues. In summary, we demonstrated for the first time that Antillean manatee somatic tissues can be cryopreserved by SF, and cells can be obtained after in vitro culture. Improvements in cryopreservation conditions, especially vitrification, of somatic samples are needed to increase the quality of somatic tissue banks in this species.

ACR Appropriateness Criteria® Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer: 2022 Update.

Imaging plays a vital role in managing patients undergoing neoadjuvant chemotherapy, as treatment decisions rely heavily on accurate assessment of response to therapy. This document provides evidence-based guidelines for imaging breast cancer before, during, and after initiation of neoadjuvant chemotherapy. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Protective Effects of Flavonoid Rutin Against Aminochrome Neurotoxicity.

Causes of dopaminergic neuronal loss in Parkinson's disease (PD) are subject of investigation and the common use of models of acute neurodegeneration induced by neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine, and rotenone contributed to advances in the study of PD. However, the use of study models more similar to the pathophysiology of PD is required for advances in early diagnosis and translational pharmacology. Aminochrome (AMI), a compound derived from dopamine oxidation and a precursor of neuromelanin, is able to induce all the mechanisms associated with neurodegeneration. Previously, we showed AMI is cytotoxic in primary culture of mesencephalic cells (PCMC) and induces in vitro and in vivo neuroinflammation. On the other hand, the effect of rutin in central nervous system cells has revealed anti-inflammatory, antioxidative, and neuroprotective potential. However, there have been no data studies on the effect of rutin against aminochrome neurotoxicity. Here, we show that rutin prevents lysosomal dysfunction and aminochrome-induced cell death in SHSY-5Y cells, protects PCMC against aminochrome cytotoxicity, and prevents in vivo loss of dopaminergic neurons in substantia nigra pars compacta (SNPc), as well as microgliosis and astrogliosis. Additionally, we show that rutin decreases levels of interleukin-1ß (IL-1ß) mRNA and increases levels of glia-derived neurotrophic factor (GDNF) and nerve-derived neurotrophic factor (NGF) mRNA. We evidence for the first time the protective effect of rutin on PD aminochrome-induced models and suggest the potential role of the anti-inflammatory activity and upregulation of NGF and GDNF in the mechanism of rutin action against aminochrome neurotoxicity.

Influence of Intracellular Cryoprotectants on the Conservation of Dermal Somatic Tissues Derived from Antillean Manatees (Trichechus manatus manatus Linnaeus, 1758).

Cryopreservation of somatic tissue has been studied as a tool for the knowledge and conservation of endangered species, such as Antillean manatees. The use of vitrification protocols is an important step in the establishment of biological banks. To decrease the damage caused by this technique, a reduction in the concentration of cryoprotectants has been proposed. Therefore, we aimed to evaluate combinations and concentrations of intracellular cryoprotectants for the conservation of somatic tissues derived from Antillean manatees. Dulbecco's modified Eagle's medium, F-12 composed of 10% fetal bovine serum and 0.25 M sucrose, was supplemented with 3.0 M ethylene glycol (EG) plus 3.0 M dimethyl sulfoxide (DMSO), or 1.5 M EG plus 1.5 M DMSO or 3.0 M EG or 3.0 M DMSO, to produce four solutions for solid-surface vitrification. Noncryopreserved tissues were used as the controls. After warming, tissues derived from four Antillean manatees were evaluated for ultrastructure, histology, and in vitro culture. No differences were observed among the cryopreserved and noncryopreserved tissues in terms of ultrastructure. The dermis thickness of the cryopreserved fragments in solutions containing 3.0 M EG plus 3.0 M DMSO, 3.0 M EG, and 3.0 DMSO was similar to that of the control. Moreover, cryopreservation with 3.0 M EG plus 3.0 M DMSO maintained tissue proliferative capacity potential evaluated by quantification of nucleolar organizing regions. Nevertheless, none of the cryopreserved fragments were able to maintain the number of fibroblasts and the collagen percentage as compared with that of the noncryopreserved fragments. Also, none of the cryopreserved fragments in the different solutions were able to produce cells in vitro. In summary, even reducing the concentration of intracellular cryoprotectants as well as their association did not guarantee the maintenance of cells after in vitro culture. Further studies are needed to optimize the cryopreservation protocols in Antillean manatee somatic tissues.

A series of heterogeneous lymphoproliferative diseases with CD3 and MUM1 co-expressed in cats and dogs.

Lymphoma diagnosis in dogs and cats is continually evolving as new subtypes and human correlates are being recognized. In humans, T-cell lymphomas with MUM1 expressed and plasma cell neoplasia or B-cell lymphomas with CD3 expressed aberrantly are reported only rarely. We report here a case series of tumors in dogs and cats with CD3 and MUM1 co-expressed as determined by immunocytochemistry or immunohistochemistry. Lineage was assigned for these tumors by 3 board-certified pathologists and a veterinary immunologist based on review of clinical and cellular features and the results of ancillary testing including PCR for antigen receptor rearrangements, flow cytometry, and serum protein electrophoresis with immunofixation. In cats, 7 of 7 tumors, and in dogs, 3 of 6 tumors with CD3 and MUM1 co-expressed had clonal rearrangement of the immunoglobulin gene or serum monoclonal immunoglobulin, consistent with a diagnosis of a plasma cell neoplasia or myeloma-related disorder with CD3 expressed aberrantly. Disease was often disseminated; notably, 3 of 7 feline cases had cutaneous and/or subcutaneous involvement in the tarsal area. In dogs, 3 of 6 cases had a clonal T-cell receptor gamma result and no clonal immunoglobulin gene rearrangement and were diagnosed as a T-cell tumor with MUM1 expressed. The use of multiple testing modalities in our series of tumors with plasma-cell and T-cell antigens in dogs and cats aided in the comprehensive identification of the lymphoproliferative disease subtype.

New Horizons: Artificial Intelligence for Digital Breast Tomosynthesis.

The use of digital breast tomosynthesis (DBT) in breast cancer screening has become widely accepted, facilitating increased cancer detection and lower recall rates compared with those achieved by using full-field digital mammography (DM). However, the use of DBT, as compared with DM, raises new challenges, including a larger number of acquired images and thus longer interpretation times. While most current artificial intelligence (AI) applications are developed for DM, there are multiple potential opportunities for AI to augment the benefits of DBT. During the diagnostic steps of lesion detection, characterization, and classification, AI algorithms may not only assist in the detection of indeterminate or suspicious findings but also aid in predicting the likelihood of malignancy for a particular lesion. During image acquisition and processing, AI algorithms may help reduce radiation dose and improve lesion conspicuity on synthetic two-dimensional DM images. The use of AI algorithms may also improve workflow efficiency and decrease the radiologist's interpretation time. There has been significant growth in research that applies AI to DBT, with several algorithms approved by the U.S. Food and Drug Administration for clinical implementation. Further development of AI models for DBT has the potential to lead to improved practice efficiency and ultimately improved patient health outcomes of breast cancer screening and diagnostic evaluation. See the invited commentary by Bahl in this issue. ©RSNA, 2022.

A paradoxical switch: the implications of excitatory GABAergic signaling in neurological disorders.

Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. In the mature brain, inhibitory GABAergic signaling is critical in maintaining neuronal homeostasis and vital human behaviors such as cognition, emotion, and motivation. While classically known to inhibit neuronal function under physiological conditions, previous research indicates a paradoxical switch from inhibitory to excitatory GABAergic signaling that is implicated in several neurological disorders. Various mechanisms have been proposed to contribute to the excitatory switch such as chloride ion dyshomeostasis, alterations in inhibitory receptor expression, and modifications in GABAergic synaptic plasticity. Of note, the hypothesized mechanisms underlying excitatory GABAergic signaling are highlighted in a number of neurodevelopmental, substance use, stress, and neurodegenerative disorders. Herein, we present an updated review discussing the presence of excitatory GABAergic signaling in various neurological disorders, and their potential contributions towards disease pathology.

ACR Appropriateness Criteria® Evaluation of Nipple Discharge: 2022 Update.

The type of nipple discharge dictates the appropriate imaging study. Physiologic nipple discharge is common and does not require diagnostic imaging. Pathologic nipple discharge in women, men, and transgender patients necessitates breast imaging. Evidence-based guidelines were used to evaluate breast imaging modalities for appropriateness based on patient age and gender. For an adult female or male 40 years of age or greater, mammography or digital breast tomosynthesis (DBT) is performed initially. Breast ultrasound is usually performed at the same time with rare exception. For males or females 30 to 39 years of age, mammography/DBT or breast ultrasound is performed based on institutional preference and individual patient considerations. For young women less than 30 years of age, ultrasound is performed first with mammography/DBT added if there are suspicious findings or if the patient is at elevated lifetime risk for developing breast cancer. There is a high incidence of breast cancer in males with pathologic discharge. Men 25 years and older should be evaluated using mammography/DBT and ultrasound added when indicted. In transfeminine (male-to-female) patients, mammography/DBT and ultrasound are useful due to the increased incidence of breast cancer. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer-reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer-reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Gut and Breast Microbiota as Endocrine Regulators of Hormone Receptor-positive Breast Cancer Risk and Therapy Response.

Despite advances in treatment strategies, breast cancer (BC) remains one of the most prevalent cancers worldwide. Recent studies implicate the gut microbiome as a potential risk factor for BC development. Alterations in gut microbial diversity resulting in dysbiosis have been linked to breast carcinogenesis by modulating host immune responses and inflammatory pathways, favoring tumorigenesis and progression. Moreover, gut microbiota populations are different between women with BC vs those that are cancer free, further implicating the role of the gut microbiome in cancer development. This alteration in gut microbiota is also associated with changes in estrogen metabolism, which strongly correlates with BC development. Gut microbiota that express the enzyme ß-glucuronidase (GUS) may increase estrogen bioavailability by deconjugating estrogen-glucuronide moieties enabling reabsorption into circulation. Increased circulating estrogens may, in turn, drive estrogen receptor-positive BC. GUS-expressing microbiota also affect cancer therapy efficacy and toxicity by modifying glucuronide-conjugated drug metabolites. Therefore, GUS inhibitors have emerged as a potential antitumor treatment. However, the effectiveness of GUS inhibitors is still exploratory. Further studies are needed to determine how oral endocrine-targeting therapies may influence or be influenced by the microbiota and how that may affect carcinogenesis initiation and tumor recurrence.

Examining the Biopsychosocial Factors Related to Lifetime History of Concussion in Children and Youth.

This study investigated the prevalence of lifetime concussions, related psychosocial problems, and post-concussion recovery rates in a clinical sample of children and youth. Participants were 24,186 children and youth (M = 11.9 years, SD = 3.5) who completed an interRAI Child and Youth Mental Health Assessment at mental health agencies across Ontario, Canada. In addition to the expected physiological correlates, results found concussions to be more prevalent in children and youth with attention deficit hyperactivity disorders, anxiety disorders, disruptive behaviour disorders, mood disorders, and those involved in self-harm, harm to others, destructive aggression, and internalizing and externalizing symptoms. The results of this study add to our understanding of children and youth's experiences with concussions. Clinical implications and recommendations are discussed to maximize the effectiveness of evidence-based interventions related to concussion recovery.

ACR Appropriateness Criteria® Imaging of the Axilla.

This publication reviews the current evidence supporting the imaging approach of the axilla in various scenarios with broad differential diagnosis ranging from inflammatory to malignant etiologies. Controversies on the management of axillary adenopathy results in disagreement on the appropriate axillary imaging tests. Ultrasound is often the appropriate initial imaging test in several clinical scenarios. Clinical information (such as age, physical examinations, risk factors) and concurrent complete breast evaluation with mammogram, tomosynthesis, or MRI impact the type of initial imaging test for the axilla. Several impactful clinical trials demonstrated that selected patient's population can received sentinel lymph node biopsy instead of axillary lymph node dissection with similar overall survival, and axillary lymph node dissection is a safe alternative as the nodal staging procedure for clinically node negative patients or even for some node positive patients with limited nodal tumor burden. This approach is not universally accepted, which adversely affect the type of imaging tests considered appropriate for axilla. This document is focused on the initial imaging of the axilla in various scenarios, with the understanding that concurrent or subsequent additional tests may also be performed for the breast. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.