Optimizing in silico drug discovery: simulation of connected differential expression signatures and applications to benchmarking.

BACKGROUND: We present a novel simulation method for generating connected differential expression signatures. Traditional methods have struggled with the lack of reliable benchmarking data and biases in drug-disease pair labeling, limiting the rigorous benchmarking of connectivity-based approaches. OBJECTIVE: Our aim is to develop a simulation method based on a statistical framework that allows for adjustable levels of parametrization, especially the connectivity, to generate a pair of interconnected differential signatures. This could help to address the issue of benchmarking data availability for connectivity-based drug repurposing approaches. METHODS: We first detailed the simulation process and how it reflected real biological variability and the interconnectedness of gene expression signatures. Then, we generated several datasets to enable the evaluation of different existing algorithms that compare differential expression signatures, providing insights into their performance and limitations. RESULTS: Our findings demonstrate the ability of our simulation to produce realistic data, as evidenced by correlation analyses and the log2 fold-change distribution of deregulated genes. Benchmarking reveals that methods like extreme cosine similarity and Pearson correlation outperform others in identifying connected signatures. CONCLUSION: Overall, our method provides a reliable tool for simulating differential expression signatures. The data simulated by our tool encompass a wide spectrum of possibilities to challenge and evaluate existing methods to estimate connectivity scores. This may represent a critical gap in connectivity-based drug repurposing research because reliable benchmarking data are essential for assessing and advancing in the development of new algorithms. The simulation tool is available as a R package (General Public License (GPL) license) at https://github.com/cgonzalez-gomez/cosimu.

Direct oral challenge for immediate and non-immediate beta-lactam allergy in children: A real-world multicenter study.

BACKGROUND: Allergy to beta-lactam antibiotics (BLA) is frequently suspected in children, but a drug provocation test (DPT) rules it out in over 90% of cases. Direct oral DPT (DODPT), without skin or other previous tests, is increasingly been used to delabel non-immediate BLA reactions. This real-world study aimed to assess the safety and effectiveness of DODPT in children with immediate and non-immediate reactions to BLAs. METHODS: Ambispective registry study in children (<15 years), attended between 2016 and 2023 for suspected BLA allergy in 15 hospitals in Spain that routinely perform DODPT. RESULTS: The study included 2133 patients with generally mild reactions (anaphylaxis 0.7%). Drug provocation test with the implicated BLA was performed in 2014 patients (94.4%): 1854 underwent DODPT (86.9%, including 172 patients with immediate reactions). One hundred forty-five (7.2%) had symptoms associated with DPT, although only four reactions were severe: two episodes of anaphylaxis and two of drug-induced enterocolitis syndrome, which resolved rapidly with treatment. Of the 141 patients with mild reactions in the first DPT, a second DPT was considered in 87 and performed in 57, with 52 tolerating it without symptoms. Finally, BLA allergy was ruled out in 90.9% of the sample, confirmed in 3.4%, and remained unverified, usually due to loss to follow-up, in 5.8%. CONCLUSIONS: Direct oral DPT is a safe, effective procedure even in immediate mild reactions to BLA. Many reactions observed in DPT are doubtful and require confirmation. Severe reactions are exceptional and amenable to treatment. Direct oral DPT can be considered for BLA allergy delabeling in pediatric primary care.

Active lupus in Argentina: Results of a multicenter and national registry.

OBJECTIVE: To evaluate the association between patients' characteristics and disease activity in an Argentine lupus registry. METHODS: Cross-sectional study. Disease activity was stratified into: Remission off-treatment: SLEDAI = 0, without prednisone and immunosuppressive drugs. Low disease activity Toronto Cohort (LDA-TC): SLEDAI ≤2, without prednisone or immunosuppressive drugs. Modified lupus low disease activity (mLLDAS): SLEDAI score of ≤4, with no activity in major organ systems and no new features, prednisone of ≤10 mg/day and/or immunosuppressive drugs (maintenance dose) and Active disease: SLEDAI score of >4 and prednisone >10 mg/day and immunosuppressive drugs. A descriptive analysis and logistic regression model were performed. RESULTS: A total of 1346 patients were included. Of them, 1.6% achieved remission off steroids, 0.8% LDA-TC, 12.1% mLLDAS and the remaining 85.4% had active disease. Active disease was associated with younger age (p ≤ 0.001), a shorter time to diagnosis (p ≤ 0.001), higher frequency of hospitalizations (p ≤ 0.001), seizures (p = 0.022), serosal disease (p ≤ 0.001), nephritis (p ≤ 0.001), higher SDI (p ≤ 0.001), greater use of immunosuppressive therapies and higher doses of prednisone compared to those on mLLDAS. In the multivariable analysis, the variables associated with active disease were the presence of pleuritis (OR 2.1, 95% CI 1.2-3.9; p = 0.007), persistent proteinuria (OR 2.5, 95% CI 1.2-5.5; p ≤ 0.011), nephritis (OR 2.5, 95% CI 1.2-5.6; p = .018) and hospitalizations (OR 8.9, 95% CI 5.3-16.0; p ≤ 0.001) whereas age at entry into the registry was negatively associated with it (OR 0.9, 95% CI 0.9-1.0; p = 0.029). CONCLUSION: Active disease was associated with shorter time to diagnosis, worse outcomes (SDI and hospitalizations) and renal, neurological and serosal disease.

Multicenter lupus register from Argentina, the RELESSAR database: Influence of ethnicity on disease phenotype.

OBJECTIVE: The objective is to describe the main characteristics of patients with systemic lupus erythematosus (SLE) in Argentina and to examine the influence of ethnicity on the expression of the disease. PATIENTS AND METHODS: RELESSAR is a multicentre register carried out by 106 researchers from 67 rheumatologic Argentine centres. It is a cross-sectional study of SLE (1982/1997 ACR) patients. RELESSAR electronic database includes demographic, cumulative SLE manifestations, SELENA-SLEDAI, SLICC-SDI, Katz's severity and Charlson's comorbidity indexes and treatment patterns. RESULTS: We included 1,610 patients, 91.7% were female with a median age at diagnosis of 28.1 ± 12.8; 96.2% met ≥4 ACR 1982/97 criteria. Frequent manifestations were arthritis (83.5%), malar rash (79.5%), photosensitivity (75.3%), haematological (63.8%) and renal disease (47.4%), antinuclear antibodies (96%), anti-dsDNA (66.5%) and anti-Smith antibodies (29%). The mean Selena-SLEDAI score at last visit was 3.18 (SD 4.3) and mean SDI was 1 (SD 1.3). The accumulated treatments most frequently used were antimalarials (90.4%), corticosteroids (90%), azathioprine (31.8%), intravenous cyclophosphamide (30.2%), mycophenolate mofetil or mycophenolic acid (24.5%), methotrexate (19.3%), belimumab 5.3% and rituximab 5.1%. Refractory lupus was diagnosed in 9.3% of the cases. The main causes of death were lupus activity (25.0%), activity and concomitant infections (25.0%), infections (18.2%), vascular disease (13.6%) and cancer (4.5%). Mortality was associated with higher SLEDAI, Katz, damage indexes and comorbidities. Of the 1610 patients included, 44.6% were Caucasian, 44.5% Mestizo, 8.1% Amerindian and 1.2% Afro-Latin American. Mestizo patients had higher male representation, low socioeconomic status, more inadequate medical coverage, fewer formal years of education and shorter disease duration. Polyadenopathies and Raynaud's phenomenon were more frequent in Caucasians. In the logistic regression analysis higher damage index (OR 1.28, CI 95% 1.02-1.61, p = 0.03) remained associated to mestizo ethnicity. CONCLUSIONS: This study represents the largest number of adult patients with SLE studied in Argentina. Caucasian patients were differentiated by having Raynaud's phenomenon and polyadenopathy more frequently, while patients of Mestizo origin had higher damage indexes.

Impact of house dust mite-driven asthma on children's school performance and activity.

Evidence regarding asthma's impact on children's daily lives is limited. This prospective and cross-sectional, observational, multicenter study assessed school/work and activity impairment in children and adolescents with allergic asthma and their caregivers and allergen immunotherapy (AIT) effects. Included patients were schooled children and adolescents (5 to 17 years) with allergic asthma due to house dust mites (HDM). Impairment of school/work (i.e., absenteeism and presenteeism) and activity was measured in patients and their caregivers using the Work Productivity Impairment Questionnaire plus Classroom Impairment Questions: Allergy Specific (WPAI + CIQ:AS). HDM allergic patients with school impairment received subcutaneous AIT with a MicroCrystalline Tyrosine-associated allergoid. WPAI + CIQ:AS and effectiveness variables were compared between baseline and 1-year post-AIT. Of the 113 patients included, 59 (52.2%) and 51 (45.1%) showed school and activity impairment, respectively, missing a mean (SD) of 37.6 (24.4) % and 42.6 (25.6) % of school and activity time, respectively. Twenty-six (23%) caregivers reported activity impairment and, of the 79 (69.9%) employed, 30 (38%) reported work impairment. Of the 65 patients with school/activities impairment, 41 (63.1%) received AIT, of which 21 (51.2%) completed 1 year of treatment. Effectiveness variables and WPAI + CIQ:AS significantly improved: Mean (SD) school impairment decreased from 39.7 (26.7) to 2.1 (7.1) % (p < 0.001) and activity impairment from 46.2 (34.6) to 1.4 (3.6) % (p < 0.001). CONCLUSION: Allergic asthma due to HDMs results in school/work and activity impairment in children and adolescents and their caregivers. One year of AIT provided clinical benefits and reduced school and activity impairment. WHAT IS KNOWN: • Allergic asthma impairs children's school performance and daily activities. • Allergen immunotherapy modifies allergic disease course and ameliorates its symptoms. WHAT IS NEW: • Asthma symptoms due to allergy to house dust mites impair children's school attendance and productivity and daily activity and their caregivers' work performance and daily lives. • Allergen immunotherapy with a house dust mite MicroCrystalline Tyrosine (MCT)-associated allergoid seems to provide clinical benefits, associated with decreased school and activity impairment, supporting it as an effective treatment option.

Imaging of the Acromioclavicular Joint: Anatomy, Function, Pathologic Features, and Treatment.

The acromioclavicular joint is an important component of the shoulder girdle; it links the axial skeleton with the upper limb. This joint, a planar diarthrodial articulation between the clavicle and the acromion, contains a meniscus-like fibrous disk that is prone to degeneration. The acromioclavicular capsule and ligaments stabilize the joint in the horizontal direction, while the coracoclavicular ligament complex provides vertical stability. Dynamic stability is afforded by the deltoid and trapezius muscles during clavicular and scapular motion. The acromioclavicular joint is susceptible to a broad spectrum of pathologic entities, traumatic and degenerative disorders being the most common. Acromioclavicular joint injury typically affects young adult males and can be categorized by using the Rockwood classification system as one of six types on the basis of the direction and degree of osseous displacement seen on conventional radiographs. MRI enables the radiologist to more accurately assess the regional soft-tissue structures in the setting of high-grade acromioclavicular separation, helping to guide the surgeon's selection of the appropriate management. Involvement of the acromioclavicular joint and its stabilizing ligaments is also important for understanding and classifying distal clavicle fractures. Other pathologic processes encountered at this joint include degenerative disorders; overuse syndromes; and, less commonly, inflammatory arthritides, infection, metabolic disorders, and developmental malformations. Treatment options for acromioclavicular dysfunction include conservative measures, resection arthroplasty for recalcitrant symptoms, and surgical reconstruction techniques for stabilization after major trauma.

Egg OIT in clinical practice (SEICAP II): Maintenance patterns and desensitization state after normalizing the diet.

BACKGROUND: It is unknown which are the most suitable maintenance pattern and egg consumption to maintain the desensitization state after ending the oral immunotherapy (OIT). This multicenter, randomized, controlled trial compared two OIT maintenance patterns with pasteurized egg white (PEW), evaluating the egg consumption effect on the desensitization state after ending the OIT. METHODS: One hundred and one children with confirmed egg allergy were randomized: 25 to an egg-free diet (CG) and 76 to an OIT year with PEW and two maintenance patterns, 38 patients to daily 3.3 g proteins (AG) and 38 to every two days (BG). PEW challenge (DBPCFC), adverse reactions, and immune markers were assessed at baseline, at the end of the OIT, and at 6 and 12 months later on ad libitum egg consumption (T0, T12, T18, and T24). A questionnaire evaluated the egg consumption at T18. RESULTS: At T12, 64 of 76 (84.21%) OIT patients had reached total desensitization (32 AG and 32 BG) vs 4 of 25 (16.00%) CG who passed the PEW DBPCFC. Thirty (93.75%) AG vs 25 (78.12%) BG patients completed an OIT year. At T18, 27 of 29 (93.1%) AG vs 20 of 24 (83.3%) BG passed the PEW DBPCFC, 96% consuming at least two egg servings/week. At T24, 97.43% OIT patients passed the challenge. Most patients had adverse reactions, more frequent in the BG patients; frequency and severity of reactions decreased through the study. PEW skin prick test wheal and sIgE antibody serum levels similarly decreased in AG or BG, but AG patients had greater increase in PEW sIgG4 (P < 0.05). CONCLUSIONS: Daily OIT maintenance achieves better adherence, effectiveness, and safety. Two egg servings/week ensure maintained desensitization after the end of an OIT year.

Egg oral immunotherapy in children (SEICAP I): Daily or weekly desensitization pattern.

BACKGROUND: Studies are required before incorporating egg oral immunotherapy (OIT) into clinical practice. The Spanish Society of Pediatric Allergy, Asthma and Clinical Immunology (SEICAP) conducted a multicenter, randomized controlled study assessing the effectiveness and safety of the OIT using pasteurized egg white (PEW) in egg-allergic children. METHODS: One hundred and one egg-allergic children (6-9 years) were randomized for 1 year: 25 to an egg-free-diet (CG) and 76 to OIT (target dose 3.3 g PEW proteins), PI (30% weekly plus 5% daily increments) or PII (only 30% weekly increments) buildup patterns. Egg skin prick test, sIgE and sIgG4 serum levels, PEW double-blind placebo-controlled food challenge (DBPCFC), and dosing adverse reactions (DARs) were evaluated in all patients from inclusion (T0) until completing 1 year of follow-up (T12). At T12, egg-allergic control patients could start OIT. The effectiveness and safety of OIT and the effect of the buildup pattern were analyzed. RESULTS: At T12, 4/25 (16.0%) CG patients passed the PEW DBPCFC vs 64/76 (84.2%) OIT that reached total desensitization (P = 0.000); 12 egg-allergic control patients started OIT. Finally, 72/88 (81.81%) patients reached total desensitization, 96.15% PI vs 75.80% on PII (P = 0.01). Induction period (121.12 ± 91.43, median 98.00 days) was longer in patients on PII buildup pattern, and those with allergic asthma, minor threshold dose, or higher egg sIgE (P < 0.05). Most patients (89.06%) developed DARs: 74.53% were mild; 21.90% moderate; and 3.5% requiring adrenaline-treatment. Moderate reactions and those requiring adrenaline were more frequent in patients with allergic asthma, PII pattern, or higher egg sIgE serum antibody levels (P < 0.05). CONCLUSIONS: PEW OIT is an effective treatment for children with persistent egg allergy. A 30% weekly plus 5% daily increment pattern could be more effective and safer than one with only 30% weekly increments.

Adult Acquired Flatfoot Deformity: Anatomy, Biomechanics, Staging, and Imaging Findings.

Adult acquired flatfoot deformity (AAFD) is a common disorder that typically affects middle-aged and elderly women, resulting in foot pain, malalignment, and loss of function. The disorder is initiated most commonly by degeneration of the posterior tibialis tendon (PTT), which normally functions to maintain the talonavicular joint at the apex of the three arches of the foot. PTT degeneration encompasses tenosynovitis, tendinosis, tendon elongation, and tendon tearing. The malaligned foot is initially flexible but becomes rigid and constant as the disorder progresses. Tendon dysfunction commonly leads to secondary damage of the spring ligament and talocalcaneal ligaments and may be associated with injury to the deltoid ligament, plantar fascia, and other soft-tissue structures. Failure of multiple stabilizers appears to be necessary for development of the characteristic planovalgus deformity of AAFD, with a depressed plantar-flexed talus bone, hindfoot and/or midfoot valgus, and an everted flattened forefoot. AAFD also leads to gait dysfunction as the foot is unable to change shape and function adequately to accommodate the various phases of gait, which require multiple rapid transitions in foot position and tone for effective ambulation. The four-tier staging system for AAFD emphasizes physical examination findings and metrics of foot malalignment. Mild disease is managed conservatively, but surgical procedures directed at the soft tissues and/or bones become necessary and progressively more invasive as the disease progresses. Although much has been written about the imaging findings of AAFD, this article emphasizes the anatomy and function of the foot's stabilizing structures to help the radiologist better understand this disabling disorder. Online supplemental material is available for this article. ©RSNA, 2019.

Layered Approach to the Anterior Knee: Normal Anatomy and Disorders Associated with Anterior Knee Pain.

Anterior knee pain is a common complaint that can be caused by a wide spectrum of disorders affecting the many varied tissues at the anterior knee. The anatomy and pathologic conditions of the anterior knee can be approached systematically by organizing the region into four layers: (a) superficial layer of fat, fascia, and bursae; (b) functional layer composed of the extensor mechanism and patellar stabilizers; (c) intracapsular extrasynovial layer containing the fat pads; and (d) intra-articular layer. The superficial layer is composed of delicate tissues that are predisposed to blunt and penetrating trauma, irritation, and infection. The extensor mechanism forms the functional layer, is responsible for knee extension and patellar stabilization, and is engaged in repetitive movements; overuse disorders dominate in this layer. The fat pads of the anterior knee are discussed collectively as an extracapsular extrasynovial layer, functioning to improve congruence and protect the articular surfaces during motion. Diseases involving the fat pads can be primary or secondary to pathologic conditions in the rest of the joint. The synovial lining and cartilage surface are in the fourth and final intra-articular layer; pathologic conditions are centered around arthritides and internal derangement. Symptoms in the anterior knee may be due to conditions affecting one or more of these interrelated layers. ©RSNA, 2018.

MR Imaging of Atraumatic Muscle Disorders.

Atraumatic disorders of skeletal muscles include congenital variants; inherited myopathies; acquired inflammatory, infectious, or ischemic disorders; neoplastic diseases; and conditions leading to muscle atrophy. These have overlapping appearances at magnetic resonance (MR) imaging and are challenging for the radiologist to differentiate. The authors organize muscle disorders into four MR imaging patterns: (a) abnormal anatomy with normal signal intensity, (b) edema/inflammation, (c) mass, and (d) atrophy, highlighting each of their key clinical and imaging findings. Anatomic muscle variants, while common, do not produce signal intensity alterations and therefore are easily overlooked. Muscle edema is the most common pattern but is nonspecific, with a broad differential diagnosis. Autoimmune, paraneoplastic, and drug-induced myositis tend to be symmetric, whereas infection, radiation-induced injury, and myonecrosis are focal asymmetric processes. Architectural distortion in the setting of muscle edema suggests one of these latter processes. Intramuscular masses include primary neoplasms, metastases, and several benign masslike lesions that simulate malignancy. Some lesions, such as lipomas, low-flow vascular malformations, fibromatoses, and subacute hematomas, are distinctive, but many intramuscular masses ultimately require a biopsy for definitive diagnosis. Atrophy is the irreversible end result of any muscle disease of sufficient severity and is the dominant finding in disorders such as the muscular dystrophies, denervation myopathy, and sarcopenia. This imaging-based classification, in correlation with clinical and laboratory data, will aid the radiologist in interpreting MR imaging findings in patients with atraumatic muscle disorders. ©RSNA, 2018.

MR Imaging of Muscle Trauma: Anatomy, Biomechanics, Pathophysiology, and Imaging Appearance.

Muscle is an important component of the muscle-tendon-bone unit, driving skeletal motion through contractions that alter the length of the muscle. The muscle and myotendinous junction (MTJ) are most commonly injured in the young adult, as a result of indirect mechanisms such as overuse or stretching, direct impact (penetrating or nonpenetrating), or dysfunction of the supporting connective tissues. Magnetic resonance (MR) imaging is widely used for assessment of muscle injuries. This review illustrates the MR imaging appearance of a broad spectrum of acute, subacute, and chronic traumatic lesions of muscle, highlighting the pathophysiology, biomechanics, and anatomic considerations underlying these lesions. Concentric (shortening) contractions are more powerful, but it is eccentric (lengthening) contractions that produce the greatest muscle tension, leading to indirect injuries such as delayed-onset muscle soreness (DOMS) and muscle strain. Strain is the most commonly encountered muscle injury and is characteristically located at the MTJ, where maximal stress accumulates during eccentric exercise. The risk of strain varies among muscles based on their fiber composition, size, length, and architecture, with pennate muscles being at highest risk. Direct impact to muscle results in laceration or contusion, often accompanied by intramuscular interstitial hemorrhage and hematoma. Disorders related to the muscle's collagen framework include compartment syndrome, which is related to acute or episodic increases in pressure, and muscle herniation through anatomic defects in the overlying fascia. The healing response after muscle trauma can result in regeneration, degeneration with fibrosis and fatty replacement, or disordered tissue proliferation as seen in myositis ossificans. In athletes, accurate grading of the severity and precise location of injury is necessary to guide rehabilitation planning to prevent reinjury and ensure adequate healing. In elite athletes, MR imaging grading of muscle trauma plays an increasingly important role in recently developed comprehensive grading systems that are replacing the imprecise three-grade injury classification system currently used. ©RSNA, 2017.

Hepatitis A, cardiomyopathy, aplastic anemia, and acute liver failure: A devastating scenario.

Hepatitis A virus (HAV) causes an acute infection and is usually asymptomatic in children. When clinical manifestations appear, these include choluria, jaundice, and abdominal pain. Although infrequent, extra-hepatic manifestations related to HAV have been described, affecting the heart, bone marrow, blood vessels, and other tissues.A 10-year-old boy from a rural area presented with a 15-day history of malaise, fever, and jaundice; laboratory examinations were compatible with HAV infection. The patient turned encephalopathic and was remitted to our center, where laboratory examinations showed a medullary aplasia and fulminant hepatitis requiring a liver transplant that was performed 72 hours after admission. At 24 hours post transplant, the patient developed a cardiomyopathy secondary to HAV, and intravenous immunoglobulin was administered. The patient is still alive and attending his medical check-ups.Although rare, extra-hepatic manifestations of HAV infection have been described in 14% of cases. The groups of patients affected are usually aged and present with high bilirubin levels. Acquired aplastic anemia and myocarditis caused by HAV are uncommon, and its pathophysiology has not yet been elucidated.HAV infection is usually asymptomatic in children, although extra-hepatic manifestations can appear requiring early detection and management.

[Invasive pulmonary aspergillosis in children with hepatic transplant: a survivor]. / Aspergilosis pulmonar invasora en pacientes pediátricos con trasplante hepático, a propósito de una sobreviviente.

INTRODUCTION: Mycotic infections due to Aspergillus spp, are the main mycotic associated infections in liver transplant patients, with mortality rates up to 90% of the cases. Almost 50% of patients will de velop an infection during the first months after transplantation, of which 10% are associated with op portunistic agents. OBJECTIVE: To describe the diagnosis and management of an Invasive Pulmonary Aspergillosis (IPA) episode in a liver transplant patient. CASE REPORT: 11-months-old patient with liver transplant due to a biliary atresia who developed severe pneumonia associated with mechanical ventilation. The bronchoalveolar lavage showed high levels of galactomannan and positive culture for Aspergillus fumigatus leading to an IPA diagnosis. This episode was treated with antifungal with a favorable outcome. CONCLUSION: The IPA is an opportunistic infection in liver transplant patients, with high mortality rates, that must be suspected in this group of patients since an early diagnosis and treatment reduce mortality.

Community delivery of semiautomated fractal analysis tool in cardiac mr for trabecular phenotyping.

PURPOSE: To report the development of easy-to-use magnetic resonance imaging (MRI) fractal tools deployed on platforms accessible to all. The trabeculae of the left ventricle vary in health and disease but their measurement is difficult. Fractal analysis of cardiac MR images can measure trabecular complexity as a fractal dimension (FD). MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act (HIPAA)-compliant study was approved by the local Institutional Review Board. Participants provided written informed consent. The original MatLab implementation (region-based level set segmentation and box-counting algorithm) was recoded for two platforms (OsiriX and a clinical MR reporting platform [cvi42 , Circle Cardiovascular Imaging, Calgary, Canada]). For validation, 100 subjects were scanned at 1.5T and 20 imaged twice for interstudy reproducibility. Cines were analyzed by the three tools and FD variability determined. Manual trabecular delineation by an expert reader (R1) provided ground truth contours for validation of segmentation accuracy by point-to-curve (P2C) distance estimates. Manual delineation was repeated by R1 and a second reader (R2) on 15 cases for intra/interobserver variability. RESULTS: FD by OsiriX and the clinical MR reporting platform showed high correlation with MatLab values (correlation coefficients: 0.96 [95% CI: 0.95-0.97] and 0.96 [0.95-0.96]) and high interstudy and intraplatform reproducibility. Semiautomated contours in OsiriX and the clinical MR reporting platform were highly correlated with ground truth contours evidenced by low P2C errors: 0.882 ± 0.76 mm and 0.709 ± 0.617 mm. Validity of ground truth contours was inferred from low P2C errors between readers (R1-R1: 0.798 ± 0.718 mm; R1-R2: 0.804 ± 0.649 mm). CONCLUSION: This set of accessible fractal tools that measure trabeculation in the heart have been validated and released to the cardiac MR community (http://j.mp/29xOw3B) to encourage novel clinical applications of fractals in the cardiac imaging domain. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1082-1088.

Utility of Real Time 3D Echocardiography for the Assessment of Left Ventricular Mass in Patients with Hypertrophic Cardiomyopathy: Comparison with Cardiac Magnetic Resonance.

INTRODUCTION AND OBJECTIVES: Patients with hypertrophic cardiomyopathy (HCM) have irregular ventricular shapes with small and sometimes obliterated cavities at end-systole that affect the quantification of left ventricular mass (LVM) by conventional methods, such as M-mode or two-dimensional echocardiography. The goal of this study was to validate the use of real time three-dimensional echocardiography (RT3DE) to quantify LVM using cardiac magnetic resonance imaging (CMR) as a reference, in a large population of patients with different types of HCM. METHODS: Forty-eight consecutive patients with HCM had a complete transthoracic examination and CMR performed within 7 days. LVM was calculated by M-mode and RT3DE and compared to CMR that served as gold standard. RESULTS: Left ventricular mass calculated by RT3DE was 195 ± 41 g and 187 ± 49 g by CMR. The correlation between the two methods was moderate, with a Lin index of 0.63 and good linear correlation (r = 0.63, P < 0.0001). The correlation was high when RT3DE was of high or adequate image quality. The correlation between LVM by M-mode and CMR was poor. CONCLUSION: Three-dimensional echocardiography is an accurate method for the quantification of LVM in patients with different subtypes of HCM that is in better agreement with CMR reference values than M-mode measurements.

Natural and semisynthetic diterpenoids with antiviral and immunomodulatory activities block the ERK signaling pathway.

The pathogenesis of many viral infections lies on the damage caused by the immune response against the virus. Current antiviral drugs do not act on the inflammatory component of the disease. Thus, new compounds that inhibit both viral multiplication and the immunopathology elicited by the virus are an approach that should be considered. In the present study, we identified two jatropholones (2A and 5B) and one carnosic acid derivative (9C) that significantly inhibited multiplication of TK+ and TK- strains of HSV-1 in Vero cells. Compounds 2A, 5B and 9C also prevented HSV-1- and TLRs-induced inflammatory response in cultivated murine macrophages. In macrophages infected with HSV-1, the inhibitory effect of compounds 2A, 5B and 9C on TNF-α and IL-6 production could be associated with the block of ERK pathway, whereas NF-κB pathway was not hampered by any of the compounds. Besides, 2A, 5B and 9C also inhibited ERK pathway and reduced TNF-α production in macrophages stimulated with TLR2, TLR4 or TLR9 agonists and were able to hinder IL-6 secretion after activation with TLR2 or TLR4, but not with TLR9. The immunomodulatory effect of 2A, 5B and 9C in macrophages infected with HSV-1 may be a consequence of the inhibition of ERK pathway activated by TLRs. The availability of compounds with both antiviral and immunomodulatory properties which affect TLR signaling pathways might be a useful strategy to control the progress of virus-induced disease.

Fractal frontiers in cardiovascular magnetic resonance: towards clinical implementation.

Many of the structures and parameters that are detected, measured and reported in cardiovascular magnetic resonance (CMR) have at least some properties that are fractal, meaning complex and self-similar at different scales. To date however, there has been little use of fractal geometry in CMR; by comparison, many more applications of fractal analysis have been published in MR imaging of the brain.This review explains the fundamental principles of fractal geometry, places the fractal dimension into a meaningful context within the realms of Euclidean and topological space, and defines its role in digital image processing. It summarises the basic mathematics, highlights strengths and potential limitations of its application to biomedical imaging, shows key current examples and suggests a simple route for its successful clinical implementation by the CMR community.By simplifying some of the more abstract concepts of deterministic fractals, this review invites CMR scientists (clinicians, technologists, physicists) to experiment with fractal analysis as a means of developing the next generation of intelligent quantitative cardiac imaging tools.

Automatic cardiac LV segmentation in MRI using modified graph cuts with smoothness and interslice constraints.

PURPOSE: Magnetic resonance imaging (MRI), specifically late-enhanced MRI, is the standard clinical imaging protocol to assess cardiac viability. Segmentation of myocardial walls is a prerequisite for this assessment. Automatic and robust multisequence segmentation is required to support processing massive quantities of data. METHODS: A generic rule-based framework to automatically segment the left ventricle myocardium is presented here. We use intensity information, and include shape and interslice smoothness constraints, providing robustness to subject- and study-specific changes. Our automatic initialization considers the geometrical and appearance properties of the left ventricle, as well as interslice information. The segmentation algorithm uses a decoupled, modified graph cut approach with control points, providing a good balance between flexibility and robustness. RESULTS: The method was evaluated on late-enhanced MRI images from a 20-patient in-house database, and on cine-MRI images from a 15-patient open access database, both using as reference manually delineated contours. Segmentation agreement, measured using the Dice coefficient, was 0.81±0.05 and 0.92±0.04 for late-enhanced MRI and cine-MRI, respectively. The method was also compared favorably to a three-dimensional Active Shape Model approach. CONCLUSION: The experimental validation with two magnetic resonance sequences demonstrates increased accuracy and versatility.