a comparative study with ultrasonography

Background Valid detection of arthritis is essential in differential diagnosis of joint pain. Indocyanin green (ICG)-enhanced fluorescence optical imaging (FOI) is a new imaging method that visualizes inflammation in wrist and finger joints. Objectives of this study were to compare FOI with ultrasonography (US, by gray-scale (GS) and power Doppler (PD)) and clinical examination (CE) and to estimate the predictive power of FOI for discrimination between inflammatory and non-inflammatory juvenile joint diseases. Methods FOI and GSUS/PDUS were performed in both hands of 76 patients with joint pain (53 with juvenile idiopathic arthritis (JIA), 23 with non-inflammatory joint diseases). Inflammation was graded by a semiquantitative score (grades 0–3) for each imaging method. Joints were defined clinically active if swollen or tender with limited range of motion. Sensitivity and specificity of FOI in three phases dependent on ICG enhancement (P1–P3) were analyzed with CE and GSUS/PDUS as reference. Results For JIA patients, FOI had an overall sensitivity of 67.3%/72.0% and a specificity of 65.0%/58.8% with GSUS/PDUS as reference; specificity was highest in P3 (GSUS 94.3%/PDUS 91.7%). FOI was more sensitive for detecting clinically active joints than GSUS/PDUS (75.2% vs 57.3%/32.5%). In patients with non-inflammatory joint diseases both FOI and US showed positive (i.e., pathological) findings (25% and 14% of joints). The predictive value for discrimination between inflammatory and non-inflammatory joint diseases was 0.79 for FOI and 0.80/0.85 for GSUS/PDUS. Conclusions Dependent on the phase evaluated, FOI had moderate to good agreement with CE and US. Both imaging methods revealed limitations and should be interpreted cautiously. FOI may provide an additional diagnostic method in pediatric rheumatology. Trial registration Deutsches Register Klinischer Studien DRKS00012572. Registered 31 July 2017

Fluorescence optical imaging in patients with juvenile rheumatic diseases

Hintergrund: Gelenkschmerzen sind bei Kindern und Jugendlichen ein häufiges Symptom. Zur Unterscheidung zwischen entzündlichen und nicht-entzündlichen Ursachen ist das verlässliche Erkennen einer Arthritis essentiell. Indocyaningrün-gestützte Fluoreszenzoptische Bildgebung (FOI) ist eine neue Technologie, die mithilfe von nahinfrarotem Licht Entzündungen in Hand- und Fingergelenken darstellen kann. Ziele: i) Vergleich von FOI mit Gelenkultraschall (US) im B-Bild und power Doppler (PD) Modus und klinischer Untersuchung, ii) Ermittlung des positiven prädiktiven Wertes (PPW) von FOI zur Unterscheidung zwischen entzündlichen und nicht-entzündlichen juvenilen Gelenkerkrankungen. Methodik: Beide Hände von 76 Patienten mit Schmerzen in Hand- und/oder Fingergelenken (53 mit juveniler idiopathischer Arthritis (JIA), 23 mit nicht-entzündlichen Gelenkerkrankungen) wurden mittels FOI und B-Bild/PDUS untersucht. Entzündliche Veränderungen wurden jeweils mittels semiquantitativem Score (0-3) erfasst und Gelenke mit Wertungen >0 als aktiv definiert. Anhand der Signalanreicherung in den Fingerbeeren wurden für jeden Patienten drei FOI-Phasen (P1-3) bestimmt. Als klinisch aktiv galten Gelenke mit Schwellung oder schmerzhafter Bewegungseinschränkung. Sensitivität und Spezifität der FOI-Phasen sowie des automatisch generierten PrimaVista-Modus (PVM) wurden jeweils mit klinischer Untersuchung und B-Bild/PDUS als Referenzmethoden analysiert. Der PPW wurde mittels „area under curve (AUC)”-Analysen berechnet. Ergebnisse: Von allen Methoden zeigte die FOI die höchste Rate an positiven Befunden (36% aller Gelenke). Mit B-Bild/PDUS als Standardreferenz erreichte sie eine Sensitivität von 67,3%/72,0% und eine Spezifität von 65,0%/58,8% für die Detektion einer Arthritis bei JIA- Patienten. Die Spezifität war am höchsten in P3 (B-Bild: 94,3%/PDUS: 91,7%), die Sensitivität in P1 (B-Bild: 51,8%/PDUS:59,8%). FOI erkannte klinisch aktive Gelenke mit höherer Sensitivität als B-Bild/PDUS (75,2% vs. 57,3%/32,5%). Sowohl FOI als auch US zeigten positive/pathologische Befunde bei Patienten ohne entzündlich-rheumatische Erkrankungen (25% bzw. 14% der Gelenke). Der prädiktive Wert für die Unterscheidung zwischen entzündlichen und nicht-entzündlichen Gelenkerkrankungen lag bei 0,79 für FOI und 0,80/0,85 für B-Bild/PDUS. Schlussfolgerung: Die Übereinstimmung zwischen Fluoreszenzoptischer Bildgebung und Ultraschall bzw. klinischer Untersuchung war - je nach betrachteter FOI-Phase - moderat bis gut. FOI und US hatten einen vergleichbaren prädiktiven Wert für die Unterscheidung zwischen entzündlichen und nicht-entzündlichen Gelenkerkrankungen, zeigten aber jeweils Limitationen und sollten daher mit Vorsicht interpretiert werden. Die FOI könnte in Zukunft eine ergänzende diagnostische Methode in der Kinderrheumatologie darstellen.Background: Joint pain is a common complaint in children and adolescents. Valid detection of arthritis is essential for distinguishing inflammatory from noninflammatory causes. Indocyanine green-enhanced fluorescence optical imaging (FOI) is a new technology that visualizes inflammation in arthritic wrist and finger joints. Objectives: (i) To compare FOI with ultrasonography (US, by gray-scale (GS) and power Doppler (PD)) and clinical examination (CE), (ii) to estimate the predictive power of FOI to distinguish between inflammatory and noninflammatory juvenile joint diseases. Methods: A total of 76 patients describing pain in wrist and/or finger joints were enrolled (53 with juvenile idiopathic arthritis (JIA), 23 with non-inflammatory joint diseases). Joints were defined as clinically active if either joint swelling or tenderness combined with limited range of motion were present. FOI and GS/PDUS were performed in both hands of each patient. A semiquantitative score grading inflammation from 0–3 was applied for each imaging method and joints were defined as active with scores >0. Three phases of FOI (P1-3) were determined according to signal intensity in the fingertips. Sensitivity and specificity of FOI phases and automatically generated PrimaVista Mode (PVM) were analyzed using CE and GS/PDUS as references. Positive predictive values for FOI and US were evaluated by calculating the ‘area under receiver operating characteristics curve (AUC)’. Results: Of all methods, FOI showed the highest rate of positive results (36% of all joints). Taking GS/PDUS as standard of reference, FOI had a sensitivity of 67.3%/72.0% and a specificity of 65.0%/58.8% for detecting arthritis in JIA patients. Specificity reached highest values in P3 (GSUS: 94.3%/PDUS: 91.7%), whereas sensitivity was highest in P1 (GSUS: 51.8%/PDUS:59.8%). Clinically active joints were detected by FOI with higher sensitivity than by GS/PDUS (75.2% vs. 57.3%/32.5%). Remarkably, both imaging methods showed positive findings in patients without any sign of inflammatory joint diseases (FOI: 25%, US: 14% of joints). The predictive value for discrimination between inflammatory and noninflammatory joint diseases was 0.80/0.85 for GS/PDUS and 0.79 for any FOI phase. Conclusions: Dependent on the phase evaluated, agreement of FOI with CE and US was moderate to good. FOI and US had a comparable predictive power to discriminate between inflammatory and noninflammatory joint diseases. However, both methods showed limitations and should be interpreted cautiously in order not to overestimate pathologic findings. In future, FOI may provide an additional method to evaluate inflammation of wrist and finger joints of pediatric patients

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field