Multimodal positron emission tomography (PET) imaging in non-oncologic musculoskeletal radiology.

Musculoskeletal (MSK) disorders are associated with large impacts on patient's pain and quality of life. Conventional morphological imaging of tissue structure is limited in its ability to detect pain generators, early MSK disease, and rapidly assess treatment efficacy. Positron emission tomography (PET), which offers unique capabilities to evaluate molecular and metabolic processes, can provide novel information about early pathophysiologic changes that occur before structural or even microstructural changes can be detected. This sensitivity not only makes it a powerful tool for detection and characterization of disease, but also a tool able to rapidly assess the efficacy of therapies. These benefits have garnered more attention to PET imaging of MSK disorders in recent years. In this narrative review, we discuss several applications of multimodal PET imaging in non-oncologic MSK diseases including arthritis, osteoporosis, and sources of pain and inflammation. We also describe technical considerations and recent advancements in technology and radiotracers as well as areas of emerging interest for future applications of multimodal PET imaging of MSK conditions. Overall, we present evidence that the incorporation of PET through multimodal imaging offers an exciting addition to the field of MSK radiology and will likely prove valuable in the transition to an era of precision medicine.

Effect of osteophyte removal on simulated range of motion using 3-dimensional preoperative planning software for reverse total shoulder arthroplasty.

Background: Glenohumeral osteophytes (OPs) can adversely influence postoperative range of motion (ROM) following shoulder arthroplasty due to mechanical impingement. Though commercial three-dimensional preoperative planning software (3D PPS) is available to simulate ROM before and after OP resection, little is known about the magnitude of effect OPs and their subsequent removal have on simulated glenohumeral ROM. Methods: Included patients were 1) indicated for reverse total shoulder arthroplasty (rTSA) using 3D PPS and 2) presented with glenoid and/or humeral head OPs on preoperative two-dimensional computed tomography (2D-CT) imaging. Thirty patients met the inclusion criteria (9 females, 21 males; mean age 70.45 ± 4.99 years, range 63-80 years). All subjects (n = 30) presented with humeral OPs (mean volume: 2905.16 mm3, range 109.1-11,246 mm3), while 11 subjects also presented with glenoid OPs (mean volume 108.06 mm3, range 37.59-791.4 mm3). Preoperative CTs were used to calculate OP volume (mm3) and OP circumferential extent (clockface). Mean clockface position for circumferential humeral OPs originated at 6:09 (range 4:30-7:15) and extended to 8:51 (range 8:15-10:15). Mean clockface position for glenoid OPs originated at 3:00 (range 2:00-5:00) and extended to 6:16 (range 3:00-7:30). 3D implants on PPS were standardized to achieve 0° of version, 0° of inclination and 4 mm of net lateralization. Thirty-nine and thirty-six mm glenospheres were used for males and females, respectively. 3D PPS was used to evaluate simulated ROM differences before and after OP removal in the planes of adduction (ADD), abduction, internal rotation (IR), external rotation (ER), extension, and flexion. Impact of OP volume and circumferential extent on pre and postop removal ROM were also analyzed. Results: Humeral OP removal significantly increased impingement-free ADD, IR, ER, extension, and flexion. Removal of larger (mm3) humeral OPs positively correlated with improvement in IR (R = 0.452, P = .011), ER (R = 0.394, P = .033), and flexion (R = 0.500, P < .01). Greater circumferential extent of humeral OPs correlated with worse preremoval ROM in the planes of ADD (R = 0.364, P = .02) and extension (R = 0.403, P = .04), and improvements in ER postop removal (R = 0.431, P = .03). Conclusion: Humeral OP removal significantly increases impingement-free ADD, IR, ER, extension, and flexion in simulated 3D PPS models following rTSA. Magnitude of simulated ROM improvement is influenced by initial humeral OP volume and circumferential clockface extent. Surgeons should consider these effects when using 3D PPS for rTSA planning to optimize postoperative ROM prognostics.

Changes in tissue sodium concentration and sodium relaxation times during the maturation of human knee cartilage: Ex vivo 23 Na MRI study at 10.5 T.

PURPOSE: To evaluate the influence of skeletal maturation on sodium (23 Na) MRI relaxation parameters and the accuracy of tissue sodium concentration (TSC) quantification in human knee cartilage. METHODS: Twelve pediatric knee specimens were imaged with whole-body 10.5 T MRI using a density-adapted 3D radial projection sequence to evaluate 23 Na parameters: B1 + , T1 , biexponential T 2 * $$ {\mathrm{T}}_2^{\ast } $$ , and TSC. Water, collagen, and sulfated glycosaminoglycan (sGAG) content were calculated from osteochondral biopsies. The TSC was corrected for B1 + , relaxation, and water content. The literature-based TSC (TSCLB ) used previously published values for corrections, whereas the specimen-specific TSC (TSCSP ) used measurements from individual specimens. 23 Na parameters were evaluated in eight cartilage compartments segmented on proton images. Associations between 23 Na parameters, TSCLB - TSCSP difference, biochemical content, and age were determined. RESULTS: From birth to 12 years, cartilage water content decreased by 18%; collagen increased by 59%; and sGAG decreased by 36% (all R2 ≥ 0.557). The short T 2 * $$ {\mathrm{T}}_2^{\ast } $$ ( T 2 * S $$ {{\mathrm{T}}_2^{\ast}}_{\mathrm{S}} $$ ) decreased by 72%, and the signal fraction relaxing with T 2 * S $$ {{\mathrm{T}}_2^{\ast}}_{\mathrm{S}} $$ ( fT 2 * S $$ {{\mathrm{fT}}_2^{\ast}}_{\mathrm{S}} $$ ) increased by 55% during the first 5 years but remained relatively stable after that. TSCSP was significantly correlated with sGAG content from biopsies (R2 = 0.739). Depending on age, TSCLB showed higher or lower values than TSCSP . The TSCLB - TSCSP difference was significantly correlated with T 2 * S $$ {{\mathrm{T}}_2^{\ast}}_{\mathrm{S}} $$ (R2 = 0.850), fT 2 * S $$ {{\mathrm{fT}}_2^{\ast}}_{\mathrm{S}} $$ (R2 = 0.651), and water content (R2 = 0.738). CONCLUSION: TSC and relaxation parameters measured with 23 Na MRI provide noninvasive information about changes in sGAG content and collagen matrix during cartilage maturation. Cartilage TSC quantification assuming fixed relaxation may be feasible in children older than 5 years.

[Formula: see text] Field inhomogeneity correction for qDESS [Formula: see text] mapping: application to rapid bilateral knee imaging.

PURPOSE: [Formula: see text] mapping is a powerful tool for studying osteoarthritis (OA) changes and bilateral imaging may be useful in investigating the role of between-knee asymmetry in OA onset and progression. The quantitative double-echo in steady-state (qDESS) can provide fast simultaneous bilateral knee [Formula: see text] and high-resolution morphometry for cartilage and meniscus. The qDESS uses an analytical signal model to compute [Formula: see text] relaxometry maps, which require knowledge of the flip angle (FA). In the presence of [Formula: see text] inhomogeneities, inconsistencies between the nominal and actual FA can affect the accuracy of [Formula: see text] measurements. We propose a pixel-wise [Formula: see text] correction method for qDESS [Formula: see text] mapping exploiting an auxiliary [Formula: see text] map to compute the actual FA used in the model. METHODS: The technique was validated in a phantom and in vivo with simultaneous bilateral knee imaging. [Formula: see text] measurements of femoral cartilage (FC) of both knees of six healthy participants were repeated longitudinally to investigate the association between [Formula: see text] variation and [Formula: see text]. RESULTS: The results showed that applying the [Formula: see text] correction mitigated [Formula: see text] variations that were driven by [Formula: see text] inhomogeneities. Specifically, [Formula: see text] left-right symmetry increased following the [Formula: see text] correction ([Formula: see text] = 0.74 > [Formula: see text] = 0.69). Without the [Formula: see text] correction, [Formula: see text] values showed a linear dependence with [Formula: see text]. The linear coefficient decreased using the [Formula: see text] correction (from 24.3 ± 1.6 ms to 4.1 ± 1.8) and the correlation was not statistically significant after the application of the Bonferroni correction (p value > 0.01). CONCLUSION: The study showed that [Formula: see text] correction could mitigate variations driven by the sensitivity of the qDESS [Formula: see text] mapping method to [Formula: see text], therefore, increasing the sensitivity to detect real biological changes. The proposed method may improve the robustness of bilateral qDESS [Formula: see text] mapping, allowing for an accurate and more efficient evaluation of OA pathways and pathophysiology through longitudinal and cross-sectional studies.

Imaging of joint response to exercise with MRI and PET.

Imaging of the joint in response to loading stress may provide additional measures of joint structure and function beyond conventional, static imaging studies. Exercise such as running, stair climbing, and squatting allows evaluation of the joint response to larger loading forces than during weight bearing. Quantitative MRI (qMRI) may assess properties of cartilage and meniscus hydration and organization in vivo that have been investigated to assess the functional response of these tissues to physiological stress. [18F]sodium fluoride ([18F]NaF) interrogates areas of newly mineralizing bone and provides an opportunity to study bone physiology, including perfusion and mineralization rate, as a measure of joint loading stress. In this review article, methods utilizing quantitative MRI, PET, and hybrid PET-MRI systems for assessment of the joint response to loading from exercise in vivo are examined. Both methodology and results of various studies performed are outlined and discussed. Lastly, the technical considerations, challenges, and future opportunities for these approaches are addressed.

Generalizability of Deep Learning Segmentation Algorithms for Automated Assessment of Cartilage Morphology and MRI Relaxometry.

BACKGROUND: Deep learning (DL)-based automatic segmentation models can expedite manual segmentation yet require resource-intensive fine-tuning before deployment on new datasets. The generalizability of DL methods to new datasets without fine-tuning is not well characterized. PURPOSE: Evaluate the generalizability of DL-based models by deploying pretrained models on independent datasets varying by MR scanner, acquisition parameters, and subject population. STUDY TYPE: Retrospective based on prospectively acquired data. POPULATION: Overall test dataset: 59 subjects (26 females); Study 1: 5 healthy subjects (zero females), Study 2: 8 healthy subjects (eight females), Study 3: 10 subjects with osteoarthritis (eight females), Study 4: 36 subjects with various knee pathology (10 females). FIELD STRENGTH/SEQUENCE: A 3-T, quantitative double-echo steady state (qDESS). ASSESSMENT: Four annotators manually segmented knee cartilage. Each reader segmented one of four qDESS datasets in the test dataset. Two DL models, one trained on qDESS data and another on Osteoarthritis Initiative (OAI)-DESS data, were assessed. Manual and automatic segmentations were compared by quantifying variations in segmentation accuracy, volume, and T2 relaxation times for superficial and deep cartilage. STATISTICAL TESTS: Dice similarity coefficient (DSC) for segmentation accuracy. Lin's concordance correlation coefficient (CCC), Wilcoxon rank-sum tests, root-mean-squared error-coefficient-of-variation to quantify manual vs. automatic T2 and volume variations. Bland-Altman plots for manual vs. automatic T2 agreement. A P value < 0.05 was considered statistically significant. RESULTS: DSCs for the qDESS-trained model, 0.79-0.93, were higher than those for the OAI-DESS-trained model, 0.59-0.79. T2 and volume CCCs for the qDESS-trained model, 0.75-0.98 and 0.47-0.95, were higher than respective CCCs for the OAI-DESS-trained model, 0.35-0.90 and 0.13-0.84. Bland-Altman 95% limits of agreement for superficial and deep cartilage T2 were lower for the qDESS-trained model, ±2.4 msec and ±4.0 msec, than the OAI-DESS-trained model, ±4.4 msec and ±5.2 msec. DATA CONCLUSION: The qDESS-trained model may generalize well to independent qDESS datasets regardless of MR scanner, acquisition parameters, and subject population. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Gadolinium-free assessment of synovitis using diffusion tensor imaging.

The dynamic contrast-enhanced (DCE)-MRI parameter Ktrans can quantify the intensity of synovial inflammation (synovitis) in knees with osteoarthritis (OA), but requires the use of gadolinium-based contrast agent (GBCA). Diffusion tensor imaging (DTI) measures the diffusion of water molecules with parameters mean diffusivity (MD) and fractional anisotropy (FA), and has been proposed as a method to detect synovial inflammation without the use of GBCA. The purpose of this study is to (1) determine the ability of DTI to quantify the intensity of synovitis in OA by comparing MD and FA with our imaging gold standard Ktrans within the synovium and (2) compare DTI and DCE-MRI measures with the semi-quantitative grading of OA severity with the Kellgren-Lawrence (KL) and MRI Osteoarthritis Knee Score (MOAKS) systems, in order to assess the relationship between synovitis intensity and OA severity. Within the synovium, MD showed a significant positive correlation with Ktrans (r = 0.79, p < 0.001), while FA showed a significant negative correlation with Ktrans (r = -0.72, p = 0.0026). These results show that DTI is able to quantify the intensity of synovitis within the whole synovium without the use of exogenous contrast agent. Additionally, MD, FA, and Ktrans values did not vary significantly when knees were separated by KL grade (p = 0.15, p = 0.32, p = 0.41, respectively), while MD (r = 0.60, p = 0.018) and Ktrans (r = 0.62, p = 0.013) had a significant positive correlation and FA (r = -0.53, p = 0.043) had a negative correlation with MOAKS. These comparisons indicate that quantitative measures of the intensity of synovitis may provide information in addition to morphological assessment to evaluate OA severity. Using DTI to quantify the intensity of synovitis without GBCA may be helpful to facilitate a broader clinical assessment of the severity of OA.

Non-contrast MRI of synovitis in the knee using quantitative DESS.

OBJECTIVES: To determine whether synovitis graded by radiologists using hybrid quantitative double-echo in steady-state (qDESS) images can be utilized as a non-contrast approach to assess synovitis in the knee, compared against the reference standard of contrast-enhanced MRI (CE-MRI). METHODS: Twenty-two knees (11 subjects) with moderate to severe osteoarthritis (OA) were scanned using CE-MRI, qDESS with a high diffusion weighting (qDESSHigh), and qDESS with a low diffusion weighting (qDESSLow). Four radiologists graded the overall impression of synovitis, their diagnostic confidence, and regional grading of synovitis severity at four sites (suprapatellar pouch, intercondylar notch, and medial and lateral peripatellar recesses) in the knee using a 4-point scale. Agreement between CE-MRI and qDESS, inter-rater agreement, and intra-rater agreement were assessed using a linearly weighted Gwet's AC2. RESULTS: Good agreement was seen between CE-MRI and both qDESSLow (AC2 = 0.74) and qDESSHigh (AC2 = 0.66) for the overall impression of synovitis, but both qDESS sequences tended to underestimate the severity of synovitis compared to CE-MRI. Good inter-rater agreement was seen for both qDESS sequences (AC2 = 0.74 for qDESSLow, AC2 = 0.64 for qDESSHigh), and good intra-rater agreement was seen for both sequences as well (qDESSLow AC2 = 0.78, qDESSHigh AC2 = 0.80). Diagnostic confidence was moderate to high for qDESSLow (mean = 2.36) and slightly less than moderate for qDESSHigh (mean = 1.86), compared to mostly high confidence for CE-MRI (mean = 2.73). CONCLUSIONS: qDESS shows potential as an alternative MRI technique for assessing the severity of synovitis without the use of a gadolinium-based contrast agent. KEY POINTS: The use of the quantitative double-echo in steady-state (qDESS) sequence for synovitis assessment does not require the use of a gadolinium-based contrast agent. Preliminary results found that low diffusion-weighted qDESS (qDESSLow) shows good agreement to contrast-enhanced MRI for characterization of the severity of synovitis, with a relative bias towards underestimation of severity. Preliminary results also found that qDESSLow shows good inter- and intra-rater agreement for the depiction of synovitis, particularly for readers experienced with the sequence.

Characterizing the transient response of knee cartilage to running: Decreases in cartilage T2 of female recreational runners.

Cartilage transmits and redistributes biomechanical loads in the knee joint during exercise. Exercise-induced loading alters cartilage hydration and is detectable using quantitative magnetic resonance imaging (MRI), where T2 relaxation time (T2 ) is influenced by cartilage collagen composition, fiber orientation, and changes in the extracellular matrix. This study characterized short-term transient responses of healthy knee cartilage to running-induced loading using bilateral scans and image registration. Eleven healthy female recreational runners (33.73 ± 4.22 years) and four healthy female controls (27.25 ± 1.38 years) were scanned on a 3T GE MRI scanner with quantitative 3D double-echo in steady-state before running over-ground (runner group) or resting (control group) for 40 min. Subjects were scanned immediately post-activity at 5-min intervals for 60 min. T2 times were calculated for femoral, tibial, and patellar cartilage at each time point and analyzed using a mixed-effects model and Bonferroni post hoc. There were immediate decreases in T2 (mean ± SEM) post-run in superficial femoral cartilage of at least 3.3% ± 0.3% (p = .002) between baseline and Time 0 that remained for 25 min, a decrease in superficial tibial cartilage T2 of 2.9% ± 0.4% (p = .041) between baseline and Time 0, and a decrease in superficial patellar cartilage T2 of 3.6% ± 0.3% (p = .020) 15 min post-run. There were decreases in the medial posterior region of superficial femoral cartilage T2 of at least 5.3 ± 0.2% (p = .022) within 5 min post-run that remained at 60 min post-run. These results increase understanding of transient responses of healthy cartilage to repetitive, exercise-induced loading and establish preliminary recommendations for future definitive studies of cartilage response to running.

Rapid volumetric gagCEST imaging of knee articular cartilage at 3 T: evaluation of improved dynamic range and an osteoarthritic population.

Chemical exchange saturation transfer of glycosaminoglycans, gagCEST, is a quantitative MR technique that has potential for assessing cartilage proteoglycan content at field strengths of 7 T and higher. However, its utility at 3 T remains unclear. The objective of this work was to implement a rapid volumetric gagCEST sequence with higher gagCEST asymmetry at 3 T to evaluate its sensitivity to osteoarthritic changes in knee articular cartilage and in comparison with T2 and T1ρ measures. We hypothesize that gagCEST asymmetry at 3 T decreases with increasing severity of osteoarthritis (OA). Forty-two human volunteers, including 10 healthy subjects and 32 subjects with medial OA, were included in the study. Knee Injury and Osteoarthritis Outcome Scores (KOOS) were assessed for all subjects, and Kellgren-Lawrence grading was performed for OA volunteers. Healthy subjects were scanned consecutively at 3 T to assess the repeatability of the volumetric gagCEST sequence at 3 T. For healthy and OA subjects, gagCEST asymmetry and T2 and T1ρ relaxation times were calculated for the femoral articular cartilage to assess sensitivity to OA severity. Volumetric gagCEST imaging had higher gagCEST asymmetry than single-slice acquisitions (p = 0.015). The average scan-rescan coefficient of variation was 6.8%. There were no significant differences in average gagCEST asymmetry between younger and older healthy controls (p = 0.655) or between healthy controls and OA subjects (p = 0.310). T2 and T1ρ relaxation times were elevated in OA subjects (p < 0.001 for both) compared with healthy controls and both were moderately correlated with total KOOS scores (rho = -0.181 and rho = -0.332 respectively). The gagCEST technique developed here, with volumetric scan times under 10 min and high gagCEST asymmetry at 3 T, did not vary significantly between healthy subjects and those with mild-moderate OA. This further supports a limited utility for gagCEST imaging at 3 T for assessment of early changes in cartilage composition in OA.

Flexible and efficient optimization of quantitative sequences using automatic differentiation of Bloch simulations.

PURPOSE: To investigate a computationally efficient method for optimizing the Cramér-Rao Lower Bound (CRLB) of quantitative sequences without using approximations or an analytical expression of the signal. METHODS: Automatic differentiation was applied to Bloch simulations and used to optimize several quantitative sequences without the need for approximations or an analytical expression. The results were validated with in vivo measurements and comparisons to prior art. Multi-echo spin echo and DESPO T1 were used as benchmarks to verify the CRLB implementation. The CRLB of the Magnetic Resonance Fingerprinting (MRF) sequence, which has a complicated analytical formulation, was also optimized using automatic differentiation. RESULTS: The sequence parameters obtained for multi-echo spin echo and DESPO T1 matched results obtained using conventional methods. In vivo, MRF scans demonstrate that the CRLB optimization obtained with automatic differentiation can improve performance in presence of white noise. For MRF, the CRLB optimization converges in 1.1 CPU hours for NTR = 400 and has O(NTR) asymptotic runtime scaling for the calculation of the CRLB objective and gradient. CONCLUSIONS: Automatic differentiation can be used to optimize the CRLB of quantitative sequences without using approximations or analytical expressions. For MRF, the runtime is computationally efficient and can be used to investigate confounding factors as well as MRF sequences with a greater number of repetitions.

Acellular and cellular high-density, collagen-fibril constructs with suprafibrillar organization.

Collagen is used extensively for tissue engineering due to its prevalence in connective tissues and its role in defining tissue biophysical and biological signalling properties. However, traditional collagen-based materials fashioned from atelocollagen and telocollagen have lacked collagen densities, multi-scale organization, mechanical integrity, and proteolytic resistance found within tissues in vivo. Here, highly interconnected low-density matrices of D-banded fibrils were created from collagen oligomers, which exhibit fibrillar as well as suprafibrillar assembly. Confined compression then was applied to controllably reduce the interstitial fluid while maintaining fibril integrity. More specifically, low-density (3.5 mg mL(-1)) oligomer matrices were densified to create collagen-fibril constructs with average concentrations of 12.25 mg mL(-1) and 24.5 mg mL(-1). Control and densified constructs exhibited nearly linear increases in ultimate stress, Young's modulus, and compressive modulus over the ranges of 65 to 213 kPa, 400 to 1.26 MPa, and 20 to 150 kPa, respectively. Densification also increased construct resistance to collagenase degradability. Finally, this process was amenable to creating high-density cellularized tissues; all constructs maintained high cell viability (at least 97%) immediately following compression as well as after 1 day and 7 days of culture. This method, which integrates the suprafibrillar assembly capacity of oligomers and controlled fluid reduction by confined compression, supports the rational and scalable design of a broad range of collagen-fibril materials and cell-encapsulated tissue constructs for tissue engineering applications.

MCC inhibits beta-catenin transcriptional activity by sequestering DBC1 in the cytoplasm.

The mutated in colorectal cancer (MCC) is a multifunctional gene showing loss of expression in colorectal and liver cancers. MCC mutations can drive colon carcinogenesis in the mouse and in vitro experiments suggest that loss of MCC function promotes cancer through several important cellular pathways. In particular, the MCC protein is known to regulate beta-catenin (ß-cat) signaling, but the mechanism is poorly understood. Here we show that the ß-cat repressor function of MCC is strongly impaired by the presence of a disease-associated mutation. We also identify deleted in breast cancer 1 (DBC1) as a new MCC interacting partner and regulator of ß-cat signaling. RNA interference experiments show that DBC1 promotes ß-cat transcriptional activity and that the presence of DBC1 is required for MCC-mediated ß-cat repression. In contrast to all other DBC1 interacting partners, MCC does not interact through the DBC1 Leucine Zipper domain but with a glutamic-acid rich region located between the Nudix and EF-hand domains. Furthermore, MCC overexpression relocalizes DBC1 from the nucleus to the cytoplasm and reduces ß-cat K49 acetylation. Treatment of cells with the SIRT1 inhibitor Nicotinamide reverses MCC-induced deacetylation of ß-cat K49. These data suggest that the cytoplasmic MCC-DBC1 interaction sequesters DBC1 away from the nucleus, thereby removing a brake on DBC1 nuclear targets, such as SIRT1. This study provides new mechanistic insights into the DBC1-MCC axis as a new APC independent ß-cat inhibitory pathway.

Health education interventions to raise awareness of rheumatic fever: a systematic review protocol.

BACKGROUND: There is a significant global health burden associated with acute rheumatic fever (ARF) and rheumatic heart disease (RHD), especially in developing countries. ARF and RHD most often strike children and young adults living in impoverished settings, where unhygienic conditions and lack of awareness and knowledge of streptococcal infection progression are common. Secondary prophylactic measures have been recommended in the past, but primary prevention measures have been gaining more attention from researchers frustrated by the perpetual prevalence of ARF and RHD in developing countries. Health education aims to empower people to take responsibility for their own well-being by gaining control over the underlying factors that influence health. We therefore conducted a review of the current best evidence for the use of health education interventions to increase awareness and knowledge of streptococcal pharyngitis and ARF. METHODS AND DESIGN: This article describes the protocol for a systematic review of the effectiveness of health education interventions aimed at increasing awareness and knowledge of the symptoms, causes and consequences of streptococcal pharyngitis, rheumatic fever and/or rheumatic heart disease. Studies will be selected in which the effect of an intervention is compared with either a pre-intervention or a control, targeting all possible audience types. Primary and secondary outcomes of interest are pre-specified. Randomized controlled trials, quasi-randomized trials, controlled before-after studies and controlled clinical trials will be considered. We will search several bibliographic databases (for example, PubMed, EMBASE, World Health Organization Library databases, Google Scholar) and search sources for gray literature. We will meta-analyze included studies. We will conduct subgroup analyses according to intervention subtypes: printed versus audiovisual and mass media versus training workshops. DISCUSSION: This review will provide evidence for the effectiveness of educational components in health promotion interventions in raising public awareness in regard to the symptoms, causes and consequences of streptococcal pharyngitis, ARF and/or RHD. Our results may provide guidance in the development of future intervention studies and programs.