A perfect storm and patient-provider breakdown in communication: two mechanisms underlying practice gaps in cancer-related fatigue guidelines implementation.

PURPOSE: Cancer-related fatigue (CRF) is a debilitating symptom experienced by many cancer patients. Although guidelines provide evidence-based recommendations for screening, assessing, and managing CRF, there is limited evidence of their implementation in practice. This study aimed to explore patients', healthcare providers' (HCPs), community support providers' (CSPs) experiences and opinions on CRF guidelines and the underlying causes of CRF treatment gaps following the Knowledge-to-Action model. METHODS: A total of 62 participants were recruited-16 patients, 32 HCPs, and 14 CSPs-for a total of 9 focus groups and 4 individual interviews. Sessions were recorded and transcribed verbatim. Transcripts were analyzed using thematic analysis. RESULTS: There were gaps in the application of CRF guidelines and patient dissatisfaction with care. Two underlying mechanisms may contribute to these gaps. First, professionals' lack of knowledge and resources paired with systemic obstacles created difficult conditions to adequately address CRF-A Perfect Storm. Further, patient-provider communication gaps lead to patients feeling discouraged to report issues to their healthcare teams and turning to community services for help-A Breakdown in Communication. CONCLUSIONS: There is little indication that CRF guidelines are routinely implemented in clinical practice. This study provides insights from various perspectives to aid understanding of the critical issues that require consideration to increase implementation of CRF guidelines by HCPs. As patients are currently dissatisfied with CRF-related care, implementation of CRF guidelines is needed.

Translating guidelines to practice: a training session about cancer-related fatigue.

Background: Cancer-related fatigue (crf) is the highest unmet need in cancer survivors. The Canadian Association of Psychosocial Oncology (capo) has developed guidelines for screening, assessment, and intervention in crf; however, those guidelines are not consistently applied in practice because of patient, health care provider (hcp), and systemic barriers. Notably, previous studies have identified a lack of knowledge of crf guidelines as an impediment to implementation. Methods: In this pilot study, we tested the preliminary outcomes, acceptability, and feasibility of a training session and a knowledge translation (kt) tool designed to increase knowledge of the capo crf guidelines among hcps and community support providers (csps). A one-time in-person training session was offered to a diverse sample of hcps and csps (n = 18). Outcomes (that is, knowledge of the capo crf guidelines, and intentions and self-efficacy to apply guidelines in practice) were assessed before and after training. Acceptability and feasibility were also assessed after training to guide future testing and implementation of the training. Results: After training, participants reported increased knowledge of the capo crf guidelines and greater self-efficacy and intent to apply guidelines in practice. Participant satisfaction with the training session and the kt tool was high, and recruitment time, participation, and retention rates indicated that the training was acceptable and feasible. Conclusions: The provided training is both acceptable to hcps and csps and feasible. It could increase knowledge of the capo crf guidelines and participant intentions and self-efficacy to implement evidence-based recommendations. Future studies should investigate actual changes in practice and how to optimize follow-up assessments. To promote practice uptake, kt strategies should be paired with guideline development.

Bone replaces articular cartilage in the rat knee joint after prolonged immobilization.

BACKGROUND: Lost joint range of motion (ROM) is common in chronic osteoarthritis, alters regional weight-bearing across the articular surfaces, and contributes to loss of cartilage and bone alterations. Limited data exist on the regional effects on joints subjected to chronic losses of ROM. OBJECTIVE: To characterize the regional replacement by bone as part of articular cartilage degeneration after prolonged immobilization. METHODS: Eleven rat knees were rigidly-immobilized in flexion for 32weeks with contralateral and sham-operated (n=6) knees as controls. Sagittal medial tibial epiphysis histological sections assessed the anterior (non-weight-bearing), middle and posterior (both weight-bearing) regions. We quantified the distribution of collagen I, collagen II, cartilage thickness, glycosaminoglycan (GAG) staining, Mankin scoring, and subchondral bone plate cross-sectional area. Using immunohistochemistry (IHC), we visualized blood vessels, osteoblasts, and mesenchymal stem cells (MSCs). RESULTS: Immobilized cartilage had increased collagen I content in the anterior tibial region with picrosirius red staining (immobilized=61±20%; contralateral=43±12%, p=0.033; sham=20±10%, p=0.028) and collagen I IHC (immobilized=40±10%; contralateral=11±4%, p=0.003; sham=5±3%, p=0.043). Articular cartilage was thinner anteriorly (18±30µm) in immobilized knees versus contralateral (124±40µm, p<0.001) and sham (125±43µm, p=0.043). GAG staining covered 2±4% of the anterior articular area in immobilized knees versus 28±12% contralaterally (p=0.003) and 26±7% in sham (p=0.043). Mankin scores in immobilized knees were 4.7±1.7 versus 0.2±0.4 and 0±0 for contralateral and sham (p=0.003, p=0.042), respectively. The trabecular bone plate area of anterior and posterior regions showed relative loss of cross-sectional area in immobilized knees compared to controls (immobilized/contralateral area ratios of 0.67 and 0.46 respectively, both p=0.003), while the area in the middle region was preserved. Movat's pentachrome stain and CD31 staining showed chondral vascular ingrowth from subchondral bone. Osteocalcin and CD90 MSC staining were decreased in immobilized knees versus contralateral (p=0.003, p=0.036 respectively). CONCLUSIONS: Bony replacement characterizes articular cartilage degeneration of knees immobilized for 32weeks in the anterior, non-weight bearing region of the tibia. Replacement of cartilage by bone may have been mediated by chondral vascularization, suggesting irreversible changes. These findings stress the importance of weight-bearing and joint motion to maintain cartilage structure.

Loss and re-adaptation of lumbar intervertebral disc water signal intensity after prolonged bedrest.

The adaptation and re-adaptation process of the intervertebral disc (IVD) to prolonged bedrest is important for understanding IVD physiology and IVD herniations in astronauts. Little information is available on changes in IVD composition. In this study, 24 male subjects underwent 60-day bedrest and In/Out Phase magnetic resonance imaging sequences were performed to evaluate IVD shape and water signal intensity. Scanning was performed before bedrest (baseline), twice during bedrest, and three, six and twenty-four months after bedrest. Area, signal intensity, average height, and anteroposterior diameter of the lumbar L3/4 and L4/5 IVDs were measured. At the end of bedrest, disc height and area were significantly increased with no change in water signal intensity. After bedrest, we observed reduced IVD signal intensity three months (p=0.004 versus baseline), six months (p=0.003 versus baseline), but not twenty-four months (p=0.25 versus baseline) post-bedrest. At these same time points post-bedrest, IVD height and area remained increased. The reduced lumbar IVD water signal intensity in the first months after bedrest implies a reduction of glycosaminoglycans and/or free water in the IVD. Subsequently, at two years after bedrest, IVD hydration status returned towards pre-bedrest levels, suggesting a gradual, but slow, re-adaptation process of the IVD after prolonged bedrest.

Intramuscular fat accumulation and muscle atrophy in the absence of muscle retraction.

OBJECTIVES: Although many clinical and experimental investigations have shed light on muscle atrophy and intramuscular accumulation of fat after rotator cuff disruption, none have reported on their onset in the absence of muscle retraction. METHODS: In 30 rabbits, we detached one supraspinatus (SSP) tendon and repaired it immediately, thus preventing muscle retraction. The animals were killed in groups of 10 at one, two and six weeks. Both shoulders of 15 non-operated rabbits served as controls. We measured the weight and volume of SSP muscles and quantified the cross-sectional area of intramuscular fat (i-fat) histologically. RESULTS: There was significant loss of muscle weight and volume after one week (p = 0.004 and 0.003, respectively), and two weeks (both p < 0.001) in the experimental group; which recovered to control values after six weeks. I-fat accumulated one week after immediate repair, greater than in the control group and statistically significant at the mid-part of the muscle (mean 2.7% vs 1.5%, p = 0.008). I-fat continued to accumulate up to six weeks at all sites of the SSP muscle (all 3, p < 0.001). More fat accumulated closer to the musculotendinous junction than at the mid-part after two and six weeks (p = 0.012 and 0.019, respectively). CONCLUSION: Muscle atrophy and i-fat accumulation occur early after SSP tendon tear and immediate repair. While early repair benefitted muscle recovery, it did not prevent fat accumulation. SSP muscle retraction was not essential to the muscle alterations. The divergent evolution of muscle and fat points to different pathophysiologies. Cite this article: Bone Joint Res 2014;3:117-22.

Increased expression of chitinase 3-like protein 1 secondary to joint immobility.

Previous studies have established mechanical stimulation of joints is necessary to maintain the structure and function of the articular cartilage. Immobilization of the rat knee joint induces cartilage degeneration and reduces the joint range of motion, two of the clinical parameters used to define a joint contracture. We hypothesized chondrocytes from articular cartilage increase their expression of the chitinase 3-like protein 1 (CHI3L1) gene in response to joint immobility. We selected the CHI3L1 gene on the basis of its identification as a differentially expressed gene in the articular cartilage obtained from immobilized rat knee joints. Expression of CHI3L1 mRNA was increased after 2 and 4 weeks of immobility. A time-course study revealed that CHI3L1 immuno-reactivity was increased at 2 and 4 weeks and return to basal levels at all later time points. CHI3L1 gene adds to the list of differentially expressed genes defining the response of cartilage to joint immobility. Our data confirm a protective role for CHI3L1 in the initial phase of degeneration induced by immobility.

Knee joint immobility induces Mcl-1 gene expression in articular chondrocytes.

The capacity of chondrocytes to synthesize and remodel the extracellular matrix of the articular cartilage is influenced by mechanical forces applied to joints. Either abnormally high or low loads are detrimental to articular cartilage. Experimental work on animals suggests that immobilization can alter proteoglycan synthesis and result in thinning and softening of the articular cartilage. Little is known of the effects of joint immobility on the pattern of genes expressed by chondrocytes. This study focused on the induction of Mcl-1 gene expression in a rat model of knee joint immobilization by the method of differential display PCR. Increase in Mcl-1 gene expression in chondrocytes induced by joint immobilization was confirmed by RT-PCR, Northern blotting, and immunohistochemistry. Our results indicate that chondrocytes respond to the complete absence of joint motion by expressing Mcl-1 gene. This expression may be part of a defense strategy by chondrocytes to overcome the impending chondrocyte death and cartilage degeneration induced by joint immobility.

Different levels of COX-1 and COX-2 enzymes in synoviocytes and chondrocytes during joint contracture formation.

OBJECTIVE: To measure the levels of prostaglandin endoperoxide H synthase (PGHS) isozymes (or cyclooxygenase, COX) in vivo during the development of joint contractures secondary to immobilization in rats. METHODS: Rats had one knee joint immobilized for up to 32 weeks. Three groups were compared: 47 rats had knee joints immobilized, 38 animals had sham surgery, and 13 unoperated animals served as controls. Levels of PGHS-1 and PGHS-2 enzymes were characterized in the chondrocytes and synoviocytes of the knee joint by immunohistochemistry. Immunostaining intensity was quantified by microscopy using conventional analysis. RESULTS: PGHS-1 level was lower in synoviocytes of the anterior capsule compared with shams (1.3 vs 2.0; p < 0.05). PGHS-2 level was also lower in synoviocytes of the posterior capsule (1.8 vs 2.3; p < 0.05), but higher in chondrocytes at the anterior aspect of the tibia compared with shams (1.6 vs 0.8; p < 0.05). PGHS-2 staining was increased in chondrocytes at the posterior, opposed, and anterior aspects of the tibia compared with controls (1.1, 0.6, 0.8 vs 0.2, 0.1, 0.2, respectively; all p < 0.05). CONCLUSION: Immobility induced joint contractures are characterized by a contrasting cellular pattern of PGHS enzyme levels: decreased in the synovium and increased in the chondrocytes. These findings suggest that chondrocytic PGHS isoenzymes are important in cartilage degradation of contractured joints.

Growth in width of the metacarpals--an investigation in human fetuses.

The process of growth in width of the human hand during fetal life has never been described. Do metacarpals grow concentrically and separation between the bones occurs through expansion of soft tissues? Or is growth eccentric, a process termed drift by Enlow, a relocation in space of organs? Hands of 10 spontaneously aborted fetuses (age range: between 14.5 and 24 weeks of gestation) were examined paying special attention to the bone bark. A thicker bone bark was taken as an indication of growth in that direction. The thickness of the bone bark was measured at the radial and ulnar sides at the level of the proximal and of the distal physes of the second to fifth metacarpals. A ratio of radial over ulnar bone bark thickness (R/U ratio) was calculated. The third metacarpal grew almost concentrically (R/U ratio 1.12 +/- 0.06). The second metacarpal grew in a radial direction (R/U ratio 3.29 +/- 0.19) and the fourth and more so the fifth metacarpal grew in an ulnar direction (R/U ratio 0.70 +/- 0.04 and 0.42 +/- 0.02, respectively). The differences in R/U ratios between every metacarpal were statistically significant for all comparisons P < or = 0.001. Fetal growth in width of the human metacarpals is eccentric and not concentric. It is concluded that during growth in width the metacarpals move away from the midline of the hand and that growth occurs through eccentric bone apposition rather than through soft tissue expansion.

Bone growth increases the knee flexion contracture angle: A study using rats.

OBJECTIVES: To assess the impact of bone growth on the flexion contracture angle at the knee, to measure the bone growth pattern in rats, and to assess the impact of immobility on bone growth. DESIGN: Experimental, controlled study. SETTING: Bone and joint laboratory. ANIMALS: Sixty Sprague-Dawley rats. INTERVENTIONS: Knee joints of 40 rats were immobilized unilaterally in flexion. Sham-operated animals (n = 20) were controls. MAIN OUTCOME MEASURES: The contracture angle and the femur and tibia lengths on radiographs. RESULTS: The angle of flexion increased over time and was largely explained by bone growth (r =.725, p <.01). Femur and tibia grew in rats until they were 11 months old. Immobility enhanced growth in bone length, especially of the femur, after 16 and 32 weeks of immobility (p <.05). CONCLUSIONS: Knee flexion contracture angle increased as a consequence of normal bone growth, a situation that is also encountered in skeletally immature children. The continued growth in length of bones in children may influence the progression of contractures and add to the therapeutic challenge. Ongoing bone growth should be considered when interpreting reports that use animal models for bone and joint diseases.

Optimization of perfusion decalcification for bones and joints in rats.

Decalcification of osseous tissues by perfusion of decalcifying solution into the vascular system has never been applied to the study of peripheral joints. To optimize perfusion methods, rats were decalcified by direct immersion or by one of two perfusion techniques: 1) systemic perfusion circulating the decalcifying solution from the ascending aorta; and 2) regional perfusion circulating the solution to the lower extremities from the abdominal aorta. The process of decalcification was monitored by serial radiographic examinations. After decalcification, bone and joint samples were stained for histochemistry and immunohistochemistry. With systemic perfusion, the decalcification time, dependent on weight, was markedly reduced compared to immersion. Regional perfusion decalcification was faster than all other methods studied. Microstructural preservation was comparable and immunostaining quality often improved. Applications of this work will improve the study of basic skeletal and articular problems.

Early reactions after reimplantation of the tendon of supraspinatus into bone. A study in rabbits.

In 14 rabbits we determined the origin of the cells effecting healing of the tendon of supraspinatus inserted into a bony trough. After two weeks both the cellularity of the underlying bone and the thickness of the subacromial bursa were significantly increased in the operated compared with the control shoulders. The cellularity of the stump of the tendon, however, was significantly decreased in the operated shoulders. In this model, both the underlying bone and the subacromial bursa but not the stump of the tendon contributed to the process of repair. We conclude that the medial stump should be debrided judiciously but that cutting back to bleeding tissue is not necessary during repair of the rotator cuff. Moreover, great care should be taken to preserve the subacromial bursa since it seems to play an important role in the healing process.

A mechanical arthrometer to measure knee joint contracture in rats.

Animal models for joint diseases are necessary for in vivo studies. Joint contractures are characterized by lack of the normal range of motion of a joint most often due to increased soft tissue stiffness. Biological and biochemical data have been obtained but biomechanical data on small animals are rare. An instrument was developed to measure rat knee angular displacement at various soft tissue loads in normal and pathological circumstances. This article describes the instrument and reports its reproducibility and accuracy. The reproducibility and accuracy of this instrument was found to be acceptable thereby validating its use for research purposes with adult rat knees.

Synovial adhesions are more important than pannus proliferation in the pathogenesis of knee joint contracture after immobilization: an experimental investigation in the rat.

OBJECTIVE: To measure intraarticular pannus proliferation after early and prolonged joint immobility using an animal model. METHODS: Forty rats underwent unilateral immobilization of a knee joint with an internal fixator for periods of 2, 4, 8, 16, and 32 weeks. Twenty rats received sham surgery. The knee joints were harvested and processed for histological examination. The synovial intima length and the subintimal area were measured on standardized sagittal sections with image analysis software. The measurements were recorded with regard to their location (anterior or posterior; superior or inferior). RESULTS: Intra and interrater reliabilities for all measurements were > 87.9%. The synovial intima length was smaller in immobilized knees than in controls at all time points. At 4 and 32 weeks, the difference was statistically significant (p < 0.05). The differences were marked in the posterior synovium, where the intima length of immobilized knees was significantly smaller than in controls after 4, 8, 16, and 32 weeks of immobilization (p < 0.05). The subintimal area was comparable in immobilized and control knees at all time points. CONCLUSION: We standardized the quantification of intraarticular pannus in a joint contracture model after immobility of up to 32 weeks' duration. This study revealed a significant decrease in synovial intima length but no change in the subintimal area of immobilized knees compared with controls. The decrease in synovial intima length with immobility suggests that adhesions of synovium villi rather than pannus proliferation are the major pathophysiological changes leading to contracture after immobility.

Contractures secondary to immobility: is the restriction articular or muscular? An experimental longitudinal study in the rat knee.

OBJECTIVES: To measure articular structures' contribution to the limitation of range of motion after joint immobility. STUDY DESIGN: Experimental, controlled study involving 40 adult rats that had one knee joint immobilized in flexion for durations of 2, 4, 8, 16, and 32 weeks; 20 rats underwent a sham procedure. The angular displacement was measured both in flexion and extension at three different torques. Myotomy of transarticular muscles allowed isolation of the arthrogenic component of the contracture. RESULTS: A contracture developed in all immobilized knees. The articular structures were incrementally responsible for the limitation in range of motion (from 12.6 degrees +/-6.7 degrees at 2 weeks to 51.4 degrees +/-5.4 degrees at 32 weeks). The myogenic restriction proportionately decreased over time (from 20.1 degrees +/-8.4 degrees at 2 weeks to only 0.8 degrees +/-7.2 degrees at 32 weeks). The increase in the arthrogenic component of contracture was predominant in extension. CONCLUSION: This study quantified the increasing role of arthrogenic changes in limiting the range of motion of joints after immobility, especially as the period of immobility extended past 2 weeks. These data provide a better understanding of joint contracture development and can be used to guide therapeutic approaches.

Extent and direction of joint motion limitation after prolonged immobility: an experimental study in the rat.

OBJECTIVES: To test the hypotheses that contractures progress at different rates in relation to the time after immobilization, that immobilization in flexion leads to loss of extension range of motion, and that joints of sham-operated animals are better controls than the contralateral joint of experimental animals. STUDY DESIGN: Experimental, controlled study in which 40 adult rats had one knee joint immobilized at 135 degrees of flexion for up to 32 weeks and 20 animals underwent a sham procedure. At intervals of 2, 4, 8, 16, and 32 weeks, 8 experimental and 4 sham-operated animals were killed and their knee motion measured in flexion and extension. RESULTS: In the experimental group, the range of motion decreased in the first 16 weeks of immobility at an average rate of 3.8 degrees per week (p<.0001) to reach 61.1 degrees of restriction. A plateau was then observed from which the contracture did not progress further. The loss in range of motion occurred in extension, not in flexion. CONCLUSION: This study defined an acute stage of contractures starting at the onset of immobility and lasting 16 weeks, during which the range of motion was progressively restricted, and a chronic stage during which no additional limitation was detected. The loss in motion was attributed to posterior knee structures not under tension during immobilization in flexion. Contrary to the hypothesis, the contralateral joint was validated as a control choice for range-of-motion experiments.

Histologic evidence of degeneration at the insertion of 3 rotator cuff tendons: a comparative study with human cadaveric shoulders.

We determined on histologic examination the degree of degeneration at the insertion of 3 rotator cuff tendons in 76 cadaveric shoulders, 17 of which had a partial tear of the supraspinatus. Fiber thinning, the presence of granulation tissue, and incomplete tearing of fibers, all evidence of degeneration, were quantified separately for each tendon. Among the shoulders that were intact on macroscopy, no significant difference in degeneration score could be found. In all 3 tendons degeneration was more prominent on the articular sides compared with the bursal sides (P < .0001). The degeneration score of partially torn supraspinatus was significantly higher than that of the intact tendons (P < .0001). The extent of granulation tissue, 1 criterion of degeneration, seemed to contribute mostly to this difference. Intrinsic degeneration occurred foremost in the articular side of the rotator cuff and might constitute the primary cause of rotator cuff tearing.

Structural disorders at the insertion of the supraspinatus tendon. Relation to tensile strength.

We examined macroscopically and microscopically 55 cadaver rotator-cuff tendons attached to their humeral heads to determine the distance between the edge of the articular cartilage and the tendon insertion of the supraspinatus (the width of the sulcus) and the score of regressive changes at the sulcus. In 33 specimens we measured the tensile strength. The width of the sulcus was correlated with the score of regressive changes and with the ultimate tensile strength of the supraspinatus tendon. The width of the sulcus correlated positively with the score of regressive changes (r = 0.66, p < 0.0001), but there was a negative correlation between the latter and the ultimate tensile strength (r = -0.81, p = 0.001) and between the width of the sulcus and the ultimate tensile strength (r = -0.74, p = 0.004). We believe that the width of the sulcus is a simple and useful clinical indicator of the integrity and the tensile strength of the supraspinatus tendon.

Multiple sclerosis of the spinal cord: diagnosis and follow-up with contrast-enhanced MR and correlation with clinical activity.

PURPOSE: Although MR findings in multiple sclerosis (MS) are well known, the relationship between MR-detected lesions and clinical activity has not been studied in the spinal cord. The purpose of this study was to determine whether serial MR imaging provides evidence of disease activity unsuspected on clinical examination and to determine whether it is useful in monitoring patients with MS primarily affecting the spinal cord. METHODS: Twenty-five consecutive patients with MS and with signs and symptoms of myelopathy underwent a full neurologic examination and contrast-enhanced MR imaging of the spinal cord at intervals of 0, 2, 6, and 12 months. Disability was rated according to Kurtzke's functional systems and the expanded disability status scale (EDSS). Clinical status of myelopathy (improved, deteriorated, or stable) was also assessed. Hyperintense lesions were counted on T2-weighted images and a weighted lesion load was calculated for each patient. The number of enhancing lesions was also determined. RESULTS: We found a moderate correlation between lesion load and sensory function and EDSS. Seventy percent of patients with new clinical manifestations of myelopathy had one or more enhancing lesions. Agreement between MR findings and clinical examination in evincing disease activity was found in 60% of follow-up examinations. MR images showed lesion progression in seven (44%) of 16 occurrences of clinical deterioration and in 21 (35%) of 60 occurrences of clinical improvement or stability. CONCLUSION: Serial MR imaging provides evidence of disease activity unsuspected on clinical examination and could be useful in monitoring patients with MS primarily affecting the spinal cord.

Intraarticular tissue proliferation after immobility: methods of assessment and preliminary results in rat knee joints.

OBJECTIVE: To develop methods to quantify intraarticular connective tissue proliferation after immobility and to report results in an animal model of joint contracture. METHODS: Six rats had their right knee joints immobilized with an internal fixator for 3 weeks. The joints were harvested and sectioned. We measured the length of synovial intima and the subintimal area with image analysis software. Proliferating synoviocytes were identified by immunohistochemistry using the "proliferating cell nuclear antigen" antibody and were counted under optical microscopy on whole joint sections. Two outcomes were analyzed: the subintimal area and a synoviocyte proliferation index (number of proliferating synoviocytes/synovial intima length). Both were obtained for posterior and anterior aspects of the knee. RESULTS: Intra and interobserver reliabilities over 87% were found with these measurement techniques. Subintimal area means were not statistically different between immobilized and contralateral knees. In all subjects, the synoviocyte proliferation index (SPI) posteriorly was higher in immobilized than in contralateral knees (p<0.05), due to an increase in proliferating cells (p<0.05) rather than a change in synovial intima length (p>0.05). The SPI anteriorly was comparable in immobilized and contralateral knees (p>0.05). CONCLUSION: We developed methods to measure intraarticular connective tissue proliferation in a contracture model in vivo. Proliferative changes in the posterior aspect of the knee suggest local mediation of connective tissue proliferation in the contracture process. These methods and preliminary results will benefit investigators assessing interventions in similar models.