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Writers are often judged by their audience, and these evaluations can encompass both the text and the authors. This study built upon prior research on writing evaluation and error perceptions to examine how interconnected or separable are these judgments. Using a within-subjects design, college students evaluated four essays demonstrating no errors, lower-level errors, higher-level errors, or both types. Evaluations included writing quality traits (e.g., conventions, ideas, organization, sentence fluency, and voice) and author characteristics (e.g., creativity, intelligence, generosity, and kindness). Exploratory factor analyses identified latent constructs within these ratings. One construct, Writing Quality and Skill, appeared to combine writing traits and authors’ intellectual ability (e.g., intelligence and knowledgeability). The second construct, Author Personality, seemed to comprise interpersonal author traits (e.g., kindness and loyalty). The two constructs were significantly and positively correlated. These results suggest that students tended to form holistic impressions of writing quality and authors rather than distinct judgments about individual traits. The spillover onto perceptions of authors’ personal characteristics may be representative of latent biases. Student raters were also more sensitive to lower-level errors than higher-level errors. Implications for biases and training related to peer assessment are discussed.

Knee pain is among the most common problems in active patients, with common causes of medial knee pain including meniscal injury, osteoarthritis, medial collateral ligament (MCL) injury, and pes anserine bursopathy/distal hamstring tendinopathy. Some cases of medial knee pain are refractory to standard treatment options and may be caused by rare pathology. We present a case of medial knee pain secondary to medial tibial crest friction syndrome (MTCFS) in a 22-year-old male training for a sprint triathlon after rapidly increasing his training program. Magnetic resonance imaging revealed bone marrow and soft-tissue edema about the MTC deep to the MCL consistent with MTCFS. The patient failed a period of relative rest and activity modification, but improved with corticosteroid injection deep to the MCL in the location of his symptoms. This case highlights a potential management option for MTCFS, a disorder previously described only in radiologic literature.

Background Ultrasound has become a useful instrument in evaluating musculoskeletal pathology. Recent studies suggest that ultrasound imaging of weight-bearing menisci may enhance the assessment of knee pathology, such as osteoarthritis (OA) and meniscal injuries. Objective The primary aim of this study was to determine the intrarater and interrater reliability of ultrasound measurements of medial meniscal extrusion (MME) after a brief training session. Design Prospective reliability study. Setting Physical medicine and rehabilitation (PM&R) department within a tertiary care institution. Participants Forty-five participants (29 female, 16 male) were recruited to serve as models, 24 of whom had healthy knees and 21 of whom had radiographically confirmed medial compartment knee OA. Three physician sonographers (1 = experienced, 1 = sports medicine fellow, 1 = post-graduate year [PGY]-4 PM&R resident) were recruited to serve as operators. Methods or interventions Operators received a brief training session on identifying and measuring MME. All operators measured bilateral MME in each model in the standing and supine positions on two separate days. Operators were blinded to all measurements. Main outcome measurements Primary outcomes were inter- and intrarater intraclass correlation coefficients (ICCs) of MME measurements among operators with different levels of ultrasound experience. Results Supine MME intrarater reliability ICCs were 0.927, 0.885, and 0.780 for the experienced physician, sports medicine fellow, and PGY-4 operators, respectively. Standing MME intrarater reliability ICCs were 0.941, 0.902, and 0.824 for the experienced physician, sports medicine fellow, and PGY-4 operators, respectively. Interrater reliability ICCs were 0.896 and 0.842 for supine and standing measurements, respectively. There was a statistically significant increase in intrarater reliability with experience between the PGY-4 resident and experienced physician operators. Conclusions Operators with different levels of ultrasound experience demonstrated good MME measurement intra- and interrater reliabilities in both supine and standing positions.

The purpose of this study was to describe meniscus extrusion, present imaging characteristics, and provide clinical correlations for patients with isolated meniscus extrusion. Of the 3244 MRI reports identified as having meniscus extrusion, 20 patients were identified to have isolated meniscus extrusion (0.62%). Patients with moderate to severe chondromalacia, meniscus tears, intra-articular fractures, tumours, and ligament tears were excluded. Radiographs were reviewed and graded using Kellgren–Lawrence (K–L) scores. MRI’s were reviewed for the extent of extrusion and whether or not the meniscotibial ligament was intact. Clinical presentation and management were recorded. The study population consisted of 12 females and 8 males with a mean age of 40.5, diagnosed with meniscus extrusion and minimal concomitant knee pathology. 68% of patients were considered symptomatic as their knee pain correlated with the side of their meniscus extrusion and no other reason for pain was identified. The mean amount of meniscus extrusion was 2.5 mm (SD ± 1.1 mm) with 45% (9 of 20) having 3 + mm of extrusion. Meniscotibial ligament abnormality was identified in 65% of cases (13 of 20). Patients with 3 + mm of meniscus extrusion were much more likely to have associated meniscotibial ligament abnormality (100%, 9 of 9) compared to those with

Objective The primary aim of this study was to determine the inter- and intrarater reliability of ultrasound (US) measurements of the ischiofemoral space (IFS) following a brief training session. A secondary aim was to determine if reliability correlated with sonographer experience. Design Prospective. Setting Physical medicine and rehabilitation department within a tertiary care institution. Participants Seven male and 3 female individuals were recruited to serve as models. Nine physician sonographers (3 postgraduate year [PGY]-2 residents, 3 PGY-4 residents, 3 physicians) were recruited to serve as sonographers. Methods or Interventions Sonographers received a 15-minute educational session on identifying the IFS with US, followed by 20 minutes of practice. Models were then placed in a prone position and secured to prevent hip movement. All operators measured bilateral IFSs in each model twice with a washout period between measurements. Operators were blinded to all measurements. Main Outcome Measures Primary outcomes were inter- and intrarater reliability interclass coefficients (ICCs) of IFS measurements among the groups with different levels of US experience. Secondary outcomes included comparisons of inter- and intrarater reliability ICCs of IFS measurements between groups, and the difference of mean IFS measurements between groups. Results Intrarater reliability ICCs were 0.829, 0.680, and 0.596 for physician, PGY-4, and PGY-2 groups, respectively. Interrater reliability ICCs were 0.722, 0.427, and 0.558 for physician, PGY-4, and PGY-2 groups, respectively. No statistically significant differences in reliability were identified between groups. Mean IFS measurements were 31.2, 33.4, and 34.0 mm for physician, PGY-4, and PGY-2 groups, respectively. Physician measurements were significantly smaller than the PGY-4 and PGY-2 measurements (P Conclusions Following a brief training session, experienced sonographers demonstrated excellent IFS measurement intrarater reliability, whereas PGY-4 and PGY-2 sonographers demonstrated fair intrarater reliability. All sonographers demonstrated fair interrater reliability. Level of Evidence II

Background:Prospective studies evaluating second-look imaging of meniscus root repair using a transtibial pull-out technique are limited; therefore, optimal surgical indications and the technique for meniscus root repair remain uncertain.Hypothesis:It was hypothesized that there would be a high rate of healing, improvement in meniscal extrusion, and prevention of articular cartilage degeneration and subchondral bone abnormalities after meniscus root repair.Study Design:Case series; Level of evidence, 4.Methods:Consecutive patients undergoing transtibial root repair were prospectively enrolled at 2 orthopaedic centers between March 2017 and January 2019. Pre- and postoperative magnetic resonance imaging (MRI) scans were reviewed by a musculoskeletal radiologist in a blinded fashion for meniscal healing, quantification of extrusion, articular cartilage grade, subchondral bone changes, and coronary/meniscotibial ligament abnormalities. Given persistent extrusion observed on postoperative MRI scans, an additional 10 patients gave consent and were enrolled for immediate (before weightbearing) postoperative MRI scans.Results:A total of 45 patients (16 male, 29 female; mean ± standard deviation age, 42.3 ± 12.9 years; body mass index, 31.6) were prospectively enrolled in the study; there were 47 meniscus root repairs: 29 medial and 18 lateral (2 with both). Postoperative MRI was obtained at an average of 6.3 months (range, 5.1-8 months); 98% of meniscal repairs had evidence of healing. Mean extrusion increased significantly, from 1.9 ± 1.5 mm preoperatively to 2.6 ± 1.4 mm postoperatively ( P = .03). There was no significant progression of chondromalacia grade, subchondral edema, insufficiency fracture, subchondral cysts, or subchondral collapse. In the additional 10-patient cohort, the mean preoperative extrusion (1.6 ± 1.2 mm) was not significantly different from that immediately postoperatively (2.0 ± 1.0 mm; P = .23).Conclusion:Prospective MRI analysis of transtibial meniscus root repair confirmed a high rate of meniscal healing and no observable progression of cartilage degeneration or subchondral bone abnormalities at the short-term follow-up. However, meniscal extrusion worsened in the first 6 months after surgery.Registration:NCT03037242 ( ClinicalTrials.gov identifier).

BACKGROUND Medial meniscal extrusion (MME) has been correlated with medial meniscal injury and progression of medial knee osteoarthritis (OA). OBJECTIVE To examine the difference in MME between non-weight-bearing (supine) and weight-bearing (standing) positions in patients with and without medial knee OA. Determine the correlation between body mass index (BMI), Kellgren-Lawrence (KL) grade, Knee Osteoarthritis Outcome Score (KOOS), and MME. DESIGN Prospective. SETTING Tertiary institution PM&R Department. PARTICIPANTS Forty five participants (29 female, 16 male), 24 with healthy knees and 21 with OA. METHODS OR INTERVENTIONS A single physician sonographer measured supine and standing MME with ultrasound (US) on each participant. The physician was blinded to all measurements. BMI was recorded on all participants. KL grades and KOOS questionnaires were obtained for the OA group. MAIN OUTCOME MEASURES MME in supine and standing positions, change in MME from supine to standing, BMI, KL grade, and KOOS subscale scores. RESULTS MME increased .52 mm from supine to standing (P

We describe a 51-year-old woman who over 5 years had 9 painful monophasic attacks affecting the brachial plexus before a fascicular plexus biopsy diagnosed large B-cell lymphoma. The initial attacks were responsive to steroids with clinical resolution. At last attack, magnetic resonance imaging showed multifocal T2 hyperintensities and nodular gadolinium enhancement in the right brachial plexus not seen previously. Also seen were similar changes in the thoracic spinal cord, basal ganglia, cerebellum, and brainstem. Positron emission tomography revealed marked hypermetabolic activity of the plexus facilitating targeted fascicular brachial plexus biopsy, making the pathological diagnosis. Neurolymphomatosis affecting the peripheral nervous system typically presents with insidious painful progressive infiltration of nerves, roots, or plexi. Recurrent idiopathic brachial neuritis attacks (ie, Parsonage-Turner syndrome) in contrast most commonly are seen in persons with a family history and a discoverable genetic cause by SEPT9 mutations, which tested negative in this patient. This case illustrates how neurolymphomatosis, which represents a malignant transformation of B cells within peripheral nerves, can sometimes present with paraneoplastic immune-responsive neuritis mimicking Parsonage-Turner syndrome. Recurrence, an immune-refractory course or insidious progressive involvement of the nervous system, should raise suspicion of neurolymphomatosis.

Automated writing evaluation (AWE) is a popular form of educational technology designed to supplement writing instruction and feedback, yet research on the effectiveness of AWE has observed mixed findings. The current study considered how students' perceptions of automated essay scoring and feedback influenced their writing performance, revising behaviors, and future intentions toward the technology. The manner in which the software was presentedclaims about the accuracy and quality of the automated scoring and feedbackwere modestly related to students' expectations and perceptions. However, students' direct experiences with the software were most strongly associated with their perceptions. Importantly, students' perceptions seemed to have minimal impact on their in the moment use of the software to write and revise successfully. Students revised and improved their essays regardless of their positive or negative views of the system. However, positive and negative perceptions significantly predicted future intentions to use the software again or to recommend the software to a friend. Implications for AWE design, implementation, and evaluation are discussed. Automated writing evaluation (AWE) supports writing practice with feedback.College student perceptions of AWE were favorable overall.AWE perceptions were predicted by both software expectations and direct experience.College students were able to use AWE feedback to improve essay quality.Perceptions did not predict revising but did predict future intentions of use.

We present 2 cases where the initial history and examination were similar to a Morton's/interdigital neuroma. In both cases, however, diagnostic ultrasound revealed symptomatic snapping of the proper digital nerve of the fifth toe. The anatomy of the proper digital nerve of the fifth toe may predispose it to a snapping phenomenon. Clinical awareness of this atypical cause of forefoot pain can help guide the diagnosis and treatment in those patients with persistent and refractory lateral forefoot pain and paresthesias.

Background: Meniscus root tears are increasingly being recognized. Meniscal extrusion has previously been associated with medial root tears; however, the relationship between secondary meniscal restraints, such as the meniscotibial (MT) ligament, extrusion, and root tears has yet to be formally evaluated. Purpose: To better understand the association between MT ligament competence, medial meniscal extrusion, and medial meniscus posterior root tears (MMPRTs) as well as to determine the progression of meniscal extrusion over time. Study Design: Case series; Level of evidence, 4. Methods: Serial magnetic resonance imaging (MRI) scans were reviewed for patients who showed evidence of medial meniscal extrusion and MMPRTs on at least 1 of ≥2 available MRI scans. All patients were symptomatic at the time of diagnosis. All MRI scans were analyzed independently by 2 board-certified musculoskeletal radiologists. MT ligament disruption, medial meniscal extrusion, and MMPRTs were recorded for each MRI scan. The time between MRI scans, presence of insufficiency fractures, and Outerbridge classification for the medial femur and tibia were also evaluated. Results: Overall, 27 knees in 26 patients were included in this study, with a total of 63 MRI scans analyzed (21 knees with 2 MRI scans, 3 with 3 MRI scans, and 3 with 4 MRI scans). All patients demonstrated clear medial meniscal extrusion and MT ligament disruption before the subsequent development of MMPRTs ( P < .001). Mean extrusion at the time of initial MRI was 3.3 ± 1.1 mm and increased significantly to 5.5 ± 1.8 mm at the time of first imaging with an identified MMPRT ( P < .001). The mean time between initial MRI and the first identification of an MMPRT on later MRI was 1.7 ± 1.6 years. Conclusion: In a sample of 27 symptomatic knees with serial MRI scans both before and after an MMPRT diagnosis, all patients demonstrated MT ligament disruption and associated meniscal extrusion before the development of subsequent medial meniscus root tears. These findings suggest that MT ligament disruption and medial meniscal extrusion represent early and predisposing events contributing to MMPRTs. Therefore, this provides a possible explanation of why meniscal extrusion is not corrected with medial meniscus root repair.

To describe the imaging findings on computed tomography (CT) and skeletal survey (SS) in patients with POEMS syndrome. We retrospectively reviewed, with institutional review board approval, the dysproteinemia database at our institution for patients with new diagnosis of POEMS syndrome between January 1998 and December 2008. Twenty-four patients were identified with PET/CT or CT and had skeletal survey (SS) available for review. Twenty-four patients were included in the study group with median age of 47 years. All CTs demonstrated at least one sclerotic lesion. The most common pattern was multiple small lesions, with 18 patients (75 %) having at least 5 lesions less than 1 cm. The larger lesions had a central lytic component and were FDG avid. SS had a false negative rate of 36 % (8 patients). Serial CT after treatment showed a decrease in size and number of sclerotic lesions in 53 % of cases (13 patients), the majority showing increased sclerosis. Two patients had complete resolution of sclerotic lesions. CT identified sclerotic lesions in all study patients with POEMS syndrome, the majority being less than 1 cm in size, which were not identified radiographically. CT may demonstrate increased sclerosis or even resolution of sclerotic lesions corresponding to treatment response. • CT has high sensitivity in identifying sclerotic lesions in POEMS syndrome • Most common CT patterns are multiple, less than 1 cm, sclerotic lesions • Larger lesions have lytic centres and sclerotic margins • Skeletal surveys may have a false negative rate of 36 % • Treatment response includes increased sclerosis, decrease in size or resolution of lesions

The primary aim of this study was to determine if ischiofemoral space (IFS) dimensions vary with changes in hip flexion as a result of placing a bolster behind the knees during magnetic resonance imaging (MRI). A secondary aim was to determine if IFS dimensions vary between supine and prone hip neutral positions. The study employed a prospective design. Sports medicine center within a tertiary care institution. Five male and five female adult subjects (age mean = 29.2, range = 23–35; body mass index [BMI] mean = 23.5, range = 19.5–26.6) were recruited to participate in the study. An axial, T1-weighted MRI sequence of the pelvis was obtained of each subject in a supine position with their hips in neutral and flexed positions, and in a prone position with their hips in neutral position. Supine hip flexion was induced by placing a standard, 9-cm-diameter MRI knee bolster under the subject’s knees. The order of image acquisition (supine hip neutral, supine hip flexed, prone hip neutral) was randomized. The IFS dimensions were then measured on a separate workstation. The investigator performing the IFS measurements was blinded to the subject position for each image. The main outcome measurements were the IFS dimensions acquired with MRI. The mean IFS dimensions in the prone position were 28.25 mm (SD 5.91 mm, standard error mean 1.32 mm). In the supine hip neutral position, the IFS dimensions were 25.1 (SD 5.6) mm. The mean difference between the two positions of 3.15 (3.6) mm was statistically significant (95 % CI of the difference = 1.4 to 4.8 mm, t19 = 3.911, p = .001). The mean IFS dimensions in the hip flexed position were 36.9 (SD 5.7) mm. The mean difference between the two supine positions of 11.8 (4.1) mm was statistically significant (95 % CI of the difference = 9.9 to 13.7 mm, t19 = 12.716, p

Background Ischiofemoral impingement is a potential cause of hip and buttock pain. It is evaluated commonly with magnetic resonance imaging (MRI). To our knowledge, no study previously has evaluated the ability of ultrasound to measure the ischiofemoral space (IFS) dimensions reliably. Objective To determine whether ultrasound could accurately measure the IFS dimensions when compared with the gold standard imaging modality of MRI. Design A methods comparison study. Setting Sports medicine center within a tertiary-care institution. Participants A total of 5 male and 5 female asymptomatic adult subjects (age mean=29.2 years, range=23-35 years; body mass index mean=23.5, range=19.5-26.6) were recruited to participate in the study. Methods Subjects were secured in a prone position on a MRI table with their hips in a neutral position. Their IFS dimensions were then acquired in a randomized order using diagnostic ultrasound and MRI. Main Outcome Measurements The main outcome measurements were the IFS dimensions acquired with ultrasound and MRI. Results The mean IFS dimensions measured with ultrasound was 29.5 mm (standard deviation [SD] 4.99 mm, standard error mean 1.12 mm), whereas those obtained with MRI were 28.25 mm (SD 5.91 mm, standard error mean 1.32 mm). The mean difference between the ultrasound and MRI measurements was 1.25 mm, which was not statistically significant (SD 3.71 mm, standard error mean 3.71 mm, 95% confidence interval −0.49 mm to 2.98 mm, t 19 = 1.506, P = .15). The Bland-Altman analysis indicated that the 95% limits of agreement between the 2 measurement was −6.0 to 8.5 mm, indicating that there was no systematic bias between the ultrasound and MRI measurements. Conclusions Our findings suggest that the IFS measurements obtained with ultrasound are very similar to those obtained with MRI. Therefore, when evaluating individuals with suspected ischiofemoral impingement, one could consider using ultrasound to measure their IFS dimensions. Level of Evidence III

Our intent is to review pediatric tibial eminence fractures treated at a Level I Trauma Center and to note the incidence of associated knee pathology. All pediatric patients treated operatively for a tibial eminence fracture over a 10-year period were identified. A chart review was performed to identify patient demographics, injury pattern, presence of associated pathology, and magnetchic resonance imaging (MRI) findings. In our series of 20 pediatric tibial eminence fractures, 6 patients had associated meniscal tears. Meniscal tears occurred more commonly in type III injuries (5 of 13) than type II injuries (1 of 6). Two patients sustained associated ligamentous injury; there were no patients with associated chondral defects. A displaced pediatric tibial eminence fracture is a relatively infrequent injury. The incidence of associated meniscal injury in our study was 30%, and associated ligamentous injury was uncommon. Arthroscopic evaluation before definitive treatment of displaced tibial eminence fractures should be considered given the associated incidence of meniscal tears. MRI does not appear to provide additional information if arthroscopic treatment is pursued. This study is level IV, case series.

Background: Femoroacetabular impingement (FAI) can be a source of hip pain in young adults. Repetitive kicking associated with youth soccer may lead to morphologic changes of the proximal femur that predispose a person to the development of FAI. Hypothesis: Young adults who participated in high-level soccer competition as youths are more likely to demonstrate radiographic changes consistent with FAI and to have increased alpha angles as compared with controls. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Pelvic radiographs (anteroposterior and frog-lateral) were obtained on 50 individuals who participated in high-level soccer during skeletal immaturity and 50 controls who did not participate in high-level soccer. There were 25 men and 25 women in each group. All subjects were between 18 and 30 years of age, had a body mass index of less than 30, and had not sought or received treatment for hip disorders. Radiographs were analyzed independently for the presence of FAI, and alpha angles were measured. Hips with alpha angles that measured greater than or equal to 55° were deemed to have cam deformity. Results: Fifteen of the 25 male subjects had evidence of cam deformity, compared with 14 male controls. Nine of the 25 female subjects had evidence of cam deformity, compared with 8 female controls. Neither of these differences was statistically significant. There was a significantly higher prevalence of cam deformity in men as compared with women (29 vs 17, P = .016). Conclusion: Participation in high-level soccer during skeletal immaturity is not associated with a higher risk of development of cam deformity in the young adult years. There is a high prevalence of cam deformity in the young adult population. Males demonstrate a higher prevalence of cam deformity than do females.

To determine whether resurfacing submacular human Bruch's membrane with a cell-deposited extracellular matrix (ECM) improves retinal pigment epithelial (RPE) survival.Bovine corneal endothelial (BCE) cells were seeded onto the inner collagenous layer of submacular Bruch's membrane explants of human donor eyes to allow ECM deposition. Control explants from fellow eyes were cultured in medium only. The deposited ECM was exposed by removing BCE. Fetal RPE cells were then cultured on these explants for 1, 14, or 21 days. The explants were analyzed quantitatively by light microscopy and scanning electron microscopy. Surviving RPE cells from explants cultured for 21 days were harvested to compare bestrophin and RPE65 mRNA expression. Mass spectroscopy was performed on BCE-ECM to examine the protein composition.The BCE-treated explants showed significantly higher RPE nuclear density than did the control explants at all time points. RPE expressed more differentiated features on BCE-treated explants than on untreated explants, but expressed very little mRNA for bestrophin or RPE65. The untreated young (50 years) and African American submacular Bruch's membrane explants supported significantly higher RPE nuclear densities (NDs) than did the Caucasian explants. These differences were reduced or nonexistent in the BCE-ECM-treated explants. Proteins identified in the BCE-ECM included ECM proteins, ECM-associated proteins, cell membrane proteins, and intracellular proteins.Increased RPE survival can be achieved on aged submacular human Bruch's membrane by resurfacing the latter with a cell-deposited ECM. Caucasian eyes seem to benefit the most, as cell survival is the worst on submacular Bruch's membrane in these eyes.

Background: Transcranial magnetic stimulation (TMS) is a relatively novel, noninvasive method of altering cerebral electrophysiological activity that produces localized and reversible changes in brain tissue. TMS has been shown to have antidepressant properties in both human trials and animal models. Additionally, TMS may alter hypothalamic–pituitary–adrenal (HPA) function resulting in a normalized dexamethasone suppression test in some depressed subjects and an attenuated stress-induced increase in adrenocorticotropic hormone (ACTH) and a possibly lowered basal corticosterone (CORT) concentration in rats. This research was undertaken to investigate the duration of these behavioral and neuroendocrine effects of TMS in rats. Methods: In this study, serum ACTH, CORT, testosterone, and luteinizing hormone (LH) concentrations following and immobility parameters during a forced-swim test in adult male rats were evaluated immediately and 1, 3, 5, 7, and 14 days subsequent to a 10-day course of once-daily TMS or sham application. Results: TMS animals had significantly higher ACTH and CORT concentrations immediately following the 10-day course of TMS compared to sham controls. Higher CORT concentrations (numerically but not statistically) were displayed by TMS-treated animals 1 and 3 days after the 10-day application course, although there were no significant differences between TMS and sham groups for ACTH or CORT levels 1, 3, 5, 7, and 14 days following application of sham or TMS. No significant differences were found between groups for serum testosterone and LH levels at any given collection time point. Immobility time, a measure of coping ability that is predictive of human antidepressant response, was significantly decreased (i.e., time spent actively swimming was significantly increased) immediately after the 10-day course of TMS. Thereafter, a nonsignificant numerical trend at 1 and 3 days after TMS application for immobility times between the TMS and control groups was observed (TMS

Cell-based therapy involving RPE transplantation might preserve or restore vision in AMD patients with evolving atrophy or in patients with other diseases in which vision loss is associated with dysfunctional RPE. Cell transplantation in patients with AMD has been attempted using a number of cell types and preparations, including fetal and adult RPE (autologous and allogeneic), translocated autologous choroid/RPE, and autologous iris pigment epithelium (IPE; see review by Binder1). Transplantation of autologous RPE and IPE is attractive because there is no risk of immune rejection. However, older cells: (1) do not behave as robustly as those from young donors,2–4 (2) may carry AMD-related gene defects or modifications caused by aging,1,5,6 and (3) may not have the ability to perform all the functions necessary to maintain the photoreceptors.5 Because fetal human RPE begin to show morphologic abnormalities after five to six passages, they are not suitable as a “universal” donor source, regardless of the possible immunogenicity of such cells.7 In addition, the supply of RPE from young donors is limited, so it would not be practical to develop a RPE transplant paradigm based on the use of such cells. Embryonic stem cells offer an advantage over fetal or adult RPE because of their ability to undergo large-scale expansion, assuring an abundant supply of well characterized, pathogen-free cells that can be manufactured in a manner compatible with clinical practice.8 Genetic analysis of such cells shows a high degree of similarity to in situ RPE.9 The method to generate RPE derived from human embryonic stem cells (hES-RPE) is reproducible and can be achieved in a manner that does not cause embryo destruction.10 Manipulation of hES-RPE in culture could take advantage of stem cell plasticity to optimize their ability to attach and survive on aged or diseased Bruch's membrane (BM) and to minimize rejection.11 To assess the potential of hES-RPE for cell replacement therapy in AMD patients, we compared the attachment and survival of hES-RPE of different degrees of pigmentation on BM with cultured human fetal RPE (fRPE) whose behavior has been characterized previously on aged and AMD BM.4,12,13 The goals of this study were to determine: (1) whether hES-RPE have the potential to attach and survive on aged BM; (2) whether a characteristic integrin mRNA profile can predict attachment and/or survival; (3) whether hES-RPE and fRPE have similar morphology after attachment to and growth on BM; and (4) whether hES-RPE secrete neurotrophic proteins after attachment and survival on aged human BM. Using the same hES-RPE preparations as in the present study, Lu et al.8 demonstrated long-term safety and functionality of hES-RPE after subretinal injection in rodents. These and other studies using hES-RPE derived in a similar fashion from spontaneously forming pigmented colonies in confluent hES cultures have shown that hES-RPE express RPE-specific genes, phagocytose outer segments, show polarization of Na+/K+ ATPase, and exhibit morphologic features of RPE.8,9,14–16 Therefore, hES-RPE might serve well for RPE replacement therapy in patients with retinal degenerations where the primary cause of vision loss is diseased or missing RPE. Although animal studies show that hES-RPE can survive in the subretinal space and rescue photoreceptors,8,14,16,17 such studies do not always predict the ability of cells to survive on diseased BM in AMD patients.18 Integrins are important for RPE attachment to BM (reviewed by Afshari19), and alpha integrin subunits have an important role in RPE adhesion to this surface.20 In cultured cells, integrin expression can be modulated by the degree of and time at confluence,21 and integrin upregulation through culturing improves RPE and iris pigment epithelium (IPE) adhesion to BM.4,20,22 One criterion by which one might assess hES-RPE as candidates for transplantation in AMD eyes is the presence of an integrin mRNA profile compatible with attachment to BM (e.g., a profile similar to that of cultured fRPE), which show robust attachment to BM by 24 hours after seeding.4,12,20 To determine whether the integrin mRNA profile can predict successful hES-RPE adhesion and survival on aged submacular human BM, we compared integrin mRNA expression and survival on BM of three different batches of hES-RPE of different degrees of pigmentation (harvested at increasing times in culture) with that of fRPE. In addition to replacing lost or diseased RPE cells with cells capable of performing RPE functions, transplanted cells could rescue dying photoreceptors through the secretion of proteins such as neurotrophic factors and cytokines. This idea is supported by in vivo studies showing that non-RPE cells can rescue photoreceptors despite their inability to phagocytose outer segments.23–26 Therefore, even if the cells do not appear to be fully differentiated on BM after transplantation, secretion of neuroprotective growth factors might have a rescue effect on the overlying retina. As a result, in the studies reported here, we also compared growth factor and cytokine secretion into the media overlying BM explants on which hES-RPE and fRPE were seeded.