An Intraocular Pressure Polygenic Risk Score Stratifies Multiple Primary Open-Angle Glaucoma Parameters Including Treatment Intensity.

PURPOSE: To examine the combined effects of common genetic variants associated with intraocular pressure (IOP) on primary open-angle glaucoma (POAG) phenotype using a polygenic risk score (PRS) stratification. DESIGN: Cross-sectional study. PARTICIPANTS: For the primary analysis, we examined the glaucoma phenotype of 2154 POAG patients enrolled in the Australian and New Zealand Registry of Advanced Glaucoma, including patients recruited from the United Kingdom. For replication, we examined an independent cohort of 624 early POAG patients. METHODS: Using IOP genome-wide association study summary statistics, we developed a PRS derived solely from IOP-associated variants and stratified POAG patients into 3 risk tiers. The lowest and highest quintiles of the score were set as the low- and high-risk groups, respectively, and the other quintiles were set as the intermediate risk group. MAIN OUTCOME MEASURES: Clinical glaucoma phenotype including maximum recorded IOP, age at diagnosis, number of family members affected by glaucoma, cup-to-disc ratio, visual field mean deviation, and treatment intensity. RESULTS: A dose-response relationship was found between the IOP PRS and the maximum recorded IOP, with the high genetic risk group having a higher maximum IOP by 1.7 mmHg (standard deviation [SD], 0.62 mmHg) than the low genetic risk group (P = 0.006). Compared with the low genetic risk group, the high genetic risk group had a younger age of diagnosis by 3.7 years (SD, 1.0 years; P < 0.001), more family members affected by 0.46 members (SD, 0.11 members; P < 0.001), and higher rates of incisional surgery (odds ratio, 1.5; 95% confidence interval, 1.1-2.0; P = 0.007). No statistically significant difference was found in mean deviation. We further replicated the maximum IOP, number of family members affected by glaucoma, and treatment intensity (number of medications) results in the early POAG cohort (P ≤ 0.01). CONCLUSIONS: The IOP PRS was correlated positively with maximum IOP, disease severity, need for surgery, and number of affected family members. Genes acting via IOP-mediated pathways, when considered in aggregate, have clinically important and reproducible implications for glaucoma patients and their close family members.

Spectral CT and its specific values in the staging of patients with non-small cell lung cancer: technical possibilities and clinical impact.

AIM: To investigate how spectral computed tomography (SCT) values impact the staging of non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: One hundred and thirteen patients with confirmed NSCLC were included in a prospective cohort study. All patients underwent single-phase contrast-enhanced SCT (using the fast tube voltage switching technique, 80-140 kV). SCT values (iodine content [IC], spectral slope pitch, and radiodensity increase) of malignant tissue (primary and metastases) and lymph nodes (LNs) were measured. Adrenal masses were evaluated in a virtual non-contrast series (VNS). If pulmonary embolism was present, pulmonary perfusion was analysed as an additional finding. RESULTS: Fifty-two untreated primary NSCLC lesions were evaluable. Lung adenocarcinoma had significantly higher normalised IC (NIC: 19.37) than squamous cell carcinoma (NIC: 12.03; p=0.035). Pulmonary metastases were not significantly different from benign lung nodules. A total of 126 LNs were analysed and histologically proven metastatic LNs (2.08 mg/ml) had significantly lower IC than benign LNs (2.58 mg/ml; p=0.023). Among 34 adrenal masses, VNS identified adenomas with high sensitivity (91%) and specificity (100%). In two patients, a perfusion defect due to pulmonary embolism was detected in the iodine images. CONCLUSION: SCT may contribute to the differentiation of histological NSCLC subtypes and improve the identification of LN metastases. VNS differentiates adrenal adenoma from metastasis. In case of pulmonary embolism, iodine imaging can visualise associated pulmonary perfusion defects.

Factors influencing patients' willingness-to-pay for disease-modifying therapies for multiple sclerosis.

BACKGROUND: High and ever-increasing costs of Multiple Sclerosis (MS) disease-modifying therapies (DMTs) have impaired patient access to DMTs in the US. Patients' willingness-to-pay (WTPs) for DMTs were recently examined, but their influencers were not determined. Thus, the objective of this study was to examine factors influencing patients' WTPs for DMTs for multiple sclerosis (MS). METHODS: Data were obtained from a previous survey of 1,200 US patients with MS on their preferences and WTPs for DMTs. Patients' characteristics (i.e., age, gender, race, marital status, education, employment status, comorbidity, health status, and health insurance) and their MS experiences (i.e., number of years with MS, MS type, number of relapses, fatigue, mood-change, MS symptom, and DMTs experience) were investigated as influencing factors. Patient's WTP for a DMT was obtained from a direct question in the survey. A two-part model was estimated using logistic regression and generalized linear regression. RESULTS: Responses from 480 patients were analyzed. Their average age was 53 years old. Most of them were female (79%), white (97%), and married (71%). Approximately 61% of them had a four-year college degree or lower, 54% were either unemployed, retired, or students, 59% were enrolled in private insurance, 81% had at least one comorbid condition, and 73% considered themselves having good or better health status. Approximately 44% had at least one relapse in two years, 89% experienced fatigue, 37% experienced mood-change, and on average had MS for more than 13 years. The majority of them had relapsing-remitting MS (66%), considered themselves to have some levels of disability for MS (78%), and had used or were currently using DMTs (97%). The average WTP for a DMT was $579 per month. Patients with professional degrees, or with one or more comorbid conditions were more likely willing to pay for a DMT. Patients who were white, had a professional degree, or were in fair or better health status were willing to pay a significantly higher amount for a DMT. Patients, who were female, were employed, did not have private insurance, had a higher number of MS experience years, or who experienced mood change were willing to pay significantly less amount for a DMT. CONCLUSION: Various patients' characteristics and MS experiences, including gender, race, education, employment, health insurance, comorbidity, health status, DMT experience, and mood change influenced patients' WTPs for a DMT.

The immune microenvironment in EGFR- and ERBB2-mutated lung adenocarcinoma.

BACKGROUND: Targeted therapies have improved survival and quality of life for patients with non-small-cell lung cancer with actionable driver mutations. However, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 gene (HER2, also known as ERBB2) exon 20 insertions (Ex20mut) are characterized by a poor response to currently approved tyrosine kinase inhibitors and immunotherapies. The underlying immune biology is not well understood. MATERIALS AND METHODS: We carried out messenger RNA expression profiling of lung adenocarcinomas (ADCs) with ERBB2 (n = 19) and EGFR exon 20-insertion mutations (n = 13) and compared these to tumors with classical EGFR mutations (n = 40, affecting EGFR exons 18, 19 or 21) and EGFR/ERBB2 mutation-negative lung ADC (EGFR/ERBB2wt, n = 26) focusing on immunologically relevant transcripts. Tumor-infiltrating immune cells were estimated from gene expression profiles. RESULTS: Cytotoxic cells were significantly lower in EGFR-mutated tumors regardless of the affected exon, while Th1 cells were significantly lower in EGFR-Ex20mut compared to EGFR/ERBB2wt tumors. We assessed the differentially expressed genes of ERBB2-Ex20mut and EGFR-Ex20mut tumors compared to EGFR-Ex18/19/21mut and EGFR/ERBB2wt tumors. Of these, the genes GUSB, HDAC11, IFNGR2, PUM1, RASGRF1 and RBL2 were up-regulated, while a lower expression of CBLC, GBP1, GBP2, GBP4 and MYC was observed in all three comparison groups. The omnibus test revealed 185 significantly (FDR = 5%) differentially expressed genes and we found these four most significant gene expression changes in the study cohort: VHL and JAK1 were overexpressed in ERBB2-Ex20mut and EGFR-Ex20mut tumors compared to both EGFR-Ex18/19/21mut and EGFR/ERBB2wt tumors. RIPK1 and STK11IP showed the highest expression in ERBB2-Ex20mut tumors. CONCLUSIONS: Targeted gene expression profiling is a promising tool to read out the characteristics of the tumor microenvironment from routine diagnostic lung cancer biopsies. Significant immune reactivity and specific immunosuppressive characteristics in ERBB2-Ex20mut and EGFR-Ex20mut lung ADC with at least some degree of immune infiltration support further clinical evaluation of immune-modulators as partners of immune checkpoint inhibitors in such tumors.

Efficacy of Multiple Dexamethasone Intravitreal Implants for Refractory Retinal Vein Occlusion-Related Macular Edema and Effect of Prior Vitrectomy.

Purpose: To evaluate the efficacy of dexamethasone intravitreal implants (DEX implant) in patients with treatment-resistant macular edema (ME) owing to branch and central retinal vein occlusion (BRVO/CRVO), and the influence of prior vitrectomy on this treatment. Methods: Multicenter retrospective chart review was performed on 40 CRVO and 32 BRVO eyes with persistent ME despite intravitreal anti-vascular endothelial growth factor agents and/or intravitreal triamcinolone, and/or laser therapy. Each patient received ≥1 dexamethasone 700 µg implant between March 2011 and December 2015. Thirteen patients underwent prior vitrectomy. Data were collected on best-corrected visual acuity (BCVA), central macular thickness (CMT), time to relapse, and adverse events. Results: At the end of follow-up, BRVO eyes had a lesser CMT reduction from baseline compared to CRVO eyes (-122.50 ± 152.47 µm and -202.26 ± 194.09 µm, respectively). Neither BRVO nor CRVO eyes had a sustained BCVA benefit (P = 0.7041 and P = 0.7027, respectively). Vitrectomized and nonvitrectomized eyes overall had a sustained significant CMT reduction throughout the study with -192.46 ± 172.62 µm and -164.02 ± 180.36 µm, respectively, at final follow-up. Similar time to relapse of 24.4 ± 6.5 and 23.3 ± 13.5 weeks, respectively, was observed. By the end of follow-up, BCVA had only improved in vitrectomized eyes. However, multivariable regression analyses showed no significant association between vitrectomy status and CMT or BCVA change after the first and last injection. Cataract formation and ocular hypertension occurred in 25% and 17%, respectively. Conclusions: Multiple DEX implant are effective in reducing CMT in patients resistant to previous treatments and appear to be similarly effective in vitrectomized and nonvitrectomized eyes.

Cataract surgery patient-reported outcome measures: a head-to-head comparison of the psychometric performance and patient acceptability of the Cat-PROM5 and Catquest-9SF self-report questionnaires.

Background Cataract surgery is the most frequently undertaken NHS surgical procedure. Visual acuity (VA) provides a poor indication of visual difficulty in a complex visual world. In the absence of a suitable outcome metric, recent efforts have been directed towards the development of a cataract patient-reported outcome measure (PROM) of sufficient brevity, precision, and responsiveness to be implementable in routine high volume clinical services.Aim To compare and contrast the two most promising candidate PROMs for routine cataract surgery.Method The psychometric performance and patient acceptability of the recently UK developed five-item Cat-PROM5 questionnaire was compared with the English translation of the Swedish nine-item Catquest-9SF using Rasch-based performance metrics and qualitative semistructured interviews.Results Rasch-based performance was assessed in 822 typical NHS cataract surgery patients across four centres in England. Both questionnaires demonstrated good to excellent performance for all metrics assessed, including Person Reliability Indices of 0.90 (Cat-PROM5) and 0.88 (Catquest-9SF), responsiveness to surgery (Cohen's standardized effect size) of 1.45 SD (Cat-PROM5) and 1.47 SD (Catquest-9SF) and they were highly correlated with each other (R=0.85). Qualitative assessments confirmed that both questionnaires were acceptable to patients, including in the presence of ocular comorbidities. Preferences were expressed for the shorter Cat-PROM5, which allowed patients to map their own issues to the questions as opposed to the more restrictive specific scenarios of Catquest-9SF.Conclusion The recently UK developed Cat-PROM5 cataract surgery questionnaire is shorter, with performance and patient acceptability at least as good or better than the previous 'best of class' Catquest-9SF instrument.

Cat-PROM5: a brief psychometrically robust self-report questionnaire instrument for cataract surgery.

PurposeTo develop a short, psychometrically robust and responsive cataract patient reported outcome measure suitable for use in high-volume surgical environments.MethodsA prospective study in which participants completed development versions of questionnaires exploring the quality of their eyesight using items harvested from two existing United Kingdom developed parent questionnaires. Participants were 822 patients awaiting cataract surgery recruited from 4 cataract surgical centres based in the UK. Exclusion criteria were other visually significant comorbidities and age <50 years. An iterative multi-stage process of evaluation using Rasch and factor analyses with sequential item reduction was undertaken.ResultsA definitive item set of just five items delivered performance in accordance with the requirements of the Rasch model: no threshold disordering, no misfitting items, Rasch-based reliability 0.90, person separation 2.98, Cronbach's α 0.89, good targeting of questions to patients with cataract with pre-operative item mean -0.41 logits and absence of significant floor or ceiling effects, minor deviations of item invariance, and confirmed unidimensionality. The test-re-test repeatability intra-class correlation coefficient was 0.89 with excellent responsiveness to surgery, Cohen's d -1.45 SD. Rasch calibration values are provided for Cat-PROM5 users.ConclusionsA psychometrically robust and highly responsive five-item cataract surgery patient reported outcome measure has been developed, which is suitable for use in high-volume cataract surgical services.

Validity of using vision-related quality of life as a treatment end point in intermediate and posterior uveitis.

AIM: To evaluate the responsiveness of the Vision core module 1 (VCM1) vision-related quality of life (VR-QOL) questionnaire to changes in visual acuity in patients with posterior and intermediate uveitis and to validate its use as a clinical end point in uveitis. METHODS: Logarithm of the minimum angle of resolution visual acuity and VR-QOL using the VCM1 questionnaire were prospectively recorded in 37 patients with active posterior segment intraocular inflammation before starting systemic immunosuppression with ciclosporin, tacrolimus or the anti-tumour necrosis factor (TNF) agent, p55TNFr-Ig, and again 3 months later. Spearman analysis was used to correlate improvements in visual acuity and VR-QOL between baseline and 3 months. RESULTS: The correlation between changes in visual acuity and VR-QOL was moderate to good for the worse eye (r = 0.47, p = 0.003), but poor for the better eye (r = -0.05, p = 0.91). The responsiveness indices effect size and standardised response mean were 0.57 and 0.59, respectively, showing that the VCM1 questionnaire is moderately responsive to immunsosuppressive therapy for active uveitis. CONCLUSION: Changes in VR-QOL measured with the VCM1 questionnaire correlated moderately well with changes in the worse eye visual acuity, suggesting that the VCM1 is a valid instrument for monitoring response to treatment in uveitis.

A review of randomized controlled trials of penetrating keratoplasty techniques.

PURPOSE: To assess the effects of variations in operative technique on the outcomes of penetrating keratoplasty (PK). METHOD: Systematic literature review of published randomized controlled trials of operative techniques in PK. MAIN OUTCOME MEASURES: Visual acuity, refractive error, endothelial cell density, graft rejection, intraocular pressure (IOP), and other surgical complications. RESULTS: Twenty-seven trials were identified. Many involved small numbers, some of which were probably compromised by inadequate statistical power. There was some limited evidence from a small number of studies (usually 1 or 2) for preoperative cauterization of the cone in keratoconus, excimer laser trephination, taking into account the effect of trephine sizing on postoperative IOP, taking into account the effect of trephine sizing on postoperative spherical equivalent, using sodium hyaluronate, avoiding vitrectomy if possible, using an iris-fixated posterior chamber lens implant in the absence of capsular support, and adjusting a single continuous suture intraoperatively if used. However, there was little convincing evidence for choosing interrupted suturing versus continuous suturing or for an effect of suturing on final sutures-out astigmatism. Likewise, there was no convincing evidence for the superiority of any lamellar alternative to PK for deep stromal disease. Overall, most of the effects of changing technique were small, and there was no evidence for the superiority of any specific technique in terms of improved quality of life or cost-effectiveness. CONCLUSIONS: There is a need for further studies with which to refine decision-making as regards the choice of operative techniques in PK.

Cyclosporine vs tacrolimus therapy for posterior and intermediate uveitis.

OBJECTIVES: To compare the efficacy and tolerability of tacrolimus and cyclosporine therapy for noninfectious posterior segment intraocular inflammation and to evaluate their effect on peripheral blood CD4(+) T-cell phenotype and activation status. METHODS: Thirty-seven patients who required second-line immunosuppression for posterior segment intraocular inflammation were enrolled in this prospective randomized trial of tacrolimus vs cyclosporine therapy. The main outcome measures were visual acuity, binocular indirect ophthalmoscopy score, adverse effects, and quality of life. In addition, peripheral blood CD4(+) T-cell phenotype and activation status were evaluated by flow cytometry before treatment and at 2, 4, and 12 weeks using CD69, chemokine receptor (CCR4, CCR5, and CXCR3), and intracellular cytokine (tumor necrosis factor alpha, interferon-gamma, and interleukin 10) expression. RESULTS: Thirteen patients (68%) taking tacrolimus and 12 patients (67%) taking cyclosporine responded to treatment. Cyclosporine therapy was associated with a higher incidence of reported adverse effects. Mean arterial pressure and serum cholesterol level were significantly higher at 3 months in the cyclosporine group than the tacrolimus group. No significant difference was detected with regard to effect on quality of life or CD4(+) T-cell phenotype. CONCLUSIONS: Tacrolimus and cyclosporine were similar with regard to efficacy for posterior segment intraocular inflammation, but the results suggested a more favorable safety profile for tacrolimus therapy.

Bereavement and psychiatric hospitalization.

Two hundred forty-nine psychiatric inpatients were compared with 249 matched controls and with a psychiatric hospital survey group of 95 patients for incidence of recent bereavement. There were no significant differences between the groups for loss of a first-degree relative in six months and one year prior to admission. There was a preponderance of affective disorder among the psychiatric patients with recent loss. Severe subjective grief reactions were found in the four patients who had lost a spouse or a child and in some patients who had lost a parent, while loss of a sibling usually evoked a mild reaction. Patients with alcoholism tended to increase their drinking during the bereavement period, resulting in incapacitation and hospitalization or, in the case of a control patient, in severe trauma.

Quality of life and visual function in patients with intermediate uveitis.

AIMS: To assess visual function, vision related quality of life (VR-QOL), and general health related quality of life (HR-QOL) in intermediate uveitis (IU). METHODS: VR-QOL and HR-QOL were evaluated in 42 patients with IU using the VCM1 and SF-36 questionnaires, respectively. LogMAR visual acuity (VA), Pelli-Robson contrast sensitivity (CS), Farnsworth-Munsell 100 hue colour vision (CV), and Estermann visual field (VF) were recorded monocularly and binocularly. RESULTS: Median (interquartile range) visual acuity (VA) and CS of 72 affected eyes were 0.1 (0.015-0.3) and 1.55 (1.35-1.65), respectively. 9.5% of patients had a VCM1 score of more than 2.0, indicating "more than a little" concern over vision. Worse eye VA (p=0.045) and CS (p=0.042) were predictive of a VCM1 score of more than 2.0 independently of age, sex, uveitis duration, laterality and activity, systemic uveitis therapy, and medical co-morbidity. The physical and mental component summary scores of the SF-36 were significantly worse in those who reported significant impairment of vision on the VCM1 than those who did not. CONCLUSIONS: The majority of patients with IU maintain good visual function and quality of life. VR-QOL impairment in IU correlates with vision in the worse eye and is associated with impaired HR-QOL.

Cost effectiveness of collagen crosslinking for progressive keratoconus in the UK NHS.

BACKGROUND: Keratoconus is a progressive degenerative corneal disorder of children and young adults that is traditionally managed by refractive error correction, with corneal transplantation reserved for the most severe cases. UVA collagen crosslinking is a novel procedure that aims to prevent disease progression, currently being considered for use in the UK NHS. We assess whether it might be a cost-effective alternative to standard management for patients with progressive keratoconus. METHODS: We constructed a Markov model in which we estimated disease progression from prospective follow-up studies, derived costs derived from the NHS National Tariff, and calculated utilities from linear regression models of visual acuity in the better-seeing eye. We performed deterministic and probabilistic sensitivity analyses to assess the impact of possible variations in the model parameters. RESULTS: Collagen crosslinking is cost effective compared with standard management at an incremental cost of £ 3174 per QALY in the base case. Deterministic sensitivity analysis shows that this could rise above £ 33,263 per QALY if the duration of treatment efficacy is limited to 5 years. Other model parameters are not decision significant. Collagen crosslinking is cost effective in 85% of simulations at a willingness-to-pay threshold of £ 30,000 per QALY. CONCLUSION: UVA collagen crosslinking is very likely to be cost effective, compared with standard management, for the treatment of progressive keratoconus. However, further research to explore its efficacy beyond 5 years is desirable.

Associations of human crystalline lens retrodots and waterclefts with visual impairment: an observational study.

PURPOSE: To investigate the relationships between visual acuity, contrast sensitivity, and 11 clinicopathologic classes of opacity in the human crystalline lens. METHODS: The Somerset and Avon Eye Study is an observational population study of age-related sight-threatening eye disease, based in Bristol, UK. After excluding eyes with other visually relevant disease, data from 902 individuals aged 55 years or older were analyzed. The associations of lens features (posterior subcapsular cataract, nuclear color, nuclear white scatter, cortical spokes, anterior subcapsular cataract, vacuoles, waterclefts, coronary flakes, focal dots, retrodots, fiber folds), with refracted log minimum angle of resolution (MAR) distance acuity and Pelli-Robson contrast sensitivity, were investigated. Multivariable linear regression models using data from both eyes and taking account of the intraclass correlation between eyes were used for analysis, with the lens features and age included as potential explanatory variables. RESULTS: As anticipated from earlier studies, posterior subcapsular, nuclear, and cortical cataracts were associated with visual impairment. In addition, retrodots were strongly and independently associated in the multivariable models with both impaired visual acuity (P < 0.001) and contrast sensitivity (P < 0.001). Waterclefts were strongly associated with impaired visual acuity (P < 0.001). CONCLUSIONS: Retrodots and waterclefts are associated with visual impairment. A causal relationship between these lens features and retinal image degradation is plausible.

Visual function and subjective quality of life compared in subjects with acquired macular disease.

PURPOSE: To determine the objective measures of visual function that are most relevant to subjective quality of vision and perceived reading ability in patients with acquired macular disease. METHODS: Twenty-eight patients with macular disease underwent a comprehensive assessment of visual function. The patients also completed a vision-related quality-of-life questionnaire that included a section of general questions about perceived visual performance and a section with specific questions on reading. RESULTS: Results of all tests of vision correlated highly with reported vision-related quality-of-life impairment. Low-contrast tests explained most of the variance in self-reported problems with reading. Text-reading speed correlated highly with overall concern about vision. CONCLUSIONS: Reading performance is strongly associated with vision-related quality of life. High-contrast distance acuity is not the only relevant measure of visual function in relation to the perceived visual performance of a patient with macular disease. The results suggest the importance of print contrast, even over print size, in reading performance in patients with acquired macular disease.

Responses of ectostriatal neurons during delayed matching-to-sample behavior in pigeons (Columba livia).

We recorded from 71 neurons in the ectostriatum of awake behaving pigeons performing the delayed matching-to-sample task. The ectostriatum is considered to be equivalent to the primate extrastriate cortex. Many of the neurons (n=56, 78.9%) were visually responsive to either or both the red and green stimuli. In addition, a large number of neurons (n=51, 71.8%) exhibited delay activity, that is, a change in activity during the delay period when memory was required compared to the baseline intertrial interval period when memory was not required. We were more likely to encounter a delay neuron when the subjects performed well (>75% correct) compared to when the subjects performed poorly (<75% correct), suggesting that delay activity may carry some functional significance. Finally, the magnitude of the delay activity did not vary across the delay period but remained at a constant elevated or depressed level. Overall, our findings in pigeons are very similar to those reported for primates, and suggest that the pigeon may be an excellent model in which to study the neural mechanisms of visual information processing.

The role of the avian hippocampus in orientation in space and time.

We examined the effects of hippocampus (Hp) and area parahippocampalis (APH) lesions in pigeons on their ability to perform a battery of tasks including autoshaping, time discrimination, spatial memory, and pattern discrimination. Pigeons with Hp-APH lesions were impaired in the acquisition of an autoshaped response, emitting fewer pecks to the stimulus than control animals. Hp-APH pigeons were also impaired in the acquisition of a radial-arm maze analogue task, and those birds that did learn the task seemed to do so by adopting a stereotypic response strategy. In contrast, Hp-APH lesions had no effect on the ability of the birds to discriminate on the basis of either temporal or visual information. Overall, these studies complement our earlier studies and suggest that the avian hippocampus is important for the processing and retention of spatial rather than non-spatial information.

Repair of patellar tendon injuries using a cell-collagen composite.

Collagen gels were seeded with rabbit bone marrow-derived mesenchymal stem cells (MSCs) and contracted onto sutures at initial cell densities of 1, 4, and 8 million cells/ml. These MSC-collagen composites were then implanted into full thickness, full length, central defects created in the patellar tendons of the animals providing the cells. These autologous repairs were compared to natural repair of identical defects on the contralateral side. Biomechanical, histological, and morphometric analyses were performed on both repair tissue types at 6, 12, and 26 weeks after surgery. Repair tissues containing the MSC-collagen composites showed significantly higher maximum stresses and moduli than natural repair tissues at 12 and 26 weeks postsurgery. However, no significant differences were observed in any dimensional or mechanical properties of the repair tissues across seeding densities at each evaluation time. By 26 weeks, the repairs grafted with MSC-collagen composites were one-fourth of the maximum stress of the normal central portion of the patellar tendon with bone ends. The modulus and maximum stress of the repair tissues grafted with MSC-collagen composites increased at significantly faster rates than did natural repairs over time. Unexpectedly, 28% of the MSC-collagen grafted tendons formed bone in the regenerating repair site. Except for increased repair tissue volume, no significant differences in cellular organization or histological appearance were observed between the natural repairs and MSC-collagen grafted repairs. Overall, these results show that surgically implanting tissue engineered MSC-collagen composites significantly improves the biomechanical properties of tendon repair tissues, although greater MSC concentrations produced no additional significant histological or biomechanical improvement.