Clinical outcomes of ranibizumab treatment in diabetic eye disease

Background: The vascular endothelial growth factor (VEGF) inhibitor ranibizumab is emerging as an efficacious treatment for diabetic macular oedema. Large clinical trials have shown improvements in visual acuity and reduced central retinal thickness. Details of its effect on other retinal functional parameters are lacking. There is a concern that repeated ranibizumab treatment could exacerbate macular ischaemia or lead to global retinal dysfunction by inhibiting physiological isoforms of VEGF. Outcomes of surgery for advanced proliferative retinopathy remain variable and post-operative complications including recurrent haemorrhage can limit visual recovery. VEGF is strongly implicated in the pathogenesis of advanced retinopathy, so VEGF inhibition prior to surgery may improve outcomes. Trials have failed to demonstrate a clear benefit for bevacizumab, so investigation of the licensed intraocular agent ranibizumab represents a logical next step. Aims: To investigate the effects of ranibizumab and laser treatment in diabetic macular oedema on the following parameters: visual acuity, protan and tritan colour contrast sensitivity, 4° and 12° macular sensitivity by microperimetry, electrophysiological indices from pattern and full field electroretinograms. To report structural retinal changes following ranibizumab and laser treatment in terms of qualitative and quantitative optical coherence tomography outcomes, and to quantify macular ischaemia by fluorescein angiography. To investigate the effect on visual acuity at three months post-surgery of ranibizumab pre-treatment in patients undergoing vitrectomy for advanced proliferative diabetic retinopathy. Methods: Randomised clinical trial of intravitreal ranibizumab vs. laser in 36 subjects with centre-involving diabetic macular oedema (The LUCIDATE study). Randomised clinical trial of pre-operative intravitreal ranibizumab vs. subconjunctival saline injection in 30 subjects undergoing vitrectomy-delamination for advanced proliferative diabetic retinopathy (The RaDiVit study). Results: Thirty six subjects with diabetic macular oedema were recruited and 33 completed the trial. Ranibizumab treated subjects gained a mean of 6 letters compared with 0.9 letter loss for laser at 48 weeks. Retinal sensitivity improved in the central macular 4° and 12° in both groups but to a greater extent with ranibizumab. There was no evidence of worsening global retinal dysfunction by electroretinograms in either group. Retinal thickness decreased in both groups: there was a 132 µm reduction in central macular thickness with ranibizumab compared with 103 µm for laser. Fluorescein angiography showed no evidence of significantly increased macular ischaemia in either group. Thirty subjects with advanced proliferative diabetic retinopathy were recruited, underwent surgery, and completed the study. At three months post-surgery, visual acuity in the ranibizumab group was 53 letters compared with 47 letters in the control group. Conclusion: In diabetic macular oedema, there is evidence that ranibizumab leads to greater improvements in visual acuity and retinal sensitivity than laser, with a corresponding greater reduction in retinal thickness. There is no evidence that it worsens macular ischaemia or indices of global retinal electrophysiological function, but larger trials designed to address each of the outcomes investigated here would be required to confirm these findings. In proliferative diabetic retinopathy, there is evidence from this small pilot study that ranibizumab treatment leads to better visual acuity at 3 months post-surgery. An appropriately powered trial would be required to confirm this

Development of a Multi-Site Phase II Clinical Trial of Valproic Acid for Retinitis Pigmentosa

The body of work presented here is a compendium of the multiple steps required for an investigator initiated trial of an existing medication (Valproic Acid- VPA) for a new indication (Retinitis Pigmentosa – RP). The chapters are listed in logical and chronological order of the process. In order to access patient records an expedited Institutional Review Board (IRB) application for retrospective chart review was submitted (Chapter 1). These records enabled the statistical analysis which not only laid the framework for the trial design, but also became the basis for two manuscripts (Chapter 2). Protocol development informed by the preliminary human studies (Chapter 3) was an instrumental part of the Investigational New Drug (IND) application (Chapter 3.5). This protocol along with the extensive case report forms that detail the intended data to be collected are included in the IND application. Because the Phase II clinical trial proposed attempting to identify the specific RP mutations of the subjects utilizing a National Eye Institute (NEI) study that enabled free genotyping services, two IRB applications were submitted (Chapter 3.6). The first was for approval of the NEI genotyping protocol, the second involved the VPA intervention. Two very different sources of funding for this trial were attempted (Chapter 4) – the NIH via the Challenge Grant mechanism and a private eye disease foundation (Foundation Fighting Blindness). In Chapter 5 I detail the alternate study designs that were considered and developed for this trial (and ultimately abandoned). Finally, in Chapter 6, I formally detail my suggestions to aid in the development of a comprehensive investigator initiated core facility at UMMMC. The goal of this project was two-fold. The first was to learn the entire process of trial and protocol design both from a Umass Institutional perspective as well as from the perspective of the FDA. The second goal was the very real prospect of helping patients with a blinding disease. This work was successful on both counts. IRB approval was received for all the submitted applications. The complexity and uniqueness of many aspects of these submissions culminated in a comprehensive learning experience. The process of working with the Umass Research Pharmacy as well as developing the industry contacts and know-how to develop a workable and financially feasible placebo were both particularly important learning experiences. FDA approval of the IND submission was also received, and the process of pre-communication and delving into the considerable and ever-changing rules and regulations resulted in an extensive and valuable knowledge base. While the practicality of funding has limited the ability of this trial to move forward at this point, given the extensive framework laid by this body of work, we are actively pursuing other opportunities. The third outcome of this work, while not as intentional, was the considerable process of determining the specific competencies and infrastructure that exist at UMMMC to enable investigator initiated drug intervention studies. While this institution is clearly moving rapidly in the direction of translational research, the many needs of these studies are often only clearly understood when the process is specifically undertaken. In completing the approval of this Phase II clinical trial, I was not only able to better understand and define the existing capabilities of UMMMC for this kind of research, I was able to add to that infrastructure when the existing knowledge or skill set was not available. In this manner, I was able to inform and guide many of the support personnel who guided me and have become a part of the strategic direction of UMMMC towards clinical translational research

Doctor of Philosophy

dissertationUsing eye-tracking technology to capture the visual scanpaths of a sample of laypersons (N = 92), the current study employed a 2 (training condition: ABCDE vs. Ugly Duckling Sign) Ã- 2 (visual condition: photorealistic images vs. illustrations) factorial design to assess whether SSE training succeeds or fails in facilitating increases in sensitivity and specificity. Self-efficacy and perceived importance were tested as moderators, and eye-tracking fixation metrics as mediators, within the framework of Visual Skill Acquisition Theory (VSAT). For sensitivity, results indicated a significant main effect for visual condition, F(1,88) = 7.102, p = .009, wherein illustrations (M = .524, SD = .197) resulted in greater sensitivity than photos (M = .425, SD = .159, d = .55). For specificity, the main effect for training was not significant, F(1,88) = 2.120, p = .149; however, results indicated a significant main effect for visual condition, F(1,88) = 4.079, p = .046, wherein photos (M = .821, SD = .108) resulted in greater specificity than illustrations (M = .770, SD = .137, d = .41). The interaction for training Ã- visual condition, F(1,88) = 3.554, p = .063, was significant within a 90% confidence interval, such that those within the UDS Photo condition displayed greater specificity than all other combinations of training and visual condition. No significant moderated mediation manifested for sensitivity, but for specificity, the model was significant, r = .59, R2 = .34, F(9,82) = 4.7783, p =.001, with Percent of Time in Lookzone serving as a significant mediator, and both self-efficacy and visual condition significantly moderating the mediation. For those in the photo condition with very high self-efficacy, UDS increased specificity directly. For those in the photo condition with self-efficacy levels at the mean or lower, there was a conditional indirect effect through Percent of Time in Lookzoneâ€"which is to say that these individuals spent a larger amount of their viewing time on target (observing the atypical nevi)â€"and time on target is positively related to specificity. Findings suggest that existing SSE training techniques may be enhanced by maximizing visual processing efficiency

Evaluation of tongue squamous cell carcinoma resection margins using ex-vivo MR

Contains fulltext : 174271.pdf (publisher's version ) (Open Access)PURPOSE: Purpose of this feasibility study was (1) to evaluate whether application of ex-vivo 7T MR of the resected tongue specimen containing squamous cell carcinoma may provide information on the resection margin status and (2) to evaluate the research and developmental issues that have to be solved for this technique to have the beneficial impact on clinical outcome that we expect: better oncologic and functional outcomes, better quality of life, and lower costs. METHODS: We performed a non-blinded validation of ex-vivo 7T MR to detect the tongue squamous cell carcinoma and resection margin in 10 fresh tongue specimens using histopathology as gold standard. RESULTS: In six of seven specimens with a histopathologically determined invasion depth of the tumor of [Formula: see text] mm, the tumor could be recognized on MR, with a resection margin within a 2 mm range as compared to histopathology. In three specimens with an invasion depth of [Formula: see text] mm, the tumor was not visible on MR. Technical limitations mainly included scan time, image resolution, and the fact that we used a less available small-bore 7T MR machine. CONCLUSION: Ex-vivo 7T probably will have a low negative predictive value but a high positive predictive value, meaning that in tumors thicker than a few millimeters we expect to be able to predict whether the resection margin is too small. A randomized controlled trial needs to be performed to show our hypothesis: better oncologic and functional outcomes, better quality of life, and lower costs

A Graduatte Level Immersive-Simulattion Program for Teaching and Assessing Fundamental Skills in Entry Level Clinical Perfusionists.

Background: The clinical perfusionist is a member of the open-heart-surgery team and responsible for operating the life support equipment that replaces the function of the patient\u27s heart and lungs and arrests and restarts the patient\u27s heart in the course of a Cardiopulmonary Bypass (CPB) procedure. In the perfusionists scope of practice, the consequence of unskilled actions, inaccurate understanding or delayed decision making may result in significant patient morbidity or even death. Historically, perfusion students have learned and practiced their skills within a clinical preceptorship program in which an experienced clinician allows the novice student to operate the life support equipment under their direct supervision and consultation. While there is clinical evidence from numerous surgical specialties which establishes that learning curve associated errors have a negative effect on patient outcomes, this has not been researched for clinical perfusionists. Despite this evidence gap, the professions leaders have been instrumental in driving educational innovation and the development of medical simulation models that may reduce the patient\u27s exposure to learning curve associated morbidity by developing competence with high-risk clinical skills prior to patient contact. The purpose of this research is to develop, validate and apply novel medical simulation techniques and technologies to the preparation of entry level clinical perfusionists and demonstrate pre-clinical competence with the fundamental perfusion skills.Methods and Results: To inform the development of a skills curriculum we conducted two national surveys using online survey tools. Through these surveys we validated a list of fundamental skills, and the deconstructed sub-elements involved in the conduct of these skills. Additionally, we identified the typical ranges of physiologic and technical parameters that clinicians maintain during clinical procedures. With this foundational benchmark data we validated the performance of a simulated patient to establish that the patient surrogate generates data that is substantially similar to the physiologic and technical data that a perfusionist would manage during a live clinical procedure. This validated simulation technology was then incorporated into a high-fidelity simulation suite and applied to an innovative immersive curriculum which included hands on repetitive practice, live and video supported self, peer and expert observation and feedback as well as a battery of high-stakes assessments. The validity and fidelity of the simulated experience was established through analysis of over 800 opinions generated over 10 years by novice and expert perfusionists after performing simulated cases. Finally, the efficacy of the simulation curriculum was assessed by comparing our simulation trained students to a national pool of their peers from other schools and expert clinicians. Through this process we generated the first measurements of the typical learning curve for the fundamental skills of CPB, the first estimates of error rates for students navigating the learning curve and the first benchmark measures of competent performance in a simulated environment. This data establishes that students learning in traditional clinical training programs conduct three-fold more errors than experts and will have approximately 99 high-risk patient encounters prior to developing competence with fundamental skills. By comparison, simulation trained students demonstrated competence with fundamental skills that was similar to the experts with almost no high-risk patient encounters. Discussion: The implications to patient safety are clearly implied. These studies establish that there is a high level of agreement among clinicians regarding the skills that are necessary to operate perfusion equipment and that realistic simulation environments can be designed and applied to the development of student\u27s fundamental perfusion skills without exposing patients to the threat of students learning curve associated errors. This data may catalyze a larger national dialog regarding Entrustable Professional Activities for perfusionists and influence national accreditation standards for educational programs