Topical rosiglitazone is an effective anti-scarring agent in the cornea

Corneal scarring remains a major cause of blindness world-wide, with limited treatment options, all of which have side-effects. Here, we tested the hypothesis that topical application of Rosiglitazone, a Thiazolidinedione and ligand of peroxisome proliferator activated receptor gamma (PPARγ), can effectively block scar formation in a cat model of corneal damage. Adult cats underwent bilateral epithelial debridement followed by excimer laser ablation of the central corneal stroma to a depth of ~160 µm as a means of experimentally inducing a reproducible wound. Eyes were then left untreated, or received 50 µl of either 10 µM Rosiglitazone in DMSO/Celluvisc, DMSO/Celluvisc vehicle or Celluvisc vehicle twice daily for 2 weeks. Cellular aspects of corneal wound healing were evaluated with in vivo confocal imaging and post-mortem immunohistochemistry for alpha smooth muscle actin (αSMA). Impacts of the wound and treatments on optical quality were assessed using wavefront sensing and optical coherence tomography at 2, 4, 8 and 12 weeks post-operatively. In parallel, cat corneal fibroblasts were cultured to assess the effects of Rosiglitazone on TGFβ-induced αSMA expression. Topical application of Rosiglitazone to cat eyes after injury decreased αSMA expression and haze, as well as the induction of lower-order and residual, higher-order wavefront aberrations compared to vehicle-treated eyes. Rosiglitazone also inhibited TGFβ-induced αSMA expression in cultured corneal fibroblasts. In conclusion, Rosiglitazone effectively controlled corneal fibrosis in vivo and in vitro, while restoring corneal thickness and optics. Its topical application may represent an effective, new avenue for the prevention of corneal scarring with distinct advantages for pathologically thin corneas

Clinical Utilization of Patient Reported Outcome (PROMIS) Scores for Surgical Reconstruction of Posterior Tibialis Tendon Dysfunction

Introduction/Purpose: Previous studies have demonstrated that preoperative Patient Reported Outcome Instrumentation System (PROMIS) scores effectively predict improvement in foot and ankle surgery. Adult acquired flatfoot deformity (AAFD) and Posterior Tibialis Tendon Dysfunction (PTTD) are a common surgical problem, but it is unclear if the specific thresholds for the physical function (PF), pain interference (PI) and depression published previously for all foot and ankle surgeries apply to a specific diagnosis. Furthermore, the interplay of PROMIS scores and clinical variables has not been evaluated. The purpose of this study was: 1) to investigate the change in PROMIS scales and radiographic measurements from pre- to postoperative follow up in AAFD/PTTD patients, 2) to determine if preoperative PROMIS scales predict post-surgical improvement, 3) to determine if demographic, clinical variables combined with pre-operative PROMIS scales predict post-surgical improvement

Integrity of SRP RNA is ensured by La and the nuclear RNA quality control machinery

The RNA component of signal recognition particle (SRP) is transcribed by RNA polymerase III, and most steps in SRP biogenesis occur in the nucleolus. Here, we examine processing and quality control of the yeast SRP RNA (scR1). In common with other pol III transcripts, scR1 terminates in a U-tract, and ma-ture scR1 retains a U4–5 sequence at its 3 ′ end. In cells lacking the exonuclease Rex1, scR1 terminates in a longer U5–6 tail that presumably represents the primary transcript. The 3 ′ U-tract of scR1 is protected from aberrant processing by the La homologue, Lhp1 and overexpressed Lhp1 apparently competes with both the RNA surveillance system and SRP assem-bly factors. Unexpectedly, the TRAMP and exosome nuclear RNA surveillance complexes are also impli-cated in protecting the 3 ′ end of scR1, which accu-mulates in the nucleolus of cells lacking the activities of these complexes. Misassembled scR1 has a pri-mary degradation pathway in which Rrp6 acts early, followed by TRAMP-stimulated exonuclease degra-dation by the exosome. We conclude that the RNA surveillance machinery has key roles in both SRP biogenesis and quality control of the RNA, poten-tially facilitating the decision between these alterna-tive fates

Preliminary Evaluation of the Impact of Sustained Overvoltage on Low Voltage Electronics-Based Equipment

Low voltage devices connected to public electricity supply networks can be subjected to a wide range of voltage quality, including sustained overvoltage. Assessing the impact of sustained overvoltage on devices connected to the distribution network is important in determining the appropriate variance of standard voltage levels without unduly impacting the utility and customers from a technical and economic perspective. Therefore, a clear understanding of the impact that sustained overvoltage has on the lifetime of the connected equipment is a necessary task. This paper investigates the impact of sustained overvoltage through a series of accelerated-life testing experiments on a custom designed test device representative of a common interface between the power supply and distribution network, a switch mode power supply. The switch mode power supply with combined rectifier and filtering capacitor represents one of the most common front ends of LV equipment in modern appliances, and the work here concentrates on the impact of overvoltage on capacitor ageing. The results of the testing indicate that there is an accelerated ageing impact correlated with the applied voltage magnitude. Furthermore, analysis shows that mismatches between appliance voltage rating and sustained network voltage, leading to accelerated ageing, may result in premature device failure without the consumer being aware of the root cause

Sound and Interaction for K-12 Mediated Education

Through experiences with developing technologies available on the Internet, in video games, and in new media entertainment, many of our students ’ social and intellectual experiences utilize digital media in some fashion. The ever increasing accessibility of sophisticated media tools suggests that such enabling technologies could be ubiquitous in our classrooms and might soon serve as a foundation for learning. However, meaningful integration of interactive digital media is limited by a number of challenges relating to tools, curricula, and evaluation. Our work in K-12 Mediated Education takes an innovative approach to these challenges and utilizes methodologies drawn from interactive computer music for the realization of constructive learning environments that enrich students’ understanding of sound and movement.

The impact of PV inverters on audio frequency injection load control signals

This project investigates the impact of common solar PV inverters on audio frequency injection control (AFIC) signal levels. Anecdotal evidence has been reported by electricity network operators suggesting that solar inverters may be interacting with AFIC signalling. The Australian Power Quality and Reliability Centre (APQRC) employed a range of investigative techniques in order to determine the impact that inverters are having on AFIC signal levels. The process included field measurements on a commercial sized solar installation, measurements conducted within a laboratory environment and computer modelling and analysis to determine the interaction between AFIC signals and PV inverters. The computer simulation and analysis was able to replicate measurements taken in the laboratory and confirmed that the major impact occurring was due to the inverter front-end filter interacting with the high frequency AFIC signals

Osteochondral Defects in Hallux Rigidus

Category: Midfoot/Forefoot Introduction/Purpose: Hallux rigidus, or 1st metatarsophalangeal (MTP) joint degeneration, is commonly encountered in foot and ankle practice. Operative management can include a dorsal cheilectomy, a motion sparing procedure to reduce impingement. Hallux rigidus affects patients across all age groups, and etiologies may include trauma, first ray hypermobility, pes planus, or hallux valgus. First MTP joint trauma may result in an osteochondral defect (OCD). Literature is sparse regarding OCD management in the 1st MTPJ, as is follow-up data on cheilectomy using validated outcome measures. We hypothesize that the presence of an OCD is associated with symptomatic hallux rigidus at a lower Coughlin and Shurnas grade. We also hypothesize that OCD treatment concurrent with cheilectomy leads to outcomes equivalent to patients treated with isolated hallux rigidus. Methods: A retrospective review of prospectively collected data was performed. All patients of a single surgeon were reviewed based on the CPT code (28289) for cheilectomy from 1/1/2011 to 12/31/2015. Demographic data, presence/drilling of an OCD on operative reports, and Coughlin grading were recorded. All patients had taken the FAAM and SF-36 preoperatively per the surgeon’s routine preoperative data collection. After approval by the institutional review board, all patients were contacted by telephone for follow-up and answered the FAAM, SF-36 and Patient Acceptable Symptom State (PASS) questionnaires. Visual analog scores (VAS), patient satisfaction, complications, and whether they would opt for surgery again were recorded.Paired T-tests were performed to evaluate improvement in FAAM activity of daily living (ADL), FAAM sport, SF-36 physical component scores (PCS), and SF-36 mental component scores (MCS). Two-tailed T-tests were performed to evaluate the difference in groups with and without OCDs. Results: Seventy-one patients met inclusion criteria. Follow-up was obtained from 28 patients (29 feet) for analysis, 10 with OCDs. Mean responder age was 53.1 years (32.6-70.9), with average 4 year follow-up (minimum 2 years). Patients with OCDs had lower Coughlin grade (p<0.01) and trended towards lower age (p=0.07), but similar improvement in FAAM sport (p=0.43), SF-36 PCS (p=0.33), and MCS (p=0.46). Patients with OCDs trended towards greater improvement in FAAM ADL (p=0.07). The entire cohort demonstrated significant improvements (p<0.01) in ADL, Sport, PCS, and MCS after cheilectomy. ADL and Sport scores met the MCID of 8 and 9 points, respectively. MCID is not well-defined for SF-36. One patient required subsequent fusion. Conclusion: Cheilectomy is an effective surgical option for improving function and pain in the setting of hallux rigidus, as measured at intermediate-term follow-up with validated patient outcome measures. Patients with a 1st MTP joint OCD become symptomatic at a younger age and with a lower radiographic grade of hallux rigidus. These patients demonstrate equivalent improvements in the FAAM sport, SF-36 PCS and MCS while trending towards greater improvement in the FAAM ADL score as those without OCDs. The presence and treatment of a 1st MTP joint OCD should be considered in younger patients with symptomatic hallux rigidus and lower radiographic severity

Risk Factors of Early Complications, Readmission, and Reoperation After Below Knee Amputation

Category: Diabetes, Hindfoot, Trauma, Limb Salvage Introduction/Purpose: The number of below knee amputation (BKA) patients experiencing complications requiring readmission and reoperation remains significant despite improvements in BKA technique and identification of potential hazards. Analysis of this population is critical due to increased risk of mortality following amputation and the economic burden placed on the healthcare system. With the introduction of Hospital Readmission Reduction Program, prevention of early complication and readmission has become an area of interest for both policy makers and clinicians. The purpose of this study is to investigate risk factors and comorbidities associated with early occurrences of complication, unexpected readmission, and unplanned reoperations after BKA. Methods: Current Procedural Terminology (CPT) code 27880 was used to retrospectively identify 4,631 below knee amputation patients between the years 2012 and 2014 from the National Surgical Quality Improvement Program (NSQIP) database, a nationally collected clinical database. Primary outcomes of unplanned reoperation or readmission were investigated, with independent predictors evaluated using multivariate logistic regression. Secondary outcomes of interest were mortality and major or minor complications within 30 days of index procedure. Major complications included deep surgical site infection (SSI), unplanned intubation, pulmonary embolism, failure to wean, acute renal failure, cerebrovascular accident, cardiac arrest, myocardial infarction, deep vein thrombosis, sepsis, shock, wound dehiscence, and renal insufficiency. Minor complications included superficial SSI, pneumonia, and urinary tract infection. Results: Within 30 days of the 4,631 BKAs, one or more complications occurred in 858 (18.5%) patients; 12.8% major and 8.7% minor (Table 1). Unplanned readmission occurred in 405 (8.75%) patients with SSI being the leading cause. Patients with significantly increased risk of readmission included age greater than 79 years old, transfer from another facility, smoking, and bleeding disorder. A total of 446 (9.63%) patients underwent unplanned reoperations. The 30-day mortality rate was 5.14% (n = 238). The most common procedures for unplanned reoperation were above knee amputation (n = 128, 28.7%), debridement/secondary closure (n = 114, 25.6%), and revision BKA (n = 46, 10.32%). Variables resulting in a significantly increased risk of reoperation included transport from another facility, smoking, bleeding disorder, and preoperative ventilator use. Conclusion: This study represents the largest multicenter cohort examining BKA complications, readmission, and reoperation. Patients that required transport from another facility, were smokers, or had diagnosed bleeding disorders experienced the highest risk of reoperation or readmission. Statistically significant risk factors for reoperation and readmission also included preoperative ventilator use and age, respectively. Surgical site complications were the leading reason for readmission. Complication rates may be improved with more stringent surgical planning of BKA including smoking cessation and coagulation or vascular evaluations. Facility transfer, age, and preoperative ventilator use should play a role in considerations for surgical intervention and patient counseling

Clinical Association of Achilles Tendinopathy and Hypertension Mediated by CaV1.2 Voltage-gated Ca2+ Channel

Category: Basic Sciences/Biologics; Hindfoot Introduction/Purpose: The Achilles tendon is subject to acute- and overuse-injuries, which may result in degenerative tendinopathy. Achilles tendinopathy is associated with pain, disability, and functional limitations. While some patients benefit from therapy and conservative measures, many progress to operative intervention. The pathogenic mechanisms of Achilles tendinopathy are largely unknown. Using novel transgenic mouse models with CaV1.2 (a voltage gated calcium channel) wildtype or a gain-of-function mutant channel, we observed potent regulatory effects of increased Ca2+ influx through CaV1.2 on Achilles tendinopathy development. CaV1.2 expression and activity has also been shown to contribute to hypertension amongst other systemic disease. We hypothesized that aberrant CaV1.2 function is a common pathogenic mechanism both hypertension and Achilles tendinopathy. To test this hypothesis, we performed an association study between two diseases. Methods: A case-control study was performed to investigate the association between Achilles tendinopathy and hypertension using TriNetX mulit-center clinical database. We identified Achilles tendinopathy and hypertension patients based on their ICD-10 codes. Chi-squared test, odds ratio (OR) and 95% confidence interval (CI) were used to detect the correlation between these two diseases. To elucidate the role of CaV1.2 in the association of Achilles tendinopathy and hypertension, we performed a retrospective cohort study with the exposure cohort defined as all subjects with hypertension and a calcium channel blocker (CCB) prescription preceding a diagnosed tendinopathy from January 1, 2011 to December 31, 2015. A matched cohort was defined as the subjects with hypertension but on medications other than CCBs. A 7-year follow-up was obtained for the outcome Achilles tendinopathy. Relative risk (RR) and hazard ratio (HR) were used to detect the effect of CCBs and other anti- hypertensives on the development of tendinopathy. Results: We determined that hypertension is more prevalent in patients with Achilles tendinopathy (42.4%) compared to those without (12.6%). The incidence of Achilles tendinopathy is significantly correlated with hypertension (p < 0.0001; OR=3.17, 95%CI=3.11-3.22). Furthermore, hypertension patients on CCBs had a 28% decrease in Achilles tendinopathy risk when compared with hypertensive patients on medications other than CCBs (RR=0.72, 95%CI=0.60-0.86, p< 0.0001). A cox proportional hazards model corroborated the findings, with hypertensive patients on CCBs having 26% decreased incidence of Achilles tendinopathy than patients on other medications (HR=0.74, 95%CI=0.62-0.88, p< 0.0001). In contrast, we found no significant effect of angiotensin-converting enzyme inhibitors (no direct effect on Calcium channel activity) on the incidence of Achilles tendinopathy (HR=0.99, 95%CI=0.88-1.10, p=0.8273). Conclusion: There may be a correlation between Achilles tendinopathy and other common systemic diseases such as hypertension, as well as potential treatment pathways. Our study of the TriNetX clinical database provides evidence that CaV1.2 expression/activity is a potential molecular mechanism underlying Achilles tendinopathy. Additionally, an effect of CCBs in hypertensive patients may be to lower the incidence of Achilles tendinopathy by inhibiting L-type voltage-gated Ca2+ channel (including CaV1.2) signaling in tenocytes. Our finding will provide a rationale for further investigation of this association, including a potential for repurposing FDA-approved generic CCBs to prevent or treat Achilles tendinopathy