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This first-in-kind, perfused, and amputated human limb model allows for the collection of human data in preclinical selection of lead fluorescent agents. The model facilitates more accurate selection and testing of fluorophores with human-specific physiology, such as differential uptake and signal in fat between animal and human models with zero risk to human patients. Preclinical testing using this approach may also allow for the determination of tissue toxicity, clearance time of fluorophores, and the production of harmful metabolites. This study was conducted to determine the fluorescence intensity values and tissue specificity of a preclinical, nerve tissue targeted fluorophore, as well as the capacity of this first-in-kind model to be used for lead fluorescent agent selection in the future. Freshly amputated human limbs were perfused for 30 min prior to and imaging of nerves with both open-field and closed-field commercial fluorescence imaging systems. , open-field imaging demonstrated a signal-to-background ratio (SBR) of 4.7 when comparing the nerve with adjacent muscle tissue. Closed-field imaging demonstrated an SBR of 3.8 when the nerve was compared with adipose tissue and 4.8 when the nerve was compared with muscle. This model demonstrates an opportunity for preclinical testing, evaluation, and selection of fluorophores for use in clinical trials as well as an opportunity to study peripheral pathologies in a controlled environment.

Significance Selecting a nerve-specific lead fluorescent agent for translation in fluorescence-guided surgery is time-consuming and expensive. Preclinical fluorescent agent studies rely primarily on animal models, which are a critical component of preclinical testing, but these models may not predict fluorophore performance in human tissues. Aim The primary aim of this study was to evaluate and compare two preclinical models to test tissue-specific fluorophores based on discarded human tissues. The secondary aim was to use these models to determine the ability of a molecularly targeted fluorophore, LGW16-03, to label ex vivo human nerve tissues. Approach Patients undergoing standard-of-care transtibial or transfemoral amputation were consented and randomized to topical or systemic administration of LGW16-03 following amputation. After probe administration, nerves and background tissues were surgically resected and imaged to determine nerve fluorescence signal-to-background tissue ratio (SBR) and signal-to-noise ratio (SNR) metrics. Analysis of variance (ANOVA) determined statistical differences in metric means between administration cohorts and background tissue groups. Receiver operating characteristic (ROC) curve-derived statistics quantified the discriminatory performance of LGW16-03 fluorescence for labeling nerve tissues. Results Tissue samples from 18 patients were analyzed. Mean nerve-to-adipose SBR was greater than nerve-to-muscle SBR (p = 0.001), but mean nerve-to-adipose SNR was not statistically different from mean nerve-to-muscle SNR (p = 0.069). Neither SBR nor SNR means were statistically different between fluorophore administration cohorts (p ≥ 0.448). When administration cohorts were combined, nerve-to-adipose SBR was greater than nerve-to-muscle SBR (mean ± standard deviation; 4.2 ± 2.9 vs. 1.8 ± 1.9; p < 0.001), but SNRs for nerve-to-adipose and nerve-to-muscle were not significantly different (5.1 ± 4.0 vs. 3.1 ± 3.4; p = 0.055). ROC curve-derived statistics to quantify LGW16-03 nerve labeling performance varied widely between patients, with sensitivities and specificities ranging from 0.2–99.9% and 0.4–100.0%. Conclusion Systemic and topical administration of LGW16-03 yielded similar fluorescence labeling of nerve tissues. Both administration approaches provided nerve-specific contrast similar to that observed in preclinical animal models. Fluorescence contrast was generally higher for nerve-to-adipose versus nerve-to-muscle. Ex vivo human tissue models provide safe evaluation of fluorophores in the preclinical phase and can aid in the selection of lead agents prior to first-in-human trials.

(1) Summarize revisions made to the implantable resonator (IR) design and results of testing to characterize biocompatibility; (2) Demonstrate safety of implantation and feasibility of deep tissue oxygenation measurement using electron paramagnetic resonance (EPR) oximetry. In vitro testing of the revised IR and in vivo implantation in rabbit brain and leg tissues. Revised IRs were fabricated with 1–4 OxyChips with a thin wire encapsulated with two biocompatible coatings. Biocompatibility and chemical characterization tests were performed. Rabbits were implanted with either an IR with 2 oxygen sensors or a biocompatible-control sample in both the brain and hind leg. The rabbits were implanted with IRs using a catheter-based, minimally invasive surgical procedure. EPR oximetry was performed for rabbits with IRs. Cohorts of rabbits were euthanized and tissues were obtained at 1 week, 3 months, and 9 months after implantation and examined for tissue reaction. Biocompatibility and toxicity testing of the revised IRs demonstrated no abnormal reactions. EPR oximetry from brain and leg tissues were successfully executed. Blood work and histopathological evaluations showed no significant difference between the IR and control groups. IRs were functional for up to 9 months after implantation and provided deep tissue oxygen measurements using EPR oximetry. Tissues surrounding the IRs showed no more tissue reaction than tissues surrounding the control samples. This pre-clinical study demonstrates that the IRs can be safely implanted in brain and leg tissues and that repeated, non-invasive, deep-tissue oxygen measurements can be obtained using in vivo EPR oximetry.

Fluorescence guided surgery (FGS) is an evolving field that aims to improve patient outcomes by using fluorophores to identify important tissues during surgery, such as tumors and nerves. In this thesis work, we explored different methods of identifying nerve and tumor tissues for FGS and a novel fluorescence-based method to determine the depths of these structures. Researchers have explored using fluorescence guided surgery for surgical resection of cancerous tissues, including recent work by our group focusing on identifying soft tissue sarcomas with ABY-029, an epidermal growth factor receptor targeting probe. However, our preclinical and clinical work shows no single reporter characterizes all areas of the tumor, which compromises our ability to reliably detect residual cancer in the tumor bed. We developed an innovative strategy to enhance tumor contrast by using multiple near-infrared fluorophore reporters with similar emission wavelengths that target different regions of the tumor milieu. In this work, fluorescence from single fluorophores (ABY-029, bevacizumab-IRDye800, indocyanine green (ICG), and 6QC-ICG) were compared in a murine STS model. Fluorescence guided surgery can not only be used to identify structures for removal, such as tumors, but also to distinguish structures that surgeons aim to avoid, such as nerves. Presently, intraoperative guidance for nerve and other normal structure identification is limited. In this work, we aimed to test the ability of a novel nerve targeting agent, LGW16-03, to label human nerve tissue in two ex vivo preclinical models using innovative methods that utilize freshly resected human specimens. We demonstrated that signal-to-background ratios could be achieved that are similar to preclinical studies of similar fluorophores. Therefore, ex vivo human tissue models appear to provide physiologically relevant preclinical evaluation of fluorophores with no known risks to patients and may aid in improved selection of lead agents prior to first-in-human trials. We then aimed to quantitatively evaluate depth of structures of interest using a newly developed multi-excitation wavelength emission ratio (MEWER) methodology tested in validated tissue simulating gelatin phantoms. Results suggest that MEWER has the potential to discern depths less than 6 mm. However, improved identification methods for optical properties of tissue are necessary to determine unknown depths.

A century ago, the prospect of a person with a disability becoming a physician in Canada would have been dismissed out right. Medical schools emphasized physical endurance, dexterity, and the ability to perform demanding tasks without error. These expectations were rooted in a deep-seated understanding of what a physician should be: a body that appeared strong, efficient, and unencumbered. Applicants whose bodies did not meet the ideal of the perfect physician -- such as those with missing limbs, impaired vision, or hearing loss -- were commonly excluded under the guise of professional unfitness. These assumptions were reinforced by laws in provinces such as Alberta and British Columbia and that explicitly linked social worth to physical fitness, legitimizing discrimination under the pretext of scientific and moral progress. Such policies were not fringe expressions of prejudice but instead were embedded within mainstream social, medical, and political views. Physicians were central actors in the implementation of sterilization laws against those with disabilities, such as the Alberta Sexual Sterilization Act (1927 to 1972), positioning eugenics as a rational and preventive health strategy.

Background: Lacosamide, a new antiepileptic drug (AED) with a different pharmacological action that enhances sodium channel slow inactivation, is approved for the adjunctive treatment of partial-onset seizures in adults. Previous analyses of pooled phase II/III trials have demonstrated that lacosamide provides additional efficacy when added to a broad range of AEDs. Objective: To further evaluate the efficacy and safety of lacosamide by grouping patients based upon the sodium channel-blocking properties of their concomitant AEDs. Study Design: Post hoc exploratory analyses were performed on pooled data in which patients were grouped based upon inclusion or non-inclusion of at least one ‘traditional’ sodium channel-blocking AED (defined as carbamazepine, lamotrigine, oxcarbazepine and phenytoin derivatives) as part of their concomitant AED regimen. Setting: Data pooled from previously conducted phase II/III clinical trials of lacosamide. Patients: Adult patients with partial-onset seizures with or without secondary generalization (N = 1308). Intervention: Four- to six-week Titration Phase followed by 12-week maintenance treatment with adjunctive lacosamide (Vimpat®) [200, 400 or 600 mg/day] or placebo. Main Outcome Measure: Efficacy variables included change in seizure frequency per 28 days and the proportion of patients experiencing a ≥50% reduction in seizure frequency (50% responder rate) from Baseline to the Maintenance Phase. The proportion of patients experiencing a ≥75% reduction in seizure frequency from Baseline to the Maintenance Phase (75% responder rate) was also assessed. Safety parameters assessed were treatment-emergent adverse events (TEAEs) and discontinuation due to TEAEs. Additional safety assessments were changes in ECG and laboratory parameters as well as vital signs (including bodyweight). Results: Of 1308 patients in the pooled phase II/III population, the majority (82%) were using at least one ‘traditional’ sodium channel-blocking concomitant AED. In this subgroup of patients, adjunctive lacosamide showed significant reductions in seizure frequency (p<0.01, all dosages) and significantly greater 50% and 75% responder rates (p < 0.01 for 400 mg/day; p < 0.01 [50% responder rate] and p<0.05 [75% responder rate] for 600 mg/day) compared with placebo; these effects were similar to the results seen in the pooled phase II/III population. TEAEs and discontinuations due to TEAEs in this subgroup were dose related and similar to the pooled phase II/III population. In the remaining subgroup of patients, i.e. those not taking ‘traditional’ sodium channel-blocking AEDs as part of their concomitant AED regimen (n = 231; 18%), a pronounced, dose-related seizure reduction was observed with lacosamide (p<0.01, 400 and 600mg/day for median percent seizure reduction and 50% or 75% responder rates). Also in this group, incidences of TEAEs were low, and discontinuations due to TEAEs did not appear to increase with dose. Analyses of ECG, laboratory and vital signs (including bodyweight) assessments did not identify abnormalities in either subgroup that were outside of the known safety profile of lacosamide observed in the pooled phase II/III population. Conclusion: In this post hoc exploratory analysis, adjunctive lacosamide demonstrated significant seizure reduction over placebo regardless of the inclusion of ‘traditional’ sodium channel blockers in the concomitant AED regimen. Future prospective studies evaluating single AED combinations (e.g. lacosamide plus one other drug) are needed to better evaluate the potential for additive or synergistic effects of lacosamide in combination with AEDs not considered ‘traditional’ sodium channel blockers.

Background Older adults in long term care (LTC) spend over 90% of their day engaging in sedentary behaviour. Sedentary behaviour may exacerbate functional decline and frailty, increasing the risk for falls. The purpose of this study is to explore the impact of a 22-week standing intervention on falls among LTC residents at 12-month follow-up. Methods This was a planned secondary analysis of the Stand if You Can randomized controlled trial. The original trial randomized 95 participants (n = 47 control; n = 48 intervention) to either a sitting control or a supervised standing intervention group (100 minutes/week) for 22 weeks. Falls data were available to be collected over 12 months post-intervention for 89 par-ticipants. The primary outcome was a hazard of fall (Yes/No) during the 12-month follow-up period. Results A total of 89 participants (average age 86 years ± 8.05; 71.9% female) were followed for 12-months post-intervention. Par-ticipants in the intervention group (n=44) had a significantly greater hazard ratio of falls (2.01; 95% CI = 1.11 to 3.63) than the control group (n=45) when accounting for the history of falls, frailty status, cognition level, and sex. Conclusion Participants who received a standing intervention over 22 weeks were twice as likely to fall 12 months after the inter-vention compared with the control group. However, the prevalence of falls did not surpass what would be typically observed in LTC facilities. It is imperative that future stud-ies describe in detail the context in which falls happen and collect more characteristics of participants in the follow-up period to truly understand the association between standing more and the risk of falls.

In just 18 months, she had more than 30 hospital admissions, multiple procedures and surgeries. Despite countless tests and input from multiple physicians, her condition continued to decline. Here'smore info on how to pitch to us Kendra Hebert is a third-year medical student from rural New Brunswick, studying at Dalhousie University.