SZN-413, a FZD4 Agonist, as a Potential Novel Therapeutic for the Treatment of Diabetic Retinopathy.

Purpose: There remains a high unmet need for therapies with new mechanisms of action to achieve reperfusion of ischemic retina in diabetic retinopathy. We examined whether a novel frizzled class receptor 4 (FZD4) agonist could promote regeneration of functional blood vessels in animal models of retinopathy. Methods: We developed a novel Norrin mimetic (SZN-413-p) targeting FZD4 and low-density lipoprotein receptor-related protein 5 (LRP5) and examined its effect on retinal and brain endothelial cells in vitro. SZN-413-p was subsequently humanized, resulting in the therapeutic candidate SZN-413, and was examined in animal models of retinopathy. In an oxygen-induced retinopathy mouse model, avascular and neovascularization areas were measured. Furthermore, in a vascular endothelial growth factor (VEGF)-induced retinal vascular leakage rabbit model, the impact on vascular leakage by SZN-413 was examined by measuring fluorescein leakage. Results: SZN-413-p induced Wnt/ß-catenin signaling and upregulated blood-brain barrier/blood-retina barrier gene expressions in endothelial cells. In the oxygen-induced retinopathy mouse model, SZN-413-p and SZN-413 significantly reduced the neovascularization area size (P < 0.001) to a level comparable to, or better than the positive control aflibercept. Both agonists also showed a reduction in avascular area size compared to vehicle (P < 0.001) and aflibercept groups (P < 0.05 and P < 0.01 for SZN-413-p and SZN-413, respectively). In the VEGF-induced retinal vascular leakage rabbit model, SZN-413 reduced retinal vascular leakage by ∼80%, compared to the vehicle-treated group (P < 0.01). Conclusions: Reduction of neovascular tufts and avascular areas and of VEGF-driven retinal vascular leakage suggests that SZN-413 can simultaneously address retinal non-perfusion and vascular leakage. Translational Relevance: FZD4 signaling modulation by SZN-413 is a novel mechanism of action that can offer a new therapeutic strategy for diabetic retinopathy.

The Effects of Dog Walking on Gait and Mobility in People with Parkinson Disease: A Pilot Study.

The objective of this study was to assess the effects of dog walking on gait and mobility in people with Parkinson disease (PD). This single-group, single-session, observational pilot study included nineteen participants with PD in Hoehn and Yahr stages II (n = 9) and III (n = 10). Primary measures were a gait analysis and the Timed Up and Go (TUG). Three trials of two conditions (walking with and without a dog) were completed. Walking with a dog resulted in slower gait velocity (mean difference = 0.11 m/s, p = 0.003, d = 0.77), shorter step length (left: mean difference = 7.11 cm, p = 0.000; right: mean difference = 3.05, p = 0.01), and stride length (left: mean difference = 7.52, p = 0.003; right: mean difference = 8.74, p = 0.001). The base of support was more narrowed (Z = -2.13, p = 0.03), with increased double limb stance time (left: Z = -2.89, p = 0.004; right: Z = -2.59, p = 0.01). Walking with a dog caused slower TUG times (mean difference = -1.67, p = 0.000) and increased number of steps (Z = -3.73, p = 0.000). No significant change shown in step time (left: mean difference = -0.001, p = 0.81; right: mean difference = 0.002, p = 0.77) or cadence (Z = -1.67, p = 0.10). In conclusion, there was an overall decline of gait parameters in people with PD when walking with a dog.

The Integrated Clinical Education Strategic Initiatives Project-Development of Parameters to Guide Harmonization in Clinical Education: A Scoping Review.

BACKGROUND: Clinical education curricular models specifically related to integrated clinical education (ICE) vary across physical therapist education programs. The interconnectedness of ICE to the advancement of a shared vision for clinical education in professional physical therapist education needs investigating. PURPOSE: The purpose of this scoping review was to: (1) define ICE, (2) define baseline expectations and parameters of ICE, and (3) discern and describe current ICE models. DATA SOURCES: Databases accessed included Medline, MedlinePlus with Full, CINAHL, and CINAHL Plus with full text. STUDY SELECTION: A multimodal data collection scoping review was completed. Data collection included survey research, a systematic review of the literature, and a series of focus groups. The McMaster Critical Appraisal Tool assessed methodological study quality. A qualitative, metasynthesis approach was used for data synthesis. Consensus agreement produced results. DATA EXTRACTION: Twenty-two articles were included in the literature review from the health disciplines of medicine, nursing, physical therapy, occupational therapy, and speech-language pathology. Data synthesis produced 8 parameters defining the factors essential to categorizing clinical education experiences as ICE in physical therapist education. The 8 parameters and ICE definition are supported by a description of models of ICE that currently exist within health profession curricula. DATA SYNTHESIS: Data synthesis followed a qualitative, metasynthesis approach. Themes emerged from the surveys, literature review, and focus group data. Patterns were compared, analyzed, and synthesized to generate the themes and ICE parameters. LIMITATIONS: Selection bias from the literature search could have limited the richness of the model descriptions by unintentional exclusion of articles, and might limit the applicability of results beyond the United States. Sampling bias from survey and focus groups, although purposeful, might have limited a broader description of current viewpoints about ICE. However, the data sources, including multiple health profession perspectives coupled with consensus agreement, provide sound evidence in development of profession-based parameters. CONCLUSIONS: The results of this scoping review provide the profession with a standard definition of ICE and parameters that can guide a program in designing a curriculum using ICE experiences as a foundation. A recommended next step is to design education research studies using reliable and valid outcome measures across programs to determine impact and effectiveness of ICE as an educational intervention.

Wheelchair coasting downhill is a reliable work task.

OBJECTIVE: To measure test-retest reliability of physiological responses during submaximal wheelchair downhill and horizontal treadmill ergometry. DESIGN: A test-retest design was used on a convenience sample. Four male and three female non-wheelchair users, (22-43 years of age) propelled or coasted in a wheelchair under steady-state conditions. Four minute work bouts were performed at 1, 2, 3, and 4 km/hr. (0.62, 1.24, 1.86 and 2.5 mph, respectively) at 0 degrees, -2 degrees, and -4 degrees. Subjects were studied twice under each of the 12 conditions. Six tests were performed daily, with testing occurring over four days. Dependent variables included oxygen consumption, minute ventilation and heart. Intraclass correlation coefficients were determined for each set of paired tests. RESULTS: Intraclass correlation coefficients were high for absolute VO_{2}(R=0.84-0.99), V_{E} (R=0.86-0.98) and HR (R=0.95-1.0) over the range of 4 speeds and 3 inclinations studied. On average, % differences from test 1 to test 2 were less than 3%. CONCLUSION: At the treadmill speeds and inclinations (positive and negative) studied in this investigation, untrained wheelchair users responded in a physiologically reliable manner.