From Blur to Brilliance: The Ascendance of Advanced Microscopy in Neuronal Cell Biology.

The intricate network of the brain's neurons and synapses poses unparalleled challenges for research, distinct from other biological studies. This is particularly true when dissecting how neurons and their functional units work at a cell biological level. While traditional microscopy has been foundational, it was unable to reveal the deeper complexities of neural interactions. However, an imaging renaissance has transformed our capabilities. Advancements in light and electron microscopy, combined with correlative imaging, now achieve unprecedented resolutions, uncovering the most nuanced neural structures. Maximizing these tools requires more than just technical proficiency. It is crucial to align research aims, allocate resources wisely, and analyze data effectively. At the heart of this evolution is interdisciplinary collaboration, where various experts come together to translate detailed imagery into significant biological insights. This review navigates the latest developments in microscopy, underscoring both the promise of and prerequisites for bending this powerful tool set to understanding neuronal cell biology.

The provision of general surgery in rural Australia: a narrative review.

Rural surgery is most commonly provided by general surgeons to the 29% of people (7 million) living in rural Australia. The provision of rural general surgery to enable equitable and safe surgical care for rural Australians is a multifaceted issue concerning recruitment, training, retention, surgical procedures and surgical outcomes. Sustaining the rural general surgical workforce will be dependent upon growing an increased number of resident rural general surgeons, as well as changed models of care, with a need for ongoing review to track the outcomes of these changes. To increase recruitment, rural general surgical training must improve to be less stressful for trainees and to be incorporated alongside a rural-facing generalist curriculum. Rural general surgical outcomes (excluding some oncology conditions) achieve comparable results to metropolitan centres. Access to, and outcomes of, surgical oncology services continues to be inequitable for rural Australians and should be a major focus for improved service delivery.

Discovery of small molecule guanylyl cyclase A receptor positive allosteric modulators.

The particulate guanylyl cyclase A receptor (GC-A), via activation by its endogenous ligands atrial natriuretic peptide (ANP) and b-type natriuretic peptide (BNP), possesses beneficial biological properties such as blood pressure regulation, natriuresis, suppression of adverse remodeling, inhibition of the renin-angiotensin-aldosterone system, and favorable metabolic actions through the generation of its second messenger cyclic guanosine monophosphate (cGMP). Thus, the GC-A represents an important molecular therapeutic target for cardiovascular disease and its associated risk factors. However, a small molecule that is orally bioavailable and directly targets the GC-A to potentiate cGMP has yet to be discovered. Here, we performed a cell-based high-throughput screening campaign of the NIH Molecular Libraries Small Molecule Repository, and we successfully identified small molecule GC-A positive allosteric modulator (PAM) scaffolds. Further medicinal chemistry structure-activity relationship efforts of the lead scaffold resulted in the development of a GC-A PAM, MCUF-651, which enhanced ANP-mediated cGMP generation in human cardiac, renal, and fat cells and inhibited cardiomyocyte hypertrophy in vitro. Further, binding analysis confirmed MCUF-651 binds to GC-A and selectively enhances the binding of ANP to GC-A. Moreover, MCUF-651 is orally bioavailable in mice and enhances the ability of endogenous ANP and BNP, found in the plasma of normal subjects and patients with hypertension or heart failure, to generate GC-A-mediated cGMP ex vivo. In this work, we report the discovery and development of an oral, small molecule GC-A PAM that holds great potential as a therapeutic for cardiovascular, renal, and metabolic diseases.

Evolution of cisplatin resistance through coordinated metabolic reprogramming of the cellular reductive state.

BACKGROUND: Cisplatin (CDDP) is a mainstay treatment for advanced head and neck squamous cell carcinomas (HNSCC) despite a high frequency of innate and acquired resistance. We hypothesised that tumours acquire CDDP resistance through an enhanced reductive state dependent on metabolic rewiring. METHODS: To validate this model and understand how an adaptive metabolic programme might be imprinted, we performed an integrated analysis of CDDP-resistant HNSCC clones from multiple genomic backgrounds by whole-exome sequencing, RNA-seq, mass spectrometry, steady state and flux metabolomics. RESULTS: Inactivating KEAP1 mutations or reductions in KEAP1 RNA correlated with Nrf2 activation in CDDP-resistant cells, which functionally contributed to resistance. Proteomics identified elevation of downstream Nrf2 targets and the enrichment of enzymes involved in generation of biomass and reducing equivalents, metabolism of glucose, glutathione, NAD(P), and oxoacids. This was accompanied by biochemical and metabolic evidence of an enhanced reductive state dependent on coordinated glucose and glutamine catabolism, associated with reduced energy production and proliferation, despite normal mitochondrial structure and function. CONCLUSIONS: Our analysis identified coordinated metabolic changes associated with CDDP resistance that may provide new therapeutic avenues through targeting of these convergent pathways.

Effectiveness of wheelchair skills training for improving manual wheelchair mobility in children and adolescents: protocol for a multicenter randomized waitlist-controlled trial.

BACKGROUND: Self-directed mobility during childhood can influence development, social participation, and independent living later in life. For children who experience challenges with walking, manual wheelchairs (MWCs) provide a means for self-directed mobility. An effective MWC skills training program exists for adults, but controlled trials have not yet been documented in children and adolescents. This paper outlines the protocol for a multi-centre randomized wait-list controlled trial. The primary objective is to test the hypothesis that children and adolescents who receive MWC skills training will have higher MWC skills capacity compared to children and adolescents in the control group who receive usual care. The secondary objectives are to explore the influence of MWC skills training in children and adolescents (MWC use self-efficacy and satisfaction with participation in meaningful activities), and parents (perceived MWC skills); and to measure retention three months later. METHODS: A multi-centre, parallel-group, single-blind randomized wait-list controlled trial will be conducted. A sample of 60 children and adolescents who use MWCs will be recruited in rehabilitation centres, specialized schools, and the communities of three Canadian cities. Participants will be randomized (1:1) to the experimental (Wheelchair Skills Training Program [WSTP]) or wait-list control group (usual care). Performance-based and self-report measures will be completed at baseline (T1), three months (post-intervention, T2), and three months post-intervention (T3). The primary outcome will be MWC skills capacity post-intervention. Secondary outcomes will be MWC use self-efficacy and satisfaction with participation of the child/adolescent, and parent-perceived MWC skills. The WSTP will consist of 12 sessions, 45-60 min each, delivered 1-2 times per week by trained personnel with health professions education. Training will be customized according to the child's baseline skills and participation goals that require the use of the MWC. The wait-list control group will receive usual care for 3 months and then receive the WSTP after completing T2 evaluations. Data will be analysed using ANCOVA (controlling for baseline scores). DISCUSSION: MWC skills training may be one way to improve self-directed mobility and related outcomes for children and adolescents. The results of this multi-centre randomized wait-list controlled trial will allow for the effectiveness of the intervention to be evaluated in a variety of clinical contexts and geographical regions. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05564247, Version October 3, 2022.

Trends in Residency Academic Productivity of Ophthalmic Plastic and Reconstructive Surgery Fellows Between 2012 and 2019.

PURPOSE: To characterize research productivity of ophthalmic plastic and reconstructive surgery (OPRS) fellows during residency. METHODS: A database was compiled of OPRS fellows listed on the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS) Annual Fall Scientific Symposium program books who began their fellowship between 2012 and 2019. PubMed was searched for all publications published between July 1st of the year they began residency and September 30th of the year they began fellowship training. Bibliometric variables captured for each fellow included: the number of publications, first-author publications, and ophthalmology-related publications. RESULTS: A total of 197 OPRS fellows who began their fellowship training between 2012 and 2019 published a mean (± SD) of 2.42 ± 2.80 publications, 1.43 ± 1.85 first-author publications, and 2.33 ± 2.74 ophthalmology-related publications during residency. Linear regression revealed that the number of publications ( P < 0.001), first-author publications ( P < 0.001), and ophthalmology-related publications ( P < 0.001) that OPRS fellows published during residency have all significantly increased over the time assessed. CONCLUSIONS: The academic productivity of OPRS fellows during residency was quantified through bibliometric analysis to establish a national benchmark for the benefit of both prospective applicants and program directors. Residency research output of OPRS fellows has significantly increased between 2012 and 2019. Since ASOPRS program requirements necessitate academic productivity and thesis completion, publication records and involvement in research become valuable considerations when evaluating fellowship applicants. The knowledge of what accepted fellows have published provides the opportunity to make historical comparisons and may prove useful in the evaluation of the competitiveness of a given year's applicant pool.

Rural general surgeon confidence with managing vascular emergencies: A national survey.

OBJECTIVE(S): Life and limb threatening vascular emergencies often present to rural hospitals where only general surgery services are available. It is known that Australian rural general surgical centres encounter 10-20 emergency vascular surgery procedures annually. This study aimed to assess rural general surgeons' confidence managing emergent vascular procedures. SETTING, PARTICIPANTS AND DESIGN: A survey was distributed to Australian rural general surgeons to determine their confidence (Yes/No) in performing emergent vascular procedures including limb revascularisation, revising arterio-venous (AV) fistulas, open repair of ruptured abdominal aortic aneurysm (AAA), superior mesenteric artery (SMA)/coeliac embolectomy, limb embolectomy, vascular access catheter insertion and limb amputation (digit, forefoot, below knee and above knee). Confidence level was compared with surgeon demographics and training. Variables were compared using univariate logistic regression. RESULTS: Sixteen per cent (67/410) of all Australian rural general surgeons responded to the survey. Increased age, years since fellowship and training prior to 1995 (when separation of Australian vascular and general surgery occurred) were associated with greater confidence in limb revascularisation, revising AV fistulas, open repair of ruptured AAA, SMA/coeliac embolectomy, and limb embolectomy (p < 0.05). Surgeons who completed >6 months of vascular surgery training were more comfortable with SMA/coeliac embolectomy (49% vs. 17%, p = 0.01) and limb embolectomy (59% vs. 28%, p = 0.02). Confidence in performing limb amputation was similar across surgeon demographics and training (p > 0.05). CONCLUSION: Recently graduated rural general surgeons do not feel confident in managing vascular emergencies. Additional vascular surgery training should be considered as part of general surgical training and rural general surgical fellowships.

Creating a sustainable rural general surgery workforce: what enables fellows to return as rural general surgeons?

INTRODUCTION: In the context of shortfalls in rural general surgeon supply, this research aims to explore why rural general surgical Fellows returned and remained after fellowship at a single rural centre in Victoria, Australia. Fellowship positions post achievement of Fellowship of the Australasian College of Surgeons are traditionally not funded by government because they currently fall outside the accredited rural training post funding provided by the federal government. This article aims to explore if fellowship positions can be an important part in sustaining the rural general surgery workforce. METHODS: Semi-structured interviews were conducted with nine former general surgery Fellows from a single rural Australian institution. Interviews were recorded, transcribed, coded and themed to undertake analysis according to thematic analysis. RESULTS: This research demonstrates that consultant rural general surgeons can be recruited from a fellowship year when emphasis is placed on: (1) creating a positive workplace culture with safe working hours, (2) ensuring diversification of the general surgical case mix, (3) facilitating opportunities for schooling and work for the surgeon's family, and (4) preferentially selecting for those who identify as rural general surgeons. Rural towns can effectively recruit general surgeons when families are supported with career and school opportunities, and the newly qualified surgeon can initially commit to a 12-month position so that opportunities can be assessed by the entire family unit. Fellowship positions (post completion of general surgical training) allow young surgeons to 'try before they buy' prior to moving to a rural area. CONCLUSION: Ensuring a sustainable general surgical workforce in a rural community requires employee and surgical leadership to ensure a collaborative and progressive culture, which offers work diversity, supports the family lifestyle and petitions for selecting those who embody the rural general surgeon identity. Post-fellowship positions can enable young general surgeons to have exposure to the realities of a rural lifestyle, which is likely to have a positive effect on recruitment. Due to the return investment of the fellowship program, we propose that the federal government should look at funding post-fellowship positions to improve rural recruitment.

Diagnosing with a TWIST: Systematic Review and Meta-Analysis of a Testicular Torsion Risk Score.

PURPOSE: The Testicular Workup for Ischemia and Suspected Torsion (TWIST) score is a 7-point tool to evaluate acute scrotal pain. Parameters include testicular swelling (2 points), hard testis (2), high-riding testis (1), absent cremasteric reflex (1) and nausea/vomiting (1). This review aimed to determine the diagnostic utility of TWIST and its role in risk stratification. MATERIALS AND METHODS: A systematic review and meta-analysis of diagnostic test accuracy was conducted. Five risk stratification systems were explored, including the Barbosa (0-2, 3-4, 5-7) and Sheth (0, 1-5, 6-7) scoring systems, to obtain sensitivity, specificity and area under the receiver operating curve. RESULTS: Thirteen studies were identified, 9 prospective studies proceeded to meta-analysis of diagnostic test accuracy and 5 pediatric studies (1,060 patients, 199 torsions) were included in the primary analysis. The most accurate risk stratification system was Barbosa (0-2, 3-4, 5-7), with an AUC of 0.924 (95% CI: 0.865, 0.956). Barbosa showed favorable sensitivity in low-risk patients (0.984), facilitating rule out of torsion, and favorable specificity (0.975) in high-risk patients, facilitating urgent surgical exploration. Sensitivity and specificity in intermediate-risk patients were 0.922 and 0.682, respectively, indicating a need for further workup with ultrasound. Using this stratification, 65.2% of patients were low-risk, 19.9% were intermediate-risk and 14.9% were high-risk. Per 100 presentations of acute scrotum, there was a missed torsion rate of 1.6/100, ultrasound rate of 19.9/100 and negative exploration rate of 2.5/100. CONCLUSIONS: TWIST is an effective tool for suspected testicular torsion and is appropriate for widespread adoption. The Barbosa scoring system is reliable and reduces reliance on scrotal ultrasound.

Efficacy of a Remote Train-the-Trainer Model for Wheelchair Skills Training Administered by Clinicians: A Cohort Study With Pre- vs Posttraining Comparisons.

OBJECTIVE: To test the hypotheses that remote training improves trainer confidence and when these trainers train others the capacity and confidence of the trainees improves. DESIGN: Cohort study with pre- vs posttraining comparisons. SETTING: Four spinal cord injury model systems centers. PARTICIPANTS: Convenience sample of 7 clinician trainers and 19 able-bodied trainees (N=26). INTERVENTIONS: Part 1 focused on trainer skill acquisition with self-study of the Wheelchair Skills Program Manual and instructional videos focused on motor learning, spotting, and 10 intermediate and advanced wheelchair skills. Trainers practiced in pairs, receiving asynchronous feedback on video recordings from a remote instructor. Part 2 included additional video modules targeted at "how to" assess and train others in 4 wheelchair skills: gets over obstacle, ascends low curb, ascends high curb with caregiver assistance, and performs stationary wheelie. Upon completion, the trainers each provided 1:1 in-person training for 2-3 trainees. MAIN OUTCOME MEASURES: Trainer confidence was assessed using the Self-Efficacy on Assessing, Training, and Spotting Test for Manual Wheelchairs. Trainee capacity ("Can you do it?") and confidence ("How confident are you?") were evaluated using the Wheelchair Skills Test Questionnaire (WST-Q). RESULTS: Trainer confidence increased for assessment (P=.003) and training (P=.002) but not spotting (P=.056). Trainee 4-item median (interquartile range) WST-Q scores significantly increased with training for capacity (13% [6-31] to 88% [75-88], P<.001) and confidence (13% [0-31] to 88% [81-100], P<.001). CONCLUSIONS: Remote training improves trainers' confidence with respect to wheelchair skills testing and training and the wheelchair skills capacity and confidence of their trainees.

Evaluation of pediatric-specific resources to support utilization of the Wheelchair Skills Training Program by the users of the resources: a descriptive qualitative study.

BACKGROUND: Children's ability to engage in meaningful activities is positively influenced by their ability to move independently. Preliminary evidence in children suggests that wheelchair skills training improves wheelchair skills, which are important for independent mobility. The Wheelchair Skills Training Program is a standardized program to teach wheelchair skills. However, it is underutilized in pediatric rehabilitation settings. To increase its utilization, 3 pediatric-specific Wheelchair Skills Training Program resources related to indoor skills were developed (i.e., a storybook, four instructional posters, and a training workbook). This study aimed to describe occupational therapists' (OTs) and pediatric manual wheelchair users' (PMWUs) perceived satisfaction with the storybook, instructional posters and training workbook, and to explore their perceptions regarding the usability, relevance, and feasibility of these resources in pediatric rehabilitation settings. METHODS: A descriptive qualitative design was used. Convenience samples of OTs and PMWUs were recruited in a rehabilitation center and affiliated schools. A focus group with OTs and semi-structured interviews with PMWUs were conducted by videoconference to obtain participants' feedback on the resource prototypes and suggestions for improvement. Data were deductively analyzed using the Framework method. RESULTS: Eight OTs and 5 PMWUs expressed general satisfaction with the resources, describing them as usable, relevant, and feasible to integrate into wheelchair skills training with novice wheelchair users and younger children. All OTs and 3 PMWUs expressed the desire to use the resources for wheelchair skills training. Two PMWUs perceived the resources were not relevant to them because they already mastered the skills. The participants suggested minor modifications for improving the resources (e.g., more action in the story, increased precision of illustrations related to the characters' position in the wheelchair). CONCLUSION: OTs and PMWUs were satisfied with the resources, perceiving them to be applicable for training wheelchair skills among young children and novice wheelchair users. The resources represent a concrete solution to facilitate the use of the Wheelchair Skills Training Program in pediatric rehabilitation settings. Additional resources are needed to better reach older and more experienced PMWUs (i.e., of intermediate and advanced skill levels).

Open versus Endovascular Abdominal Aortic Aneurysm Repair in the Australian Private Sector Over Twenty Years.

PURPOSE: Over the past two decades, the proliferation of endovascular surgery has changed the approach to abdominal aortic aneurysm (AAA) repair. In Australia, close to two-thirds of surgical procedures are performed in the private healthcare system. We aimed to describe the trends in AAA repair in the Australian private sector throughout the early 21st century. MATERIALS AND METHODS: Medicare Benefits Schedule (MBS) statistics were accessed to determine the number of infrarenal open AAA repair (OAR) and endovascular AAA repair (EVAR) procedures performed between January 2000 and December 2019. Population data were extracted from the Australian Bureau of Statistics and used to calculate incidence per 100,000 population. Further analysis was performed according to age, gender, and state. RESULTS: During the study period, 13,193 (67.0%) EVARs and 6504 (33.0%) OARs were performed in the Australian private sector. OARs fell from 70.5% (n=567) of AAA repairs in 2000 to 15.7% (n=237) in 2019, while EVARs rose from 29.5% (n=151) to 84.3% (n=808). The frequency of EVAR surpassed OAR in 2004. The overall incidence of AAA repair varied minimally over the time period (range: 4.9-6.5 per 100,000 adults per year). AAA repair was more common in males than females (9.7 vs 1.7 per 100,000 population) and more common in older age groups. There was a 4-fold increase in EVAR among males older than 85 years (12.8-57.4 per 100,000 population), the largest rise of any group. The overall EVAR:OAR ratio increased from 0.4 to 5.4. There were considerable state-based discrepancies. CONCLUSION: The landscape of AAA repair in Australian private sector has drastically changed with a clear preference toward EVAR. EVAR saw increased use across all genders, age groups and states, despite stable rates of AAA surgery. Further research is necessary to compare our findings to national trends in the Australian public sector.

Simulation of airfoil surface pressure due to incident turbulence using realizations of uncorrelated wall plane waves.

A numerical technique is proposed for synthesizing realizations of airfoil surface pressure induced by incoming turbulence. In this approach, realization of the surface pressure field is expressed as a set of uncorrelated wall plane waves. The amplitude of these plane waves is determined from the power spectrum density function of the incoming upwash velocity fluctuation and the airfoil aeroacoustic transfer function. The auto-spectrum of the surface pressure is obtained from an ensemble average of different realizations. The numerical technique is computationally efficient as it rapidly converges using a relatively small number of realizations. The surface pressures for different airfoils excited by incoming turbulence are numerically predicted, and the results are compared with experimental data in the literature. Further, the unsteady force exerted on an airfoil due to the airfoil-turbulence interaction is also computed, and it is shown to be in very good agreement with analytical results.

Discovery of small molecule antagonists of chemokine receptor CXCR6 that arrest tumor growth in SK-HEP-1 mouse xenografts as a model of hepatocellular carcinoma.

The chemokine system plays an important role in mediating a proinflammatory microenvironment for tumor growth in hepatocellular carcinoma (HCC). The CXCR6 receptor and its natural ligand CXCL16 are expressed at high levels in HCC cell lines and tumor tissues and receptor expression correlates with increased neutrophils in these tissues contributing to poor prognosis in patients. Availability of pharmacologcal tools targeting the CXCR6/CXCL16 axis are needed to elucidate the mechanism whereby neutrophils are affected in the tumor environment. We report the discovery of a series of small molecules with an exo-[3.3.1]azabicyclononane core. Our lead compound 81 is a potent (EC50 = 40 nM) and selective orally bioavailable small molecule antagonist of human CXCR6 receptor signaling that significantly decreases tumor growth in a 30-day mouse xenograft model of HCC.

Pluripotent Stem Cell-Derived Hepatocytes Phenotypic Screening Reveals Small Molecules Targeting the CDK2/4-C/EBPα/DGAT2 Pathway Preventing ER-Stress Induced Lipid Accumulation.

Non-alcoholic fatty liver disease (NAFLD) has a large impact on global health. At the onset of disease, NAFLD is characterized by hepatic steatosis defined by the accumulation of triglycerides stored as lipid droplets. Developing therapeutics against NAFLD and progression to non-alcoholic steatohepatitis (NASH) remains a high priority in the medical and scientific community. Drug discovery programs to identify potential therapeutic compounds have supported high throughput/high-content screening of in vitro human-relevant models of NAFLD to accelerate development of efficacious anti-steatotic medicines. Human induced pluripotent stem cell (hiPSC) technology is a powerful platform for disease modeling and therapeutic assessment for cell-based therapy and personalized medicine. In this study, we applied AstraZeneca's chemogenomic library, hiPSC technology and multiplexed high content screening to identify compounds that significantly reduced intracellular neutral lipid content. Among 13,000 compounds screened, we identified hits that protect against hiPSC-derived hepatic endoplasmic reticulum stress-induced steatosis by a mechanism of action including inhibition of the cyclin D3-cyclin-dependent kinase 2-4 (CDK2-4)/CCAAT-enhancer-binding proteins (C/EBPα)/diacylglycerol acyltransferase 2 (DGAT2) pathway, followed by alteration of the expression of downstream genes related to NAFLD. These findings demonstrate that our phenotypic platform provides a reliable approach in drug discovery, to identify novel drugs for treatment of fatty liver disease as well as to elucidate their underlying mechanisms.

Relationships Between Wheelchair Services Received and Wheelchair User Outcomes in Less-Resourced Settings: A Cross-Sectional Survey in Kenya and the Philippines.

OBJECTIVE: To explore the relationships between wheelchair services received during wheelchair provision and positive outcomes for users of wheelchairs. DESIGN: Secondary analysis of cross-sectional data. SETTING: Urban and periurban communities in Kenya and the Philippines. PARTICIPANTS: Adult basic manual wheelchair users (N=852), about half of whom reported having received some wheelchair services with the provision of their current wheelchairs. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants completed a survey that included questions related to demographic, clinical, and wheelchair characteristics. The survey also included questions about the past receipt of 13 wheelchair services and 4 positive outcomes for users of wheelchairs. The relationships between individual services received and positive outcomes were assessed using logistic regression analyses. In addition to assessing individual services and outcomes, we analyzed a composite service score (the total number of services received) and a composite outcome score (≥3 positive outcomes). RESULTS: The top 3 individual services from the perspective of relationships with the composite outcome score were "provider did training" (P=.0009), "provider assessed wheelchair fit while user propelled the wheelchair" (P=.002), and "peer group training received" (P=.033). The composite service score was significantly related to "daily wheelchair use" (P<.0001), "outdoor unassisted wheelchair use" (P<.0001), "high performance of activities of daily living" (P=.046) and the composite outcome score (P=.005), but not to the "absence of serious falls" (P=.73). CONCLUSIONS: The receipt of wheelchair services is associated with positive outcomes for users of wheelchairs, but such relationships do not exist for all services and outcomes. These findings are highly relevant to ongoing efforts to optimize wheelchair service delivery.

Discovery of Novel Small-Molecule Inducers of Heme Oxygenase-1 That Protect Human iPSC-Derived Cardiomyocytes from Oxidative Stress.

Oxidative injury to cardiomyocytes plays a critical role in cardiac pathogenesis following myocardial infarction. Transplantation of stem cell-derived cardiomyocytes has recently progressed as a novel treatment to repair damaged cardiac tissue but its efficacy has been limited by poor survival of transplanted cells owing to oxidative stress in the post-transplantation environment. Identification of small molecules that activate cardioprotective pathways to prevent oxidative damage and increase survival of stem cells post-transplantation is therefore of great interest for improving the efficacy of stem cell therapies. This report describes a chemical biology phenotypic screening approach to identify and validate small molecules that protect human-induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) from oxidative stress. A luminescence-based high-throughput assay for cell viability was used to screen a diverse collection of 48,640 small molecules for protection of hiPSC-CMs from peroxide-induced cell death. Cardioprotective activity of "hit" compounds was confirmed using impedance-based detection of cardiomyocyte monolayer integrity and contractile function. Structure-activity relationship studies led to the identification of a potent class of compounds with 4-(pyridine-2-yl)thiazole scaffold. Examination of gene expression in hiPSC-CMs revealed that the hit compound, designated cardioprotectant 312 (CP-312), induces robust upregulation of heme oxygenase-1, a marker of the antioxidant response network that has been strongly correlated with protection of cardiomyocytes from oxidative stress. CP-312 therefore represents a novel chemical scaffold identified by phenotypic high-throughput screening using hiPSC-CMs that activates the antioxidant defense response and may lead to improved pharmacological cardioprotective therapies.

Extent to Which Caregivers Enhance the Wheelchair Skills Capacity and Confidence of Power Wheelchair Users: A Cross-Sectional Study.

OBJECTIVE: To test the hypothesis that caregivers enhance the wheelchair skills capacity and confidence of the power wheelchair users to whom they provide assistance, and to describe the nature of that assistance. DESIGN: Multicenter cross-sectional study. SETTING: Rehabilitation centers and communities. PARTICIPANTS: Participants (N=152) included caregivers (n=76) and wheelchair users (n=76). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Version 4.3 of the Wheelchair Skills Test (WST) and the Wheelchair Skills Test-Questionnaire (WST-Q). For each of the 30 individual skills, we recorded data about the wheelchair user alone and in combination (blended) with the caregiver. RESULTS: The mean total WST capacity scores ± SD for the wheelchair users alone and blended were 78.1%±9.3% and 92.4%±6.1%, respectively, with a mean difference of 14.3%±8.7% (P<.0001). The mean WST-Q capacity scores ± SD were 77.0%±10.6% and 93.2%±6.4%, respectively, with a mean difference of 16.3%±9.8% (P<.0001). The mean WST-Q confidence scores ± SD were 75.5%±12.7% and 92.8%±6.8%, respectively, with a mean difference of 17.5%±11.7% (P<.0001). The mean differences corresponded to relative improvements of 18.3%, 21.0%, and 22.9%, respectively. The nature and benefits of the caregivers' assistance could be summarized in 7 themes (eg, caregiver provides verbal support [cueing, coaching, reporting about the environment]). CONCLUSIONS: Caregivers significantly enhance the wheelchair skills capacity and confidence of the power wheelchair users to whom they provide assistance, and they do so in a variety of ways. These findings have significance for wheelchair skills assessment and training.