The lateralized effects of Parkinson's Disease on motor imagery: Evidence from mental chronometry.

Alterations to the content of action representations may contribute to the movement challenges that characterize Parkinson's Disease (PD). One way to investigate action representations is through motor imagery. As PD motor symptoms typically have a unilateral onset, disease-related deficits related to action representations may follow a similarly lateralized pattern. The present study examined if temporal accuracy of motor imagery in individuals with PD differed according to the side of the body involved in the task. Thirty-eight participants with PD completed a mental chronometry task using their more affected and less affected side. Participants had significantly shorter mental versus physical movement times for the more affected. Higher imagery vividness in the kinaesthetic domain predicted shorter mental versus physical movement times for the more affected side, as did lower imagery vividness in the visual domain and poorer cognitive function. These results indicate that people with PD imagine movements differently when the target actions their more affected versus less affected side. It is additionally possible that side-specific deficits in the accurate processing of kinaesthetic information lead to an increased reliance on visual processes and cognitive resources to successfully execute motor imagery involving the more affected side.

Multidimensional digital biomarker phenotypes for mild cognitive impairment: considerations for early identification, diagnosis and monitoring.

Mild Cognitive Impairment (MCI) poses a challenge for a growing population worldwide. Early identification of risk for and diagnosis of MCI is critical to providing the right interventions at the right time. The paucity of reliable, valid, and scalable methods for predicting, diagnosing, and monitoring MCI with traditional biomarkers is noteworthy. Digital biomarkers hold new promise in understanding MCI. Identifying digital biomarkers specifically for MCI, however, is complex. The biomarker profile for MCI is expected to be multidimensional with multiple phenotypes based on different etiologies. Advanced methodological approaches, such as high-dimensional statistics and deep machine learning, will be needed to build these multidimensional digital biomarker profiles for MCI. Comparing patients to these MCI phenotypes in clinical practice can assist clinicians in better determining etiologies, some of which may be reversible, and developing more precise care plans. Key considerations in developing reliable multidimensional digital biomarker profiles specific to an MCI population are also explored.

Functional Brain Regions Linked to Tinnitus Pathology and Compensation During Task Performance: A Systematic Review.

OBJECTIVE: To systematically search the literature and organize relevant advancements in the connection between tinnitus and the activity of different functional brain regions using functional magnetic resonance imaging (fMRI). DATA SOURCES: MEDLINE (OVID), EMBASE (OVID), CINAHL (EBSCO), Web of Science, ProQuest Dissertations & Theses Global, Cochrane Database of Systematic Reviews, and PROSPERO from inception to April 2022. REVIEW METHODS: Studies with adult human subjects who suffer from tinnitus and underwent fMRI to relate specific regions of interest to tinnitus pathology or compensation were included. In addition, fMRI had to be performed with a paradigm of stimuli that would stimulate auditory brain activity. Exclusion criteria included non-English studies, animal studies, and studies that utilized a resting state magnetic resonance imaging or other imaging modalities. RESULTS: The auditory cortex may work to dampen the effects of central gain. Results from different studies show variable changes in the Heschl's gyrus (HG), with some showing increased activity and others showing inhibition and volume loss. After controlling for hyperacusis and other confounders, tinnitus does not seem to influence the inferior colliculus (IC) activation. However, there is decreased connectivity between the auditory cortex and IC. The cochlear nucleus (CN) generally shows increased activation in tinnitus patients. fMRI evidence indicates significant inhibition of thalamic gating. Activating the thalamus may be of important therapeutic potential. CONCLUSION: Patients with tinnitus have significantly altered neuronal firing patterns, especially within the auditory network, when compared to individuals without tinnitus. Tinnitus and hyperacusis commonly coexist, making differentiation of the effects of these 2 phenomena frequently difficult.

Optimizing Lipid Nanoparticles for Delivery in Primates.

Lipid nanoparticles (LNPs) are clinically proven to successfully deliver both small interfering RNA (siRNA) therapeutics and larger mRNA payloads for prophylactic vaccine applications. Non-human primates (NHPs) are generally considered to be the most predictive of human responses. However, for ethical and economic reasons, LNP compositions have historically been optimized in rodents. It has been difficult to translate LNP potency data from rodents to NHPs for intravenously (IV) administered products in particular. This presents a major challenge for preclinical drug development. An attempt to investigate LNP parameters, which have historically been optimized in rodents, is carried out, and seemingly innocuous changes are found to result in large potency differences between species. For example, the ideal particle size for NHPs (50-60 nm) is found to be smaller than for rodents (70-80 nm). Surface chemistry requirements are also different, with almost double the amount of poly(ethylene glycol) (PEG)-conjugated lipid needed for maximal potency in NHPs. By optimizing these two parameters, approximately eight-fold increase in protein expression from intravenously administered messenger RNA (mRNA)-LNP in NHP is gained. The optimized formulations are well tolerated when administered repeatedly with no loss of potency. This advancement enables the design of optimal LNP products for clinical development.

Transcranial direct current stimulation over the right dorsolateral prefrontal cortex increases oxyhemoglobin concentration and cognitive performance dependent on cognitive load.

Transcranial direct current stimulation (tDCS) has been explored as a potential method for cognitive enhancement. tDCS may induce a cascade of neurophysiological changes including alterations in cerebral oxygenation. However, the effects of tDCS on the cognitive-cerebral oxygenation interaction remains unclear. Further, oxygenation variability across individuals remains minimally controlled for. The purpose of this sham-controlled study was to test the effects of anodal tDCS over the right dorsolateral prefrontal cortex (DLPFC) on the interaction between working memory and cerebral oxygenation while controlling for individual oxygenation variability. Thirty-three adults received resting-state functional near-infrared spectroscopy (fNIRS) recordings over bilateral prefrontal cortices. Following this, working memory was tested using a Toulouse n-back task concurrently paired with fNIRS, with measurements taken before and after 20 min of anodal or sham tDCS at 1.5 mA. With individual oxygenation controlled for, anodal tDCS was found to increase the oxyhemoglobin concentration over the right DLPFC during the 2-back (q = .015) and 3-back (q = .008) conditions. Additionally, anodal tDCS was found to improve accuracy during the 3-back task by 13.4 % (p = .028) and decrease latency by 250 ms (p = .013). The increase in oxyhemoglobin was strongly correlated with increases in accuracy (p = .041) and decreases in latency during the 3-back span (p = .017). Taken together, anodal tDCS over the right DLPFC was found to regionally increase oxyhemoglobin concentrations and improve working memory performance in higher cognitive load conditions.

The frontoparietal multiple demand network interacts with the dual pathways in auditory working memory.

The frontoparietal multiple demand (MD) network has been proposed as a control network that regulates processing demands while enabling goal-directed actions. This study tested the MD network account in auditory working memory (AWM) and identified its functional role and relationship with the dual pathways model in AWM, where segregation of function was based on the sound domain. Forty-one healthy young adults performed an n-back task consisting of an orthogonal combination of the sound domain (spatial versus nonspatial) and cognitive operation (low load versus high load). Functional connectivity and correlation analyses were performed to assess the connectivity of the MD network and the dual pathways. Our results confirmed the contribution of the MD network to AWM and identified its interactions with the dual pathways in both sound domains and during high and low load levels. At high loads, the strength of connectivity with the MD network correlated with task accuracy, indicating the key role of the MD network in supporting successful performance as cognitive load increases. This study contributed to the auditory literature by showing that both the MD network and dual pathways collaborate with each other to support AWM, and neither of them alone is adequate to explain auditory cognition.

Profiling the Research Activities of Canadian Occupational Therapy and Occupational Science Faculty Members.

Background. There is a lack of knowledge on the scope and nature of the research by faculty members in occupational science (OS) and/or occupational therapy (OT) programs in Canada. Purpose. To describe the research activities of faculty members in these programs and directions. Method. A cross-sectional survey was distributed to 173 faculty members across all 14 Canadian OT that addressed: 1) research topics and methods, 2) populations, and 3) funding. Findings. Based on respondents (N = 121), research is focused on a range of topics and populations with most conducting qualitative research. Many conduct research examining the effectiveness of interventions, with few respondents focused on OS research. Federal and provincial grants agencies were the largest source of funding. Implications. Research topics studied were not always proportional to practice although emerging areas were being investigated that can expand the evidence base and scope of practice. Despite limited occupation-specific funding options, respondents were accessing funding from varied sources. Collaborations among faculty members, clinicians, and individuals with lived experience can create priorities for future OS and/or OT research in Canada.

Unsaturated, Trialkyl Ionizable Lipids are Versatile Lipid-Nanoparticle Components for Therapeutic and Vaccine Applications.

Lipid nanoparticles (LNPs) have proven a successful platform for the delivery of nucleic acid (NA)-based therapeutics and vaccines, with the ionizable lipid component playing a key role in modulating potency and tolerability. Here, a library of 16 novel ionizable lipids is screened hypothesizing that short, branched trialkyl hydrophobic domains can improve LNP fusogenicity or endosomal escape, and potency. LNPs formulated with the top-performing trialkyl lipid (Lipid 10) encapsulating transthyretin siRNA elicit significantly greater gene silencing and are better tolerated than those with the benchmark Onpattro lipid DLin-MC3-DMA. Lipid 10 also demonstrates superior liver delivery of mRNA when compared to other literature ionizable lipids, is well tolerated, and successfully repeat-doses in nonhuman primates. In a prime-boost hemagglutinin rodent vaccine model, intramuscular administration of Lipid-10 LNP elicits comparable or better antibody titers to the SM-102 and ALC-0315 lipid compositions used in the U.S. Food and Drug Administration approved mRNA COVID vaccines. These data suggest that Lipid 10 is a particularly versatile ionizable lipid, well-suited for both systemic therapeutic and intramuscular vaccine applications and able to successfully deliver diverse NA payloads.

tDCS over the left prefrontal Cortex improves mental flexibility and inhibition in geriatric inpatients with symptoms of depression or anxiety: A pilot randomized controlled trial.

Background: Patients with depression and/or anxiety are commonly seen in inpatient geriatric settings. Both disorders are associated with an increased risk of cognitive impairments, notably in executive functioning. Transcranial direct current stimulation (tDCS), a type of non-invasive brain stimulation, involves the administration of a low-dose electrical current to induce neuromodulation, which ultimately may act on downstream cognitive processing. Objective: The purpose of this study was to determine the effects of tDCS on executive functioning in geriatric inpatients with symptoms of depression and/or anxiety. Design: Pilot Randomized Controlled Trial. Setting: Specialized geriatric wards in a tertiary rehabilitation hospital. Methods: Thirty older-aged adults were recruited, of which twenty completed ten-to-fifteen sessions of 1.5 mA anodal or sham tDCS over the left dorsolateral prefrontal cortex. Cognitive assessments were administered at baseline and following the tDCS protocol; analyses examined the effects of tDCS on cognitive performance between groups (anodal or sham tDCS). Results: tDCS was found to increase inhibitory processing and cognitive flexibility in the anodal tDCS group, with significant changes on the Stroop test and Trail Making Test-Part B. No significant changes were observed on measures of attention or working memory. Discussion: These results provide preliminary evidence that tDCS-induced neuromodulation may selectively improve cognitive processing in older adults with symptoms of depression and/or anxiety. Clinical Trials Registration: www.clinicaltrials.gov, NCT04558177.

DMPC/Chol liposomal copper CX5461 is therapeutically superior to a DSPC/Chol formulation.

CX5461, a compound initially identified as an RNA polymerase inhibitor and more recently as a G-quadruplex binder, binds copper to form a complex. Our previous publication showed that the complexation reaction can be leveraged to formulate copper-CX5461 inside liposomes, improving the apparent solubility of CX5461 by over 500-fold and reducing the elimination of CX5461 from the plasma compartment following intravenous administration. In mouse models of acute myeloid leukemia, the resulting formulation was more effective than the free drug solution of CX5461 (pH 3.5) currently used in clinical trials. However, the gains observed with the liposomal formulation were minimal, despite significant increases in circulation half-life. Since the formulation technology used relied on liposomes and the fate of most compounds associated with liposomes is dependent on liposomal lipid composition, the studies described here were designed to evaluate how simple changes in lipid composition could affect therapeutic activity. The previously reported formulation method was simplified to ensure an easy scale-up process. In the modified method, pre-measured solid CX5461 was added to copper-containing liposomes prior to an incubation at 60 °C, which enabled copper-CX5461 complexation inside DSPC/Chol or DMPC/Chol liposomes. Efficacy was determined in BRCA-normal (BxPC3) and BRCA-deficient (Capan-1) models of pancreatic cancer. Both liposomal formulations enhanced the circulation lifetime of CX5461 compared to the free drug solution (pH 3.5). Unlike most compounds that are loaded using a transmembrane pH-gradient, the dissociation of CX5461 from liposomes prepared using the copper complexation method were comparable for DSPC/Chol and DMPC/Chol liposomes, in vitro and in vivo. Nonetheless, copper CX5461 prepared using DMPC/Chol liposomes exhibited superior efficacy. The reason for the improved activity of DMPC/Chol copper-CX5461 was not readily explained by the release data and may be due to the fact that DMPC/Chol liposomes are less stable following localization in the tumor. The results indicate that the therapeutic effects of copper-CX5461 will be dependent on liposomal lipid composition and that liposomal CX5461 should exhibit superior benefits when used to treat BRCA-deficient cancers.

Central Processing in Tinnitus: fMRI Study Outlining Patterns of Activation Using an Auditory Discrimination Task in Normal Versus Tinnitus Patients.

OBJECTIVE: Elucidate brain activity differences between patients with tinnitus and controls. STUDY DESIGN: Cross-sectional cohort study. SETTING: Outpatient Otolaryngology clinic. PATIENTS: Three cohorts; 8 controls, 12 with subjective idiopathic tinnitus (tinnitus without hearing loss), and 12 with both tinnitus and hearing loss. INTERVENTION: An auditory oddball identification task was performed in fMRI scanner. MAIN OUTCOME MEASURES: Task performance and Tinnitus Handicap Inventory (THI) scores were recorded. Brain activation maps were generated comparing deviant and standard tones as well as at rest. One-way and two-way T-contrasts were generated in addition to multiple regression modeling which identified significant brain regions predicting tinnitus, disease severity, duration, and task performance. RESULTS: Task performance worsened in tinnitus patients with increased auditory workload, in terms of additional hearing loss. THI score and grade correlated with false alarms. The limbic system, heschel's gyrus, angular gyrus and cerebellum have a significant effect on both brain behavior in patients with tinnitus, and predictability of tinnitus and its behavioral implications. CONCLUSION: Increased auditory workload resulted in poorer task performance. Moreover, it is possible to predict auditory task performance in patients with tinnitus by looking at the activity of specific regions of interest. Heschl's gyrus, angular gyrus, cerebellar, and limbic system activity are important contributors to neurological activity associated with tinnitus. Finally, predictive modeling may influence further research surrounding tinnitus treatment.

Development and characterization of a novel flavopiridol formulation for treatment of acute myeloid leukemia.

For more than 30 years, treatment of acute myeloid leukemia (AML) has remained largely unchanged and reliant on chemotherapeutic drug combinations, specifically cytarabine and daunorubicin (the 7 + 3 regimen). One broad spectrum drug, flavopiridol (also known as Alvocidib) has shown significant activity against AML through the inhibition of cyclin-dependent kinases. Flavopiridol is a semisynthetic flavonoid and our research team recently described methods to formulate another flavonoid, quercetin, through the ability of flavonoids to bind divalent metals. This method relies on use of copper-containing liposomes to enhance the apparent solubility of flavopiridol and to create formulations suitable for intravenous (i.v.) use. Similar to quercetin, flavopiridol is defined as an aqueous-insoluble compound (< 1 mg/mL in water) and this research sought to evaluate whether the copper-binding capabilities of flavopiridol could be used to prepare an injectable formulation that would exhibit enhanced exposure and improved efficacy. Flavopiridol powder was added directly to preformed copper-containing liposomes (DSPC:Chol or DSPC:DSPE-PEG2000) and the resulting formulations were characterized. Pharmacokinetic and efficacy studies were then conducted. The liposomal flavopiridol formulations were well-tolerated in mice following i.v. administration at a dose of 5 mg/kg with no apparent acute or chronic toxicities. In vivo pharmacokinetics of the optimized DSPC/DSPE-PEG2000 liposomal flavopiridol formulation demonstrated a 30-fold increase in AUC (0.804 µg-hr/mL versus 26.92 µg-hr/mL) compared to the free flavopiridol formulation. The resultant liposomal formulation also demonstrated significant therapeutic activity in MV4-11 and MOLM-13 subcutaneous AML models. Additional studies will be required to define whether formulation changes can be made to enhance flavopiridol retention in the selected composition. The results suggest that further increases in flavopiridol retention will result in improved therapeutic activity.

The relationship of resting-state EEG oscillations to executive functions in middle childhood.

Executive functions (EFs) play important roles in children's development, but their neural mechanisms are rarely investigated, especially for the different components of EFs in middle childhood. Therefore, this study aimed to explore the links between resting-state EEG in the frontal scalp region and EFs in children aged 7-9 years. Fifty-nine typically developing children from the second and third grades performed two core EF tasks, i.e., inhibition and working memory, and a high-level EF task, i.e., planning, followed by the recording of EEG signals during eyes-open and eyes-closed resting states. The results showed that distinct EEG activities in the frontal scalp region predicted different EF components. More specifically, after controlling for age and verbal ability, alpha to theta power ratio (ATR) and beta to theta power ratio (BTR) during the eyes-open resting state positively predicted inhibition, and beta to theta power ratio (BTR) during the eyes-open resting state positively predicted planning. However, we did not find any EEG features related to working memory. Our results contributed to the understanding of inter-individual differences in EFs and provided insights into the regulation of corresponding EEG activities through EEG neurofeedback for enhancing children's EFs.

Exploring the Predictive Ability of the Motor-Free Visual Perception Test (MVPT) and Trail Making Test (TMT) for On-Road Driving Performance.

IMPORTANCE: Resuming driving after a change in functional ability is challenging for patients with a neurological condition. Although a combination of assessment tools has been suggested for use in driving evaluation, resources and availability of tools have been a problem. OBJECTIVE: To examine the predictive ability of two commonly used tools, the Motor-Free Visual Perception Test (MVPT) and the Trail Making Test, Parts A and B (TMTA and TMTB), on on-road driving performance. DESIGN: Retrospective chart review of 82 patient charts between 2015 and 2016. SETTING: Local rehabilitation hospital. PARTICIPANTS: Eighty-two patients with a primary neurological diagnosis (general neurological condition, n = 13; spinal cord injury, n = 11; stroke, n = 58). OUTCOMES AND MEASURES: MVPT, TMTA, and TMTB. RESULTS: Among the patients, 36 passed and 46 failed the on-road evaluation. The TMTA and TMTB scores were significantly different between those who passed or failed the on-road evaluation. Logistic regression analyses revealed that the TMTB completion time was the only significant predictor of on-road driving performance (for the all-patient model, 66% prediction accuracy, -2 log-likelihood [LL] = 93.47, exp ß = 0.98; for the stroke-only model, 76% prediction accuracy, -2LL = 59.61, exp ß = 0.97). CONCLUSIONS AND RELEVANCE: Our findings suggest that the TMTB is a better predictor of on-road driving performance for patients with a neurological condition than the MVPT. The findings shed light on the importance of selecting proper tools when assessing driving performance. Future prospective studies with a wider array of predictive variables are recommended to support the present findings. WHAT THIS ARTICLE ADDS: Occupational therapists should revisit the use of the MVPT in driving assessment and consider multiple assessment tools when evaluating and predicting driving performance.

Individual differences under acute stress: Higher cortisol responders performs better on N-back task in young men.

Exposure to stress has a variety of consequences on human behavior and cognition. Although widely investigated, the impact of stress on working memory remains inhomogeneous. Individual differences in neuroendocrine responsiveness, for example, cortisol responses, may be factors that explain previous inconsistent results. This study assessed the role of cortisol responsiveness in the effects of psychosocial stress on working memory. To examine working memory processes, we analyzed both behavioral performances such as accuracy, response time, the inverse efficiency score, and event-related potentials (ERPs), including N1, P2, and P3. A total of 67 male college students completed a numerical 2-back task after being exposed to the Trier Social Stress Task (TSST) or a control task. The results showed shorter response time, better efficiency, and larger N1 and P2 amplitudes in the high-cortisol-responders compared to the low-cortisol-responders and the control group. This indicates a better working memory performance likely due to the enhancements in the orientation and mobilization of attention. Furthermore, a correlation analysis revealed a positive association between the cortisol change rate and the working memory performance and ERP data among the stressed individuals, suggesting that increased cortisol may facilitate working memory under acute psychosocial stress. These findings emphasize that the individual differences in cortisol responses may affect the impact of stress on working memory.

Characterization of a liposomal copper(II)-quercetin formulation suitable for parenteral use.

Quercetin (3,3',4',5,7-pentahydroxyflavone) is a naturally derived flavonoid that is commonly found in fruits and vegetables. There is mounting evidence to suggest that quercetin has potential anticancer effects and appears to interact synergistically when used in combination with approved chemotherapeutic agents such as irinotecan and cisplatin. Unfortunately, quercetin has shown limited clinical utility, partly due to low bioavailability related to its poor aqueous solutions (< 10 µg/mL). In this study, liposomal formulations of quercetin were developed by exploiting quercetin's ability to bind copper. Quercetin powder was added directly to pre-formed copper-containing liposomes (2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol (CHOL) (55:45 M ratio)). As a function of time and temperature, the formation of copper-quercetin was measured. Using this methodology, a final quercetin-to-lipid (mol:mol) ratio of 0.2 was achievable and solutions containing quercetin at concentrations of > 5 mg/mL were attained, representing at least a > 100-fold increase in apparent solubility. The resulting formulation was suitable for intravenous dosing with no overt toxicities when administered at doses of 50 mg/kg in mice. Pharmacokinetic studies demonstrated that the copper-quercetin formulations had an AUC0-24H of 8382.1 µg h/mL when administered to mice at 50 mg/kg. These studies suggested that quercetin (not copper-quercetin) dissociates from the liposomes after administration. The resulting formulation is suitable for further development and also serves as a proof-of-concept for formulating other flavonoids and flavonoid-like compounds. Given that quercetin exhibits an IC50 of >10 µM when tested against cancer cell lines, we believe that the utility of this novel quercetin formulation for cancer indications will ultimately be as a component of a combination product.

Recent Treatment Advances and the Role of Nanotechnology, Combination Products, and Immunotherapy in Changing the Therapeutic Landscape of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is the most common acute leukemia that is becoming more prevalent particularly in the older (65 years of age or older) population. For decades, "7 + 3" remission induction therapy with cytarabine and an anthracycline, followed by consolidation therapy, has been the standard of care treatment for AML. This stagnancy in AML treatment has resulted in less than ideal treatment outcomes for AML patients, especially for elderly patients and those with unfavourable profiles. Over the past two years, six new therapeutic agents have received regulatory approval, suggesting that a number of obstacles to treating AML have been addressed and the treatment landscape for AML is finally changing. This review outlines the challenges and obstacles in treating AML and highlights the advances in AML treatment made in recent years, including Vyxeos®, midostaurin, gemtuzumab ozogamicin, and venetoclax, with particular emphasis on combination treatment strategies. We also discuss the potential utility of new combination products such as one that we call "EnFlaM", which comprises an encapsulated nanoformulation of flavopiridol and mitoxantrone. Finally, we provide a review on the immunotherapeutic landscape of AML, discussing yet another angle through which novel treatments can be designed to further improve treatment outcomes for AML patients.

What Drives Innovation: The Canadian Touch on Liposomal Therapeutics.

Liposomes are considered one of the most successful drug delivery systems (DDS) given their established utility and success in the clinic. In the past 40⁻50 years, Canadian scientists have made ground-breaking discoveries, many of which were successfully translated to the clinic, leading to the formation of biotech companies, the creation of research tools, such as the Lipex Extruder and the NanoAssemblr™, as well as contributing significantly to the development of pharmaceutical products, such as Abelcet®, MyoCet®, Marqibo®, Vyxeos®, and Onpattro™, which are making positive impacts on patients' health. This review highlights the Canadian contribution to the development of these and other important liposomal technologies that have touched patients. In this review, we try to address the question of what drives innovation: Is it the individual, the teams, the funding, and/or an entrepreneurial spirit that leads to success? From this perspective, it is possible to define how innovation will translate to meaningful commercial ventures and products with impact in the future. We begin with a brief history followed by descriptions of drug delivery technologies influenced by Canadian researchers. We will discuss recent advances in liposomal technologies, including the Metaplex technology from the author's lab. The latter exemplifies how a nanotechnology platform can be designed based on multidisciplinary groups with expertise in coordination chemistry, nanomedicines, disease, and business to create new therapeutics that can effect better outcomes in patient populations. We conclude that the team is central to the effort; arguing if the team is entrepreneurial and well positioned, the funds needed will be found, but likely not solely in Canada.