The utility of community-based participatory research: Increasing research engagement among minoritized ethnoracial groups.

OBJECTIVE: This article conceptually examined the need for and utility of community-based participatory research (CBPR) approaches for increasing rates of engagement in psychological research among underserved minoritized ethnoracial groups. METHODS: This article examined the literature for relevant studies examining rates of research engagement by minoritized ethnoracial groups, significant factors precluding research engagement, and the consequences of this disparity for mental health outcomes. The theoretical literature outlining the development and utility of alternative, community-based participatory research methods was included. Key features of CBPR were examined along with limitations of current approaches. A case study example of CBPR is provided. RESULTS: The use of CBPR approaches has been documented to improve health outcomes, reduce stigma toward mental health research and treatment, and build the professional capacity of community partners, particularly among minoritized ethnoracial groups. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: CBPR engagement practices are a means of reducing the mental health research gap for ethnic and racial minoritized groups. The use of such approaches in future research and practice will directly inform how existing psychological treatments may be modified per the needs of the patient, address long standing issues of cultural mistrust toward professional institutions, and reduce mental health stigma in underserved communities. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Reduced serum pyridoxine and 25-hydroxyvitamin D levels in adults with chronic pruritic dermatoses.

Little is known about the role nutritional factors play in the pathogenesis of chronic pruritic dermatoses (CPD). In this study, we analyzed nutritional deficiencies in CPD patients compared to matched controls. We conducted a population-based study from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2006. The main outcomes of the study were laboratory data on serum vitamin levels in participants who answered affirmatively to the questionnaires on CPD as well as matched healthy controls. We identified 877 cases of CPD among 9817 adults in the US aged 20 to 59 years. These findings revealed a slightly higher percentage of females with CPD. Low vitamin B6 (OR 0.697; 95% CI: 0.696-0.699, p = 0.025) and vitamin D (OR 0.794; 95% CI: 0.789-0.799, p = 0.037) levels were associated with a higher rate of CPD compared to healthy controls. Our study suggests that low levels of Vitamin B6 and Vitamin D inversely correlates with the presence of CPD. These vitamin deficiencies suggest further studies on the effect of vitamin supplementation may help in patients with CPD.

Correlation of Skin Carotenoid Content with 3-Day Dietary Intake in Community Dwelling Older Adults.

Pressure-mediated reflection spectroscopy (RS) measures skin carotenoid content (SCC). Continued validation of this method is pertinent to validate its use as an objective measure of fruit and vegetable intake. This study aimed to assess relationships between SCC scores and self-reported dietary carotenoid intake from 3-day food records in community dwelling older adults. This was a cross-sectional analysis of baseline data among cognitively normal older adults (n=95) participating in the Nutrition Interventions for Cognitive Enhancement (NICE) study. Food-derived vitamin A (R=0.24, p<0.05) and food plus supplemental vitamin A (R=0.29, p<0.01) were correlated with SCC. All food-derived carotenoids (R: 0.20-0.39, p<0.05) except beta-cryptoxanthin and lycopene were correlated with SCC. Lutein + zeaxanthin from food more strongly correlated with SCC (R=0.38, p<0.001) than combined food plus supplemental intake (R=0.31, p=0.002). Correlations for total fruit and SCC (R=0.23, p=0.02), total vegetable and SCC (R= 0.31, p=0.002), and combined total fruit and vegetable and SCC (R=0.35, p<0.001) were significant; no sub-categories of fruit or vegetables except dark green vegetables (Rho=0.4, p<0.001) had significant correlations with SCC. The current study demonstrates RS-derived SCC scores correlate with 3-day self-reported intakes of F/V and certain carotenoids in community dwelling older adults.

Direct and indirect freedom in addiction: Folk free will and blame judgments are sensitive to the choice history of drug users.

People view addiction as a source of diminished free will and moral responsibility. Yet, people are also sensitive to the personal histories of moral actors, including, perhaps, the way by which people became addicted. Across two studies (N = 806), we compare people's moral intuitions about cases in which the actor becomes addicted by force or by choice. We find that perceptions of reduced free will partially mediate an association between choice (vs. no choice) in addiction and moral blame for a bad act (Study 1). We replicate this pattern and show that blame judgments are stronger when the bad act is related (vs. unrelated) to obtaining the addictive substance (Study 2). Our work is novel in demonstrating that lay people evince relatively nuanced intuitions about the role of free will in addiction and morality-they track direct and indirect paths to choices when making free will and blame judgments.

Use of complementary therapies for chronic pain management in patients with reported Ehlers-Danlos syndrome or hypermobility spectrum disorders.

Ehlers-Danlos Syndromes (EDS) and related Hypermobility Spectrum Disorders (HSD) are debilitating connective tissue disorders that feature a prominent pain component for which there are limited therapeutic options for pain management. Consequently, many patients try various non-prescribed treatments, including complementary and alternative therapies that have not been well studied in the EDS/HSD patient population. We surveyed over 500 individuals through the EDS Society who reported having been diagnosed with EDS or HSD to ascertain what complementary and alternative therapies were used and their reported effectiveness in alleviating pain and improving quality of life. Specifically, we focused on the use of traditional Chinese therapies, herbal medications, and marijuana. The most commonly reported therapies, used by 70-92% of participants, were non-steroidal anti-inflammatory drugs, acetaminophen, opioids, and physical therapy. Therapies rated by participants as most efficacious were opioids, physical therapy, and marijuana with 10-24% of those using these therapies rating them as extremely helpful. Patient-initiated complementary therapy use in EDS/HSD patients is widespread at 56%. Complementary therapies were largely utilized by EDS/HSD patients with higher reported pain levels. Providers caring for EDS/HSD patients should be aware of these data showing broad usage of predominantly non-prescribed therapies and be prepared to consider such usage in working collaboratively with these patients to develop comprehensive treatment plans to manage their chronic pain complications.

Plant expression of NifD protein variants resistant to mitochondrial degradation.

To engineer Mo-dependent nitrogenase function in plants, expression of the structural proteins NifD and NifK will be an absolute requirement. Although mitochondria have been established as a suitable eukaryotic environment for biosynthesis of oxygen-sensitive enzymes such as NifH, expression of NifD in this organelle has proven difficult due to cryptic NifD degradation. Here, we describe a solution to this problem. Using molecular and proteomic methods, we found NifD degradation to be a consequence of mitochondrial endoprotease activity at a specific motif within NifD. Focusing on this functionally sensitive region, we designed NifD variants comprising between one and three amino acid substitutions and distinguished several that were resistant to degradation when expressed in both plant and yeast mitochondria. Nitrogenase activity assays of these resistant variants in Escherichia coli identified a subset that retained function, including a single amino acid variant (Y100Q). We found that other naturally occurring NifD proteins containing alternate amino acids at the Y100 position were also less susceptible to degradation. The Y100Q variant also enabled expression of a NifD(Y100Q)-linker-NifK translational polyprotein in plant mitochondria, confirmed by identification of the polyprotein in the soluble fraction of plant extracts. The NifD(Y100Q)-linker-NifK retained function in bacterial nitrogenase assays, demonstrating that this polyprotein permits expression of NifD and NifK in a defined stoichiometry supportive of activity. Our results exemplify how protein design can overcome impediments encountered when expressing synthetic proteins in novel environments. Specifically, these findings outline our progress toward the assembly of the catalytic unit of nitrogenase within mitochondria.

White Paper: Yoga Therapy and Pain-How Yoga Therapy Serves in Comprehensive Integrative Pain Management, and How It Can Do More.

This paper examines the role of yoga therapy in comprehensive integrative pain management (CIPM). The pain crisis is described, and how yoga therapists can contribute to its solution is explained. Yoga therapy can be an essential component of the multidisciplinary undertaking that will be required to improve patient outcomes and alter the trajectory of the global public health crisis constituted by an epidemic of poorly understood and inadequately addressed pain. Additional context and evidence are presented to document the effectiveness of yoga therapy interventions to support people living with pain. The white paper concludes by listing recommendations to providers, consumers, payers, and legislators, who together can address systemic and structural barriers to CIPM, as well as suggestions for enabling the yoga therapy profession to more fully participate in these solutions.

Determining Physical Therapists' Readiness for Integrating Yoga Therapeutics into Rehabilitation.

The positive health effects of yoga have led physical therapists (PTs) to integrate elements of the discipline into their treatments in some settings. Formal PT education includes limited, if any, training in yoga, and there is no system in place to provide education on safely implementing therapeutic yoga (TY) as an adjunctive treatment approach. The purposes of this study were to: (1) assess the readiness of PTs (those who do not currently prescribe TY to patients) to integrate TY into treatment, and (2) determine the feasibility of a 5-week online TY training to improve the readiness of PTs to utilize TY in their practices. Licensed PTs (n = 103) were recruited nationally through social media and email. Eligible and consented PTs registered for a 5-week online TY training course. PTs' perceptions of TY and the role of safety and confidence in prescribing TY to patients were measured at baseline and postintervention. Feasibility outcomes were measured after completion of the course. Benchmarks included: (1) > 70% of PTs would find the course acceptable; (2) > 60% would finish the course; and (3) there would be significant improvements in PTs' perceptions of TY. A total of 95 eligible PTs consented and registered for the course, with 60 (63.1%) completing the intervention. Prior to the training, most PTs felt they were not ready (n = 19/60, 31.7%) or somewhat ready (n = 25/60, 41.7%) to integrate TY. More than half thought the online training was acceptable (n = 50/60, 83.3%) and finished the course (n = 60/95, 63.1%). There were significant improvements in personal readiness and confidence to safely prescribe TY, current understanding/knowledge of TY, and feeling adequately trained to use some form of TY with patients. A 5-week online TY training course is feasible to deliver for improving PTs' readiness to prescribe TY. Future studies are proposed to test the effectiveness of TY training and education with PTs.

Are digital interventions effective in reducing suicidal ideation and self-harm? A systematic review.

Background: There is a significant lack of outcomes research examining the effectiveness of digital interventions for reducing suicidal ideation and self-harm.Aims: To systematically review the effectiveness of digital interventions for reducing suicidal ideation and self-harm in adult populations. The possible mediating effects of depression are also discussed.Methods: The databases Pubmed, Medline, PsycInfo, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, IEEEXplore, ACM and CRESP were searched. Only randomised controlled trials (RCTs) were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used. Studies were assessed for methodological quality and risk of bias using standard assessment criteria.Results: Fourteen RCTs were reviewed, reporting data on 3455 participants. Although findings were more consistent for the effectiveness of online Cognitive Behavioural Therapy (CBT), Mindfulness-Based CBT and Dialectical Behavioural Therapy, there was insufficient research to consider any as evidence-based treatments for suicidal ideation and self-harm.Conclusions: Digital interventions for suicidal ideation and self-harm can be a safe and acceptable option for individuals unwilling or unable to access face-to-face interventions. However, further research is needed to understand the types of interventions that could support people and the risk-benefit ratio of digital interventions for these individuals.

Lessons from Vienna: stakeholder perceptions of functional electrical stimulation technology and a conceptual model for practice.

Aim: Functional electrical stimulation (FES) is a technology that can be used on paralyzed muscles to allow them to move. It has been used in populations with muscle paralysis or weakness for exercise, such as spinal cord injury (SCI) and multiple sclerosis. In order to improve technology, it is vital to understand from a qualitative perspective, issues surrounding device development and implementation.Materials and Methods: In 2016, a study was conducted at the Medical University of Vienna that sought to unravel perspectives of FES exercise from the perspective of clinicians, engineers and researchers. Semi-structured, qualitative interviews were conducted on a sample of participants from the conference (n = 22). Interviews were transcribed verbatim, and text data were analysed.Results: Following this analysis, a conceptual model of FES application in the home environment was derived. We show that the likelihood of continuing FES over time may be influenced by expectations and initial education, as perceived by stakeholders.Conclusion: This model provides a tool by which researchers or clinicians may implement FES in the home environment and may assist in the increased uptake of FES exercise at home for people who may reap benefits from its use.Implications for RehabilitationFunctional electrical stimulation (FES) is a technology that enables individuals with paralysis, such as Spinal Cord Injury or Multiple Sclerosis, to exercise.Motivation and support networks, along with adequate initial education, are essential should patients be able to successfully use FES for exercise.There are unique issues associated with performing FES in the home, and compliance may be influenced by how patients perceive FES with regard to providing benefits, and what their initial expectations are.Communication and education are essential for all parties involved in the provision of FES treatment, to ensure successful treatment with FES at home.

Up-regulation of lipid biosynthesis increases the oil content in leaves of Sorghum bicolor.

Synthesis and accumulation of the storage lipid triacylglycerol in vegetative plant tissues has emerged as a promising strategy to meet the world's future need for vegetable oil. Sorghum (Sorghum bicolor) is a particularly attractive target crop given its high biomass, drought resistance and C4 photosynthesis. While oilseed-like triacylglycerol levels have been engineered in the C3 model plant tobacco, progress in C4 monocot crops has been lagging behind. In this study, we report the accumulation of triacylglycerol in sorghum leaf tissues to levels between 3 and 8.4% on a dry weight basis depending on leaf and plant developmental stage. This was achieved by the combined overexpression of genes encoding the Zea mays WRI1 transcription factor, Umbelopsis ramanniana UrDGAT2a acyltransferase and Sesamum indicum Oleosin-L oil body protein. Increased oil content was visible as lipid droplets, primarily in the leaf mesophyll cells. A comparison between a constitutive and mesophyll-specific promoter driving WRI1 expression revealed distinct changes in the overall leaf lipidome as well as transitory starch and soluble sugar levels. Metabolome profiling uncovered changes in the abundance of various amino acids and dicarboxylic acids. The results presented here are a first step forward towards the development of sorghum as a dedicated biomass oil crop and provide a basis for further combinatorial metabolic engineering.

Modelling the cost-effectiveness of tofacitinib for the treatment of rheumatoid arthritis in the United States.

BACKGROUND AND OBJECTIVES: Rheumatoid arthritis (RA) is a chronic, debilitating disease affecting an estimated 1.5 million patients in the US. The condition is associated with a substantial health and economic burden. An economic model was developed to evaluate the cost-effectiveness of tofacitinib (a novel oral Janus kinase inhibitor) versus biologic therapies commonly prescribed in the US for the treatment of RA. METHODS: A cost-utility model was developed whereby sequences of treatments were evaluated. Response to treatment was modeled by HAQ change, and informed by a network meta-analysis. Mortality, resource use and quality of life were captured in the model using published regression analyses based on HAQ score. Treatment discontinuation was linked to response to treatment and to adverse events. Patients were modeled as having had an inadequate response to methotrexate (MTX-IR), or to a first biologic therapy (TNFi-IR). RESULTS: The tofacitinib strategy was associated with cost savings compared with alternative treatment sequences across all modeled scenarios (i.e. in both the MTX-IR and TNFi-IR scenarios), with lifetime cost savings per patient ranging from $65,205 to $93,959 (2015 costs). Cost savings arose due to improved functioning and the resulting savings in healthcare expenditure, and lower drug and administration costs. The tofacitinib strategies all resulted in an increase in quality-adjusted life years (QALYs), with additional QALYs per patient ranging from 0.01 to 0.22. CONCLUSIONS: Tofacitinib as a second-line therapy following methotrexate failure and as a third-line therapy following a biologic failure produces lower costs and improved quality of life compared with the current pathway of care.

NMT1 and NMT3 N-Methyltransferase Activity Is Critical to Lipid Homeostasis, Morphogenesis, and Reproduction.

Phosphatidylcholine (PC) is a major membrane phospholipid and a precursor for major signaling molecules. Understanding its synthesis is important for improving plant growth, nutritional value, and resistance to stress. PC synthesis is complex, involving several interconnected pathways, one of which proceeds from serine-derived phosphoethanolamine to form phosphocholine through three sequential phospho-base methylations catalyzed by phosphoethanolamine N-methyltransferases (PEAMTs). The contribution of this pathway to the production of PC and plant growth has been a matter of some debate. Although a handful of individual PEAMTs have been described, there has not been any in planta investigation of a PEAMT family. Here, we provide a comparative functional analysis of two Arabidopsis (Arabidopsis thaliana) PEAMTs, NMT1 and the little known NMT3. Analysis of loss-of-function mutants demonstrates that NMT1 and NMT3 synergistically regulate PC homeostasis, phase transition at the shoot apex, coordinated organ development, and fertility through overlapping but also specific functions. The nmt1 nmt3 double mutant shows extensive sterility, drastically reduced PC concentrations, and altered lipid profiles. These findings demonstrate that the phospho-base methylation pathway makes a major contribution to PC synthesis in Arabidopsis and that NMT1 and NMT3 play major roles in its catalysis and the regulation of PC homeostasis as well as in plant growth and reproduction.

Seed-specific RNAi in safflower generates a superhigh oleic oil with extended oxidative stability.

Vegetable oils extracted from oilseeds are an important component of foods, but are also used in a range of high value oleochemical applications. Despite being biodegradable, nontoxic and renewable current plant oils suffer from the presence of residual polyunsaturated fatty acids that are prone to free radical formation that limit their oxidative stability, and consequently shelf life and functionality. Many decades of plant breeding have been successful in raising the oleic content to ~90%, but have come at the expense of overall field performance, including poor yields. Here, we engineer superhigh oleic (SHO) safflower producing a seed oil with 93% oleic generated from seed produced in multisite field trials spanning five generations. SHO safflower oil is the result of seed-specific hairpin-based RNA interference of two safflower lipid biosynthetic genes, FAD2.2 and FATB, producing seed oil containing less than 1.5% polyunsaturates and only 4% saturates but with no impact on lipid profiles of leaves and roots. Transgenic SHO events were compared to non-GM safflower in multisite trial plots with a wide range of growing season conditions, which showed no evidence of impact on seed yield. The oxidative stability of the field-grown SHO oil produced from various sites was 50 h at 110°C compared to 13 h for conventional ~80% oleic safflower oils. SHO safflower produces a uniquely stable vegetable oil across different field conditions that can provide the scale of production that is required for meeting the global demands for high stability oils in food and the oleochemical industry.

A reconfigured Kennedy pathway which promotes efficient accumulation of medium-chain fatty acids in leaf oils.

Medium-chain fatty acids (MCFA, C6-14 fatty acids) are an ideal feedstock for biodiesel and broader oleochemicals. In recent decades, several studies have used transgenic engineering to produce MCFA in seeds oils, although these modifications result in unbalance membrane lipid profiles that impair oil yields and agronomic performance. Given the ability to engineer nonseed organs to produce oils, we have previously demonstrated that MCFA profiles can be produced in leaves, but this also results in unbalanced membrane lipid profiles and undesirable chlorosis and cell death. Here we demonstrate that the introduction of a diacylglycerol acyltransferase from oil palm, EgDGAT1, was necessary to channel nascent MCFA directly into leaf oils and therefore bypassing MCFA residing in membrane lipids. This pathway resulted in increased flux towards MCFA rich leaf oils, reduced MCFA in leaf membrane lipids and, crucially, the alleviation of chlorosis. Deep sequencing of African oil palm (Elaeis guineensis) and coconut palm (Cocos nucifera) generated candidate genes of interest, which were then tested for their ability to improve oil accumulation. Thioesterases were explored for the production of lauric acid (C12:0) and myristic (C14:0). The thioesterases from Umbellularia californica and Cinnamomum camphora produced a total of 52% C12:0 and 40% C14:0, respectively, in transient leaf assays. This study demonstrated that the introduction of a complete acyl-CoA-dependent pathway for the synthesis of MFCA-rich oils avoided disturbing membrane homoeostasis and cell death phenotypes. This study outlines a transgenic strategy for the engineering of biomass crops with high levels of MCFA rich leaf oils.

Step changes in leaf oil accumulation via iterative metabolic engineering.

Synthesis and accumulation of plant oils in the entire vegetative biomass offers the potential to deliver yields surpassing those of oilseed crops. However, current levels still fall well short of those typically found in oilseeds. Here we show how transcriptome and biochemical analyses pointed to a futile cycle in a previously established Nicotiana tabacum line, accumulating up to 15% (dry weight) of the storage lipid triacylglycerol in leaf tissue. To overcome this metabolic bottleneck, we either silenced the SDP1 lipase or overexpressed the Arabidopsis thaliana LEC2 transcription factor in this transgenic background. Both strategies independently resulted in the accumulation of 30-33% triacylglycerol in leaf tissues. Our results demonstrate that the combined optimization of de novo fatty acid biosynthesis, storage lipid assembly and lipid turnover in leaf tissue results in a major overhaul of the plant central carbon allocation and lipid metabolism. The resulting further step changes in oil accumulation in the entire plant biomass offers the possibility of delivering yields that outperform current oilseed crops.

Bacteria as Emerging Indicators of Soil Condition.

Bacterial communities are important for the health and productivity of soil ecosystems and have great potential as novel indicators of environmental perturbations. To assess how they are affected by anthropogenic activity and to determine their ability to provide alternative metrics of environmental health, we sought to define which soil variables bacteria respond to across multiple soil types and land uses. We determined, through 16S rRNA gene amplicon sequencing, the composition of bacterial communities in soil samples from 110 natural or human-impacted sites, located up to 300 km apart. Overall, soil bacterial communities varied more in response to changing soil environments than in response to changes in climate or increasing geographic distance. We identified strong correlations between the relative abundances of members of Pirellulaceae and soil pH, members of Gaiellaceae and carbon-to-nitrogen ratios, members of Bradyrhizobium and the levels of Olsen P (a measure of plant available phosphorus), and members of Chitinophagaceae and aluminum concentrations. These relationships between specific soil attributes and individual soil taxa not only highlight ecological characteristics of these organisms but also demonstrate the ability of key bacterial taxonomic groups to reflect the impact of specific anthropogenic activities, even in comparisons of samples across large geographic areas and diverse soil types. Overall, we provide strong evidence that there is scope to use relative taxon abundances as biological indicators of soil condition. IMPORTANCE: The impact of land use change and management on soil microbial community composition remains poorly understood. Therefore, we explored the relationship between a wide range of soil factors and soil bacterial community composition. We included variables related to anthropogenic activity and collected samples across a large spatial scale to interrogate the complex relationships between various bacterial community attributes and soil condition. We provide evidence of strong relationships between individual taxa and specific soil attributes even across large spatial scales and soil and land use types. Collectively, we were able to demonstrate the largely untapped potential of microorganisms to indicate the condition of soil and thereby influence the way that we monitor the effects of anthropogenic activity on soil ecosystems into the future.

The management and treatment of children with Fabry disease: A United States-based perspective.

Fabry disease is an inherited X-linked disorder that presents during childhood in male and female patients. Young patients may initially experience pain, hypohidrosis, and gastrointestinal symptoms. Other manifestations of Fabry disease, such as renal and cardiac disease, manifest later in adolescence or adulthood. In the pediatric population, renal damage is typically subclinical and identifiable only through biopsy. Specialists from the United States with expertise in Fabry disease convened during 2013-2014 in order to develop these consensus guidelines about the management and treatment of children with Fabry disease. The presence of symptoms in boys and girls of any age is an indication to begin therapy. Early treatment before the onset of potentially irreversible vital organ pathology is ideal. Asymptomatic children with Fabry mutations should be followed closely for the development of renal, cardiac, neurological, or gastrointestinal signs, symptoms, or laboratory changes, which would warrant treatment initiation. A comprehensive care plan should be implemented by the treating physicians to guide the management of children with Fabry disease.

Evaluation of drug-induced QT interval prolongation in animal and human studies: a literature review of concordance.

Evaluating whether a new medication prolongs QT intervals is a critical safety activity that is conducted in a sensitive animal model during non-clinical drug development. The importance of QT liability detection has been reinforced by non-clinical [International Conference on Harmonization (ICH) S7B] and clinical (ICH E14) regulatory guidance from the International Conference on Harmonization. A key challenge for the cardiovascular safety community is to understand how the finding from a non-clinical in vivo QT assay in animals predicts the outcomes of a clinical QT evaluation in humans. The Health and Environmental Sciences Institute Pro-Arrhythmia Working Group performed a literature search (1960-2011) to identify both human and non-rodent animal studies that assessed QT signal concordance between species and identified drugs that prolonged or did not prolong the QT interval. The main finding was the excellent agreement between QT results in humans and non-rodent animals. Ninety-one percent (21 of 23) of drugs that prolonged the QT interval in humans also did so in animals, and 88% (15 of 17) of drugs that did not prolong the QT interval in humans had no effect on animals. This suggests that QT interval data derived from relevant non-rodent models has a 90% chance of predicting QT findings in humans. Disagreement can occur, but in the limited cases of QT discordance we identified, there appeared to be plausible explanations for the underlying disconnect between the human and non-rodent animal QT outcomes.