MEK1-ERK1/2 signaling regulates the cardiomyocyte non-sarcomeric actin cytoskeletal network.

During select pathological conditions, the heart can hypertrophy and remodel in either a dilated or concentric ventricular geometry, which is associated with lengthening or widening of cardiomyocytes, respectively. The mitogen-activated protein kinase kinase 1 (MEK1) and extracellular signal-related kinase 1 and 2 (ERK1/2) pathway has been implicated in these differential types of growth such that cardiac overexpression of activated MEK1 causes profound concentric hypertrophy and cardiomyocyte thickening, while genetic ablation of the genes encoding ERK1/2 in the mouse heart causes dilation and cardiomyocyte lengthening. However, the mechanisms by which this kinase signaling pathway controls cardiomyocyte directional growth as well as its downstream effectors are poorly understood. To investigate this, we conducted an unbiased phosphoproteomic screen in cultured neonatal rat ventricular myocytes treated with an activated MEK1 adenovirus, the MEK1 inhibitor U0126, or an eGFP adenovirus control. Bioinformatic analysis identified cytoskeletal-related proteins as the largest subset of differentially phosphorylated proteins. Phos-tag and traditional Western blotting were performed to confirm that many cytoskeletal proteins displayed changes in phosphorylation with manipulations in MEK1-ERK1/2 signaling. From this, we hypothesized that the actin cytoskeleton would be changed in vivo in the mouse heart. Indeed, we found that activated MEK1 transgenic mice and gene-deleted mice lacking ERK1/2 protein had enhanced non-sarcomeric actin expression in cardiomyocytes compared with wild-type control hearts. Consistent with these results, cytoplasmic ß- and γ-actin were increased at the subcortical intracellular regions of adult cardiomyocytes. Together, these data suggest that MEK1-ERK1/2 signaling influences the non-sarcomeric cytoskeletal actin network, which may be important for facilitating the growth of cardiomyocytes in length and/or width.NEW & NOTEWORTHY Here, we performed an unbiased analysis of the total phosphoproteome downstream of MEK1-ERK1/2 kinase signaling in cardiomyocytes. Pathway analysis suggested that proteins of the non-sarcomeric cytoskeleton were the most differentially affected. We showed that cytoplasmic ß-actin and γ-actin isoforms, regulated by MEK1-ERK1/2, are localized to the subcortical space at both lateral membranes and intercalated discs of adult cardiomyocytes suggesting how MEK1-ERK1/2 signaling might underlie directional growth of adult cardiomyocytes.

MCUb is an inducible regulator of calcium-dependent mitochondrial metabolism and substrate utilization in muscle.

Mitochondria use the electron transport chain to generate high-energy phosphate from oxidative phosphorylation, a process also regulated by the mitochondrial Ca2+ uniporter (MCU) and Ca2+ levels. Here, we show that MCUb, an inhibitor of MCU-mediated Ca2+ influx, is induced by caloric restriction, where it increases mitochondrial fatty acid utilization. To mimic the fasted state with reduced mitochondrial Ca2+ influx, we generated genetically altered mice with skeletal muscle-specific MCUb expression that showed greater fatty acid usage, less fat accumulation, and lower body weight. In contrast, mice lacking Mcub in skeletal muscle showed increased pyruvate dehydrogenase activity, increased muscle malonyl coenzyme A (CoA), reduced fatty acid utilization, glucose intolerance, and increased adiposity. Mechanistically, pyruvate dehydrogenase kinase 4 (PDK4) overexpression in muscle of Mcub-deleted mice abolished altered substrate preference. Thus, MCUb is an inducible control point in regulating skeletal muscle mitochondrial Ca2+ levels and substrate utilization that impacts total metabolic balance.

A human FLII gene variant alters sarcomeric actin thin filament length and predisposes to cardiomyopathy.

To better understand the genetic basis of heart disease, we identified a variant in the Flightless-I homolog (FLII) gene that generates a R1243H missense change and predisposes to cardiac remodeling across multiple previous human genome-wide association studies (GWAS). Since this gene is of unknown function in the mammalian heart we generated gain- and loss-of-function genetically altered mice, as well as knock-in mice with the syntenic R1245H amino acid substitution, which showed that Flii protein binds the sarcomeric actin thin filament and influences its length. Deletion of Flii from the heart, or mice with the R1245H amino acid substitution, show cardiomyopathy due to shortening of the actin thin filaments. Mechanistically, Flii is a known actin binding protein that we show associates with tropomodulin-1 (TMOD1) to regulate sarcomere thin filament length. Indeed, overexpression of leiomodin-2 in the heart, which lengthens the actin-containing thin filaments, partially rescued disease due to heart-specific deletion of Flii. Collectively, the identified FLII human variant likely increases cardiomyopathy risk through an alteration in sarcomere structure and associated contractile dynamics, like other sarcomere gene-based familial cardiomyopathies.

Rpl3l gene deletion in mice reduces heart weight over time.

Introduction: The ribosomal protein L3-like (RPL3L) is a heart and skeletal muscle-specific ribosomal protein and paralogue of the more ubiquitously expressed RPL3 protein. Mutations in the human RPL3L gene are linked to childhood cardiomyopathy and age-related atrial fibrillation, yet the function of RPL3L in the mammalian heart remains unknown. Methods and Results: Here, we observed that mouse cardiac ventricles express RPL3 at birth, where it is gradually replaced by RPL3L in adulthood but re-expressed with induction of hypertrophy in adults. Rpl3l gene-deleted mice were generated to examine the role of this gene in the heart, although Rpl3l -/- mice showed no overt changes in cardiac structure or function at baseline or after pressure overload hypertrophy, likely because RPL3 expression was upregulated and maintained in adulthood. mRNA expression analysis and ribosome profiling failed to show differences between the hearts of Rpl3l null and wild type mice in adulthood. Moreover, ribosomes lacking RPL3L showed no differences in localization within cardiomyocytes compared to wild type controls, nor was there an alteration in cardiac tissue ultrastructure or mitochondrial function in adult Rpl3l -/- mice. Similarly, overexpression of either RPL3 or RPL3L with adeno-associated virus -9 in the hearts of mice did not cause discernable pathology. However, by 18 months of age Rpl3l -/- null mice had significantly smaller hearts compared to wild type littermates. Conclusion: Thus, deletion of Rpl3l forces maintenance of RPL3 expression within the heart that appears to fully compensate for the loss of RPL3L, although older Rpl3l -/- mice showed a mild but significant reduction in heart weight.

Evaluation of a leadership development impact assessment toolkit: a comparative case study of experts' perspectives in three Canadian provinces.

PURPOSE: This paper aims to explore users' perceptions of whether the Leadership Development Impact Assessment (LDI) Toolkit is valid, reliable, simple to use and cost-effective as a guide to its quality improvement. DESIGN/METHODOLOGY/APPROACH: The Canadian Health Leadership Network codesigned and codeveloped the LDI Toolkit as a theory-driven and evidence-informed resource that aims to assist health-care organizational development practitioners to evaluate various programs at five levels of impact: reaction, learning, application, impact and return on investment (ROI) and intangible benefits. A comparative evaluative case study was conducted using online questionnaires and semistructured telephone interviews with three health organizations where robust leadership development programs were in place. A total of seven leadership consultants and specialists participated from three Canadian provinces. Data were analyzed sequentially in two stages involving descriptive statistical analysis augmented with a qualitative content analysis of key themes. FINDINGS: Users perceived the toolkit as cost-effective in terms of direct costs, indirect costs and intangibles; they found it easy-to-use in terms of clarity, logic and structure, ease of navigation with a coherent layout; and they assessed the sources of the evidence-informed tools and guides as appropriate. Users rated the toolkit highly on their perceptions of its validity and reliability. The analysis also informed the refinement of the toolkit. ORIGINALITY/VALUE: The refined LDI Toolkit is a comprehensive online collection of various tools to support health organizations to evaluate the leadership development investments effectively and efficiently at five impact levels including ROI.

Leaders supporting leaders: Leaders' role in building resilience and psychologically healthy workplaces during the pandemic and beyond.

The COVID-19 pandemic is now endemic and has taken a terrible toll on the health workforce and its leaders. Stress and burnout are rampant, and health workers are leaving in record numbers. Using data collected during the first four waves of the pandemic, and a longitudinal analysis of these data, the authors identify ongoing challenges to health leadership related to building resilience and psychologically healthy workplaces. The article is organized around three questions: What happened during Waves 1 to 4? What did we learn? And what should be done differently? Eight actions emerged around the theme of "leaders supporting leaders": build personal resilience; practice compassionate leadership; model effective interpersonal leadership behaviour; ensure frequent and authentic communication; participate in networks and communities of practice; balance short- and long-term commitments; apply systems thinking; and contribute to a collaborative, national strategy.

Leading through the first wave of COVID: a Canadian action research study.

PURPOSE: This first phase of a three-phase action research project aims to define leadership practices that should be used during and after the pandemic to re-imagine and rebuild the health and social care system. Specifically, the objectives were to determine what effective leadership practices Canadian health leaders have used through the first wave of the COVID-19 pandemic, to explore how these differ from pre-crisis practices; and to identify what leadership practices might be leveraged to create the desired health and care systems of the future. DESIGN/METHODOLOGY/APPROACH: The authors used an action research methodology. In the first phase, reported here, the authors conducted one-on-one, virtual interviews with 18 health leaders from across Canada and across leadership roles. Data were analyzed using grounded theory methodology. FINDINGS: Five key practices emerged from the data, within the core dimension of disrupting entrenched structures and leadership practices. These were, namely, responding to more complex emotions in self and others. Future practice identified to create more psychologically supportive workplaces. Agile and adaptive leadership. Future practice should allow leaders to move systemic change forward more quickly. Integrating diverse perspectives, within and across organizations, leveling hierarchies through bringing together a variety of perspectives in the decision-making process and engaging people more broadly in the co-creation of strategies. Applying existing leadership capabilities and experience. Future practice should develop and expand mentorship to support early career leadership. Communication was increased to build credibility and trust in response to changing and often contradictory emerging evidence and messaging. Future practice should increase communication. RESEARCH LIMITATIONS/IMPLICATIONS: The project was limited to health leaders in Canada and did not represent all provinces/territories. Participants were recruited through the leadership networks, while diverse, were not demographically representative. All interviews were conducted in English; in the second phase of the study, the authors will recruit a larger and more diverse sample and conduct interviews in both English and French. As the interviews took place during the early stages of the pandemic, it may be that health leaders' views of what may be required to re-define future health systems may change as the crisis shifts over time. PRACTICAL IMPLICATIONS: The sponsoring organization of this research - the Canadian Health Leadership Network and each of its individual member partners - will mobilize knowledge from this research, and subsequent phases, to inform processes for leadership development and, succession planning across, the Canadian health system, particularly those attributes unique to a context of crisis management but also necessary in post-crisis recovery. SOCIAL IMPLICATIONS: This research has shown that there is an immediate need to develop innovative and influential leadership action - commensurate with its findings - to supporting the evolution of the Canadian health system, the emotional well-being of the health-care workforce, the mental health of the population and challenges inherent in structural inequities across health and health care that discriminate against certain populations. ORIGINALITY/VALUE: An interdisciplinary group of health researchers and decision-makers from across Canada who came together rapidly to examine leadership practices during COVID-19's first wave using action research study design.

The relevance of the LEADS framework during the COVID-19 pandemic.

COVID-19 has created a unique context for the practice of leadership in healthcare. Given the significant use of the LEADS in a Caring Environment capabilities framework (LEADS) in Canada's health system, it is important to document the relevancy of LEADS. The authors reviewed literature, conducted research, and reflected on their own experience to identify leadership practices during the pandemic and related them to LEADS. Findings are presented in three sections: Hindsight (before), Insight (during), and Foresight (post). We profile the issue of improving long-term Care to provide an example of how LEADS can be applied in crisis times. Our analysis suggests that while LEADS appears to specify the leadership capabilities needed, it requires adaptation to context. The vision Canada has for healthcare will dictate how LEADS will be used as a guide to leadership practice in the current context or to shape a bolder vision of healthcare's future.

Thbs1 induces lethal cardiac atrophy through PERK-ATF4 regulated autophagy.

The thrombospondin (Thbs) family of secreted matricellular proteins are stress- and injury-induced mediators of cellular attachment dynamics and extracellular matrix protein production. Here we show that Thbs1, but not Thbs2, Thbs3 or Thbs4, induces lethal cardiac atrophy when overexpressed. Mechanistically, Thbs1 binds and activates the endoplasmic reticulum stress effector PERK, inducing its downstream transcription factor ATF4 and causing lethal autophagy-mediated cardiac atrophy. Antithetically, Thbs1-/- mice develop greater cardiac hypertrophy with pressure overload stimulation and show reduced fasting-induced atrophy. Deletion of Thbs1 effectors/receptors, including ATF6α, CD36 or CD47 does not diminish Thbs1-dependent cardiac atrophy. However, deletion of the gene encoding PERK in Thbs1 transgenic mice blunts the induction of ATF4 and autophagy, and largely corrects the lethal cardiac atrophy. Finally, overexpression of PERK or ATF4 using AAV9 gene-transfer similarly promotes cardiac atrophy and lethality. Hence, we identified Thbs1-mediated PERK-eIF2α-ATF4-induced autophagy as a critical regulator of cardiomyocyte size in the stressed heart.

Completion of a formal physiotherapeutic scoliosis-specific exercise training program for adolescent idiopathic scoliosis increases patient compliance to home exercise programs.

INTRODUCTION: Physiotherapeutic Scoliosis-Specific Exercise (PSSE) is a conservative approach for management of adolescent idiopathic scoliosis (AIS). Although there is Level I evidence for the efficacy of PSSE, compliance in the teenage population remains in question. The purpose of this study is to investigate the association between completion of formal PSSE training and compliance to prescribed home exercise programs (HEP). METHODS: Patients with AIS evaluated at our institution between 2013 and 2015 with a minimum of one PSSE session were enrolled. A chart review and questionnaire completed by caregivers was utilized to assess HEP compliance following the final PSSE session at 1 week, 3 months, 1 year, and 2 years. Patients were divided into two groups, those completing formal training (10 or more PSSE sessions), and those who did not complete formal training (fewer than 10 sessions). RESULTS: 81 patients were identified (mean age of 13.1 years; major curve of 31.3°). Patients who completed training demonstrated 50% compliance at 1 week (vs. 25.6% for non-completers, Odds Ratio (OR): 2.9, p = 0.027), 41.2% at 3 months (vs. 18.9% for non-completers, OR: 3.0, p = 0.044), 23.5% at 1 year (vs. 13.5% for non-completers, OR: 2.0, p = 0.281), and 25.7% at 2 years (vs. 13.5% for non-completers, OR: 2.2, p = 0.197). The mean HEP duration (minutes) in patients who completed training was higher at 1 week (80.8 vs. 48, p = 0.010), 3 months (64.6 vs. 23.7, p ≤ 0.001), 1 year (35.3 vs. 22.7, p = 0.270), and 2 years (34.3 vs. 18.9, p = 0.140). CONCLUSION: Patients who completed PSSE training maintained higher HEP compliance.

MCUb Induction Protects the Heart From Postischemic Remodeling.

RATIONALE: Mitochondrial Ca2+ loading augments oxidative metabolism to match functional demands during times of increased work or injury. However, mitochondrial Ca2+ overload also directly causes mitochondrial rupture and cardiomyocyte death during ischemia-reperfusion injury by inducing mitochondrial permeability transition pore opening. The MCU (mitochondrial Ca2+ uniporter) mediates mitochondrial Ca2+ influx, and its activity is modulated by partner proteins in its molecular complex, including the MCUb subunit. OBJECTIVE: Here, we sought to examine the function of the MCUb subunit of the MCU-complex in regulating mitochondria Ca2+ influx dynamics, acute cardiac injury, and long-term adaptation after ischemic injury. METHODS AND RESULTS: Cardiomyocyte-specific MCUb overexpressing transgenic mice and Mcub gene-deleted (Mcub-/-) mice were generated to dissect the molecular function of this protein in the heart. We observed that MCUb protein is undetectable in the adult mouse heart at baseline, but mRNA and protein are induced after ischemia-reperfusion injury. MCUb overexpressing mice demonstrated inhibited mitochondrial Ca2+ uptake in cardiomyocytes and partial protection from ischemia-reperfusion injury by reducing mitochondrial permeability transition pore opening. Antithetically, deletion of the Mcub gene exacerbated pathological cardiac remodeling and infarct expansion after ischemic injury in association with greater mitochondrial Ca2+ uptake. Furthermore, hindlimb remote ischemic preconditioning induced MCUb expression in the heart, which was associated with decreased mitochondrial Ca2+ uptake, collectively suggesting that induction of MCUb protein in the heart is protective. Similarly, mouse embryonic fibroblasts from Mcub-/- mice were more sensitive to Ca2+ overload. CONCLUSIONS: Our studies suggest that Mcub is a protective cardiac inducible gene that reduces mitochondrial Ca2+ influx and permeability transition pore opening after ischemic injury to reduce ongoing pathological remodeling.

Establishing consensus on the best practice guidelines for the use of bracing in adolescent idiopathic scoliosis.

STUDY DESIGN: Survey. OBJECTIVES: Bracing is the mainstay of conservative treatment in Adolescent Idiopathic Scoliosis (AIS). The purpose of this study was to establish best practice guidelines (BPG) among a multidisciplinary group of international bracing experts including surgeons, physiatrists, physical therapists, and orthotists utilizing formal consensus building techniques. Currently, there is significant variability in the practice of brace treatment for AIS and, therefore, there is a strong need to develop BPG for bracing in AIS. METHODS: We utilized the Delphi process and the nominal group technique to establish consensus among a multidisciplinary group of bracing experts. Our previous work identified areas of variability in brace treatment that we targeted for consensus. Following a review of the literature, three iterative surveys were administered. Topics included bracing goals, indications for starting and discontinuing bracing, brace types, brace prescription, radiographs, physical activities, and physiotherapeutic scoliosis-specific exercises. A face-to-face meeting was then conducted that allowed participants to vote for or against inclusion of each item. Agreement of 80% throughout the surveys and face-to-face meeting was considered consensus. Items that did not reach consensus were discussed and revised and repeat voting for consensus was performed. RESULTS: Of the 38 experts invited to participate, we received responses from 32, 35, and 34 for each survey, respectively. 11 surgeons, 4 physiatrists, 8 physical therapists, 3 orthotists, and 1 research scientist participated in the final face-to-face meeting. Experts reached consensus on 67 items across 10 domains of bracing which were consolidated into the final best practice recommendations. CONCLUSIONS: We believe that adherence to these BPG will lead to fewer sub-optimal outcomes in patients with AIS by reducing the variability in AIS bracing practices, and provide a framework future research. LEVEL OF EVIDENCE: Level IV.

Probing Pedomorphy and Prolonged Lifespan in Naked Mole-Rats and Dwarf Mice.

Pedomorphy, maintenance of juvenile traits throughout life, is most pronounced in extraordinarily long-lived naked mole-rats. Many of these traits (e.g., slow growth rates, low hormone levels, and delayed sexual maturity) are shared with spontaneously mutated, long-lived dwarf mice. Although some youthful traits likely evolved as adaptations to subterranean habitats (e.g., thermolability), the nature of these intrinsic pedomorphic features may also contribute to their prolonged youthfulness, longevity, and healthspan.

ERK1/2 signaling induces skeletal muscle slow fiber-type switching and reduces muscular dystrophy disease severity.

Mitogen-activated protein kinase (MAPK) signaling consists of an array of successively acting kinases. The extracellular signal-regulated kinases 1/2 (ERK1/2) are major components of the greater MAPK cascade that transduce growth factor signaling at the cell membrane. Here we investigated ERK1/2 signaling in skeletal muscle homeostasis and disease. Using mouse genetics, we observed that the muscle-specific expression of a constitutively active MEK1 mutant promotes greater ERK1/2 signaling that mediates fiber-type switching to a slow, oxidative phenotype with type I myosin heavy chain expression. Using a conditional and temporally regulated Cre strategy as well as Mapk1 (ERK2) and Mapk3 (ERK1) genetically targeted mice, MEK1-ERK2 signaling was shown to underlie this fast-to-slow fiber type switching in adult skeletal muscle as well as during development. Physiologic assessment of these activated MEK1-ERK1/2 mice showed enhanced metabolic activity and oxygen consumption with greater muscle fatigue resistance. Moreover, induction of MEK1-ERK1/2 signaling increased dystrophin and utrophin protein expression in a mouse model of limb-girdle muscle dystrophy and protected myofibers from damage. In summary, sustained MEK1-ERK1/2 activity in skeletal muscle produces a fast-to-slow fiber-type switch that protects from muscular dystrophy, suggesting a therapeutic approach to enhance the metabolic effectiveness of muscle and protect from dystrophic disease.

Supporting the heart: Functions of the cardiomyocyte's non-sarcomeric cytoskeleton.

The non-contractile cytoskeleton in cardiomyocytes is comprised of cytoplasmic actin, microtubules, and intermediate filaments. In addition to providing mechanical support to these cells, these structures are important effectors of tension-sensing and signal transduction and also provide networks for the transport of proteins and organelles. The majority of our knowledge on the function and structure of these cytoskeletal networks comes from research on proliferative cell types. However, in recent years, researchers have begun to show that there are important cardiomyocyte-specific functions of the cytoskeleton. Here we will discuss the current state of cytoskeletal biology in cardiomyocytes, as well as research from other cell types, that together suggest there is a wealth of knowledge on cardiac health and disease waiting to be uncovered through exploration of the complex signaling networks of cardiomyocyte non-sarcomeric cytoskeletal proteins.

Overlapping and differential functions of ATF6α versus ATF6ß in the mouse heart.

Hemodynamic stress on the mammalian heart results in compensatory hypertrophy and activation of the unfolded protein response through activating transcription factor 6α (ATF6α) in cardiac myocytes, but the roles of ATF6α or the related transcription factor ATF6ß in regulating this hypertrophic response are not well-understood. Here we examined the effects of loss of ATF6α or ATF6ß on the cardiac response to pressure overload. Mice gene-deleted for Atf6 or Atf6b were subjected to 2 weeks of transverse aortic constriction, and each showed a significant reduction in hypertrophy with reduced expression of endoplasmic reticulum (ER) stress-associated proteins compared with controls. However, with long-term pressure overload both Atf6 and Atf6b null mice showed enhanced decompensation typified by increased heart weight, pulmonary edema and reduced function compared to control mice. Our subsequent studies using cardiac-specific transgenic mice expressing the transcriptionally active N-terminus of ATF6α or ATF6ß revealed that these factors control overlapping gene expression networks that include numerous ER protein chaperones and ER associated degradation components. This work reveals previously unappreciated roles for ATF6α and ATF6ß in regulating the pressure overload induced cardiac hypertrophic response and in controlling the expression of genes that condition the ER during hemodynamic stress.

Surgeon Attitudes Toward Physiotherapeutic Scoliosis-Specific Exercises in Adult Patients With Spinal Deformities.

BACKGROUND: Physiotherapeutic scoliosis-specific exercise (PSSE) has proven to be an important treatment for patients with adolescent idiopathic scoliosis. However, there is a lack of understanding of the role of PSSE in older adults with spinal deformity. METHODS: An electronic, 14-question survey with questions regarding the use of physical therapy (PT) and PSSE for adult spinal deformity was administered to all Scoliosis Research Society members. Physician location, age, specialty, years in experience, and management preferences were quantified using descriptive analyses. RESULTS: Of the 98 surgeons who participated in this study, the majority of respondents were from North America (71.1%), and the mean age was 51.87 ± 10.93 years; approximately 98% of respondents were orthopedic surgeons, and 48.0% had been in practice for more than 21 years. Sixty-four percent reported they prescribed PT in their practice, with 52% of respondents often using PT as nonoperative treatment; 21.4%, preoperative; and 40.8% postoperative. The primary reason for PT referral was persistent pain (40.3%), followed by impairments to the patient's balance or gait (34.3%) and difficulty with daily living activities (25.4%). The primary indications for not referring postoperative patients to PT were lack of perceived value from PT (50%), lack of evidence supporting the benefits from PT (31.3%), and a lack of physical therapists appropriately trained for scoliosis (18.8%). Of the respondents, 74% were familiar with PSSE and 66% were comfortable prescribing PSSE postoperatively. In addition, 28% of respondents agreed that >12 weeks postoperation was the ideal time for PSSE referral, followed by 6 to 8 weeks postoperation (26.2%) and immediately postoperation (18%). CONCLUSIONS: The results show that the majority of respondents prescribed PSSE solely for nonoperative treatment. Respondents who did not prescribe PSSE reported skepticism due to a lack of perceived value. This suggests the need for further research into the benefits of PSSE. LEVEL OF EVIDENCE: 5. CLINICAL RELEVANCE: Physiotherapeutic Scoliosis Specific Exercises (PSSE) is an important non-operative treatment for patients with Adolescent Idiopathic Scoliosis (AIS) but is understudied in Adult Spinal Deformity (ASD) patients, suggesting further clinical research. This study demonstrates that only two-thirds of the respondents familiar with PSSE were comfortable prescribing PSSE postoperatively suggesting the need for further research into the effectiveness and benefits of PSSE in ASD patients.

Return on investment in healthcare leadership development programs.

Purpose Strong leadership has been shown to foster change, including loyalty, improved performance and decreased error rates, but there is a dearth of evidence on effectiveness of leadership development programs. To ensure a return on the huge investments made, evidence-based approaches are needed to assess the impact of leadership on health-care establishments. As a part of a pan-Canadian initiative to design an effective evaluative instrument, the purpose of this paper was to identify and summarize evidence on health-care outcomes/return on investment (ROI) indicators and metrics associated with leadership quality, leadership development programs and existing evaluative instruments. Design/methodology/approach The authors performed a scoping review using the Arksey and O'Malley framework, searching eight databases from 2006 through June 2016. Findings Of 11,868 citations screened, the authors included 223 studies reporting on health-care outcomes/ROI indicators and metrics associated with leadership quality (73 studies), leadership development programs (138 studies) and existing evaluative instruments (12 studies). The extracted ROI indicators and metrics have been summarized in detail. Originality/value This review provides a snapshot in time of the current evidence on ROI indicators and metrics associated with leadership. Summarized ROI indicators and metrics can be used to design an effective evaluative instrument to assess the impact of leadership on health-care organizations.

The naked mole-rat exhibits an unusual cardiac myofilament protein profile providing new insights into heart function of this naturally subterranean rodent.

The long-lived, hypoxic-tolerant naked mole-rat well-maintains cardiac function over its three-decade-long lifespan and exhibits many cardiac features atypical of similar-sized laboratory rodents. For example, they exhibit low heart rates and resting cardiac contractility, yet have a large cardiac reserve. These traits are considered ecophysiological adaptations to their dank subterranean atmosphere of low oxygen and high carbon dioxide levels and may also contribute to negligible declines in cardiac function during aging. We asked if naked mole-rats had a different myofilament protein signature to that of similar-sized mice that commonly show both high heart rates and high basal cardiac contractility. Adult mouse ventricles predominantly expressed α-myosin heavy chain (97.9 ± 0.4%). In contrast, and more in keeping with humans, ß myosin heavy chain was the dominant isoform (79.0 ± 2.0%) in naked mole-rat ventricles. Naked mole-rat ventricles diverged from those of both humans and mice, as they expressed both cardiac and slow skeletal isoforms of troponin I. This myofilament protein profile is more commonly observed in mice in utero and during cardiomyopathies. There were no species differences in phosphorylation of cardiac myosin binding protein-C or troponin I. Phosphorylation of both ventricular myosin light chain 2 and cardiac troponin T in naked mole-rats was approximately half that observed in mice. Myofilament function was also compared between the two species using permeabilized cardiomyocytes. Together, these data suggest a cardiac myofilament protein signature that may contribute to the naked mole-rat's suite of adaptations to its natural subterranean habitat.