Training and Evaluation of Residents to Ensure Competent Physician Metrics to Recognize Struggling Residents.

Assessing competency across domains of knowledge, skills, and behavior is critical to ensure that graduating orthopaedic residents possess the requisite skills and attributes to enter independent orthopaedic practice. Of the domains, knowledge is most easily assessed. In addition to the AAOS Orthopaedic In-Training Examination®, which provides a yearly gauge of residents' orthopaedic knowledge relative to their peers, there are several online platforms such as Orthobullets, the American Academy of Orthopaedic Surgeons ResStudy program, and the Journal of Bone and Joint Surgery Clinical Classroom that offer online learning resources and question banks. Clinical skills are best assessed through a combination of observation tools, including live or video assessments, 360° evaluations, and objective structured clinical examinations. Surgical skills can be evaluated in two domains: live surgical cases or simulations. The American Board of Orthopaedic Surgery is attempting to standardize live surgical evaluations through the use of the O-P tool. Although most available models feature only arthroscopic procedures, surgical simulators provide for opportunity to objectively evaluate resident performance. Behavior and professionalism has traditionally been the most challenging domain to assess. The American Board of Orthopaedic Surgery's Behavior Assessment Tool has demonstrated success in pilot testing and is being introduced as the standard for measuring behavior and professionalism in orthopaedic training. Although no single assessment tool can accurately gauge a resident's overall performance, a combination of readily available tools should be used to assess competence across domains.

Effects of flanking sequences and cellular context on subcellular behavior and pathology of mutant HTT.

Huntington's disease (HD) is caused by an expansion of a poly glutamine (polyQ) stretch in the huntingtin protein (HTT) that is necessary to cause pathology and formation of HTT aggregates. Here we ask whether expanded polyQ is sufficient to cause pathology and aggregate formation. By addressing the sufficiency question, one can identify cellular processes and structural parameters that influence HD pathology and HTT subcellular behavior (i.e. aggregation state and subcellular location). Using Drosophila, we compare the effects of expressing mutant full-length human HTT (fl-mHTT) to the effects of mutant human HTTexon1 and to two commonly used synthetic fragments, HTT171 and shortstop (HTT118). Expanded polyQ alone is not sufficient to cause inclusion formation since full-length HTT and HTTex1 with expanded polyQ are both toxic although full-length HTT remains diffuse while HTTex1 forms inclusions. Further, inclusions are not sufficient to cause pathology since HTT171-120Q forms inclusions but is benign and co-expression of HTT171-120Q with non-aggregating pathogenic fl-mHTT recruits fl-mHTT to aggregates and rescues its pathogenicity. Additionally, the influence of sequences outside the expanded polyQ domain is revealed by finding that small modifications to the HTT118 or HTT171 fragments can dramatically alter their subcellular behavior and pathogenicity. Finally, mutant HTT subcellular behavior is strongly modified by different cell and tissue environments (e.g. fl-mHTT appears as diffuse nuclear in one tissue and diffuse cytoplasmic in another but toxic in both). These observations underscore the importance of cellular and structural context for the interpretation and comparison of experiments using different fragments and tissues to report the effects of expanded polyQ.

Surgical Skill Can be Objectively Measured From Fluoroscopic Images Using a Novel Image-based Decision Error Analysis (IDEA) Score.

BACKGROUND: To advance orthopaedic surgical skills training and assessment, more rigorous and objective performance measures are needed. In hip fracture repair, the tip-apex distance is a commonly used summative performance metric with clear clinical relevance, but it does not capture the skill exercised during the process of achieving the final implant position. This study introduces and evaluates a novel Image-based Decision Error Analysis (IDEA) score that better captures performance during fluoroscopically-assisted wire navigation. QUESTIONS/PURPOSES: (1) Can wire navigation skill be objectively measured from a sequence of fluoroscopic images? (2) Are skill behaviors observed in a simulated environment also exhibited in the operating room? Additionally, we sought to define an objective skill metric that demonstrates improvement associated with accumulated surgical experience. METHODS: Performance was evaluated both on a hip fracture wire navigation simulator and in the operating room during actual fracture surgery. After examining fluoroscopic image sequences from 176 consecutive simulator trials (performed by 58 first-year orthopaedic residents) and 21 consecutive surgical procedures (performed by 19 different orthopaedic residents and one attending orthopaedic surgeon), three main categories of erroneous skill behavior were identified: off-target wire adjustments, out-of-plane wire adjustments, and off-target drilling. Skill behaviors were measured by comparing wire adjustments made between consecutive images against the goal of targeting the apex of the femoral head as part of our new IDEA scoring methodology. Decision error metrics (frequency, magnitude) were correlated with other measures (image count and tip-apex distance) to characterize factors related to surgical performance on both the simulator and in the operating room. An IDEA composite score integrating decision errors (off-target wire adjustments, out-of-plane wire adjustments, and off-target drilling) and the final tip-apex distance to produce a single metric of overall performance was created and compared with the number of hip wire navigation cases previously completed (such as surgeon experience levels). RESULTS: The IDEA methodology objectively analyzed 37,000 images from the simulator and 688 images from the operating room. The number of decision errors (7 ± 5 in the operating room and 4 ± 3 on the simulator) correlated with fluoroscopic image count (33 ± 14 in the operating room and 20 ± 11 on the simulator) in both the simulator and operating room environments (R2 = 0.76; p < 0.001 and R2 = 0.71; p < 0.001, respectively). Decision error counts did not correlate with the tip-apex distance (16 ± 4 mm in the operating room and 12 ± 5 mm on the simulator) for either the simulator or the operating room (R2 = 0.08; p = 0.15 and R2 = 0.03; p = 0.47, respectively), indicating that the tip-apex distance is independent of decision errors. The IDEA composite score correlated with surgical experience (R2 = 0.66; p < 0.001). CONCLUSION: The fluoroscopic images obtained in the course of placing a guide wire contain a rich amount of information related to surgical skill. This points the way to an objective measure of skill that also has potential as an educational tool for residents. Future studies should expand this analysis to the wide variety of procedures that rely on fluoroscopic images. CLINICAL RELEVANCE: This study has shown how resident skill development can be objectively assessed from fluoroscopic image sequences. The IDEA scoring provides a basis for evaluating the competence of a resident. The score can be used to assess skill at key timepoints throughout residency, such as when rotating onto/off of a new surgical service and before performing certain procedures in the operating room, or as a tool for debriefing/providing feedback after a procedure is completed.

Miles to go (mtgo) encodes FNDC3 proteins that interact with the chaperonin subunit CCT3 and are required for NMJ branching and growth in Drosophila.

Analysis of mutants that affect formation and function of the Drosophila larval neuromuscular junction (NMJ) has provided valuable insight into genes required for neuronal branching and synaptic growth. We report that NMJ development in Drosophila requires both the Drosophila ortholog of FNDC3 genes; CG42389 (herein referred to as miles to go; mtgo), and CCT3, which encodes a chaperonin complex subunit. Loss of mtgo function causes late pupal lethality with most animals unable to escape the pupal case, while rare escapers exhibit an ataxic gait and reduced lifespan. NMJs in mtgo mutant larvae have dramatically reduced branching and growth and fewer synaptic boutons compared with control animals. Mutant larvae show normal locomotion but display an abnormal self-righting response and chemosensory deficits that suggest additional functions of mtgo within the nervous system. The pharate lethality in mtgo mutants can be rescued by both low-level pan- and neuronal-, but not muscle-specific expression of a mtgo transgene, supporting a neuronal-intrinsic requirement for mtgo in NMJ development. Mtgo encodes three similar proteins whose domain structure is most closely related to the vertebrate intracellular cytosolic membrane-anchored fibronectin type-III domain-containing protein 3 (FNDC3) protein family. Mtgo physically and genetically interacts with Drosophila CCT3, which encodes a subunit of the TRiC/CCT chaperonin complex required for maturation of actin, tubulin and other substrates. Drosophila larvae heterozygous for a mutation in CCT3 that reduces binding between CCT3 and MTGO also show abnormal NMJ development similar to that observed in mtgo null mutants. Hence, the intracellular FNDC3-ortholog MTGO and CCT3 can form a macromolecular complex, and are both required for NMJ development in Drosophila.

Systematic genetic interaction studies identify histone demethylase Utx as potential target for ameliorating Huntington's disease.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by alterations in the huntingtin gene (htt). Transcriptional dysregulation is an early event in HD progression. Protein acetylation and methylation particularly on histones regulates chromatin structure thereby preventing or facilitating transcription. Although protein acetylation has been found to affect HD symptoms, little is known about the potential role of protein methylation in HD pathology. In recent years, a series of proteins have been described that are responsible for methylating and demethylating histones as well as other proteins. We carried out systematic genetic interaction studies testing lysine and arginine methylases and demethylases in a Drosophila melanogaster HD model. We found that modulating methylation enzymes that typically affect histone positions H3K4, H3K36 or H3K79 had varying effects on HD pathology while modulating ones that typically affect constitutive heterochromatin marks at H3K9 and H4K20 generally had limited impact on HD pathology. In contrast, modulating enzymes acting on the facultative heterochromatin mark at H3K27 had specific effects on HD pathology, with reduction of the demethylase Utx rescuing HTT-induced pathology while reducing Polycomb Repressive Complex2 core methylase components led to more aggressive pathology. Further exploration of the mechanism underlying the methylation-specific interactions suggest that these lysine and arginine methylases and demethylases are likely exerting their influence through non-histone targets. These results highlight a novel therapeutic approach for HD in the form of Utx inhibition.

Phosphorylation of huntingtin at residue T3 is decreased in Huntington's disease and modulates mutant huntingtin protein conformation.

Posttranslational modifications can have profound effects on the biological and biophysical properties of proteins associated with misfolding and aggregation. However, their detection and quantification in clinical samples and an understanding of the mechanisms underlying the pathological properties of misfolding- and aggregation-prone proteins remain a challenge for diagnostics and therapeutics development. We have applied an ultrasensitive immunoassay platform to develop and validate a quantitative assay for detecting a posttranslational modification (phosphorylation at residue T3) of a protein associated with polyglutamine repeat expansion, namely Huntingtin, and characterized its presence in a variety of preclinical and clinical samples. We find that T3 phosphorylation is greatly reduced in samples from Huntington's disease models and in Huntington's disease patients, and we provide evidence that bona-fide T3 phosphorylation alters Huntingtin exon 1 protein conformation and aggregation properties. These findings have significant implications for both mechanisms of disease pathogenesis and the development of therapeutics and diagnostics for Huntington's disease.

Resident Involvement Is Not Associated With Increased Risk of Postoperative Complications After Arthroscopic Knee Surgery: A Propensity-Matched Study.

PURPOSE: To investigate whether resident involvement in knee arthroscopy procedures affects postoperative complications or operative times. METHODS: The American College of Surgeons National Surgical Quality Improvement Program registry was queried to identify patients who underwent common knee arthroscopy procedures between 2006 through 2012. Patients with a history of knee arthroplasty, septic arthritis or osteomyelitis of the knee, concomitant open or mini-open procedures, or without information on resident involvement were excluded. A 1:1 propensity score match was performed based on age, sex, obesity, smoking history, and American Society of Anesthesiologist classification to match cases with resident involved to nonresident cases. Fisher exact tests, Pearson's χ2 tests, and Wilcoxon rank sum tests were used to compare patient demographics, comorbidities, and 30-day complications. Wilcoxon rank sum tests were used to compare operative time and length of hospital stay between the 2 groups, with statistical significance defined as P < .05. RESULTS: After matching, 2954 cases (50% resident involvement) were included in the study with no significant differences in demographics or comorbidities between the 2 cohorts. The overall rate of 30-day complications was 1.1% in the nonresident and resident involved group (P = 1.000). There was no significant difference in postoperative surgical (nonresident vs resident involved: 0.48% vs 0.83%, P = .2498) or medical (nonresident vs resident involved: 0.62% vs 0.83%, P = .5111) complications. However, knee arthroscopy cases that residents were involved with had significantly longer operative times (69.8 vs 66.8 minutes, P = .0002), and length of hospital stay (0.85 vs 0.21 days, P = .0332) when compared with cases performed without a resident. CONCLUSIONS: Resident involvement in knee arthroscopy procedures is not a significant risk for medical or surgical 30-day postoperative complications. Resident participation in knee arthroscopy was associated with statistically significant but likely clinically insignificant increased operative time as well as length of hospital stay. LEVEL OF EVIDENCE: Level III: Retrospective Cohort Study.

Communication with Orthopedic Trauma Patients via an Automated Mobile Phone Messaging Robot.

BACKGROUND: Communication with orthopedic trauma patients is traditionally problematic with low response rates (RRs). The purpose of this investigation was to (1) evaluate the feasibility of communicating with orthopedic trauma patients postoperatively, utilizing an automated mobile phone messaging platform; and (2) assess the first 2 weeks of postoperative patient-reported pain and opioid use after lower extremity orthopedic trauma procedures. MATERIALS AND METHODS: This was a prospective investigation at a Level 1 trauma center in the United States. Adult patients who were capable of mobile phone messaging and were undergoing common, lower extremity orthopedic trauma procedures were enrolled in the study. Patients received a daily mobile phone message protocol inquiring about their current pain level and amount of opioid medication they had taken in the past 24 h starting on postoperative day (POD) 3 and continuing through POD 17. Our analysis considered (1) Patient completion rate of mobile phone questions, (2) Patient-reported pain level (0-10 scale), and (3) Number and percentage of daily prescribed opioid medication patients reported taking. RESULTS: Twenty-five patients were enrolled in this investigation. Patients responded to 87.5% of the pain and opioid medication inquiries they received over the 2-week study period. There were no differences in RRs by patient age, sex, or educational attainment. Patient-reported pain decreased over the initial 2-week study period from an average of 4.9 ± 1.7 on POD 3 to 3 ± 2.2 on POD 16-17. Patients took an average of 68% of their maximum daily narcotic prescription on POD 3 compared with 35% of their prescribed pain medication on POD 16-17. CONCLUSIONS: We found that in orthopedic trauma patients, an automated mobile phone messaging platform elicited a high patient RR that improved upon prior methods in the literature. This method may be used to reliably obtain pain and medication utilization data after trauma procedures.

Disruption of the nuclear membrane by perinuclear inclusions of mutant huntingtin causes cell-cycle re-entry and striatal cell death in mouse and cell models of Huntington's disease.

Accumulation of N-terminal fragments of mutant huntingtin (mHTT) in the cytoplasm, nuclei and axons of neurons is a hallmark of Huntington's disease (HD), although how these fragments negatively impact neurons remains unclear. We followed the distribution of mHTT in the striata of transgenic R6/2-J2 HD mice as their motor function declined. The fraction of cells with diffuse, perinuclear or intranuclear mHTT changed in parallel with decreasing motor function. In transgenic mice, medium spiny neurons (MSNs) that exhibited perinuclear inclusions expressed cell-cycle markers typically not seen in the striata of normal mice, and these cells are preferentially lost as disease progresses. Electron microscopy reveals that perinuclear inclusions disrupt the nuclear envelope. The progression of perinuclear inclusions being accompanied by cell-cycle activation and culminating in cell death was also observed in 1° cortical neurons. These observations provide a strong correlation between the subcellular location of mHTT, disruption of the nucleus, re-entry into the cell-cycle and eventual neuronal death. They also highlight the fact that the subcellular distribution of mHTT is highly dynamic such that the distribution of mHTT observed depends greatly on the stage of the disease being examined.

Comparative study of naturally occurring huntingtin fragments in Drosophila points to exon 1 as the most pathogenic species in Huntington's disease.

Although Huntington's disease is caused by the expansion of a CAG triplet repeat within the context of the 3144-amino acid huntingtin protein (HTT), studies reveal that N-terminal fragments of HTT containing the expanded PolyQ region can be produced by proteolytic processing and/or aberrant splicing. N-terminal HTT fragments are also prevalent in postmortem tissue, and expression of some of these fragments in model organisms can cause pathology. This has led to the hypothesis that N-terminal peptides may be critical modulators of disease pathology, raising the possibility that targeting aberrant splicing or proteolytic processing may present attractive therapeutic targets. However, many factors can contribute to pathology, including genetic background and differential expression of transgenes, in addition to intrinsic differences between fragments and their cellular effects. We have used Drosophila as a model system to determine the relative toxicities of different naturally occurring huntingtin fragments in a system in which genetic background, transgene expression levels and post-translational proteolytic processing can be controlled. These studies reveal that among the naturally occurring N-terminal HTT peptides, the exon 1 peptide is exceptionally pathogenic and exhibits unique structural and biophysical behaviors that do not appear to be incremental changes compared with other fragments. If this proves correct, efforts to specifically reduce the levels of exon 1 peptides or to target toxicity-influencing post-translational modifications that occur with the exon 1 context are likely to have the greatest impact on pathology.

Potential function for the Huntingtin protein as a scaffold for selective autophagy.

Although dominant gain-of-function triplet repeat expansions in the Huntingtin (HTT) gene are the underlying cause of Huntington disease (HD), understanding the normal functions of nonmutant HTT protein has remained a challenge. We report here findings that suggest that HTT plays a significant role in selective autophagy. Loss of HTT function in Drosophila disrupts starvation-induced autophagy in larvae and conditional knockout of HTT in the mouse CNS causes characteristic cellular hallmarks of disrupted autophagy, including an accumulation of striatal p62/SQSTM1 over time. We observe that specific domains of HTT have structural similarities to yeast Atg proteins that function in selective autophagy, and in particular that the C-terminal domain of HTT shares structural similarity to yeast Atg11, an autophagic scaffold protein. To explore possible functional similarity between HTT and Atg11, we investigated whether the C-terminal domain of HTT interacts with mammalian counterparts of yeast Atg11-interacting proteins. Strikingly, this domain of HTT coimmunoprecipitates with several key Atg11 interactors, including the Atg1/Unc-51-like autophagy activating kinase 1 kinase complex, autophagic receptor proteins, and mammalian Atg8 homologs. Mutation of a phylogenetically conserved WXXL domain in a C-terminal HTT fragment reduces coprecipitation with mammalian Atg8 homolog GABARAPL1, suggesting a direct interaction. Collectively, these data support a possible central role for HTT as an Atg11-like scaffold protein. These findings have relevance to both mechanisms of disease pathogenesis and to therapeutic intervention strategies that reduce levels of both mutant and normal HTT.

A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington's disease.

Protein acetylation, which is central to transcriptional control as well as other cellular processes, is disrupted in Huntington's disease (HD). Treatments that restore global acetylation levels, such as inhibiting histone deacetylases (HDACs), are effective in suppressing HD pathology in model organisms. However, agents that selectively target the disease-relevant HDACs have not been available. SirT1 (Sir2 in Drosophila melanogaster) deacetylates histones and other proteins including transcription factors. Genetically reducing, but not eliminating, Sir2 has been shown to suppress HD pathology in model organisms. To date, small molecule inhibitors of sirtuins have exhibited low potency and unattractive pharmacological and biopharmaceutical properties. Here, we show that highly selective pharmacological inhibition of Drosophila Sir2 and mammalian SirT1 using the novel inhibitor selisistat (selisistat; 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide) can suppress HD pathology caused by mutant huntingtin exon 1 fragments in Drosophila, mammalian cells and mice. We have validated Sir2 as the in vivo target of selisistat by showing that genetic elimination of Sir2 eradicates the effect of this inhibitor in Drosophila. The specificity of selisistat is shown by its effect on recombinant sirtuins in mammalian cells. Reduction of HD pathology by selisistat in Drosophila, mammalian cells and mouse models of HD suggests that this inhibitor has potential as an effective therapeutic treatment for human disease and may also serve as a tool to better understand the downstream pathways of SirT1/Sir2 that may be critical for HD.

Targeting H3K4 trimethylation in Huntington disease.

Transcriptional dysregulation is an early feature of Huntington disease (HD). We observed gene-specific changes in histone H3 lysine 4 trimethylation (H3K4me3) at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a chromatin signature for this mark. Reducing the levels of the H3K4 demethylase SMCX/Jarid1c in primary neurons reversed down-regulation of key neuronal genes caused by mutant Huntingtin expression. Finally, reduction of SMCX/Jarid1c in primary neurons from BACHD mice or the single Jarid1 in a Drosophila HD model was protective. Therefore, targeting this epigenetic signature may be an effective strategy to ameliorate the consequences of HD.

There is poor reliability of Böhler's angle and the crucial angle of Gissane in assessing displaced intra-articular calcaneal fractures.

BACKGROUND: Two-dimensional measurements are used to describe displaced intra-articular calcaneal fractures (DIACF). Our study evaluates the performance of Böhler's angle (BA) and the crucial angle of Gissane (CAG) among orthopedic surgeons. METHODS: Thirty-four pre- and post-operative lateral foot radiographs from patients with DIACF were shown to four orthopedic surgeons who measured BA and the CAG. The intra- and inter-observer reliability were calculated using the intra-class correlation coefficient (ICC). Additionally, we calculated frequency of consensus given an allowed discrepancy. We then determined the tolerance limit for each measurement. RESULTS: The ICC for inter-observer reliability of BA was 0.83 in the first session and 0.77 in the second. The ICC for intra-observer reliability ranged from 0.83 to 0.98. For the CAG, the inter-observer ICC was 0.28 and 0.1 in the two sessions. Intra-observer ICC ranged from 0.16 to 0.67. With an allowed discrepancy of 20°, there was lack of consensus for BA in 37.5% and for the CAG in 59% of measurements on average. The 95% confidence interval for 90% agreement in BA involved a range of 76°. For CAG, the 95% confidence interval of tolerance for 90% agreement was 56°. CONCLUSIONS: For BA and CAG, there is frequent disagreement among experienced observers, even given a wide tolerance range. We recommend use of caution when applying BA as currently measured in making treatment decisions for DIACF. LEVEL OF CLINICAL EVIDENCE: Diagnostic, level III.

A novel target for Huntington's disease: ERK at the crossroads of signaling. The ERK signaling pathway is implicated in Huntington's disease and its upregulation ameliorates pathology.

Activating the ERK pathway (extracellular signal-regulated kinase pathway) has proven beneficial in several models of Huntington's disease (HD), and drugs that are protective in HD models have recently been found to activate ERK. Thus, the ERK cascade may be a potential target for therapeutic intervention in this currently untreatable disorder. HD is caused by an expanded polyglutamine repeat in the huntingtin (Htt) protein that actuates a diverse set of pathogenic mechanisms. In response to mutant Htt, ERK is activated and directs a protective transcriptional response and inhibits caspase activation. Paradoxically, Htt also interferes with several signaling events of the ERK pathway. Mutant Htt compromises the ERK-dependent transcriptional response to corticostriatal BDNF signaling. Mutant Htt also hinders glutamate uptake from the synaptic cleft by down-regulating ERK-dependent expression of glutamate transporters, leaving cells vulnerable to excitotoxicity. Some of this cellular complexity can be capitalized on to achieve selective activation of ERK, which can be protective.

The effect of resident participation on short-term outcomes after orthopaedic surgery.

BACKGROUND: The influence of resident involvement on short-term outcomes after orthopaedic surgery is mostly unknown. QUESTIONS/PURPOSES: The purposes of our study were to examine the effects of resident involvement in surgical cases on short-term morbidity, mortality, operating time, hospital length of stay, and reoperation rate and to analyze these parameters by level of training. METHODS: The 2005­2011 American College of Surgeons National Surgical Quality Improvement Program data set was queried using Current Procedural Terminology codes for 66,817 cases across six orthopaedic procedural domains: 28,686 primary total joint arthroplasties (TJAs), 2412 revision TJAs, 16,832 basic and 5916 advanced arthroscopies, 8221 lower extremity traumas, and 4750 spine arthrodeses (fusions). Bivariate and multivariate logistic regression and propensity scores were used to build models of risk adjustment. We compared the morbidity and mortality rates, length of operating time, hospital length of stay, and reoperation rate for cases with or without resident involvement. For cases with resident participation, we analyzed the same parameters by training level. RESULTS: Resident participation was associated with higher morbidity in TJAs (odds ratio [OR], 1.6; range, 1.4­1.9), lower extremity trauma (OR, 1.3; range, 1.2­1.5), and fusion (OR, 1.4; range, 1.2­1.7) after adjustment. However, resident involvement was not associated with increased mortality. Operative time was greater (all p < 0.001) with resident involvement in all procedural domains. Longer hospital length of stay was associated with resident participation in lower extremity trauma (p < 0.001) and fusion cases (p = 0.003), but resident participation did not affect length of stay in other domains. Resident involvement was associated with greater 30-day reoperation rates for cases of lower extremity trauma (p = 0.041) and fusion (p < 0.001). Level of resident training did not consistently influence surgical outcomes. CONCLUSIONS: Results of our study suggest resident involvement in surgical procedures is not associated with increased short-term major morbidity and mortality after select cases in orthopaedic surgery. Findings of longer operating times and differences in minor morbidity should lead to future initiatives to provide resident surgical skills training and improve perioperative efficiency in the academic setting. LEVEL OF EVIDENCE: Level II, prognostic study. See the Instructions for Authors for a complete description of levels of evidence.

Methylene blue modulates huntingtin aggregation intermediates and is protective in Huntington's disease models.

Huntington's disease (HD) is a devastating neurodegenerative disorder with no disease-modifying treatments available. The disease is caused by expansion of a CAG trinucleotide repeat and manifests with progressive motor abnormalities, psychiatric symptoms, and cognitive decline. Expression of an expanded polyglutamine repeat within the Huntingtin (Htt) protein impacts numerous cellular processes, including protein folding and clearance. A hallmark of the disease is the progressive formation of inclusions that represent the culmination of a complex aggregation process. Methylene blue (MB), has been shown to modulate aggregation of amyloidogenic disease proteins. We investigated whether MB could impact mutant Htt-mediated aggregation and neurotoxicity. MB inhibited recombinant protein aggregation in vitro, even when added to preformed oligomers and fibrils. MB also decreased oligomer number and size and decreased accumulation of insoluble mutant Htt in cells. In functional assays, MB increased survival of primary cortical neurons transduced with mutant Htt, reduced neurodegeneration and aggregation in a Drosophila melanogaster model of HD, and reduced disease phenotypes in R6/2 HD modeled mice. Furthermore, MB treatment also promoted an increase in levels of BDNF RNA and protein in vivo. Thus, MB, which is well tolerated and used in humans, has therapeutic potential for HD.

ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington's disease.

Huntington's disease (HD) is an inherited, progressive and ultimately fatal neurodegenerative disorder that is characterized by psychiatric, cognitive and motor symptoms. Among the pathways implicated in HD are those involving mitogen-activated protein kinase signaling and particularly the Ras-extracellular signal-regulated kinase (ERK) cascade. Studies in both cells and animal models suggest that ERK activation might provide a novel therapeutic target for the treatment of HD but compounds that specifically activate ERK are few. To test the hypothesis that pharmaceutical activation of ERK might be protective for HD, a polyphenol, fisetin, which was previously shown to activate the Ras-ERK cascade, was tested in three different models of HD: PC12 cells expressing mutant Httex1 under the control of an inducible promoter, Drosophila expressing mutant Httex1 and the R6/2 mouse model of HD. The results indicate that fisetin can reduce the impact of mutant huntingtin in each of these disease models. Prompted by this observation, we determined that the related polyphenol, resveratrol, also activates ERK and is protective in HD models. Notably, although more than a dozen small molecule inhibitors of ERK activation are in clinical trials, very few small molecule activators of ERK signaling are reported. Thus, fisetin, resveratrol and related compounds might be useful for the treatment of HD by virtue of their unique ability to activate ERK.

SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis.

Huntington's disease (HD), an incurable neurodegenerative disorder, has a complex pathogenesis including protein aggregation and the dysregulation of neuronal transcription and metabolism. Here, we demonstrate that inhibition of sirtuin 2 (SIRT2) achieves neuroprotection in cellular and invertebrate models of HD. Genetic or pharmacologic inhibition of SIRT2 in a striatal neuron model of HD resulted in gene expression changes including significant down-regulation of RNAs responsible for sterol biosynthesis. Whereas mutant huntingtin fragments increased sterols in neuronal cells, SIRT2 inhibition reduced sterol levels via decreased nuclear trafficking of SREBP-2. Importantly, manipulation of sterol biosynthesis at the transcriptional level mimicked SIRT2 inhibition, demonstrating that the metabolic effects of SIRT2 inhibition are sufficient to diminish mutant huntingtin toxicity. These data identify SIRT2 inhibition as a promising avenue for HD therapy and elucidate a unique mechanism of SIRT2-inhibitor-mediated neuroprotection. Furthermore, the ascertainment of SIRT2's role in regulating cellular metabolism demonstrates a central function shared with other sirtuin proteins.