Trends and Contributing Factors in Medicolegal Cases Involving Spine Surgery.

STUDY DESIGN: Retrospective descriptive study. OBJECTIVE: The aim of this study was to describe closed medicolegal cases involving physicians and spine surgery in Canada from a trend and patient safety perspective. SUMMARY OF BACKGROUND DATA: Spine surgery is a source of medicolegal complaints against surgeons partly owing to the potential severity of associated complications. In previous medicolegal studies, researchers applied a medicolegal lens to their analyses without applying a quality improvement or patient safety lens. METHODS: The study comprised a 15-year medicolegal trend analysis and a 5-year contributing factors analysis of cases (civil legal and regulatory authority matters) from the Canadian Medical Protective Association (CMPA), representing an estimated 95% of physicians in Canada. Included cases were closed by the CMPA between 2004 and 2018 (trends) or 2014 and 2018 (contributing factors). We fit a linear trend line to the annual rates of spine surgery cases per 1000 physician-years of CMPA membership for physicians in a neurosurgery or orthopedic surgery specialty. We then applied an ANOVA type III sum of squares test to determine the statistical significance of the annualized change rate over time. For the contributing factors analysis, we reported descriptive statistics for patient and physician characteristics, patient harm, and peer expert criticisms in each case. RESULTS: Our trend analysis included 340 cases. Case rates decreased significantly at an annualized change rate of -4.7% (P  = 0.0017). Our contributing factors analysis included 81 civil legal and 19 regulatory authority cases. Most patients experienced health care-related harm (89/100, 89.0%). Peer experts identified intraoperative injuries (29/89, 32.6%), diagnostic errors (14/89, 15.7%), and wrong site surgeries (16/89, 18.0%) as the top patient safety indicators. The top factor contributing to medicolegal risk was physician clinical decision-making. CONCLUSION AND RELEVANCE: Although case rates decreased, patient harm was attributable to health care in the majority of recently closed cases. Therefore, crucial opportunities remain to enhance patient safety in spine surgery.Level of Evidence: 4.

Case costing in spine surgery: Can surgeons assist with accurate capture of operating room costs?

Surgical case costing is critical for health leaders to make decisions about resource utilization. Synoptic reporting offers the potential for surgeons to capture these costs and work with other leaders to make evidence-based decisions. The purpose of this study was to determine whether surgeons documented intra-operative cost drivers as part of their operative report. This article outlines a synoptic reporting system at a quaternary spine care centre. Data were captured from 2015 to 2020. Surgeon rates of documentation for specific devices, bone graft, and surgical adjuncts were evaluated. It is hoped that the results of this survey will help to guide programs to capture costs in other settings.

Seizure-induced thoracolumbar burst fractures - Not to be missed.

While rare, post-ictal thoracolumbar burst fractures are commonly missed due to confounding factors, resulting in delayed treatment and the potential for serious neurological deficits. This paper serves as a call for a high-degree of clinical suspicion when treating post-ictal patients to ensure they undergo a focused neurological examination of the lower extremities. If unresponsive/uncooperative, spinal precautions should be maintained until the spine can be cleared clinically or radiographically. In all events, if the patient is complaining of musculoskeletal pain possibly originating from the spine, radiographic evaluations are warranted to prevent possible deficits caused by a missed thoracolumbar fracture.

Will cost transparency in the operating theatre cause surgeons to change their practice?

Surgeons may not have a thorough knowledge about the costs of devices or surgical equipment. The main reason for this in many systems is price insensitivity. The purpose of this study was to determine whether spine surgical procedural expenses change once physicians are aware of the costs for surgical implants and the total associated costs with the procedure. A thorough bottom up case costing methodology was used to capture the costs of admission for three comparable spine surgical procedures at a large tertiary care center. Costs were collected for an initial 5-month period where surgeons were not aware of costs, followed by another 5-month period with detailed cost information. Instrumental costs, procedural costs and costs of admission were captured as well as health related quality of life (HRQOL) measures at 3 months. Statistical analysis was undertaken with STATA software. Costs decreased by $478 for instrumentation once actual prices were known (p = 0.069). Only ACDF procedures demonstrated statistically significant instrumental cost savings of $754 (p = 0.009). Total procedural costs were also less ($297, p = 0.194) but the total overall costs of admission increased ($401, p = 0.228). There were no differences in VAS, EQ-5D, or SF-12 scores. Although costs decrease for implants in surgery when prices are known, this appears to have little or no effect on overall costs of care. Length of stay and operating room time have greater effects on global costs. Future efforts to encourage efficient cost savings should focus on practice patterns/pathways for similar conditions rather than limiting the use of certain implants.

Enhanced IL-17 signalling following myocardial ischaemia/reperfusion injury.

BACKGROUND: IL-17A and IL-17F are pro-inflammatory cytokines which induce the expression of several cytokines, chemokines and matrix metalloproteinases (MMPs) in target cells. IL-17 cytokines have recently attracted huge interest due to their pathogenic role in diseases such as arthritis and inflammatory bowel disease although a role for IL-17 cytokines in myocardial infarction (MI) has not previously been described. METHODS: In vivo MI was performed by coronary artery occlusion in the absence or presence of a neutralizing IL-17 antibody for blocking IL-17 actions in vivo. IL-17 signaling was also assessed in isolated primary cardiomyocytes by Western blot, mRNA expression and immunostaining. RESULTS: Expression of IL-17A, IL-17F and the IL-17 receptor (IL-17RA) were all increased following MI. Expression of several IL-17 target genes, including Cxcl1, Cxcl2, IL-1ß, iNOS and IL-6 was also upregulated following MI. In addition, IL-17A promoted the expression of Cxcl1 and IL-6 in isolated cardiomyocytes in a MAPK and PI(3)K-dependent manner. IL-17A and ischaemia/reperfusion (I/R) injury were found to have an additive effect on Cxcl1 expression, suggesting that IL-17 may enhance myocardial neutrophil recruitment during MI. Moreover, protein levels of both IL-17R and IL-17A were enhanced following in vivo MI. Finally, blocking IL-17 signaling in vivo reduced the levels of apoptotic cell death markers following in vivo MI. CONCLUSIONS: These data imply that the expression of IL-17 cytokines and their receptor are elevated during myocardial I/R injury and may play a fundamental role in post infarct inflammatory and apoptotic responses.

Leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction induces a novel genetic signature resulting in T-cells refractory to transforming growth factor-ß signaling.

The immunesuppressive cytokine TGF-ß plays crucial regulatory roles in the induction and maintenance of immunologic tolerance and prevention of immunopathologies. However, it remains unclear how circulating T-cells can escape from the quiescent state maintained by TGF-ß. Here, we report that the T-cell integrin leukocyte function-associated antigen-1 (LFA-1) interaction with its ligand intercellular adhesion molecule-1 (ICAM-1) induces a genetic signature associated with reduced TGF-ß responsiveness via up-regulation of SKI, E3 ubiquitin-protein ligase SMURF2, and SMAD7 (mothers against decapentaplegic homolog 7) genes and proteins. We confirmed that the expression of these TGF-ß inhibitory molecules was dependent on STAT3 and/or JNK activation. Increased expression of SMAD7 and SMURF2 in LFA-1/ICAM-1 cross-linked T-cells resulted in impaired TGF-ß-mediated phosphorylation of SMAD2 and suppression of IL-2 secretion. Expression of SKI caused resistance to TGF-ß-mediated suppression of IL-2, but SMAD2 phosphorylation was unaffected. Blocking LFA-1 by neutralizing antibody or specific knockdown of TGF-ß inhibitory molecules by siRNA substantially restored LFA-1/ICAM-1-mediated alteration in TGF-ß signaling. LFA-1/ICAM-1-stimulated human and mouse T-cells were refractory to TGF-ß-mediated induction of FOXP3(+) (forkhead box P3) and RORγt(+) (retinoic acid-related orphan nuclear receptor γt) Th17 differentiation. These mechanistic data suggest an important role for LFA-1/ICAM-1 interactions in immunoregulation concurrent with lymphocyte migration that may have implications at the level of local inflammatory response and for anti-LFA-1-based therapies.

Lipid rafts are disrupted in mildly inflamed intestinal microenvironments without overt disruption of the epithelial barrier.

Intestinal epithelial barrier disruption is a feature of inflammatory bowel disease (IBD), but whether barrier disruption precedes or merely accompanies inflammation remains controversial. Tight junction (TJ) adhesion complexes control epithelial barrier integrity. Since some TJ proteins reside in cholesterol-enriched regions of the cell membrane termed lipid rafts, we sought to elucidate the relationship between rafts and intestinal epithelial barrier function. Lipid rafts were isolated from Caco-2 intestinal epithelial cells primed with the proinflammatory cytokine interferon-γ (IFN-γ) or treated with methyl-ß-cyclodextrin as a positive control for raft disruption. Rafts were also isolated from the ilea of mice in which colitis had been induced in conjunction with in vivo intestinal permeability measurements, and lastly from intestinal biopsies of ulcerative colitis (UC) patients with predominantly mild or quiescent disease. Raft distribution was analyzed by measuring activity of the raft-associated enzyme alkaline phosphatase and by performing Western blot analysis for flotillin-1. Epithelial barrier integrity was estimated by measuring transepithelial resistance in cytokine-treated cells or in vivo permeability to fluorescent dextran in colitic mice. Raft and nonraft fractions were analyzed by Western blotting for the TJ proteins occludin and zonula occludens-1 (ZO-1). Our results revealed that lipid rafts were disrupted in IFN-γ-treated cells, in the ilea of mice with subclinical colitis, and in UC patients with quiescent inflammation. This was not associated with a clear pattern of occludin or ZO-1 relocalization from raft to nonraft fractions. Significantly, a time-course study in colitic mice revealed that disruption of lipid rafts preceded the onset of increased intestinal permeability. Our data suggest for the first time that lipid raft disruption occurs early in the inflammatory cascade in murine and human colitis and, we speculate, may contribute to subsequent disruption of epithelial barrier function.

Autophagy in the stress-induced myocardium.

Cardiovascular disease is a leading cause of death worldwide, particularly in Western societies. During an ischaemic insult, ventricular pressure from the heart is diminished as a result of cardiac myocyte death by necrosis and apoptosis. Autophagy is a process whereby cells catabolise intracellular proteins in order to generate ATP in times of stress such as nutrient starvation and hypoxia. Emerging evidence suggests that autophagy plays a positive role in cardiac myocyte survival during periods of cellular stress performing an important damage limitation function. By promoting cell survival, cardiac myocyte loss is reduced thereby minimising the potential of heart failure. In contrast, it has been reported that autophagy can also be a form of cell death. By considering the various animal models of autophagy, we examine the role of the Signal Transducers and Activator of Transcription (STAT) proteins in the autophagic response. Additionally we review the role of the tumour suppressor, p53 and its family member p73 and their potential role in the autophagic response.

The role of minocycline in ischemia-reperfusion injury: a comprehensive review of an old drug with new implications.

Minocycline is a semi-synthetic tetracycline that inhibits bacterial protein synthesis and hence is used for the treatment of many infectious diseases. Over the years, many other interesting properties of minocycline have been identified and been used to make patents which include anti-inflammatory, anti-apoptotic, matrix metalloproteinase inhibitor and free oxygen radical scavenger activity. Ischemia-reperfusion injury is a concern for almost every clinical specialty and minocycline seems to be an attractive cytoprotective agent that can ameliorate the damage due to these properties. Ischemia-reperfusion injury is a complex process and involves various pathways that lead to cell death. This review focuses on the body of evidence describing various proposed mechanisms of action of minocycline and its current experimental use in various animal models of ischemia-reperfusion injury.

Bio-electrospraying primary cardiac cells: in vitro tissue creation and functional study.

Manifestations of myocardial infarctions have been recognized as one of the major killers in the Western world. Therefore, advancing and developing novel cardiac tissue repair and replacement therapeutics have great implications to our health sciences and well-being. There are several approaches for forming cardiac tissues, non-jet-based and jet-based methodologies. A unique advantage of jet-based approaches is the possibility to handle living cells with a matrix for cell distribution and deposition in suspension, either as single or heterogeneous cell populations. Our previous studies on bio-electrospraying of cardiac cells have shown great promise. Here, we show for the first time the ability to bio-electrospray the three major cell types of the myocardium, both independently and simultaneously, for forming a fully functional cardiac tissue. Several samples are characterized in vitro and found to be indistinguishable in comparison to controls. Thus, we are describing a swiftly emerging novel biotechnique for direct cardiac tissue generation. Moreover, the present investigations pave the way for the development and optimization of a bio-patterning approach for the fabrication of biologically viable cardiac tissue grafts for the potential treatment of severe heart failure after myocardial infarction.

STAT3 modulates the DNA damage response pathway.

The STAT3 transcription factor is well known to function as an anti-apoptotic factor, especially in numerous malignancies. Recently we showed that STAT3 is cytoprotective and that cells lacking STAT3 are more sensitive to oxidative stress. A key feature of oxidative stress involves activation of the DNA damage pathway. However, a role for STAT3 or its contribution in response to DNA damage has not been described. In the present study we show that cells lacking STAT3 are less efficient in repairing damaged DNA. Moreover, STAT3 deficient cells show reduced activity of the ATM-Chk2 and ATR-Chk1 pathways, both important pathways in sensing DNA damage. Finally we show that MDC1, a regulator of the ATM-Chk2 pathway and facilitator of the DNA damage response, is modulated by STAT3 at the transcriptional level. These findings demonstrate that STAT3 is necessary for efficient repair of damaged DNA, partly by modulating the ATM-Chk2 and ATR-Chk1 pathways.

What causes a broken heart--molecular insights into heart failure.

Our understanding of the molecular processes which regulate cardiac function has grown immeasurably in recent years. Even with the advent of ß-blockers, angiotensin inhibitors and calcium modulating agents, heart failure (HF) still remains a seriously debilitating and life-threatening condition. Here, we review the molecular changes which occur in the heart in response to increased load and the pathways which control cardiac hypertrophy, calcium homeostasis, and immune activation during HF. These can occur as a result of genetic mutation in the case of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) or as a result of ischemic or hypertensive heart disease. In the majority of cases, calcineurin and CaMK respond to dysregulated calcium signaling and adrenergic drive is increased, each of which has a role to play in controlling blood pressure, heart rate, and left ventricular function. Many major pathways for pathological remodeling converge on a set of transcriptional regulators such as myocyte enhancer factor 2 (MEF2), nuclear factors of activated T cells (NFAT), and GATA4 and these are opposed by the action of the natriuretic peptides ANP and BNP. Epigenetic modification has emerged in recent years as a major influence cardiac physiology and histone acetyl transferases (HATs) and histone deacetylases (HDACs) are now known to both induce and antagonize hypertrophic growth. The newly emerging roles of microRNAs in regulating left ventricular dysfunction and fibrosis also has great potential for novel therapeutic intervention. Finally, we discuss the role of the immune system in mediating left ventricular dysfunction and fibrosis and ways this can be targeted in the setting of viral myocarditis.

New targets of urocortin-mediated cardioprotection.

The urocortin (UCN) hormones UCN1 and UCN2 have been shown previously to confer significant protection against myocardial ischaemia/reperfusion (I/R) injury; however, the molecular mechanisms underlying their action are poorly understood. To further define the transcriptional effect of UCNs that underpins their cardioprotective activity, a microarray analysis was carried out using an in vivo rat coronary occlusion model of I/R injury. Infusion of UCN1 or UCN2 before the onset of reperfusion resulted in the differential regulation of 66 and 141 genes respectively, the majority of which have not been described previously. Functional analysis demonstrated that UCN-regulated genes are involved in a wide range of biological responses, including cell death (e.g. X-linked inhibitor of apoptosis protein), oxidative stress (e.g. nuclear factor erythroid derived 2-related factor 1/nuclear factor erythroid derived 2-like 1) and metabolism (e.g. Prkaa2/AMPK). In addition, both UCN1 and UCN2 were found to modulate the expression of a host of genes involved in G-protein-coupled receptor (GPCR) signalling including Rac2, Gnb1, Dab2ip (AIP1), Ralgds, Rnd3, Rap1a and PKA, thereby revealing previously unrecognised signalling intermediates downstream of CRH receptors. Moreover, several of these GPCR-related genes have been shown previously to be involved in mitogen-activated protein kinase (MAPK) activation, suggesting a link between CRH receptors and induction of MAPKs. In addition, we have shown that both UCN1 and UCN2 significantly reduce free radical damage following myocardial infarction, and comparison of the UCN gene signatures with that of the anti-oxidant tempol revealed a significant overlap. These data uncover novel gene expression changes induced by UCNs, which will serve as a platform to further understand their mechanism of action in normal physiology and cardioprotection.

Activation of Src protein tyrosine kinase plays an essential role in urocortin-mediated cardioprotection.

Urocortin is a 40 amino acid peptide of the corticotrophin-releasing factor (CRF) family that is synthesized and released by cardiac myocytes. Endogenous urocortin expression is increased during ischemia/reperfusion (I/R) and addition of exogenous urocortin reduces cell death caused by I/R injury. Studies have also showed that the protective action of urocortin is mediated by the activation of ERK1/2. We discovered that a non-receptor tyrosine kinase, Src, is involved in the urocortin-induced activation of ERK1/2 in mouse atrial HL-1 myocytes. The selective Src family kinase inhibitor, PP2, reduced the urocortin-induced phosphorylation of ERK1/2, and so did the expression of a dominant-negative mutant of Src in transfected HL-1 cells. Inhibition of Src by PP2 also reduced urocortin's protective effects in HL-1 cells after hypoxia/reoxygenation (H/R), as assessed by flow cytometry and caspase-3 activation assay. Titration studies indicated that as little as 10(-8)M urocortin was sufficient to induce Src activation. Maximal phosphorylation/activation of Src and ERK1/2 were both detected after 5 min incubation with urocortin. These effects of urocortin were largely mediated by CRF receptor-1, although a minor contribution of CRF receptor-2 cannot be excluded. Here we report for the first time that short-term treatment with urocortin causes rapid phosphorylation of Src, and that the urocortin-activated Src kinase serves as an upstream modulator of ERK1/2 activation, playing an essential role in urocortin-mediated cardioprotection.

STAT3 deletion sensitizes cells to oxidative stress.

The transcription factor STAT1 plays a role in promoting apoptotic cell death, whereas the related STAT3 transcription factor protects cardiac myocytes from ischemia/reperfusion (I/R) injury or oxidative stress. Cytokines belonging to the IL-6 family activate the JAK-STAT3 pathway, but also activate other cytoprotective pathways such as the MAPK-ERK or the PI3-AKT pathway. It is therefore unclear whether STAT3 is the only cytoprotective mediator against oxidative stress-induced cell death. Overexpression of STAT3 in primary neonatal rat ventricular myocytes (NRVM) protects against I/R-induced cell death. Moreover, a dominant negative STAT3 adenovirus (Ad ST3-DN) enhanced apoptotic cell death (81.2+/-6.9%) compared to control infected NRVM (46.0+/-3.1%) following I/R. Depletion of STAT3 sensitized cells to apoptotic cell death following oxidative stress. These results provide direct evidence for the role of STAT3 as a cytoprotective transcription factor in cells exposed to oxidative stress.

ERK and the F-box protein betaTRCP target STAT1 for degradation.

The transcription factor STAT1 has roles in development, homeostasis, cellular differentiation, and apoptosis and has been postulated to function as a tumor suppressor. STAT1 is activated by tyrosine or serine phosphorylation in response to specific cytokines or following a variety of stress-induced stimuli. STAT1 activity is carefully regulated to prevent sustained STAT1-mediated transcription, although the molecular mechanisms involved in the modulation of STAT1 stability are poorly understood. Here we show that activated STAT1 is degraded at the proteasome by a mechanism involving the F-box E3 ligase, SCF(betaTRCP). Active p42/p44 MAPK-ERK phosphorylates STAT1 on serine 727 and targets it for proteasomal degradation. SCF(betaTRCP) binds wild-type STAT1 but not the nonphosphorylatable mutant STAT1(S727A). Moreover, silencing betaTRCP expression or pharmacological inhibition of ERK activity stabilized STAT1 expression. These data suggest that constitutively active ERK may inappropriately degrade STAT1, with loss of its pro-apoptotic and tumor suppressor functions.

Molecular regulation of cardiac hypertrophy.

Heart failure is one of the leading causes of mortality in the western world and encompasses a wide spectrum of cardiac pathologies. When the heart experiences extended periods of elevated workload, it undergoes hypertrophic enlargement in response to the increased demand. Cardiovascular disease, such as that caused by myocardial infarction, obesity or drug abuse promotes cardiac myocyte hypertrophy and subsequent heart failure. A number of signalling modulators in the vasculature milieu are known to regulate heart mass including those that influence gene expression, apoptosis, cytokine release and growth factor signalling. Recent evidence using genetic and cellular models of cardiac hypertrophy suggests that pathological hypertrophy can be prevented or reversed and has promoted an enormous drive in drug discovery research aiming to identify novel and specific regulators of hypertrophy. In this review we describe the molecular characteristics of cardiac hypertrophy such as the aberrant re-expression of the fetal gene program. We discuss the various molecular pathways responsible for the co-ordinated control of the hypertrophic program including: natriuretic peptides, the adrenergic system, adhesion and cytoskeletal proteins, IL-6 cytokine family, MEK-ERK1/2 signalling, histone acetylation, calcium-mediated modulation and the exciting recent discovery of the role of microRNAs in controlling cardiac hypertrophy. Characterisation of the signalling pathways leading to cardiac hypertrophy has led to a wealth of knowledge about this condition both physiological and pathological. The challenge will be translating this knowledge into potential pharmacological therapies for the treatment of cardiac pathologies.