A Retrospective Comparative Analysis on the Effect of Tranexamic Acid to Reduce Perioperative Blood Loss in Patients Undergoing Cervical Spine Surgery.

STUDY DESIGN: Retrospective Cohort Study. OBJECTIVE: The purpose of this study is to assess the impact of intravenous TXA on blood loss outcomes in anterior, posterior, and combined approaches for elective cervical spine surgery. SUMMARY OF BACKGROUND DATA: Tranexamic acid (TXA) has been shown to reduce blood loss in a variety of operations, such as lumbar spine surgery. However, limited studies have evaluated the efficacy of TXA in cervical spine surgery. METHODS: We performed a retrospective review of a single surgeon's elective cervical spine operations between September 2011 and March 2017. Patients were divided into 3 groups: anterior approach, posterior approach, or combined approach. Patients were then further subdivided into TXA versus control groups based on whether they received TXA treatment. We performed multiple linear regressions to assess the relationship between the use of TXA and other dependent variables (number of vertebral levels treated, need for a vertebral corpectomy) on total perioperative blood loss, intraoperative estimated blood loss, postoperative drain output, total operative time, postoperative change in hemoglobin, and occurrence of transfusion and/or postoperative deep venous thrombus (DVT). RESULTS: We found that the use of TXA statistically significantly reduced total perioperative blood loss (P=0.04) and postoperative drain output (P=0.004) in posterior surgical approach cervical spine surgery but did not statistically significantly impact any blood loss variables in anterior or combined surgical approaches to elective cervical spine surgery. The use of TXA was a significant predictor for a decrease in intraoperative (P=0.02) and postoperative (P<0.01) blood loss. CONCLUSIONS: This study found that TXA statistically significantly decreased total blood loss and postoperative drain output when controlling for multiple confounding factors. LEVEL OF EVIDENCE: Level III.

The Effects of Blood Glucose Control in the Operative Spine Patient: A Systematic Review.

OBJECTIVE: To our knowledge, this is the first systematic review to evaluate the available literature on the effects of perioperative serum glucose (SG) on outcomes for patients undergoing spine surgery. This review will add insight into how the perioperative management of SG affects the outcomes of patients undergoing spine surgery. METHODS: Three databases were used in this review including Embase, PubMed, and Cochrane Library. The searches were from 2012 to 2022 and included the terms "spine surgery" and "glucose level" to identify studies that demonstrated a correlation between glucose level and postoperative outcomes. Pediatric studies, those that did not specify spine surgical outcomes related to glucose levels, and non-English studies were excluded. The methodological items for nonrandomized studies score was used to assess risk of bias in the included studies. RESULTS: This review included a total of 9 cohort studies, both prospective and retrospective, encompassing a total of 431,156 subjects. Seven of the 9 studies reported an increased overall complication rate among patients with diabetes or with higher SG levels, and 4 studies demonstrated an increased infection rate among this population. Two studies reported an association between decreased SG levels and improved neurological recovery when a deficit was present preoperatively, and 1 of the studies found that this association was statistically significant. LIMITATIONS: Limitations of this review include lack of standardization regarding type of surgery, location of the spine, and level of evidence. CONCLUSION: Most of the current literature suggests that elevated SG levels in patients undergoing spine surgery likely leads to higher complication rates and may lead to increased infection rates, and this review reinforced the current evidence. Additionally, perioperative SG levels may be associated with the extent of neurological recovery after surgery, but further investigation may be warranted. CLINICAL RELEVANCE: This review adds to the current body of evidence regarding perioperative SG levels and its association with complications.

PGRN deficiency exacerbates, whereas a brain penetrant PGRN derivative protects, GBA1 mutation-associated pathologies and diseases.

Mutations in GBA1, encoding glucocerebrosidase (GCase), cause Gaucher disease (GD) and are also genetic risks in developing Parkinson's disease (PD). Currently, the approved therapies are only effective for directly treating visceral symptoms, but not for primary neuronopathic involvement in GD (nGD). Progranulin (PGRN), encoded by GRN, is a novel modifier of GCase, but the impact of PGRN in GBA1 mutation-associated pathologies in vivo remains unknown. Herein, Grn-/- mice crossed into Gba9v/9v mice, a Gba1 mutant line homozygous for the Gba1 D409V mutation, generating Grn-/-Gba9v/9v (PG9V) mice. PG9V mice exhibited neurobehavioral deficits, early onset, and more severe GD phenotypes compared to Grn-/- and Gba9v/9v mice. Moreover, PG9V mice also displayed PD-like phenotype. Mechanistic analysis revealed that PGRN deficiency caused severe neuroinflammation with microgliosis and astrogliosis, along with impaired autophagy associated with the Gba1 mutation. A PGRN-derived peptide, termed ND7, ameliorated the disease phenotype in GD patient fibroblasts ex vivo. Unexpectedly, ND7 penetrated the blood-brain barrier (BBB) and effectively ameliorated the nGD manifestations and PD pathology in Gba9v/null and PG9V mice. Collectively, this study not only provides the first line of in vivo but also ex vivo evidence demonstrating the crucial role of PGRN in GBA1/Gba1 mutation-related pathologies, as well as a clinically relevant mouse model for mechanistic and potential therapeutics studies for nGD and PD. Importantly, a BBB penetrant PGRN-derived biologic was developed that may provide treatment for rare lysosomal storage diseases and common neurodegenerative disorders, particularly nGD and PD.

Lateral Lumbar Interbody Fusion at the L5-S1 Vertebral Level: A Unique Anatomical Case Report.

A 57-year-old female presented with L4-L5 and L5-S1 mobile spondylolisthesis and associated stenosis with radiculopathy who failed conservative treatment. This patient underwent lateral lumbar interbody fusion (LLIF) of L4-L5 and L5-S1, and posterior spinal fusion (PSF) with instrumentation. LLIF is a minimally invasive procedure to treat degenerative diseases of the lumbar spine. LLIF at the L5-S1 vertebral level is a relative contraindication secondary to increased risk of injury to the lumbar plexus and access issues at this level during the approach. With the help of imaging, careful preoperative planning can make this a feasible procedure in select patients.

Screening, patient identification, evaluation, and treatment in patients with Gaucher disease: Results from a Delphi consensus.

Several guidelines are available for identification and management of patients with Gaucher disease, but the most recent guideline was published in 2013. Since then, there have been significant advances in newborn screening, phenotypic characterization, identification of biomarkers and their integration into clinical practice, and the development and approval of new treatment options. Accordingly, the goal of this Delphi consensus exercise was to extend prior initiatives of this type by addressing issues related to newborn screening, diagnostic evaluations, and treatment (both disease directed and adjunctive). The iterative Delphi process involved creation of an initial slate of statements, review by a steering committee, and three rounds of consensus development by an independent panel. A preliminary set of statements was developed by the supporting agency based on literature searches covering the period from 1965 to 2020. The Delphi process reduced an initial set of 185 statements to 65 for which there was unanimous support from the panel. The statements supported may ultimately provide a framework for more detailed treatment guidelines. In addition, the statements for which unanimous support could not be achieved help to identify evidence gaps that are targets for future research.

Environmentally relevant atrazine exposure leads to increases in DNA damage and changes in morphology in the hepatopancreas of crayfish (Faxonius virilis).

The herbicide atrazine is widely used for controlling broad leaf weeds and increasing crop yields in agricultural areas. Atrazine enters aquatic environments through runoff, ground water discharge and seepage where concentrations have been recorded above 300 ppb. Exposure to the herbicide atrazine at environmentally relevant concentrations has been shown to negatively impact aquatic organisms, including crayfish. Because xenobiotics are concentrated in the crayfish hepatopancreas (digestive gland), we examined changes in morphology and DNA damage in hepatopancreatic tissue structure and cells following a 10-day exposure to atrazine (0, 10, 40, 80, 100 and 300 ppb). We found that there were marked morphological changes, post-exposure, for all atrazine concentrations tested. Hepatopancreatic tissue exhibited degenerated tubule epithelium with necrosis of microvilli, tubule lumen dilation, changes in tubular epithelium height and vacuolization of the epithelium. Likewise, we also performed a terminal deoxynucleotidyl transferase (TdT) mediated dUTP nick-end labeling (TUNEL) assay which showed the percentage of cells with DNA damage increased following atrazine exposure. Crayfish hepatopancreatic tissue displayed significant increases in TUNEL-positive cells following exposure to atrazine at 100 ppb and above. Overall, exposure to atrazine at environmentally relevant concentrations damages hepatopancreatic tissue. This impairment could lead to changes in biotransformation, detoxification, digestion and molting, subsequently reducing crayfish populations and negatively impacting the aquatic ecosystem.

C-X-C Motif Chemokine Ligand 9 and Its CXCR3 Receptor Are the Salt and Pepper for T Cells Trafficking in a Mouse Model of Gaucher Disease.

Gaucher disease is a lysosomal storage disease, which happens due to mutations in GBA1/Gba1 that encodes the enzyme termed as lysosomal acid ß-glucosidase. The major function of this enzyme is to catalyze glucosylceramide (GC) into glucose and ceramide. The deficiency of this enzyme and resultant abnormal accumulation of GC cause altered function of several of the innate and adaptive immune cells. For example, augmented infiltration of T cells contributes to the increased production of pro-inflammatory cytokines, (e.g., IFNγ, TNFα, IL6, IL12p40, IL12p70, IL23, and IL17A/F). This leads to tissue damage in a genetic mouse model (Gba19V/-) of Gaucher disease. The cellular mechanism(s) by which increased tissue infiltration of T cells occurs in this disease is not fully understood. Here, we delineate role of the CXCR3 receptor and its exogenous C-X-C motif chemokine ligand 9 (CXCL9) in induction of increased tissue recruitment of CD4+ T and CD8+ T cells in Gaucher disease. Intracellular FACS staining of macrophages (Mϕs) and dendritic cells (DCs) from Gba19V/- mice showed elevated production of CXCL9. Purified CD4+ T cells and the CD8+ T cells from Gba19V/- mice showed increased expression of CXCR3. Ex vivo and in vivo chemotaxis experiments showed CXCL9 involvement in the recruitment of Gba19V/- T cells. Furthermore, antibody blockade of the CXCL9 receptor (CXCR3) on T cells caused marked reduction in CXCL9- mediated chemotaxis of T cells in Gba19V/- mice. These data implicate abnormalities of the CXCL9-CXCR3 axis leading to enhanced tissue recruitment of T cells in Gaucher disease. Such results provide a rationale for blockade of the CXCL9/CXCR3 axis as potential new therapeutic targets for the treatment of inflammation in Gaucher disease.

Substrate Reduction Therapy Reverses Mitochondrial, mTOR, and Autophagy Alterations in a Cell Model of Gaucher Disease.

Substrate reduction therapy (SRT) in clinic adequately manages the visceral manifestations in Gaucher disease (GD) but has no direct effect on brain disease. To understand the molecular basis of SRT in GD treatment, we evaluated the efficacy and underlying mechanism of SRT in an immortalized neuronal cell line derived from a Gba knockout (Gba-/-) mouse model. Gba-/- neurons accumulated substrates, glucosylceramide, and glucosylsphingosine. Reduced cell proliferation was associated with altered lysosomes and autophagy, decreased mitochondrial function, and activation of the mTORC1 pathway. Treatment of the Gba-/- neurons with venglustat analogue GZ452, a central nervous system-accessible SRT, normalized glucosylceramide levels in these neurons and their isolated mitochondria. Enlarged lysosomes were reduced in the treated Gba-/- neurons, accompanied by decreased autophagic vacuoles. GZ452 treatment improved mitochondrial membrane potential and oxygen consumption rate. Furthermore, GZ452 diminished hyperactivity of selected proteins in the mTORC1 pathway and improved cell proliferation of Gba-/- neurons. These findings reinforce the detrimental effects of substrate accumulation on mitochondria, autophagy, and mTOR in neurons. A novel rescuing mechanism of SRT was revealed on the function of mitochondrial and autophagy-lysosomal pathways in GD. These results point to mitochondria and the mTORC1 complex as potential therapeutic targets for treatment of GD.

More Than One-third of Orthopaedic Applicants Are in the Top 10%: The Standardized Letter of Recommendation and Evaluation of Orthopaedic Resident Applicants.

BACKGROUND: The American Orthopaedic Association (AOA) released the standardized letter of recommendation (SLOR) form to provide standardized information to evaluators of orthopaedic residency applicants. The SLOR associates numerical data to an applicant's letter of recommendation. However, it remains unclear whether the new letter form effectively distinguishes among orthopaedic applicants, for whom letters are perceived to suffer from "grade inflation." In addition, it is unknown whether letters from more experienced faculty members differ in important ways from those written by less experienced faculty. QUESTIONS/PURPOSES: (1) What proportion of SLOR recipients were rated in the top 10th percentile and top one-third of the applicant pool? (2) Did letters from program leaders (program directors and department chairs) demonstrate lower aggregate SLOR scores compared with letters written by other faculty members? (3) Did letters from away rotation program leaders demonstrate lower aggregate SLOR scores compared with letters written by faculty at the applicant's home institution? METHODS: This was a retrospective, single institution study examining 559 applications from the 2018 orthopaedic match. Inclusion criteria were all applications submitted to this residency. Exclusion criteria included all letters without an associated SLOR. In all, 1852 letters were received; of these, 26% (476) were excluded, and 74% (1376) were analyzed for SLOR data. We excluded 12% (169 of 1376) of letters that did not include a final summative score. Program leaders were defined as orthopaedic chairs and program directors. Away rotation letters were defined as letters written by faculty during an applicant's away rotation. Our study questions were answered accounting for each subcategory on the SLOR (scale 1-10) and the final ranking (scale 1-5) to form an aggregated score from the SLOR form for each letter. All SLOR questions were included in the creation of these scores. Correlations between program leaders and other faculty letter writers were assessed using a chi-square test. We considered a 1-point difference on 5-point scales to be a clinically important difference and a 2-point difference on 10-point scales to be clinically important. RESULTS: We found that 36% (437 of 1207) of the letters we reviewed indicated the candidate was in the top 10th percentile of all applicants evaluated, and 51% (619 of 1207) of the letters we reviewed indicated the candidate was in the top one-third of all applicants evaluated. We found no clinically important difference between program leaders and other faculty members in terms of summative scores on the SLOR (1.9 ± 0.7 versus 1.7 ± 0.7, mean difference -0.2 [95% CI -0.3 to 0.1]; p < 0.001). We also found no clinically important difference between home program letter writers and away program letter writers in terms of the mean summative scores (1.9 ± 0.7 versus 1.7 ± 0.7, mean difference 0.2; p < 0.001). CONCLUSION: In light of these discoveries, programs should examine the data obtained from SLOR forms carefully. SLOR scores skew very positively, which may benefit weaker applicants and harm stronger applicants. Program leaders give summative scores that do not differ substantially from junior faculty, suggesting there is no important difference in grade inflation between these faculty types, and as such, there is no strong need to adjust scores by faculty level. Likewise, away rotation letter writers' summative scores were not substantially different from those of home institution letters writers, indicating that there is no need to adjust scores between these groups either. Based on these findings, we should interpret letters with the understanding that overall there is substantial grade inflation. However, while weight used to be given to letters written by senior faculty members and those obtained on away rotations, we should now examine them equally, rather than trying to adjust them for overly high or low scores. LEVEL OF EVIDENCE: Level III, therapeutic study.

Resident Wellness During the COVID-19 Pandemic: A Nationwide Survey of Orthopaedic Residents.

INTRODUCTION: The COVID-19 pandemic has influenced the resident workforce to a particularly powerful and unexpected extent. Given the drastic changes to resident roles, expectations, and responsibilities, many valuable lessons regarding resident concerns and wellness can be garnered from this unique experience. METHODS: A voluntary survey was sent to 179 Accreditation Council for Graduate Medical Education-accredited orthopaedic surgery residency program directors to distribute to their residents. Questions focused on issues that may have occurred, program's responses, and expectations of programs during the pandemic. RESULTS: In total, 507 residents completed the survey, and 10% reported being deployed to do nonorthopaedic-related care, with junior classes being more likely to receive this assignment (P < 0.001). The greatest concern for respondents was the possibility of getting family members sick (mean = 3.89, on scale of 1-5), followed by personally contracting the illness (mean = 3.38). DISCUSSION: The COVID-19 pandemic has resulted in numerous changes and novel sources of adversity for the orthopaedic surgery resident. Contrary to popular opinion, most residents are comfortable with the proposition of providing nonorthopaedic care. The possibility of bringing a pathogen to the home environment and infecting family members seems to be an overarching concern, and efforts to ensure resident and family safety are key.

Systemic enzyme delivery by blood-brain barrier-penetrating SapC-DOPS nanovesicles for treatment of neuronopathic Gaucher disease.

BACKGROUND: Enzyme replacement therapy (ERT) can positively affect the visceral manifestations of lysosomal storage diseases (LSDs). However, the exclusion of the intravenous ERT agents from the central nervous system (CNS) prevents direct therapeutic effects. METHODS: Using a neuronopathic Gaucher disease (nGD) mouse model, CNS-ERT was created using a systemic, non-invasive, and CNS-selective delivery system based on nanovesicles of saposin C (SapC) and dioleoylphosphatidylserine (DOPS) to deliver to CNS cells and tissues the corrective, functional acid ß-glucosidase (GCase). FINDINGS: Compared to free GCase, human GCase formulated with SapC-DOPS nanovesicles (SapC-DOPS-GCase) was more stable in serum, taken up into cells, mostly by a mannose receptor-independent pathway, and resulted in higher activity in GCase-deficient cells. In contrast to free GCase, SapC-DOPS-GCase nanovesicles penetrated through the blood-brain barrier into the CNS. The CNS targeting was mediated by surface phosphatidylserine (PS) of blood vessel and brain cells. Increased GCase activity and reduced GCase substrate levels were found in the CNS of SapC-DOPS-GCase-treated nGD mice, which showed profound improvement in brain inflammation and neurological phenotypes. INTERPRETATION: This first-in-class CNS-ERT approach provides considerable promise of therapeutic benefits for neurodegenerative diseases. FUNDING: This study was supported by the National Institutes of Health grants R21NS 095047 to XQ and YS, R01NS 086134 and UH2NS092981 in part to YS; Cincinnati Children's Hospital Medical Center Research Innovation/Pilot award to YS and XQ; Gardner Neuroscience Institute/Neurobiology Research Center Pilot award to XQ and YS, Hematology-Oncology Programmatic Support from University of Cincinnati and New Drug State Key Project grant 009ZX09102-205 to XQ.

Keloid and Hypertrophic Scar Formation, Prevention, and Management: Standard Review of Abnormal Scarring in Orthopaedic Surgery.

Keloid and hypertrophic scar formation after orthopaedic surgical closure is a complex issue. The nature and location of procedures maximize wound tension, leave foreign bodies, and diminish dermal supply, all potentiating keloid formation. There is little discussion regarding the pathophysiology and management of this recurrent problem in orthopaedic literature. Keloid formation is a fibroproliferative disorder resulting in extensive production of extracellular matrix and collagen, but prevention and treatment is poorly understood. Patient and surgical factors contributing to the development of this condition are discussed. The treatments include both medical and surgical therapies that work at a biologic level and attempt to produce a cosmetic and complication-free management strategy. Medical options that have been investigated include combinations of intralesional steroid therapy, laser therapy, and biologics. Preventive surgical closure and excision remain mainstays of treatment. Radiation therapy has also been used in refractory cases with mixed results. Despite medical therapies and surgical excision aimed at treating the resulting scar, recurrence rate is very high for all modalities that have been studied to this point. Future work is being done to better understand the pathophysiology leading to keloid and hypertrophic scar formation in an effort to find preventive methods as compared to treatment strategies.

Epidural Abscess Caused by Gas-Producing Clostridium Septicum: A Case Report.

CASE: Few cases have reported Clostridium species of bacteria as a source for vertebral osteomyelitis and epidural abscesses. The subspecies of Clostridium septicum has not been described as a cause. This case describes a 69-year-old man who hematogenously spread C. septicum without associated malignancy, subsequently failed conservative management in the form of intravenous antibiotics, and was definitively treated with surgical intervention through a minimally invasive approach. CONCLUSIONS: An epidural abscess occurring in a surgically naive patient is a rare phenomenon. An epidural abscess caused by C. septicum is even rarer. Appropriate imaging, early recognition, and surgical debridement can lead to a favorable outcome.

The Haitian Orthopaedic Residency Exchange Program.

After a devastating earthquake in Haiti in 2010, multiple South Carolinian orthopaedic teams, funded by the South Carolina Orthopedic Association (SCOA), developed an exchange program for Haitian residents. METHODS: SCOA teams have sequentially logged their patient experiences since 2015 for a total of six updates per year. These logs were reviewed in detail to evaluate clinical results in terms of case volumes, cases performed, follow-up obtained, and complications. RESULTS: Twenty-one orthopaedic attendings, 19 South Carolina orthopaedic residents, 22 Haitian orthopaedic residents, and 22 ancillary staff have rotated through Hospital Lumiere. The teams have seen over 2000 patients in the orthopaedic clinic and performed 554 surgeries, including 207 fractures (half of which being open), 24 nonunion and 7 malunion repairs, 15 lower extremity amputations, 27 hemiarthroplasties for femoral neck fractures, and 34 cases of chronic osteomyelitis. DISCUSSION: The SCOA Foundation has developed a coordinated service for the musculoskeletal needs of the Haitian people while collaboratively elevating the standard of orthopaedic training in Haiti. We report a collaborative model that other US residency programs can use to impart beneficial changes not only in their home program, but also in training programs abroad.

Intravenous infusion of iPSC-derived neural precursor cells increases acid ß-glucosidase function in the brain and lessens the neuronopathic phenotype in a mouse model of Gaucher disease.

Gaucher disease (GD) is caused by GBA1 mutations leading to functional deficiency of acid-ß-glucosidase (GCase). No effective treatment is available for neuronopathic GD (nGD). A subclass of neural stem and precursor cells (NPCs) expresses VLA4 (integrin α4ß1, very late antigen-4) that facilitates NPC entry into the brain following intravenous (IV) infusion. Here, the therapeutic potential of IV VLA4+NPCs was assessed for nGD using wild-type mouse green fluorescent protein (GFP)-positive multipotent induced pluripotent stem cell (iPSC)-derived VLA4+NPCs. VLA4+NPCs successfully engrafted in the nGD (4L;C*) mouse brain. GFP-positive cells differentiated into neurons, astrocytes and oligodendrocytes in the brainstem, midbrain and thalamus of the transplanted mice and significantly improved sensorimotor function and prolonged life span compared to vehicle-treated 4L;C* mice. VLA4+NPC transplantation significantly decreased levels of CD68 and glial fibrillary acidic protein, as well as TNFα mRNA levels in the brain, indicating reduced neuroinflammation. Furthermore, decreased Fluoro-Jade C and NeuroSilver staining suggested inhibition of neurodegeneration. VLA4+NPC-engrafted 4L;C* midbrains showed 35% increased GCase activity, reduced substrate [glucosylceramide (GC, -34%) and glucosylsphingosine (GS, -11%)] levels and improved mitochondrial oxygen consumption rates in comparison to vehicle-4L;C* mice. VLA4+NPC engraftment in 4L;C* brain also led to enhanced expression of neurotrophic factors that have roles in neuronal survival and the promotion of neurogenesis. This study provides evidence that iPSC-derived NPC transplantation has efficacy in an nGD mouse model and provides proof of concept for autologous NPC therapy in nGD.

Combination of acid ß-glucosidase mutation and Saposin C deficiency in mice reveals Gba1 mutation dependent and tissue-specific disease phenotype.

Gaucher disease is caused by mutations in GBA1 encoding acid ß-glucosidase (GCase). Saposin C enhances GCase activity and protects GCase from intracellular proteolysis. Structure simulations indicated that the mutant GCases, N370S (0 S), V394L (4L) and D409V(9V)/H(9H), had altered function. To investigate the in vivo function of Gba1 mutants, mouse models were generated by backcrossing the above homozygous mutant GCase mice into Saposin C deficient (C*) mice. Without saposin C, the mutant GCase activities in the resultant mouse tissues were reduced by ~50% compared with those in the presence of Saposin C. In contrast to 9H and 4L mice that have normal histology and life span, the 9H;C* and 4L;C* mice had shorter life spans. 9H;C* mice developed significant visceral glucosylceramide (GC) and glucosylsphingosine (GS) accumulation (GC¼GS) and storage macrophages, but lesser GC in the brain, compared to 4L;C* mice that presents with a severe neuronopathic phenotype and accumulated GC and GS primarily in the brain. Unlike 9V mice that developed normally for over a year, 9V;C* pups had a lethal skin defect as did 0S;C* mice resembled that of 0S mice. These variant Gaucher disease mouse models presented a mutation specific phenotype and underscored the in vivo role of Saposin C in the modulation of Gaucher disease.