Cell replacement therapy using mesenchymal (MSC) and other stem cells has been evaluated for diabetic retinopathy and glaucoma. This approach has significant limitations, including few cells ...integrated, aberrant growth, and surgical complications. Mesenchymal Stem Cell Exosomes/Extracellular Vesicles (MSC EVs), which include exosomes and microvesicles, are an emerging alternative, promoting immunomodulation, repair, and regeneration by mediating MSC's paracrine effects. For the clinical translation of EV therapy, it is important to determine the cellular destination and time course of EV uptake in the retina following administration. Here, we tested the cellular fate of EVs using in vivo rat retinas, ex vivo retinal explant, and primary retinal cells. Intravitreally administered fluorescent EVs were rapidly cleared from the vitreous. Retinal ganglion cells (RGCs) had maximal EV fluorescence at 14 days post administration, and microglia at 7 days. Both in vivo and in the explant model, most EVs were no deeper than the inner nuclear layer. Retinal astrocytes, microglia, and mixed neurons in vitro endocytosed EVs in a dose-dependent manner. Thus, our results indicate that intravitreal EVs are suited for the treatment of retinal diseases affecting the inner retina. Modification of the EV surface should be considered for maintaining EVs in the vitreous for prolonged delivery.
Nonarteritic anterior ischemic optic neuropathy (NAION) commonly causes sudden optic nerve (ON)-related vision loss. The rodent NAION model (rAION) closely resembles NAION in presentation and ...physiological responses. We identified early rAION-associated optic nerve head (ONH) inflammatory gene expression responses and the anti-inflammatory prostaglandin PGJ2’s effects on those responses. We hypothesized that blocking pro-inflammatory prostaglandin (PGE2) production by inhibiting monoacylglycerol lipase or cyclooxygenase activity and co-administering PGJ2 would potentiate RGC survival following ischemic neuropathy. Deep sequencing was performed on vehicle- and PGJ2-treated ONHs 3d post-rAION induction. Results were compared against responses from a retinal ischemia model. Animals were treated with PGJ2 and MAGL inhibitor KML29, or PGJ2 + COX inhibitor meloxicam. RGC survival was quantified by stereology. Tissue PG levels were quantified by ELISA. Gene expression was confirmed by qPCR. PGJ2 treatment nonselectively reduced inflammatory gene expression post-rAION. KML29 did not reduce PGE2 1d post-induction and KML29 alone increased RGC loss after rAION. Combined treatments did not improve ONH edema and RGC survival better than reported with PGJ2 alone. KML29′s failure to suppress PGE2 ocular synthesis, despite its purported effects in other CNS tissues may result from alternative PG synthesis pathways. Neither KML29 nor meloxicam treatment significantly improved RGC survival compared with vehicle. While exogenous PGJ2 has been shown to be neuroprotective, treatments combining PGJ2 with these PG synthesis inhibitors do not enhance PGJ2’s neuroprotection.
Despite the known association between higher estimated blood loss (EBL) and suboptimal outcomes, the threshold of EBL that negatively impacts outcomes following elective spine surgery remains ...unknown. In an open 2- and 3-level posterolateral lumbar fusion, we sought to find a threshold of surgeon-reported EBL associated with length of stay (LOS), 30-day complications, and patient-reported outcomes (PROs).
A single-center, retrospective cohort study was performed for 2- and 3-level open posterolateral lumbar fusions between October 2010 and April 2021. Surgeon-reported EBL (milliliters) was the primary independent variable for predicting LOS (days). Secondary outcomes included 30-day complications and PROs as the minimal clinically important difference (MCID). Multivariable regression and receiver operating characteristic curve with Youden's Index were calculated.
A total of 557 patients underwent 2-level fusions. Multivariable regression found EBL to be a significant risk factor for prolonged LOS. A threshold of 375 mL was associated with LOS beyond postoperative day 2 (POD2) (area under the curve AUC = 0.64, 95% CI 0.58-0.70,
< 0.001).
A total of 287 patients underwent 3-level fusions. Similarly, EBL was a significant risk factor for prolonged LOS, with a threshold of 675 mL to predict LOS beyond POD2 (AUC = 0.63, 95% CI 0.54-0.73,
= 0.012). EBL was associated with increased odds of 30-day complications, with a threshold of 538 mL (AUC = 0.63, 95% CI 0.51-0.76,
< 0.001). For both 2- and 3-level fusions, EBL was not significantly associated with MCID for any of the PROs.
In patients undergoing open, posterolateral lumbar fusions, surgeon-reported EBL thresholds at 375 mL for 2-level fusions and 675 mL for 3-level fusions were moderately associated with LOS beyond POD2. In 3-level lumbar fusions, EBL above 538 mL showed a potential association with an increased odds of 30-day complications.
Surgeons should improve their ability to manage blood loss and implement methods to keep EBL below the provided thresholds to decrease LOS and minimize the risk of complications.
Transforaminal lumbar interbody fusion (TLIF) and posterolateral fusion (PLF) without an interbody device are two common approaches for single-level, open posterior fusion. Presently, it is unknown ...whether one of these operations leads to better outcomes. We sought to compare reoperation, complication, and readmission rates between TLIF and PLF for patients undergoing elective single-level, open, posterior lumbar fusion.
A single-center, retrospective cohort study utilizing prospectively collected data was performed. Inclusion criteria were patients undergoing elective single-level, open, posterior lumbar decompression and fusion between October 2010 and April 2021 with at least 1-year follow-up. The two comparison groups were TLIF vs PLF alone without interbody. The primary outcome was need for reoperation at most recent follow-up. Secondary outcomes included 90-day complication and readmission rates. Univariate and multivariable logistic regression analyses were performed.
A total of 850 patients were included, 591 (69.5%) of whom underwent TLIF and 259 (30.5%) of whom underwent PLF. Median follow-up was 6.1 years (interquartile range 3.7-8.9). No significant difference was found in overall reoperation rates (12.4% vs 13.9%,
= 0.534). When stratified by <5-year follow-up (
= 231 TLIF,
= 85 PLF; 37.2%) and ≥5-year follow-up (
= 360 TLIF,
= 174 PLF; 62.8%), no significant differences were seen in either cohort (<5 years:
= 24 TLIF vs
= 9 PLF,
= 0.959; 5+ years:
= 49 TLIF vs
= 27 PLF,
= 0.555). On multivariable logistic regression analysis, the presence of interbody fusion was not associated with reoperation (OR 2.26, 95% CI 0.66-7.74,
= 0.194).
For patients undergoing elective single-level, open, posterior lumbar fusion without isthmic spondylolisthesis, no differences were seen in reoperation rates at long-term follow-up. Similar 90-day complication and readmission rates were seen. These results suggest that in degenerative lumbar spine disease without isthmic spondylolisthesis, TLIF and PLF achieved similar outcomes.
Despite the known association between increased estimated blood loss (EBL) and suboptimal perioperative outcomes, the exact threshold of EBL that impacts outcomes following elective spine surgery ...remains unknown. In a cohort of patients undergoing elective 1-level open posterior lumbar fusion, we sought to identify EBL thresholds associated with: (1) prolonged length of stay (LOS), (2) postoperative complications, and (3) patient-reported outcomes (PROs).
A retrospective, single-center study was performed of patients undergoing elective, 1-level open posterior lumbar fusion with and without interbody fusion between October 2010 and April 2021. The primary exposure variable was EBL. Primary outcomes included: (1) LOS, (2) 30-day complications, and (3) 3-month PROs. Minimum clinically important difference was set at 30% improvement from baseline. For purposes of receiver-operating characteristic curves, LOS was dichotomized as 1 vs ≥2 days.
Of the 2028 patients undergoing posterior lumbar fusion surgery, 1183 underwent 1-level fusions, 763 (64.5%) with interbody fusion and 420 (35.5%) without.
Median (interquartile range IQR) EBL was 350 mL (200-600), and median (IQR) LOS was 2 days (2-3). A positive linear association was found between EBL and LOS (
< 0.001) but not with PROs. EBL above 275 mL was associated with LOS beyond postoperative day 1 (POD1) (area under the curve AUC = 0.73, 95% CI 0.68-0.78,
< 0.001), with no significant association with overall complications or PROs.
Median EBL (IQR) was 300 mL (150-500), and median (IQR) LOS was 3 days (2-4). A positive linear association was found between EBL and LOS (
< 0.001) but not with PROs. EBL above 238 mL was associated with LOS beyond POD1 (AUC = 0.78, 95% CI 0.71-0.85,
< 0.001), with no impact on overall complications or PROs.
In patients undergoing 1-level posterior lumbar fusion, EBL volumes greater than 275 and 238 mL in patients with and without interbody fusion, respectively, were associated with increased LOS beyond POD1. No effect was found regarding 30-day complications and 3-month PROs. Although EBL did not directly impact complications or PROs, surgeons may expect longer LOS when higher EBL is reported.
EBL above 275 mL with an interbody and 238 mL without an interbody were associated with prolonged LOS beyond POD1 in 1-level open lumbar fusion.
We sought to determine which aspect of the upper instrumented vertebrae (UIV)-tilt angle or screw angle-was more strongly associated with: (1) proximal junctional kyphosis/failure (PJK/F), (2) other ...mechanical complications and reoperations, and (3) patient-reported outcome measures (PROMs).BACKGROUNDWe sought to determine which aspect of the upper instrumented vertebrae (UIV)-tilt angle or screw angle-was more strongly associated with: (1) proximal junctional kyphosis/failure (PJK/F), (2) other mechanical complications and reoperations, and (3) patient-reported outcome measures (PROMs).A single-institution, retrospective cohort study was undertaken for patients undergoing adult spinal deformity (ASD) surgery from 2011 to 2017. Only patients with UIV at T7 or below were included. The primary exposure variables were UIV tilt angle (the angle of the UIV inferior endplate and the horizontal) and UIV screw angle (the angle of the UIV screws and superior endplate). Multivariable logistic regression included age, body mass index, osteopenia/osteoporosis, postoperative sagittal vertical axis, postoperative pelvic-incidence lumbar lordosis mismatch, UIV tilt angle, and UIV screw angle.METHODSA single-institution, retrospective cohort study was undertaken for patients undergoing adult spinal deformity (ASD) surgery from 2011 to 2017. Only patients with UIV at T7 or below were included. The primary exposure variables were UIV tilt angle (the angle of the UIV inferior endplate and the horizontal) and UIV screw angle (the angle of the UIV screws and superior endplate). Multivariable logistic regression included age, body mass index, osteopenia/osteoporosis, postoperative sagittal vertical axis, postoperative pelvic-incidence lumbar lordosis mismatch, UIV tilt angle, and UIV screw angle.One hundred and seventeen patients underwent adult spinal deformity surgery with a minimum of 2-year follow-up. A total of 41 patients (35.0%) had PJK and 26 (22.2%) had PJF. (1) UIV tilt angle: 96 (82.1%) had lordotic UIV tilt angles, 6 (5.1%) were neutral, and 15 (12.8%) were kyphotic. (2) UIV screw angle: 38 (32.5%) had cranially directed screws, 4 (3.4%) were neutral, and 75 (64.1%) were caudally directed. Both lordotic-angled UIV endplate (OR = 1.06, 95% CI = 1.01-1.12, and P = 0.020) and cranially directed screws (OR = 1.19, 95% CI = 1.07-1.33, and P < 0.001) were associated with higher odds of PJK, with a more pronounced effect of UIV screw angle compared with UIV tilt angle (Wald test, 9.40 vs 4.42). Similar results were found for PJF. Neither parameter was associated with other mechanical complications, reoperations, or patient-reported outcome measures.RESULTSOne hundred and seventeen patients underwent adult spinal deformity surgery with a minimum of 2-year follow-up. A total of 41 patients (35.0%) had PJK and 26 (22.2%) had PJF. (1) UIV tilt angle: 96 (82.1%) had lordotic UIV tilt angles, 6 (5.1%) were neutral, and 15 (12.8%) were kyphotic. (2) UIV screw angle: 38 (32.5%) had cranially directed screws, 4 (3.4%) were neutral, and 75 (64.1%) were caudally directed. Both lordotic-angled UIV endplate (OR = 1.06, 95% CI = 1.01-1.12, and P = 0.020) and cranially directed screws (OR = 1.19, 95% CI = 1.07-1.33, and P < 0.001) were associated with higher odds of PJK, with a more pronounced effect of UIV screw angle compared with UIV tilt angle (Wald test, 9.40 vs 4.42). Similar results were found for PJF. Neither parameter was associated with other mechanical complications, reoperations, or patient-reported outcome measures.UIV screw angle was more strongly associated with development of PJK/F compared with tilt angle. Overall, these modifiable parameters are directly under the surgeon's control and can mitigate the development of PJK/F.CONCLUSIONSUIV screw angle was more strongly associated with development of PJK/F compared with tilt angle. Overall, these modifiable parameters are directly under the surgeon's control and can mitigate the development of PJK/F.Surgeons may consider selecting a UIV with a neutral or kyphotically directed UIV tilt angle when performing ASD surgery with a UIV in the lower thoracic or lumbar region, as well as use UIV screw angles that are caudally directed, for the purprose of decreasing the risk of developing PJK/F.CLINICAL RELEVANCESurgeons may consider selecting a UIV with a neutral or kyphotically directed UIV tilt angle when performing ASD surgery with a UIV in the lower thoracic or lumbar region, as well as use UIV screw angles that are caudally directed, for the purprose of decreasing the risk of developing PJK/F.
In patients undergoing spine surgery for renal cell carcinoma (RCC), we sought to: (1) describe patterns of postoperative targeted systemic therapy and radiotherapy (RT), (2) compare perioperative ...outcomes among those treated with targeted systemic therapy to those without, and (3) evaluate the impact of targeted systemic therapy and/or RT on overall survival (OS) and local recurrence (LR).BACKGROUNDIn patients undergoing spine surgery for renal cell carcinoma (RCC), we sought to: (1) describe patterns of postoperative targeted systemic therapy and radiotherapy (RT), (2) compare perioperative outcomes among those treated with targeted systemic therapy to those without, and (3) evaluate the impact of targeted systemic therapy and/or RT on overall survival (OS) and local recurrence (LR).A single-institution, retrospective cohort study of patients undergoing spine surgery for metastatic RCC from 2010 to 2021 was undertaken. Treatment groups were RT alone, targeted systemic therapy alone, dual therapy consisting of RT and targeted systemic therapy, and neither therapy. Multivariable Cox regression controlled for age, race, sex, insurance, and preoperative targeted systemic therapy.METHODSA single-institution, retrospective cohort study of patients undergoing spine surgery for metastatic RCC from 2010 to 2021 was undertaken. Treatment groups were RT alone, targeted systemic therapy alone, dual therapy consisting of RT and targeted systemic therapy, and neither therapy. Multivariable Cox regression controlled for age, race, sex, insurance, and preoperative targeted systemic therapy.Forty-nine patients underwent spine surgery for RCC. Postoperatively, 4 patients (8%) received RT alone, 19 (38.8%) targeted systemic therapy alone, 12 (24.5%) dual therapy, and 13 (28.6%) neither. All groups were similar in demographics, preoperative Karnofsky Performance Score (P = 0.372), tumor size (P = 0.413), readmissions (P = 0.884), complications (P = 0.272), Karnofsky Performance Score (P = 0.466), and Modified McCormick Scale (P = 0.980) at last follow-up. Higher 1-year survival was found in dual therapy (83.3%) compared with other therapies. OS was significantly longer in patients with dual therapy compared with other therapies (log-rank; P = 0.010). Multivariate Cox regression (HR = 0.08, 95% CI = 0.02-0.31, P < 0.001) showed longer OS in dual therapy compared with other therapies. Seven patients (14.3%) experienced LR, and a similar time to LR was found between groups (log-rank; P = 0.190).RESULTSForty-nine patients underwent spine surgery for RCC. Postoperatively, 4 patients (8%) received RT alone, 19 (38.8%) targeted systemic therapy alone, 12 (24.5%) dual therapy, and 13 (28.6%) neither. All groups were similar in demographics, preoperative Karnofsky Performance Score (P = 0.372), tumor size (P = 0.413), readmissions (P = 0.884), complications (P = 0.272), Karnofsky Performance Score (P = 0.466), and Modified McCormick Scale (P = 0.980) at last follow-up. Higher 1-year survival was found in dual therapy (83.3%) compared with other therapies. OS was significantly longer in patients with dual therapy compared with other therapies (log-rank; P = 0.010). Multivariate Cox regression (HR = 0.08, 95% CI = 0.02-0.31, P < 0.001) showed longer OS in dual therapy compared with other therapies. Seven patients (14.3%) experienced LR, and a similar time to LR was found between groups (log-rank; P = 0.190).In patients undergoing metastatic spine surgery for RCC, postoperative dual therapy demonstrated significantly higher 1-year survival and OS compared with other therapies.CONCLUSIONIn patients undergoing metastatic spine surgery for RCC, postoperative dual therapy demonstrated significantly higher 1-year survival and OS compared with other therapies.Multidisciplinary management of metastatic RCC is necessary to ensure timely implementation of targeted systemic therapy and RT to improve outcomes.CLINICAL RELEVANCEMultidisciplinary management of metastatic RCC is necessary to ensure timely implementation of targeted systemic therapy and RT to improve outcomes.
To assess the impact of screw density on: (1) rod fracture/pseudarthrosis, (2) proximal/distal junctional kyphosis/failure (PJK/DJK/PJF), and (3) deformity correction judged by sagittal vertical axis ...(SVA) and T1-pelvic angle (T1PA).
A single-center, retrospective cohort study of patients undergoing adult spinal deformity (ASD) surgery from 2013 to 2017 was undertaken. Screw density was calculated by dividing the number of screws placed by the total instrumented levels. Screw density was then dichotomized at our calculated mean density to ≥ 1.65 and < 1.65. Outcomes consisted of mechanical complications and the amount of correction obtained.
145 patients underwent ASD surgery with 2-year follow-up. Mean screw density (range) was 1.6 ± 0.3 (1.00-2.00). The most common levels with missing screws were L2 (n = 59, 40.7%), L3 (n = 57, 39.3%) and L1 (n = 51, 35.2%), located mainly along the concavity in 113(80.0%) patients and apices in 98 (67.6%) patients. Rod fracture/pseudarthrosis: 23/32 (71.8%) patients with rod fracture and 35/46 (76.0%) with pseudarthrosis had missing screws within two levels of the rod fracture/pseudarthrosis. Logistic regression showed no significant association between screw density and rod fracture/pseudarthrosis.
15/47 (31.9%) patients with PJK and 9/30 (30.0%) with PJF had missing screws within three levels of the upper instrumented vertebra (UIV). Logistic regression showed no significant association between screws density and PJK/F. Correction obtained: linear regression failed to show any significant association between screw density and SVA or T1PA correction.
These findings showed that no significant association was found between screw density and mechanical complications or the amount of correction obtained, though approximately 3 out of 4 patients with rod fracture/pseudarthrosis had missing screws at or within two levels of the pathology. The prevention of mechanical complications is likely multifactorial and subject to both patient's characteristics and surgical techniques.
III.
Retrospective cohort study.
To evaluate the association of Hemoglobin A1C (HbA1c) with surgical site infection (SSI) and patient-reported outcomes (PROs), and to identify optimal HbA1c thresholds to ...minimize the risk of SSI and maximize PROs.
Diabetes mellitus has been associated with worsened outcomes following spine surgery. HbA1c, a surrogate of glycemic control, is an important assessment tool in diabetic patients.
A single-center, retrospective cohort study using prospectively collected data was undertaken. Diabetic patients undergoing elective lumbar decompression surgery between October 2010 and May 2021 were included. HbA1c, demographics, comorbidities, and perioperative data were collected. Primary outcomes included: 1) SSI, and 2) PROs, including the Numeric Rating Scale (NRS)-back/leg pain and Oswestry Disability Index (ODI). Secondary outcomes included: complications, readmissions, and reoperations within 90-days postoperatively. The minimum clinically important difference (MCID) was set at a 30% improvement from baseline PROs.
Of 1819 patients who underwent lumbar decompression surgery, 368 patients had diabetes mellitus, and 177 had a documented preoperative HbA1c value. Of patients with available HbA1c values, the mean age was 62.5±12.3, the mean HbA1c value was 7.2±1.5%, and SSI occurred in 3 (1.7%) patients only, which prevented further analysis of SSI and HbA1c. A significant association was seen with a higher HbA1c and failure to achieve NRS-Back pain MCID30 Odds ratio(OR)=0.53, 95% confidence interval(CI) 0.42-0.78; P =0.001 and ODI MCID30 (OR=0.58, 95%CI 0.44-0.77; P =0.001), but not NRS-Leg pain MCID30 (OR=1.29, 95%CI 0.86-1.93; P =0.208). ROC-curve analysis and Youden's index revealed an HbA1c threshold of 7.8 for NRS-Back pain MCID30 (AUC=0.65, P <0.001) and 7.5 for ODI MCID30 (AUC=0.65, P =0.001).
In diabetic patients undergoing elective lumbar decompression surgery, HbA1c levels above 7.8 and 7.5 were associated with less improvement of NRS-Back and ODI scores at 12-months postoperatively, respectively. To optimize PROs, We recommend a preoperative HbA1c of 7.5 or below for diabetic patients undergoing elective lumbar decompression surgery.
Erythropoietin (EPO) plays an important role in the brain's response to neuronal injury. Systemic administration of recombinant human EPO (rhEPO) protects neurons from injury after middle cerebral ...artery occlusion, traumatic brain injury, neuroinflammation, and excitotoxicity. Protection is in part mediated by antiapoptotic mechanisms. We conducted parallel studies of rhEPO in a model of transient global retinal ischemia induced by raising intraocular pressure, which is a clinically relevant model for retinal diseases. We observed abundant expression of EPO receptor (EPO-R) throughout the ischemic retina. Neutralization of endogenous EPO with soluble EPO-R exacerbated ischemic injury, which supports a crucial role for an endogenous EPO/EPO-R system in the survival and recovery of neurons after an ischemic insult. Systemic administration of rhEPO before or immediately after retinal ischemia not only reduced histopathological damage but also promoted functional recovery as assessed by electroretinography. Exogenous EPO also significantly diminished terminal deoxynucleotidyltransferase-mediated dUTP end labeling labeling of neurons in the ischemic retina, implying an antiapoptotic mechanism of action. These results further establish EPO as a neuroprotective agent in acute neuronal ischemic injury.
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