The impact of enhanced recovery after surgery (ERAS) on opioid consumption and postoperative pain levels in elective spine surgery.

OBJECTIVE: Enhanced Recovery after Surgery (ERAS) protocols were developed to counteract the adverse effects of the surgical stress response, aiming for quicker postoperative recovery. Initially applied in abdominal surgeries, ERAS principles have extended to orthopedic spine surgery, but research in this area is still in its infancy. The current study investigated the impact of ERAS on postoperative pain and opioid consumption in elective spine surgeries. METHODS: A single-center retrospective study of patients undergoing elective spine surgery from May 2019 to July 2020. Patients were categorized into two groups: those enrolled in the ERAS pathway and those adhering to traditional surgical protocols. Data on demographics, comorbidities, length of stay (LOS), surgical procedures, and postoperative outcomes were collected. Postoperative pain was evaluated using the Numerical Rating Scale (NRS), while opioid utilization was quantified in morphine milligram equivalents (MME). NRS and MME were averaged for each patient across all days under observation. Differences in outcomes between groups (ERAS vs. treatment as usual) were tested using the Wilcoxon rank sum test for continuous variables and Pearson's or Fisher's exact tests for categorical variables. RESULTS: The median of patient's mean daily NRS scores for postoperative pain were not statistically significantly different between groups (median = 5.55 (ERAS) and 5.28 (non-ERAS), p=.2). Additionally, the median of patients' mean daily levels of MME were similar between groups (median = 17.24 (ERAS) and 16.44 (non-ERAS), p=.3) ERAS patients experienced notably shorter LOS (median=2 days) than their non-ERAS counterparts (median=3 days, p=.001). The effect of ERAS was moderated by whether the patient had ACDF surgery. ERAS (vs. non-ERAS) patients who had ACDF surgery had 1.64 lower average NRS (p=.006). ERAS (vs. non-ERAS) patients who had a different surgery had 0.72 higher average NRS (p=.02) but had almost half the length of stay, on average (p<.001). CONCLUSIONS: The current study underscores the dynamic nature of ERAS protocols within the realm of spine surgery. While ERAS demonstrates advantages such as reduced LOS and improved patient-reported outcomes, it requires careful implementation and customization to address the specific demands of each surgical discipline. The potential to expedite recovery, optimize resource utilization, and enhance patient satisfaction cannot be overstated. However, the fine balance between achieving these benefits and ensuring comprehensive patient care, especially in the context of postoperative pain management, must be maintained. As ERAS continues to evolve and find its place in diverse surgical domains, it is crucial for healthcare providers to remain attentive to patient needs, adapting ERAS protocols to suit individual patient populations and surgical contexts.

Radiographic Risk Factors for Adjacent Segment Disease Following Anterior Cervical Discectomy and Fusion (ACDF): A Systematic Review and Meta-Analysis.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVES: To assess the radiographic risk factors for adjacent segment disease (ASD) following anterior cervical discectomy and fusion (ACDF) for degenerative cervical spine pathologies. METHODS: PubMed, Embase and the Cochrane Library databases were searched up to December 2023. The primary inclusion criteria were degenerative spinal conditions treated with ACDF, comparing radiological parameters in patients with and without postoperative ASD. The radiographic parameters included intervertebral disc height, cervical sagittal alignment, sagittal segmental alignment, range of motion, segmental height, T1 slope, sagittal vertical axis (SVA), thoracic inlet angle (TIA), and plate to disc distance (PPD). Risk of bias was assessed for all studies. The Cochrane Review Manager was utilized to perform the meta-analysis. RESULTS: From 7044 articles, 13 retrospective studies were included in the final analysis. Three studies had "not serious" bias and the other 10 studies had serious or very serious bias. The total number of patients in the included studies was 1799 patients. Five studies included single-level ACDF, 2 studies included multi-level ACDF, and 6 studies included single or multi-level ACDF. On meta-analysis, the significant risk factors associated with ASD development were reduced postoperative cervical lordosis (mean difference [MD] = 3.35°, P = .002), reduced last-follow-up cervical lordosis (MD = -3.02°, P = .0003), increased preoperative to postoperative cervical sagittal alignment change (MD = -3.68°, P = .03), and the presence of developmental cervical canal stenosis (Odds ratio [OR] = 4.17, P < .001). CONCLUSIONS: Decreased postoperative cervical lordosis, greater change in cervical sagittal alignment and developmental cervical canal stenosis were associated with an increased risk of ASD following ACDF.

Human iPSC-derived Committed Cardiac Progenitors Generate Cardiac Tissue Grafts in a Swine Ischemic Cardiomyopathy Model without Triggering Ventricular Arrhythmias.

BACKGROUND: The adult human heart following a large myocardial infarction is unable to regenerate heart muscle and instead forms scar with the risk of progressive heart failure. Large animal studies have shown that intramyocardial injection of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) following a myocardial infarction result in cell grafts but also ventricular arrhythmias. We hypothesized that intramyocardial injection of committed cardiac progenitor cells (CCPs) derived from iPSCs, combined with cardiac fibroblast-derived extracellular matrix (cECM) to enhance cell retention will: i) form cardiomyocyte containing functional grafts, ii) be free of ventricular arrhythmias and iii) restore left ventricular contractility in a post-myocardial infarction (MI) cardiomyopathy swine model. METHODS: hiPSCs were differentiated using bioreactors and small molecules to produce a population of committed cardiac progenitor cells (CCPs). MI was created using a coronary artery balloon occlusion and reperfusion model in Yucatan mini pigs. Four weeks later, epicardial needle injections of CCPs+cECM were performed in a small initial feasibility cohort, and then transendocardial injections (TEI) of CCPs+cECM, CCPs alone, cECM alone or vehicle control into the peri-infarct region in a larger randomized cohort. A 4-drug immunosuppression regimen was administered to prevent rejection of human CCPs. Arrhythmias were evaluated using implanted event recorders. Magnetic resonance imaging (MRI) and invasive pressure volume assessment were used to evaluate left ventricular anatomic and functional performance, including viability. Detailed histology was performed on the heart to detect human grafts. RESULTS: A scalable biomanufacturing protocol was developed generating CCPs which can efficiently differentiate to cardiomyocytes or endothelial cells in vitro. Intramyocardial delivery of CCPs to post-MI porcine hearts resulted in engraftment and differentiation of CCPs to form ventricular cardiomyocyte rich grafts. There was no significant difference in cardiac MRI-based measured cardiac volumes or function between control, CCP and CCP+cECM groups; however, dobutamine stimulated functional reserve was improved in CCP and CCP+cECM groups. TEI delivery of CCPs with or without cECM did not result in tumors or trigger ventricular arrhythmias. CONCLUSIONS: CCPs are a promising cell source for post-MI heart repair using clinically relevant TEI with a low risk of engraftment ventricular arrhythmias.

What Is the Evidence Supporting Osteobiologic Use in Revision Anterior Cervical Discectomy and Fusion?

STUDY DESIGN: Systematic literature review. OBJECTIVE: To analyze the literature and describe the evidence supporting osteobiologic use in revision anterior cervical discectomy and fusion (ACDF) surgery. METHODS: A systematic search of PubMed/MEDLINE, EMBASE, Cochrane library, and ClinicalTrials.gov databases was conducted for literature reporting the use of osteobiologics in revision ACDF. We searched for studies reporting outcomes of using any osteobiologic use in revision ACDF surgeries (independently of the number of levels) in the above databases. RESULTS: There are currently no studies in the literature describing the outcome and comparative efficacy of diverse osteobiologic agents in the context of revision ACDF surgery. A majority of the current evidence is based only upon studies involving primary ACDF surgery. CONCLUSION: The current study highlights the paucity of literature evidence on the role of diverse osteobiologics in revision ACDF, and foregrounds the need for high-quality evidence on this subject.

AO Spine Guideline for the Use of Osteobiologics (AOGO) in Anterior Cervical Discectomy and Fusion for Spinal Degenerative Cases.

STUDY DESIGN: Guideline. OBJECTIVES: To develop an international guideline (AOGO) about the use of osteobiologics in anterior cervical discectomy and fusion (ACDF) for treating degenerative spine conditions. METHODS: The guideline development process was guided by AO Spine Knowledge Forum Degenerative (KF Degen) and followed the Guideline International Network McMaster Guideline Development Checklist. The process involved 73 participants with expertise in degenerative spine diseases and surgery from 22 countries. Fifteen systematic reviews were conducted addressing respective key topics and evidence was collected. The methodologist compiled the evidence into GRADE Evidence-to-Decision frameworks. Guideline panel members judged the outcomes and other criteria and made the final recommendations through consensus. RESULTS: Five conditional recommendations were created. A conditional recommendation is about the use of allograft, autograft or a cage with an osteobiologic in primary ACDF surgery. Other conditional recommendations are about the use of osteobiologic for single- or multi-level ACDF, and for hybrid construct surgery. It is suggested that surgeons use other osteobiologics rather than human bone morphogenetic protein-2 (BMP-2) in common clinical situations. Surgeons are recommended to choose 1 graft over another or 1 osteobiologic over another primarily based on clinical situation, and the costs and availability of the materials. CONCLUSION: This AOGO guideline is the first to provide recommendations for the use of osteobiologics in ACDF. Despite the comprehensive searches for evidence, there were few studies completed with small sample sizes and primarily as case series with inherent risks of bias. Therefore, high-quality clinical evidence is demanded to improve the guideline.

Comparison of Different Osteobiologics in Terms of Imaging Modalities and Time Frames for Fusion Assessment in Anterior Cervical Discectomy and Fusion: A Systematic Review.

STUDY DESIGN: Systematic review. OBJECTIVES: The study's primary objective was to determine how osteobiologic choice affects fusion rates in patients undergoing anterior cervical discectomy and fusion (ACDF). The study's secondary objectives were to 1) determine the optimal timing of fusion assessment following ACDF and 2) determine if osteobiologic type affects the timing and optimal modality of fusion assessment. METHODS: A systematic search of PubMed/MEDLINE was conducted for literature published from 2000 through October 2020 comparing anterior fusion in the cervical spine with various osteobiologics. Both comparative studies and case series of ≥10 patients were included. RESULTS: A total of 74 studies met the inclusion criteria. Seventeen studies evaluated the efficacy of autograft on fusion outcomes, and 23 studies assessed the efficacy of allograft on fusion outcomes. 3 studies evaluated the efficacy of demineralized bone matrix, and seven assessed the efficacy of rhBMP-2 on fusion outcomes. Other limited studies evaluated the efficacy of ceramics and bioactive glasses on fusion outcomes, and 4 assessed the efficacy of stem cell products. Most studies utilized dynamic radiographs for the assessment of fusion. Overall, there was a general lack of supportive data to determine the optimal timing of fusion assessment meaningfully or if osteobiologic type influenced fusion timing. CONCLUSIONS: Achieving fusion following ACDF appears to remain an intricate interplay between host biology and various surgical factors, including the selection of osteobiologics. While alternative osteobiologics to autograft exist and may produce acceptable fusion rates, limitations in study methodology prevent any definitive conclusions from existing literature.

Top 25 Most-Cited Articles on Robotic-Assisted Lumbar Spine Surgery.

BACKGROUND: Robot-guided lumbar spine surgery has evolved rapidly with evidence to support its utility and feasibility compared with conventional freehand and fluoroscopy-based techniques. The objective of this study was to assess trends among the top 25 most-cited articles pertaining to robotic-guided lumbar spine surgery. METHODS: An "advanced document search" using Boolean search operator terms was performed on 16 November 2022 through the Web of Science and SCOPUS citation databases to determine the top 25 most-referenced articles on robotic lumbar spine surgery. The articles were compiled into a directory and hierarchically organized based on the total number of citations. RESULTS: Cumulatively, the "Top 25" list for robot-assisted navigation in lumbar spine surgery received 2240 citations, averaging 97.39 citations annually. The number of citations ranged from 221 to 40 for the 25 most-cited articles. The most-cited study, by Kantelhardt et al, received 221 citations, averaging 18 citations per year. CONCLUSIONS: As utilization of robot-guided modalities in lumbar spine surgery increases, this review highlights the most impactful studies to support its efficacy and implementation. Practical considerations such as cost-effectiveness, however, need to be better defined through further longitudinal studies that evaluate patient-reported outcomes and cost-utility. CLINICAL RELEVANCE: Through an overview of the top 25 most-cited articles, the present review highlights the rising prominence and technical efficacy of robotic-guided systems within lumbar spine surgery, with consideration to pragmatic limitations and need for additional data to facilitate cost-effective applications.

SPINE20 recommendations 2023: One Earth, one family, one future WITHOUT spine DISABILITY.

Introduction: The purpose is to report on the fourth set of recommendations developed by SPINE20 to advocate for evidence-based spine care globally under the theme of "One Earth, One Family, One Future WITHOUT Spine DISABILITY". Research question: Not applicable. Material and methods: Recommendations were developed and refined through two modified Delphi processes with international, multi-professional panels. Results: Seven recommendations were delivered to the G20 countries calling them to:-establish, prioritize and implement accessible National Spine Care Programs to improve spine care and health outcomes.-eliminate structural barriers to accessing timely rehabilitation for spinal disorders to reduce poverty.-implement cost-effective, evidence-based practice for digital transformation in spine care, to deliver self-management and prevention, evaluate practice and measure outcomes.-monitor and reduce safety lapses in primary care including missed diagnoses of serious spine pathologies and risk factors for spinal disability and chronicity.-develop, implement and evaluate standardization processes for spine care delivery systems tailored to individual and population health needs.-ensure accessible and affordable quality care to persons with spine disorders, injuries and related disabilities throughout the lifespan.-promote and facilitate healthy lifestyle choices (including physical activity, nutrition, smoking cessation) to improve spine wellness and health. Discussion and conclusion: SPINE20 proposes that focusing on the recommendations would facilitate equitable access to health systems, affordable spine care delivered by a competent healthcare workforce, and education of persons with spine disorders, which will contribute to reducing spine disability, associated poverty, and increase productivity of the G20 nations.

Gut butyrate-producers confer post-infarction cardiac protection.

The gut microbiome and its metabolites are increasingly implicated in several cardiovascular diseases, but their role in human myocardial infarction (MI) injury responses have yet to be established. To address this, we examined stool samples from 77 ST-elevation MI (STEMI) patients using 16 S V3-V4 next-generation sequencing, metagenomics and machine learning. Our analysis identified an enriched population of butyrate-producing bacteria. These findings were then validated using a controlled ischemia/reperfusion model using eight nonhuman primates. To elucidate mechanisms, we inoculated gnotobiotic mice with these bacteria and found that they can produce beta-hydroxybutyrate, supporting cardiac function post-MI. This was further confirmed using HMGCS2-deficient mice which lack endogenous ketogenesis and have poor outcomes after MI. Inoculation increased plasma ketone levels and provided significant improvements in cardiac function post-MI. Together, this demonstrates a previously unknown role of gut butyrate-producers in the post-MI response.

Surgeon Preferences Worldwide in Wound Drain Utilization in Open Lumbar Fusion Surgery for Degenerative Pathologies.

STUDY DESIGN: Cross-sectional survey. OBJECTIVE: Although literature does not recommend routine wound drain utilization, there is a disconnect between the evidence and clinical practice. This study aims to explore into this controversy and analyze the surgeon preferences related to drain utilization, and the factors influencing drain use and criterion for removal. METHODS: A survey was distributed to AO Spine members worldwide. Surgeon demographics and factors related to peri-operative drain use in 1 or 2-level open fusion surgery for lumbar degenerative pathologies were collected. Multivariate analyses by drain utilization, and criterion of removal were conducted. RESULTS: 231 surgeons participated, including 220 males (95.2%), orthopedics (178, 77.1%), and academic/university-affiliated (114, 49.4%). Most surgeons preferred drain use (186, 80.5%) and subfascial drains (169, 73.2%). Drains were removed based on duration by 52.87% of the surgeons, but 27.7% removed drains based on outputs. On multivariable analysis, significant predictors of drain use were surgeon's aged 35-44 (OR = 11.9, 95% CI = 1.2-117.2, P = .034), 45-54 (29.1, 3.1-269.6, P = .003), 55-64 (8.9, 1.4-56.5, .019), and wound closure using coaptive films (6.0, 1.2-29.0, P = .025). Additionally, surgeons from Asia Pacific (OR = 5.19, 95% CI = 1.65-16.38, P = .005), Europe (3.55, 1.22-10.31, P = .020), and Latin America (4.40, 1.09-17.83, .038) were more likely to remove drain based on time duration, but surgeons <5 years of experience (10.23, 1.75-59.71, P = .010) were more likely to remove drains based on outputs. CONCLUSIONS: Most spine surgeons worldwide prefer to place a subfascial wound drain for degenerative open lumbar surgery. The choice for drain placement is associated with the surgeon's age and use of coaptive films for wound closure, while the criterion for drain removal is associated with the surgeons' region of practice and experience.

Using machine learning and big data for the prediction of venous thromboembolic events after spine surgery: A single-center retrospective analysis of multiple models on a cohort of 6869 patients.

Objective: Venous thromboembolic event (VTE) after spine surgery is a rare but potentially devastating complication. With the advent of machine learning, an opportunity exists for more accurate prediction of such events to aid in prevention and treatment. Methods: Seven models were screened using 108 database variables and 62 preoperative variables. These models included deep neural network (DNN), DNN with synthetic minority oversampling technique (SMOTE), logistic regression, ridge regression, lasso regression, simple linear regression, and gradient boosting classifier. Relevant metrics were compared between each model. The top four models were selected based on area under the receiver operator curve; these models included DNN with SMOTE, linear regression, lasso regression, and ridge regression. Separate random sampling of each model was performed 1000 additional independent times using a randomly generated training/testing distribution. Variable weights and magnitudes were analyzed after sampling. Results: Using all patient-related variables, DNN using SMOTE was the top-performing model in predicting postoperative VTE after spinal surgery (area under the curve [AUC] =0.904), followed by lasso regression (AUC = 0.894), ridge regression (AUC = 0.873), and linear regression (AUC = 0.864). When analyzing a subset of only preoperative variables, the top-performing models were lasso regression (AUC = 0.865) and DNN with SMOTE (AUC = 0.864), both of which outperform any currently published models. Main model contributions relied heavily on variables associated with history of thromboembolic events, length of surgical/anesthetic time, and use of postoperative chemoprophylaxis. Conclusions: The current study provides promise toward machine learning methods geared toward predicting postoperative complications after spine surgery. Further study is needed in order to best quantify and model real-world risk for such events.

Combined Treatment of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Endothelial Cells Regenerate the Infarcted Heart in Mice and Non-Human Primates.

BACKGROUND: Remuscularization of the mammalian heart can be achieved after cell transplantation of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs). However, several hurdles remain before implementation into clinical practice. Poor survival of the implanted cells is related to insufficient vascularization, and the potential for fatal arrhythmogenesis is associated with the fetal cell-like nature of immature CMs. METHODS: We generated 3 lines of hiPSC-derived endothelial cells (ECs) and hiPSC-CMs from 3 independent donors and tested hiPSC-CM sarcomeric length, gap junction protein, and calcium-handling ability in coculture with ECs. Next, we examined the therapeutic effect of the cotransplantation of hiPSC-ECs and hiPSC-CMs in nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice undergoing myocardial infarction (n≥4). Cardiac function was assessed by echocardiography, whereas arrhythmic events were recorded using 3-lead ECGs. We further used healthy non-human primates (n=4) with cell injection to study the cell engraftment, maturation, and integration of transplanted hiPSC-CMs, alone or along with hiPSC-ECs, by histological analysis. Last, we tested the cell therapy in ischemic reperfusion injury in non-human primates (n=4, 3, and 4 for EC+CM, CM, and control, respectively). Cardiac function was evaluated by echocardiography and cardiac MRI, whereas arrhythmic events were monitored by telemetric ECG recorders. Cell engraftment, angiogenesis, and host-graft integration of human grafts were also investigated. RESULTS: We demonstrated that human iPSC-ECs promote the maturity and function of hiPSC-CMs in vitro and in vivo. When cocultured with ECs, CMs showed more mature phenotypes in cellular structure and function. In the mouse model, cotransplantation augmented the EC-accompanied vascularization in the grafts, promoted the maturity of CMs at the infarct area, and improved cardiac function after myocardial infarction. Furthermore, in non-human primates, transplantation of ECs and CMs significantly enhanced graft size and vasculature and improved cardiac function after ischemic reperfusion. CONCLUSIONS: These results demonstrate the synergistic effect of combining iPSC-derived ECs and CMs for therapy in the postmyocardial infarction heart, enabling a promising strategy toward clinical translation.

The Role of Large Animal Models in Cardiac Regeneration Research Using Human Pluripotent Stem Cell-Derived Cardiomyocytes.

PURPOSE OF REVIEW: Heart failure leads to high mortality. The failing myocardium cannot often be rescued as heart regeneration is mostly compromised by disease progress. Stem cell therapy is a strategy under development to replace the impaired myocardium for recovery after heart injury. RECENT FINDINGS: Many studies have provided evidence of the beneficial effects of pluripotent stem cell-derived cardiomyocyte (CM) implantation into diseased rodent hearts, but there are still many challenges and limitations to replicating the same effects in large animal models for preclinical validation. In this review, we summarize progress in the use of pluripotent stem cell-derived CMs in large animal models based on three key parameters: species selection, cell source, and delivery. Most importantly, we discuss the current limitations and challenges that need to be solved to advance this technology to the translational stage.

ER ribosomal-binding protein 1 regulates blood pressure and potassium homeostasis by modulating intracellular renin trafficking.

BACKGROUND: Genome-wide association studies (GWASs) have linked RRBP1 (ribosomal-binding protein 1) genetic variants to atherosclerotic cardiovascular diseases and serum lipoprotein levels. However, how RRBP1 regulates blood pressure is unknown. METHODS: To identify genetic variants associated with blood pressure, we performed a genome-wide linkage analysis with regional fine mapping in the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) cohort. We further investigated the role of the RRBP1 gene using a transgenic mouse model and a human cell model. RESULTS: In the SAPPHIRe cohort, we discovered that genetic variants of the RRBP1 gene were associated with blood pressure variation, which was confirmed by other GWASs for blood pressure. Rrbp1- knockout (KO) mice had lower blood pressure and were more likely to die suddenly from severe hyperkalemia caused by phenotypically hyporeninemic hypoaldosteronism than wild-type controls. The survival of Rrbp1-KO mice significantly decreased under high potassium intake due to lethal hyperkalemia-induced arrhythmia and persistent hypoaldosteronism, which could be rescued by fludrocortisone. An immunohistochemical study revealed renin accumulation in the juxtaglomerular cells of Rrbp1-KO mice. In the RRBP1-knockdown Calu-6 cells, a human renin-producing cell line, transmission electron and confocal microscopy revealed that renin was primarily retained in the endoplasmic reticulum and was unable to efficiently target the Golgi apparatus for secretion. CONCLUSIONS: RRBP1 deficiency in mice caused hyporeninemic hypoaldosteronism, resulting in lower blood pressure, severe hyperkalemia, and sudden cardiac death. In juxtaglomerular cells, deficiency of RRBP1 reduced renin intracellular trafficking from ER to Golgi apparatus. RRBP1 is a brand-new regulator of blood pressure and potassium homeostasis discovered in this study.

Comparison of Surgical Outcomes Between Anterior and Posterior Cervical Fusions Stratified by Levels Decompressed.

STUDY DESIGN: Retrospective database study. OBJECTIVE: To compare outcomes between 1-, 2-, 3-, and 4- level anterior cervical discectomy and fusions (ACDF) and posterior cervical fusions (PCF) procedures using a national database. SUMMARY OF BACKGROUND DATA: Surgical outcomes involving 3- or 4-level ACDF and PCF cases are not well-described. As there are situations where both ACDF and PCF can be employed, it is important to compare the risks and benefits of both procedures. MATERIALS AND METHODS: Patients who underwent ACDF or PCF between 2010 and 2020 were identified in PearlDiver using current procedural terminology codes. Surgeries done for infectious, traumatic, or neoplastic etiologies were excluded. 2-year reoperations and 90-day readmissions were queried. Surgical complications and transfusions were compiled using ICD-9/10 billing codes. ACDF and PCF procedures were then matched by age, sex, Charlson Comorbidity Index, and a number of levels fused, and the above outcomes were compared. RESULTS: In all, 31,301 PCFs and 110,526 ACDFs were identified. After matching for age, sex, and Charlson Comorbidity Index, a total of 30,353 ACDF and PCF procedures were compared. Three-level and 4-level PCFs had higher rates of 90-day postoperative surgical complications compared with ACDF (OR=2.4 and 2.87, respectively; P <0.001). In addition, higher rates of 90-day readmissions were noted in 3-level PCF compared with 3-level ACDF (OR=1.24, P <0.001). Ninety-day postoperative transfusions were higher in both 3- and 4-level PCFs (OR=2.44 and 18.27, respectively; P <0.001). Two-year reoperations rates were higher for 3-level PCF procedures than 3-level ACDF (OR=1.22; P =0.01). CONCLUSIONS: Patients who underwent 3-4-level ACDF had lower rates of readmission, blood transfusions, and postoperative complications compared with 3-4-level PCF. This data suggests that in cases of 3-4-level pathology with clinical equipoise regarding approach, ACDF may be associated with less short-term morbidity, however, data on fusion rates and adjacent level disease are needed.

In Situ Hydrogelation of Cellular Monolayers Enables Conformal Biomembrane Functionalization for Xeno-Free Feeder Substrate Engineering.

The intricate functionalities of cellular membranes have inspired strategies for deriving and anchoring cell-surface components onto solid substrates for biological studies, biosensor applications, and tissue engineering. However, introducing conformal and right-side-out cell membrane coverage onto planar substrates requires cumbersome protocols susceptible to significant device-to-device variability. Here, a facile approach for biomembrane functionalization of planar substrates is demonstrated by subjecting confluent cellular monolayer to intracellular hydrogel polymerization. The resulting cell-gel hybrid, herein termed GELL (gelated cell), exhibits extraordinary stability and retains the structural integrity, membrane fluidity, membrane protein mobility, and topology of living cells. In assessing the utility of GELL layers as a tissue engineering feeder substrate for stem cell maintenance, GELL feeder prepared from primary mouse embryonic fibroblasts not only preserves the stemness of murine stem cells but also exhibits advantages over live feeder cells owing to the GELL's inanimate, non-metabolizing nature. The preparation of a xeno-free feeder substrate devoid of non-human components is further shown with HeLa cells, and the resulting  HeLa GELL feeder effectively sustains the growth and stemness of both murine and human induced pluripotent stem cells. The study highlights a novel bio-functionalization strategy that introduces new opportunities for tissue engineering and other biomedical applications.

Clinical risk factors associated with the development of adjacent segment disease in patients undergoing ACDF: A systematic review.

BACKGROUND CONTEXT: Cervical fusion for degenerative disorders carries a known risk of adjacent segment disease (ASD), a complication that often requires surgical intervention to relieve symptoms. Proposed risk factors for development of ASD include both clinical and radiographic patient characteristics. However, the true impact of these risk factors is less understood due to limitations in sample sizes and loss to follow-up in individual studies. PURPOSE: To review and critically examine current literature on the clinical risk factors associated with development of ASD in the cervical spine following ACDF. STUDY DESIGN: Systematic Review and Meta-Analysis. METHODS: We systematically reviewed the literature in December 2019 according to the PRISMA guidelines. Methodological quality of included papers and quality of evidence were evaluated according to MINORS and GRADE framework. Meta-analysis was performed to compute the odds ratio(OR)with corresponding 95% confidence interval(CI)for dichotomous data, and mean difference(MD) with 95% CI for continuous variables. RESULTS: 6,850 records were obtained using database query. Title/abstract screening resulted in 19 articles for full review, from which 10 papers met the criteria for analysis. There were no significant differences in gender (OR 0.99, 95% CI 0.75-1.30), BMI (MD -0.09, 95% CI -0.46 to 0.29), smoking (OR 1.13, 95% CI 0.80-1.59), alcohol (OR 1.07, 95% CI 0.70-1.64), diabetes (OR 0.85, 95% CI 0.56-1.31), number of segments fused (OR 0.86, 95% CI 0.64-1.16), and preoperative JOA (MD -0.50, 95% CI -1.04 to 0.04). Age (MD 3.21, 95% CI 2.00-4.42), congenital/developmental stenosis (OR 1.94, 95% CI 1.06-3.56), preoperative NDI (MD 4.18, 95% CI 2.11 to 6.26), preoperative VAS (neck) (MD 0.54 95% CI 0.09-0.99), and preoperative VAS (arm) (MD 0.98, 95% CI 0.43-1.34) were found to be statistically significant risk factors. CONCLUSION: Patients with congenital stenosis, advanced age, and high preoperative NDI are at increased risk of developing ASD.

Opportunities and Challenges of Human IPSC Technology in Kidney Disease Research.

Human induced pluripotent stem cells (iPSCs), since their discovery in 2007, open a broad array of opportunities for research and potential therapeutic uses. The substantial progress in iPSC reprogramming, maintenance, differentiation, and characterization technologies since then has supported their applications from disease modeling and preclinical experimental platforms to the initiation of cell therapies. In this review, we started with a background introduction about stem cells and the discovery of iPSCs, examined the developing technologies in reprogramming and characterization, and provided the updated list of stem cell biobanks. We highlighted several important iPSC-based research including that on autosomal dominant kidney disease and SARS-CoV-2 kidney involvement and discussed challenges and future perspectives.

Depletion of gut microbiota improves the therapeutic efficacy of cancer nanomedicine.

Rationale: Gut microbiota plays a crucial role in cancer development and treatment. Studies show that although the gut microbiota is able to promote tumor growth, its presence also improves the efficacy of cancer treatment such as immunotherapy. To date, understanding of the potential impact of the gut microbiota on other treatment modalities such as cancer nanomedicine is still limited. In this study, we aimed to establish the relationship between gut microbiota and cancer nanomedicine, which can potentially open a new path in cancer treatment that combines gut microbiota modulation along with nanotherapeutics. Methods: Mice bearing 4T1 triple-negative breast cancer cells were subjected to gut microbiota modulation by antibiotics (ABX) treatment in the drinking water. Mice given normal water was used for control. The effects of ABX treatment towards gut bacteria was studied by RT-qPCR and 16S next generation sequencing of fecal samples. The mice were then subjected to liposomal doxorubicin (LipoDox) treatment and the amount of nanotherapeutics that accumulated in the tumors was quantified. For therapeutic efficacy, the mice were subjected to ABX treatment and given three injections of LipoDox or saline, while the tumor growth was monitored throughout. Results: Analysis of fecal bacterial content showed that ABX treatment resulted in depletion of gut microbiota. Quantification of LipoDox content revealed significantly increased accumulation in ABX tumor compared to control. Compared to LipoDox treatment alone, we found that combined gut microbiota depletion and LipoDox treatment resulted in augmented long-term anti-tumor efficacy and significantly improved median survival compared to LipoDox only (control vs ABX = 58.5 vs 74 days, p = 0.0002, n = 10 for both groups), with two mice surviving until the end of the experimental end point without experiencing relapse. We also identified the increase in vascular permeability of ABX-treated tumors correlated to for improved therapeutic efficacy and outcome. Conclusion: We showed that gut microbiota depletion led to enhanced tumor vascular permeability, which allowed a larger amount of LipoDox nanoparticles to accumulate in the tumor, leading to better long-term effects. Our results suggest that gut microbiota modulation may be exploited in combination with available nanomedicine-based therapeutics to improve cancer diagnosis, therapeutic efficacy and outcome.

Commensal gut microbiota-derived acetate and propionate enhance heart adaptation in response to cardiac pressure overload in mice.

Background: The gut microbiota plays a vital role in maintaining tissue homeostasis and regulating disease pathophysiology; however, the underlying mechanisms remain to be elucidated. We previously showed that mice depleted of gut microbiota with antibiotics (ABX mice) were more prone to cardiac rupture after infarction, suggesting that the gut microbiota impacts cardiac structural remodeling following injury. Here, we aimed to determine whether the gut microbiota is required for adaptive cardiac remodeling in response to pressure overload stress. Methods: Transverse aortic constriction (TAC) surgery was performed and cardiac function was evaluated by echocardiography and catheterization, followed by mechanical tests and extracellular matrix (ECM) studies. Germ-free mice with cecal microbiota transplantation were used for validation. 16S ribosomal DNA sequencing and PICRUSt2 analysis were applied to predict the key metabolic pathways. ABX mice were supplemented with the derived metabolic products and their efficacy was tested. To elucidate the underlying mechanism, we isolated mouse primary cardiac fibroblasts and treated them with the metabolites. Lastly, G-coupled protein receptor 41 (GPR41) and GPR43 double knockdown cardiac fibroblasts were generated and the anti-fibrogenic effect of metabolites was determined. Results: Cardiac hypertrophy and dysfunction were more severe in ABX-TAC mice compared to the controls. Moreover, TAC-induced fibrosis was more profound in ABX hearts, which was accompanied by disrupted ECM structure making the heart tissues mechanically weaker and more brittle. Reconstruction of healthy gut microbiota in germ-free mice successfully restored cardiac function and prevented excessive fibrosis and ECM disarray under stress. Furthermore, functional prediction identified acetate and propionate as critical mediators in the gut microbiota-modulated cardiac mechanics. Supplementation of acetate and propionate improved heart function, attenuated fibrosis, and reversed ECM disarray after TAC. In addition, treating primary cardiac fibroblasts with acetate and propionate attenuated cell contraction, inhibited myofibroblast formation, and reduced collagen formation after TGF-ß1 stimulus. Finally, knocking down GPR41 and GPR43 receptors in cardiac fibroblasts blunted the inhibitory effects of acetate and propionate. Conclusions: The gut microbiota is a potential therapeutic target for cardiac ECM remodeling and heart structural integrity. By establishing a healthy gut microbiome or replenishing the derived metabolites, we could improve cardiac health under dysbiosis after pressure-overload stress.