Divergent landscapes of A-to-I editing in postmortem and living human brain.

Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR1 and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries illuminate the nuanced functions and intricate regulatory mechanisms of RNA editing within the human brain.

Multiomic foundations of human prefrontal cortex tissue function.

The prefrontal cortex (PFC) is a region of the brain that in humans is involved in the production of higher-order functions such as cognition, emotion, perception, and behavior. Neurotransmission in the PFC produces higher-order functions by integrating information from other areas of the brain. At the foundation of neurotransmission, and by extension at the foundation of higher-order brain functions, are an untold number of coordinated molecular processes involving the DNA sequence variants in the genome, RNA transcripts in the transcriptome, and proteins in the proteome. These "multiomic" foundations are poorly understood in humans, perhaps in part because most modern studies that characterize the molecular state of the human PFC use tissue obtained when neurotransmission and higher-order brain functions have ceased (i.e., the postmortem state). Here, analyses are presented on data generated for the Living Brain Project (LBP) to investigate whether PFC tissue from individuals with intact higher-order brain function has characteristic multiomic foundations. Two complementary strategies were employed towards this end. The first strategy was to identify in PFC samples obtained from living study participants a signature of RNA transcript expression associated with neurotransmission measured intracranially at the time of PFC sampling, in some cases while participants performed a task engaging higher-order brain functions. The second strategy was to perform multiomic comparisons between PFC samples obtained from individuals with intact higher-order brain function at the time of sampling (i.e., living study participants) and PFC samples obtained in the postmortem state. RNA transcript expression within multiple PFC cell types was associated with fluctuations of dopaminergic, serotonergic, and/or noradrenergic neurotransmission in the substantia nigra measured while participants played a computer game that engaged higher-order brain functions. A subset of these associations - termed the "transcriptional program associated with neurotransmission" (TPAWN) - were reproduced in analyses of brain RNA transcript expression and intracranial neurotransmission data obtained from a second LBP cohort and from a cohort in an independent study. RNA transcripts involved in TPAWN were found to be (1) enriched for RNA transcripts associated with measures of neurotransmission in rodent and cell models, (2) enriched for RNA transcripts encoded by evolutionarily constrained genes, (3) depleted of RNA transcripts regulated by common DNA sequence variants, and (4) enriched for RNA transcripts implicated in higher-order brain functions by human population genetic studies. In PFC excitatory neurons of living study participants, higher expression of the genes in TPAWN tracked with higher expression of RNA transcripts that in rodent PFC samples are markers of a class of excitatory neurons that connect the PFC to deep brain structures. TPAWN was further reproduced by RNA transcript expression patterns differentiating living PFC samples from postmortem PFC samples, and significant differences between living and postmortem PFC samples were additionally observed with respect to (1) the expression of most primary RNA transcripts, mature RNA transcripts, and proteins, (2) the splicing of most primary RNA transcripts into mature RNA transcripts, (3) the patterns of co-expression between RNA transcripts and proteins, and (4) the effects of some DNA sequence variants on RNA transcript and protein expression. Taken together, this report highlights that studies of brain tissue obtained in a safe and ethical manner from large cohorts of living individuals can help advance understanding of the multiomic foundations of brain function.

The Incidence of Subsequent Cervical Spine Surgery after Cervical Disc Arthroplasty, a Minimum Two-year Follow-up.

To identify the risk factors and incidence of subsequent cervical spine surgery in patients undergoing primary cervical disc arthroplasty (CDA). We analyzed the 2005-2015 NYS SPARCS database. Patients were longitudinally followed to determine the incidence of re-operation. Univariate and Multivariate analyses were used to identify demographic risk factors. Eight-hundred and thirty-five CDA patients had a cervical spine re-operation rate of 7.5%; 4.4% re-operation rate at two-year follow-up. The most common cervical re-operation was a primary anterior cervical discectomy and fusion (ACDF) (76.2%). Patients who underwent re-operation were more likely to be younger (p = 0.034) and female (p = 0.007). Logistic regression analysis found only female sex to have increased odds of re-operation (odds ration = 2.10, 95% confidence interval 1.21-3.63). There was a 4.4% rate of subsequent cervical spine surgery following CDA at 2 years and a 7.5% rate of subsequent cervical spine surgery. The most common cervical spine procedure following CDA was ACDF. Female sex was the only patient demographic factor to significantly influence the odds of cervical spine re-operation. (Journal of Surgical Orthopaedic Advances 31(1):007-011, 2022).

Prognostic value of polygenic risk scores for adults with psychosis.

Polygenic risk scores (PRS) summarize genetic liability to a disease at the individual level, and the aim is to use them as biomarkers of disease and poor outcomes in real-world clinical practice. To date, few studies have assessed the prognostic value of PRS relative to standards of care. Schizophrenia (SCZ), the archetypal psychotic illness, is an ideal test case for this because the predictive power of the SCZ PRS exceeds that of most other common diseases. Here, we analyzed clinical and genetic data from two multi-ethnic cohorts totaling 8,541 adults with SCZ and related psychotic disorders, to assess whether the SCZ PRS improves the prediction of poor outcomes relative to clinical features captured in a standard psychiatric interview. For all outcomes investigated, the SCZ PRS did not improve the performance of predictive models, an observation that was generally robust to divergent case ascertainment strategies and the ancestral background of the study participants.

Transcriptional profiling of mESC-derived tendon and fibrocartilage cell fate switch.

The transcriptional regulators underlying induction and differentiation of dense connective tissues such as tendon and related fibrocartilaginous tissues (meniscus and annulus fibrosus) remain largely unknown. Using an iterative approach informed by developmental cues and single cell RNA sequencing (scRNA-seq), we establish directed differentiation models to generate tendon and fibrocartilage cells from mouse embryonic stem cells (mESCs) by activation of TGFß and hedgehog pathways, achieving 90% induction efficiency. Transcriptional signatures of the mESC-derived cells recapitulate embryonic tendon and fibrocartilage signatures from the mouse tail. scRNA-seq further identify retinoic acid signaling as a critical regulator of cell fate switch between TGFß-induced tendon and fibrocartilage lineages. Trajectory analysis by RNA sequencing define transcriptional modules underlying tendon and fibrocartilage fate induction and identify molecules associated with lineage-specific differentiation. Finally, we successfully generate 3-dimensional engineered tissues using these differentiation protocols and show activation of mechanotransduction markers with dynamic tensile loading. These findings provide a serum-free approach to generate tendon and fibrocartilage cells and tissues at high efficiency for modeling development and disease.

Macrophage depletion impairs neonatal tendon regeneration.

Tendons are dense connective tissues that transmit muscle forces to the skeleton. After adult injury, healing potential is generally poor and dominated by scar formation. Although the immune response is a key feature of healing, the specific immune cells and signals that drive tendon healing have not been fully defined. In particular, the immune regulators underlying tendon regeneration are almost completely unknown due to a paucity of tendon regeneration models. Using a mouse model of neonatal tendon regeneration, we screened for immune-related markers and identified upregulation of several genes associated with inflammation, macrophage chemotaxis, and TGFß signaling after injury. Depletion of macrophages using AP20187 treatment of MaFIA mice resulted in impaired functional healing, reduced cell proliferation, reduced ScxGFP+ neo-tendon formation, and altered tendon gene expression. Collectively, these results show that inflammation is a key component of neonatal tendon regeneration and demonstrate a requirement for macrophages in effective functional healing.

ScxLin cells directly form a subset of chondrocytes in temporomandibular joint that are sharply increased in Dmp1-null mice.

It has been assumed that the secondary cartilage in the temporomandibular joint (TMJ), which is the most complex and mystery joint and expands rapidly after birth, is formed by periochondrium-derived chondrocytes. The TMJ condyle has rich attachment sites of tendon, which is thought to be solely responsible for joint movement with a distinct cell lineage. Here, we used a Scx-Cre ERT2 mouse line (the tracing line for progenitor and mature tendon cells) to track the fate of tendon cells during TMJ postnatal growth. Our data showed a progressive differentiation of Scx lineage cells started at tendon and the fibrous layer, to cells at the prechondroblasts (Sox9 -/Col I +), and then to cells at the chondrocytic layer (Sox9 +/Col I -). Importantly, the Scx + chondrocytes remained as "permanent" chondrocytes to maintain cartilage mass with no further cell trandifferentiation to bone cells. This notion was substantiated in an assessment of these cells in Dmp1 -null mice (a hypophosphatemic rickets model), where there was a significant increase in the number of Scx lineage cells in response to hypophosphatemia. In addition, we showed the origin of disc, which is derived from Scx + cells. Thus, we propose Scx lineage cells play an important role in TMJ postnatal growth by forming the disc and a new subset of Scx + chondrocytes that do not undergo osteogenesis as the Scx - chondrocytes and are sensitive to the level of phosphorous.

Automated Measurement of Lumbar Lordosis on Radiographs Using Machine Learning and Computer Vision.

STUDY DESIGN: Cross sectional database study. OBJECTIVE: To develop a fully automated artificial intelligence and computer vision pipeline for assisted evaluation of lumbar lordosis. METHODS: Lateral lumbar radiographs were used to develop a segmentation neural network (n = 629). After synthetic augmentation, 70% of these radiographs were used for network training, while the remaining 30% were used for hyperparameter optimization. A computer vision algorithm was deployed on the segmented radiographs to calculate lumbar lordosis angles. A test set of radiographs was used to evaluate the validity of the entire pipeline (n = 151). RESULTS: The U-Net segmentation achieved a test dataset dice score of 0.821, an area under the receiver operating curve of 0.914, and an accuracy of 0.862. The computer vision algorithm identified the L1 and S1 vertebrae on 84.1% of the test set with an average speed of 0.14 seconds/radiograph. From the 151 test set radiographs, 50 were randomly chosen for surgeon measurement. When compared with those measurements, our algorithm achieved a mean absolute error of 8.055° and a median absolute error of 6.965° (not statistically significant, P > .05). CONCLUSION: This study is the first to use artificial intelligence and computer vision in a combined pipeline to rapidly measure a sagittal spinopelvic parameter without prior manual surgeon input. The pipeline measures angles with no statistically significant differences from manual measurements by surgeons. This pipeline offers clinical utility in an assistive capacity, and future work should focus on improving segmentation network performance.

Tgfß signaling is required for tenocyte recruitment and functional neonatal tendon regeneration.

Tendon injuries are common with poor healing potential. The paucity of therapies for tendon injuries is due to our limited understanding of the cells and molecular pathways that drive tendon regeneration. Using a mouse model of neonatal tendon regeneration, we identified TGFß signaling as a major molecular pathway that drives neonatal tendon regeneration. Through targeted gene deletion, small molecule inhibition, and lineage tracing, we elucidated TGFß-dependent and TGFß-independent mechanisms underlying tendon regeneration. Importantly, functional recovery depended on canonical TGFß signaling and loss of function is due to impaired tenogenic cell recruitment from both Scleraxis-lineage and non-Scleraxis-lineage sources. We show that TGFß signaling is directly required in neonatal tenocytes for recruitment and that TGFß ligand is positively regulated in tendons. Collectively, these results show a functional role for canonical TGFß signaling in tendon regeneration and offer new insights toward the divergent cellular activities that distinguish regenerative vs fibrotic healing.

Cellular Plasticity in Musculoskeletal Development, Regeneration, and Disease.

In this review, we highlight themes from a recent workshop focused on "Plasticity of Cell Fate in Musculoskeletal Tissues" held at the Orthopaedic Research Society's 2019 annual meeting. Experts in the field provided examples of mesenchymal cell plasticity during normal musculoskeletal development, regeneration, and disease. A thorough understanding of the biology underpinning mesenchymal cell plasticity may offer a roadmap for promoting regeneration while attenuating pathologic differentiation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:708-718, 2020.

Detecting insertion, substitution, and deletion errors in radiology reports using neural sequence-to-sequence models.

BACKGROUND: Errors in grammar, spelling, and usage in radiology reports are common. To automatically detect inappropriate insertions, deletions, and substitutions of words in radiology reports, we proposed using a neural sequence-to-sequence (seq2seq) model. METHODS: Head CT and chest radiograph reports from Mount Sinai Hospital (MSH) (n=61,722 and 818,978, respectively), Mount Sinai Queens (MSQ) (n=30,145 and 194,309, respectively) and MIMIC-III (n=32,259 and 54,685) were converted into sentences. Insertions, substitutions, and deletions of words were randomly introduced. Seq2seq models were trained using corrupted sentences as input to predict original uncorrupted sentences. Three models were trained using head CTs from MSH, chest radiographs from MSH, and head CTs from all three collections. Model performance was assessed across different sites and modalities. A sample of original, uncorrupted sentences were manually reviewed for any error in syntax, usage, or spelling to estimate real-world proofreading performance of the algorithm. RESULTS: Seq2seq detected 90.3% and 88.2% of corrupted sentences with 97.7% and 98.8% specificity in same-site, same-modality test sets for head CTs and chest radiographs, respectively. Manual review of original, uncorrupted same-site same-modality head CT sentences demonstrated seq2seq positive predictive value (PPV) 0.393 (157/400; 95% CI, 0.346-0.441) and negative predictive value (NPV) 0.986 (789/800; 95% CI, 0.976-0.992) for detecting sentences containing real-world errors, with estimated sensitivity of 0.389 (95% CI, 0.267-0.542) and specificity 0.986 (95% CI, 0.985-0.987) over n=86,211 uncorrupted training examples. CONCLUSIONS: Seq2seq models can be highly effective at detecting erroneous insertions, deletions, and substitutions of words in radiology reports. To achieve high performance, these models require site- and modality-specific training examples. Incorporating additional targeted training data could further improve performance in detecting real-world errors in reports.

Hypoalbuminemia as an Independent Risk Factor for Perioperative Complications Following Surgical Decompression of Spinal Metastases.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: Malnutrition has been shown to be a risk factor for poor perioperative outcomes in multiple surgical subspecialties, but few studies have specifically investigated the effect of hypoalbuminemia in patients undergoing operative treatment of metastatic spinal tumors. The aim of this study was to assess the role of hypoalbuminemia as an independent risk factor for 30-day perioperative mortality and morbidity after surgical decompression of metastatic spinal tumors using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database from 2011 to 2014. METHODS: We identified 1498 adult patients in the ACS-NSQIP database who underwent laminectomy and excision of metastatic extradural spinal tumors. Patients were categorized into normoalbuminemic and hypoalbuminemic (ie, albumin level <3.5 g/dL) groups. Univariate and multivariate regression analyses were performed to examine the association between preoperative hypoalbuminemia and 30-day perioperative mortality and morbidity. Subgroup analysis was performed in the hypoalbuminemic group to assess the dose-dependent effect of albumin depletion. RESULTS: Hypoalbuminemia was associated with increased risk of perioperative mortality, any complication, sepsis, intra- or postoperative transfusion, prolonged hospitalization, and non-home discharge. However, albumin depletion was also associated with decreased risk of readmission. There was an albumin level-dependent effect of increasing mortality and complication rates with worsening albumin depletion. CONCLUSIONS: Hypoalbuminemia is an independent risk factor for perioperative mortality and morbidity following surgical decompression of metastatic spinal tumors with a dose-dependent effect on mortality and complication rates. Therefore, it is important to address malnutrition and optimize nutritional status prior to surgery.

An attention based deep learning model of clinical events in the intensive care unit.

This study trained long short-term memory (LSTM) recurrent neural networks (RNNs) incorporating an attention mechanism to predict daily sepsis, myocardial infarction (MI), and vancomycin antibiotic administration over two week patient ICU courses in the MIMIC-III dataset. These models achieved next-day predictive AUC of 0.876 for sepsis, 0.823 for MI, and 0.833 for vancomycin administration. Attention maps built from these models highlighted those times when input variables most influenced predictions and could provide a degree of interpretability to clinicians. These models appeared to attend to variables that were proxies for clinician decision-making, demonstrating a challenge of using flexible deep learning approaches trained with EHR data to build clinical decision support. While continued development and refinement is needed, we believe that such models could one day prove useful in reducing information overload for ICU physicians by providing needed clinical decision support for a variety of clinically important tasks.

Predicting Surgical Complications in Adult Patients Undergoing Anterior Cervical Discectomy and Fusion Using Machine Learning.

OBJECTIVE: Machine learning algorithms excel at leveraging big data to identify complex patterns that can be used to aid in clinical decision-making. The objective of this study is to demonstrate the performance of machine learning models in predicting postoperative complications following anterior cervical discectomy and fusion (ACDF). METHODS: Artificial neural network (ANN), logistic regression (LR), support vector machine (SVM), and random forest decision tree (RF) models were trained on a multicenter data set of patients undergoing ACDF to predict surgical complications based on readily available patient data. Following training, these models were compared to the predictive capability of American Society of Anesthesiologists (ASA) physical status classification. RESULTS: A total of 20,879 patients were identified as having undergone ACDF. Following exclusion criteria, patients were divided into 14,615 patients for training and 6,264 for testing data sets. ANN and LR consistently outperformed ASA physical status classification in predicting every complication (p < 0.05). The ANN outperformed LR in predicting venous thromboembolism, wound complication, and mortality (p < 0.05). The SVM and RF models were no better than random chance at predicting any of the postoperative complications (p < 0.05). CONCLUSION: ANN and LR algorithms outperform ASA physical status classification for predicting individual postoperative complications. Additionally, neural networks have greater sensitivity than LR when predicting mortality and wound complications. With the growing size of medical data, the training of machine learning on these large datasets promises to improve risk prognostication, with the ability of continuously learning making them excellent tools in complex clinical scenarios.

Predicting Surgical Complications in Patients Undergoing Elective Adult Spinal Deformity Procedures Using Machine Learning.

STUDY DESIGN: Cross-sectional database study. OBJECTIVE: To train and validate machine learning models to identify risk factors for complications following surgery for adult spinal deformity (ASD). SUMMARY OF BACKGROUND DATA: Machine learning models such as logistic regression (LR) and artificial neural networks (ANNs) are valuable tools for analyzing and interpreting large and complex data sets. ANNs have yet to be used for risk factor analysis in orthopedic surgery. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried for patients who underwent surgery for ASD. This query returned 4,073 patients, which data were used to train and evaluate our models. The predictive variables used included sex, age, ethnicity, diabetes, smoking, steroid use, coagulopathy, functional status, American Society of Anesthesiologists (ASA) class >3, body mass index (BMI), pulmonary comorbidities, and cardiac comorbidities. The models were used to predict cardiac complications, wound complications, venous thromboembolism (VTE), and mortality. Using ASA class as a benchmark for prediction, area under receiver operating characteristic curves (AUC) was used to determine the accuracy of our machine learning models. RESULTS: The mean age of patients was 59.5 years. Forty-one percent of patients were male whereas 59.0% of patients were female. ANN and LR outperformed ASA scoring in predicting every complication (p<.05). The ANN outperformed LR in predicting cardiac complication, wound complication, and mortality (p<.05). CONCLUSIONS: Machine learning algorithms outperform ASA scoring for predicting individual risk prognosis. These algorithms also outperform LR in predicting individual risk for all complications except VTE. With the growing size of medical data, the training of machine learning on these large data sets promises to improve risk prognostication, with the ability of continuously learning making them excellent tools in complex clinical scenarios. LEVEL OF EVIDENCE: Level III.

Association of traffic air pollution and rhinitis quality of life in Peruvian children with asthma.

BACKGROUND: Air pollution exposure may contribute to rhinoconjunctivitis morbidity in children with underlying airways disease. Prior studies have not assessed rhinoconjunctivitis-related quality of life (QOL) in children with asthma chronically exposed to air pollution. METHODS: Children ages 9-19 years with asthma from peri-urban Peru, self-reporting rhinoconjunctivitis symptoms (n = 484), were administered the Rhinoconjunctivitis QOL Questionnaire (RQLQ) at repeated intervals over one year, with scores dichotomized into bothered (>0) and not bothered (= 0). Individual weekly exposures to particulate matter<2.5µm (PM2.5) and its black carbon (BC) component were estimated by inverse distance weighted methods. Generalized estimating equations, adjusting for covariates, estimated associations of PM2.5 and BC with QOL. RESULTS: Participants were on average 13 years old, 55% female, and majority were atopic (77%). Mean (SD) PM2.5 and BC concentrations were 21(3.2) µg/m3 and 4.4(1.5) µg/m3, respectively. In adjusted multi-pollutant models, each 10µg/m3 increase in PM2.5 was associated with increased odds of worse rhinoconjunctivitis QOL (OR;[95% CI]: 1.83;[1.33,2.52]). A 10% increase in the BC proportion was associated with higher rhinitis burden (OR;[95% CI]: 1.80;[1.22,2.66]), while increases in the non-BC component of PM did not significantly impact rhinoconjunctivitis QOL. Associations were similar regardless of atopy. CONCLUSION: Higher PM2.5 and BC exposure is associated with worse rhinitis QOL among asthmatic children.

The Impact of Metastatic Spinal Tumor Location on 30-Day Perioperative Mortality and Morbidity After Surgical Decompression.

STUDY DESIGN: A retrospective cohort study from 2011 to 2014 was performed using the American College of Surgeons National Surgical Quality Improvement Program database. OBJECTIVE: The purpose of this study was to assess the impact of tumor location in the cervical, thoracic, or lumbosacral spine on 30-day perioperative mortality and morbidity after surgical decompression of metastatic extradural spinal tumors. SUMMARY OF BACKGROUND DATA: Operative treatment of metastatic spinal tumors involves extensive procedures that are associated with significant complication rates and healthcare costs. Past studies have examined various risk factors for poor clinical outcomes after surgical decompression procedures for spinal tumors, but few studies have specifically investigated the impact of tumor location on perioperative mortality and morbidity. METHODS: We identified 2238 patients in the American College of Surgeons National Surgical Quality Improvement Program database who underwent laminectomy for excision of metastatic extradural tumors in the cervical, thoracic, or lumbosacral spine. Baseline patient characteristics were collected from the database. Univariate and multivariate regression analyses were performed to examine the association between spinal tumor location and 30-day perioperative mortality and morbidity. RESULTS: On univariate analysis, cervical spinal tumors were associated with the highest rate of pulmonary complications. Multivariate regression analysis demonstrated that cervical spinal tumors had the highest odds of multiple perioperative complications. However, thoracic spinal tumors were associated with the highest risk of intra- or postoperative blood transfusion. In contrast, patients with metastatic tumors in the lumbosacral spine had lower odds of perioperative mortality, pulmonary complications, and sepsis. CONCLUSION: Tumor location is an independent risk factor for perioperative mortality and morbidity after surgical decompression of metastatic spinal tumors. The addition of tumor location to existing prognostic scoring systems may help to improve their predictive accuracy. LEVEL OF EVIDENCE: 3.

Examining the Ability of Artificial Neural Networks Machine Learning Models to Accurately Predict Complications Following Posterior Lumbar Spine Fusion.

STUDY DESIGN: A cross-sectional database study. OBJECTIVE: The aim of this study was to train and validate machine learning models to identify risk factors for complications following posterior lumbar spine fusion. SUMMARY OF BACKGROUND DATA: Machine learning models such as artificial neural networks (ANNs) are valuable tools for analyzing and interpreting large and complex datasets. ANNs have yet to be used for risk factor analysis in orthopedic surgery. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried for patients who underwent posterior lumbar spine fusion. This query returned 22,629 patients, 70% of whom were used to train our models, and 30% were used to evaluate the models. The predictive variables used included sex, age, ethnicity, diabetes, smoking, steroid use, coagulopathy, functional status, American Society for Anesthesiology (ASA) class ≥3, body mass index (BMI), pulmonary comorbidities, and cardiac comorbidities. The models were used to predict cardiac complications, wound complications, venous thromboembolism (VTE), and mortality. Using ASA class as a benchmark for prediction, area under receiver operating curves (AUC) was used to determine the accuracy of our machine learning models. RESULTS: On the basis of AUC values, ANN and LR both outperformed ASA class for predicting all four types of complications. ANN was the most accurate for predicting cardiac complications, and LR was most accurate for predicting wound complications, VTE, and mortality, though ANN and LR had comparable AUC values for predicting all types of complications. ANN had greater sensitivity than LR for detecting wound complications and mortality. CONCLUSION: Machine learning in the form of logistic regression and ANNs were more accurate than benchmark ASA scores for identifying risk factors of developing complications following posterior lumbar spine fusion, suggesting they are potentially great tools for risk factor analysis in spine surgery. LEVEL OF EVIDENCE: 3.

Experimental and Computational Insight Into Human Mesenchymal Stem Cell Paracrine Signaling and Heterocellular Coupling Effects on Cardiac Contractility and Arrhythmogenicity.

RATIONALE: Myocardial delivery of human mesenchymal stem cells (hMSCs) is an emerging therapy for treating the failing heart. However, the relative effects of hMSC-mediated heterocellular coupling (HC) and paracrine signaling (PS) on human cardiac contractility and arrhythmogenicity remain unresolved. OBJECTIVE: The objective is to better understand hMSC PS and HC effects on human cardiac contractility and arrhythmogenicity by integrating experimental and computational approaches. METHODS AND RESULTS: Extending our previous hMSC-cardiomyocyte HC computational model, we incorporated experimentally calibrated hMSC PS effects on cardiomyocyte L-type calcium channel/sarcoendoplasmic reticulum calcium-ATPase activity and cardiac tissue fibrosis. Excitation-contraction simulations of hMSC PS-only and combined HC+PS effects on human cardiomyocytes were representative of human engineered cardiac tissue (hECT) contractile function measurements under matched experimental treatments. Model simulations and hECTs both demonstrated that hMSC-mediated effects were most pronounced under PS-only conditions, where developed force increased ≈4-fold compared with non-hMSC-supplemented controls during physiological 1-Hz pacing. Simulations predicted contractility of isolated healthy and ischemic adult human cardiomyocytes would be minimally sensitive to hMSC HC, driven primarily by PS. Dominance of hMSC PS was also revealed in simulations of fibrotic cardiac tissue, where hMSC PS protected from potential proarrhythmic effects of HC at various levels of engraftment. Finally, to study the nature of the hMSC paracrine effects on contractility, proteomic analysis of hECT/hMSC conditioned media predicted activation of PI3K/Akt signaling, a recognized target of both soluble and exosomal fractions of the hMSC secretome. Treating hECTs with exosome-enriched, but not exosome-depleted, fractions of the hMSC secretome recapitulated the effects observed with hMSC conditioned media on hECT-developed force and expression of calcium-handling genes (eg, SERCA2a, L-type calcium channel). CONCLUSIONS: Collectively, this integrated experimental and computational study helps unravel relative hMSC PS and HC effects on human cardiac contractility and arrhythmogenicity, and provides novel insight into the role of exosomes in hMSC paracrine-mediated effects on contractility.

Association between probiotic and yogurt consumption and kidney disease: insights from NHANES.

BACKGROUND: Data from experimental animals suggest that probiotic supplements may retard CKD progression. However, the relationship between probiotic use, frequent yogurt consumption (as a natural probiotic source), and kidney parameters have not been evaluated in humans. FINDINGS: We utilized NHANES data, and analyzed the association of probiotic alone (1999-2012) and yogurt/probiotic (2003-2006) use with albuminuria and eGFR after adjustment for demographic and clinical parameters. Frequent yogurt consumption was defined as thrice or more weekly over the year prior to the interview. Frequent yogurt/probiotic consumers had lower adjusted odds of developing combined outcome (albuminuria and/or eGFR < 60 ml/min/1.73 m(2)) compared to infrequent consumers (OR = 0.76; 95 % CI = 0.61-0.94). When evaluated separately, frequent consumers had lower odds of albuminuria and nonsignificant trend towards decreased odds of low eGFR compared to infrequent consumers. In the probiotic cohort, probiotic consumers were found to have a lower adjusted odds of albuminuria compared to nonusers (OR = 0.59; 95 % CI = 0.37-0.94). CONCLUSION: Frequent yogurt and/or probiotics use is associated with decreased odds of proteinuric kidney disease. These hypothesis-generating results warrant further translational studies to further delineate the relationship between yogurt/probiotics with kidney dysfunction, as well as microbiome and dysbiosis as potential mediators.