HCC EV ECG score: An extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma.

BACKGROUND AND AIMS: The sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC. APPROACH AND RESULTS: Tissue microarray was used to evaluate four potential HCC-associated protein markers. An HCC EV surface protein assay, composed of covalent chemistry-mediated HCC EV purification and real-time immuno-polymerase chain reaction readouts, was developed and optimized for quantifying subpopulations of EVs. An HCC EV ECG score, calculated from the readouts of three HCC EV subpopulations ( E pCAM + CD63 + , C D147 + CD63 + , and G PC3 + CD63 + HCC EVs), was established for detecting early-stage HCC. A phase 2 biomarker study was conducted to evaluate the performance of ECG score in a training cohort ( n  = 106) and an independent validation cohort ( n  = 72).Overall, 99.7% of tissue microarray stained positive for at least one of the four HCC-associated protein markers (EpCAM, CD147, GPC3, and ASGPR1) that were subsequently validated in HCC EVs. In the training cohort, HCC EV ECG score demonstrated an area under the receiver operating curve (AUROC) of 0.95 (95% confidence interval [CI], 0.90-0.99) for distinguishing early-stage HCC from cirrhosis with a sensitivity of 91% and a specificity of 90%. The AUROCs of the HCC EV ECG score remained excellent in the validation cohort (0.93; 95% CI, 0.87-0.99) and in the subgroups by etiology (viral: 0.95; 95% CI, 0.90-1.00; nonviral: 0.94; 95% CI, 0.88-0.99). CONCLUSION: HCC EV ECG score demonstrated great potential for detecting early-stage HCC. It could augment current surveillance methods and improve patients' outcomes.

Long-Term Effects of Reproduction and Lactation on the Rat Supraspinatus Tendon and Proximal Humerus.

During pregnancy and breastfeeding, women undergo hormonal fluctuations required for fetal development, parturition, and infant growth. These changes have secondary consequences on the maternal musculoskeletal system, increasing the risk for joint pain and osteoporosis. Though hormone levels return to prepregnancy levels postpartum, women may experience lasting musculoskeletal pain. Sex disparities exist in the prevalence of musculoskeletal disorders, but it remains unclear how reproductive history may impact sex differences. Specifically, the effects of both reproductive history and sex on the rotator cuff have not been studied. Pregnancy and lactation affect bone microstructure, suggesting possible impairments at the enthesis of rotator cuff tendons, where tears commonly occur. Therefore, our objective was to evaluate how reproductive history affects sex differences of the supraspinatus tendon and proximal humerus using male, virgin female, and female rats with a history of reproduction (referred to as reproductive females). We hypothesized tendon mechanical properties and humeral bone microstructure would be inferior in reproductive females compared to virgin females. Results showed sex differences independent of reproductive history, including greater tendon midsubstance modulus but lower subchondral bone mineral density (BMD) in females. When considering reproductive history, reproductive rats exhibited reduced tendon insertion site modulus and trabecular bone micro-architecture compared to virgin females with no differences from males. Overall, our study identified long-term changes in supraspinatus tendon mechanical and humeral trabecular bone properties that result following pregnancy and lactation, highlighting the importance of considering reproductive history in investigations of sex differences in the physiology and pathology of rotator cuff injuries.

Circulating Tumor Cell-Based Messenger RNA Scoring System for Prognostication of Hepatocellular Carcinoma: Translating Tissue-Based Messenger RNA Profiling Into a Noninvasive Setting.

Numerous studies in hepatocellular carcinoma (HCC) have proposed tissue-based gene signatures for individualized prognostic assessments. Here, we develop a novel circulating tumor cell (CTC)-based transcriptomic profiling assay to translate tissue-based messenger RNA (mRNA) signatures into a liquid biopsy setting for noninvasive HCC prognostication. The HCC-CTC mRNA scoring system combines the NanoVelcro CTC Assay for enriching HCC CTCs and the NanoString nCounter platform for quantifying the HCC-CTC Risk Score (RS) panel in enriched HCC CTCs. The prognostic role of the HCC-CTC RS was assessed in The Cancer Genome Atlas (TCGA) HCC cohort (n = 362) and validated in an independent clinical CTC cohort (n = 40). The HCC-CTC RS panel was developed through our integrated data analysis framework of 8 HCC tissue-based gene signatures and identified the top 10 prognostic genes (discoidin domain receptor tyrosine kinase 1 [DDR1], enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase [EHHADH], androgen receptor [AR], lumican [LUM], hydroxysteroid 17-beta dehydrogenase 6[HSD17B6], prostate transmembrane protein, androgen induced 1 [PMEPA1], tsukushi, small leucine rich proteoglycan [TSKU], N-terminal EF-hand calcium binding protein 2 [NECAB2], ladinin 1 [LAD1], solute carrier family 27 member 5 [SLC27A5]) highly expressed in HCC with low expressions in white blood cells. The panel accurately discriminated overall survival in TCGA HCC cohort (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.4-2.9). The combined use of the scoring system and HCC-CTC RS panel successfully distinguished artificial blood samples spiked with an aggressive HCC cell type, SNU-387, from those spiked with PLC/PRF/5 cells (P = 0.02). In the CTC validation cohort (n = 40), HCC-CTC RS remained an independent predictor of survival (HR, 5.7; 95% CI, 1.5-21.3; P = 0.009) after controlling for Model for End-Stage Liver Disease score, Barcelona Clinic Liver Cancer stage, and CTC enumeration count. Our study demonstrates a novel interdisciplinary approach to translate tissue-based gene signatures into a liquid biopsy setting. This noninvasive approach will allow real-time disease profiling and dynamic prognostication of HCC.

Comparison of Clinical Features and Outcomes Between Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma in the United States.

BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) are the most common primary liver cancers (PLCs). Differences in their clinical features and outcomes are open for investigation in a large-scale study. We aim to investigate the differences in clinical features and outcomes between iCCA and HCC. APPROACH AND RESULTS: The Surveillance, Epidemiology, and End Results Program 18 Database (2000-2017) was used to extract demographic and clinical features of HCC and iCCA patients. Logistic regression analysis was performed to identify factors associated with iCCA diagnosis versus HCC. Cox regression analysis was used to assess factors affecting overall survival (OS). There were 13,611 iCCA and 96,151 HCC patients. Half of iCCA (50.7%) and three quarters of HCC (76.3%) patients were male. Diagnosis in recent year, age (<50 or ≥65), female sex, non-Hispanic White race, higher income, rural area, and higher tumor burden were independently associated with iCCA diagnosis versus HCC. Patients with iCCA had worse OS than those with HCC (9 vs. 13 months; P < 0.001). However, OS was comparable between iCCA and HCC in multivariable analysis (adjusted hazard ratio [aHR] = 1.02; 95% CI = 0.99-1.05). In subgroup analyses, iCCA was associated with better OS than HCC in patients with tumor ≥5 cm (aHR = 0.83; 95% CI = 0.80-0.86), lymph node involvement (aHR = 0.76; 95% CI = 0.72-0.81), distant metastasis (aHR = 0.76; 95% CI = 0.73-0.79), poorly/undifferentiated tumors (aHR = 0.88; 95% CI = 0.83-0.94), and those receiving noncurative treatment (aHR = 0.96; 95% CI = 0.93-0.98). CONCLUSIONS: We identified the demographic, socioeconomic, and clinical features associated with iCCA diagnosis over HCC among patients with PLC. Although iCCA patients presented at an advanced stage, OS was similar between iCCA and HCC in multivariable analysis. iCCA was associated with longer OS for subgroups with poor prognostic features.

State-Level HCC Incidence and Association With Obesity and Physical Activity in the United States.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with a disproportionate impact on racial/ethnic minority groups. However, state-level variation in racial/ethnic disparities and temporal trends of HCC incidence remain unknown. Therefore, we aimed to characterize (1) state-level racial/ethnic disparity in HCC incidence, (2) state-level temporal changes in HCC incidence, and (3) the ecological correlation between HCC incidence and obesity/physical activity levels in the USA. APPROACH AND RESULTS: Trends in HCC incidence between 2001 and 2017 were calculated using data from the Centers for Disease Control and Prevention's National Program of Cancer Registries and the National Cancer Institute's Surveillance, Epidemiology and End Results, and annual percent change in rates were calculated. State-level percent of obesity and level of physical activity were obtained from the Centers for Disease Control and Prevention, and the correlation among obesity, physical activity, and state-specific average annual percent change was tested by Pearson correlation coefficient. There were striking state-level racial/ethnic disparities in HCC incidence; incidence rate ratios ranged between 6.3 and 0.9 in Blacks, 6.1 and 1.7 in Asians/Pacific Islanders, 3.8 and 0.9 in Hispanics, and 6.0 and 0.9 in American Indians/Alaska Natives (compared with Whites as reference). Despite overall decreasing HCC incidence rates after 2015, HCC incidence continued increasing in 26 states over recent years. HCC incidence trends had a moderate correlation with state-level obesity (r = 0.45, P < 0.001) and a moderate inverse correlation with state-level physical activity (r = -0.40, P = 0.004). CONCLUSIONS: There is wide state-level variation in racial/ethnic disparity of HCC incidence. There are also disparate incidence trends across states, with HCC incidence continuing to increase in over half of the states. Regional obesity and lack of physical activity have moderate correlations with HCC incidence trends, suggesting that interventions targeting these factors may help curb rising HCC incidence.

Uptake and Removal of Uranium by and from Human Teeth.

Uranium-238 (238U), a long-lived radiometal, is widespread in the environment because of both naturally occurring processes and anthropogenic processes. The ingestion or inhalation of large amounts of U is a major threat to humans, and its toxicity is considered mostly chemical rather than radiological. Therefore, a way to remove uranium ingested by humans from uranium-contaminated water or from the air is critically needed. This study investigated the uranium uptake by hydroxyapatite (HAP), a compound found in human bone and teeth. The uptake of U by teeth is a result of U transport as dissolved uranyl (UO22+) in contaminated water, and U adsorption has been linked to delays in both tooth eruption and development. In this present work, the influence of pH, contact time, initial U concentration, and buffer solution on the uptake and removal of U in synthetic HAP was investigated and modeled. The influence of pH (pH of human saliva, 6.7-7.4) on the uptake of uranyl was negligible. Furthermore, the kinetics were extremely fast; in one second of exposure, 98% of uranyl was uptaken by HAP. The uptake followed pseudo-second-order kinetics and a Freundlich isotherm model. A 0.2 M sodium carbonate solution removed all the uranyl from HAP after 1 h. Another series of in vitro tests were performed with real teeth as targets. We found that, for a 50 mg/L U in PBS solution adjusted to physiological pH, ∼35% of the uranyl was uptaken by the tooth after 1 h, following pseudo-first-order kinetics. Among several washing solutions tested, a commercially available carbonate, as well as a commercially available fluoride solution, enabled removal of all the uranyl taken up by the teeth.

Emergence of Antibiotic Resistance Across Two-Stage Revision for Periprosthetic Joint Infection.

BACKGROUND: The current preferred treatment for chronic hip and knee periprosthetic joint infection (PJI) involves both surgical intervention and antibiotic treatment as part of a two-stage revision. The purpose of this study is to determine how often patients who underwent a two-stage revision for chronic PJI developed a subsequent antibiotic-resistant infection. METHODS: We retrospectively reviewed the clinical records of 142 patients who underwent a two-stage revision for a chronic culture-positive PJI from January 2014 to May 2019. Demographic data and risk factors for PJI were identified. Resistance was defined in accordance with microbiology laboratory report and minimum inhibitory concentration. Statistical analysis consisted of descriptive statistics and univariate analysis. RESULTS: Only 10 of the 142 patients (7.04%) demonstrated emergence of resistance to antibiotics across their two-stage revision. At reimplantation, 25 (17.6%) patients had positive cultures. Of these, 16 patients presented with a novel organism and 9 patients had positive culture for the same organism as the initial infection. During the entire course of the two-stage revision, including spacer exchanges and irrigation and debridement procedures, 15 (10.56%) patients demonstrated persistent infections, whereas 25 (17.6%) patients presented with novel infections. 26 (18.3%) patients had reinfection of the same joint within one year. CONCLUSION: In the given cohort, there does not appear to be a major emergence of antibiotic resistant organisms in patients undergoing two-stage exchange arthroplasty and antibiotic treatment.

The changing forms of corruption in China.

China's famed growth has created a paradox of huge proportions that is associated with how this development could happen despite the well documented issue of vast corruption. This growth has come through a specific form of corruption, changing from petty theft and speed money to grand theft and access money. The new forms of corruption were made possible through the access to assets like land, mines and State-Owned Enterprises (SOEs) after land-, property-, and SOE-reforms that were implemented during the 1990s. The opaque character of these reforms has led to what can only be described as a climate of grand collusion where officials use their access powers to redistribute what was formerly state-owned assets to themselves and crony entrepreneurs. While the character of corruption has changed over the last decade, the problem has not diminished despite continued official "anti-corruption" campaigns. The Chinese high growth/high corruption model has come with high risks growth and enormous inequality. Historically, Chinese dynasties have grown, decayed and fallen in scenarios similar to that of the present.

Matrix-assisted laser desorption/ionization imaging mass spectrometry of intraperitoneally injected danegaptide (ZP1609) for treatment of stroke-reperfusion injury in mice.

RATIONALE: This work focuses on direct matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) detection of intraperitoneally (IP)-injected dipeptide ZP1609 in mouse brain tissue. Direct analysis of drug detection in intact tissue sections provides distribution information that can impact drug development. MALDI-IMS capabilities of uncovering drug transport across the blood-brain barrier are demonstrated. METHODS: Successful peptide detection using MALDI-IMS was achieved using a MALDI TOF/TOF system. Upon optimization of sample preparation procedures for dipeptide ZP1609, an additional tissue acidification procedure was found to greatly enhance signal detection. The imaging data acquired was able to determine successful transport of ZP1609 across the blood-brain barrier. Data obtained from MALDI-IMS can help shape our understanding of biological functions, disease progression, and effects of drug delivery. RESULTS: Direct detection of ZP1609 throughout the brain tissue sections was observed from MALDI-MS images. However, in cases where there was induction of stroke, a peak of lower signal intensity was also detected in the target m/z region. Although distinct differences in signal intensity can be seen between control and experimental groups, fragments and adducts of ZP1609 were investigated using MALDI-IMS to verify detection of the target analyte. CONCLUSIONS: Overall, the data reveals successful penetration of ZP1609 across the blood-brain barrier. The benefits of tissue acidification in the enhancement of detection sensitivity for low-abundance peptides were demonstrated. MALDI-IMS has been shown to be a useful technique in the direct detection of drugs within intact brain tissue sections.

1,6-Diphenyl-1,3,5-hexatriene (DPH) as a Novel Matrix for MALDI MS Imaging of Fatty Acids, Phospholipids, and Sulfatides in Brain Tissues.

1,6-Diphenyl-1,3,5-hexatriene (DPH) is a commonly used fluorescence probe for studying cell membrane-lipids due to its affinity toward the acyl chains in the phospholipid bilayers. In this work, we investigated its use in matrix-assisted laser desorption/ionization (MALDI) as a new matrix for mass spectrometry imaging (MSI) of mouse and rat brain tissue. DPH exhibits very minimal matrix-induced background signals for the analysis of small molecules (below m/z of 1000). In the negative ion mode, DPH permits the highly sensitive detection of small fatty acids (m/z 200-350) as well as a variety of large lipids up to m/z of 1000, including lyso-phospholipid, phosphatidic acid (PA), phosphoethanolamine (PE), phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidylinositol (PI), and sulfatides (ST). The analytes were mostly detected as the deprotonated ion [M - H]-. Our results also demonstrate that sublimated DPH is stable for at least 24 h under the vacuum of our MALDI mass spectrometer. The ability to apply DPH via sublimation coupled with its low volatility allows us to perform tissue imaging of the above analytes at high spatial resolution. The degree of lipid fragmentation was determined experimentally at varying laser intensities. The results illustrated that the use of relatively low laser energy is important to minimize the artificially generated fatty acid signals. On the other hand, the lipid fragmentation obtained at higher laser energies provided tandem MS information useful for lipid structure elucidation.

Detection and Predictive Value of Fractional Anisotropy Changes of the Corticospinal Tract in the Acute Phase of a Stroke.

BACKGROUND AND PURPOSE: A decrease in fractional anisotropy (FA) of the ipsilesional corticospinal tract (CST) distal to stroke lesions in the subacute (eg, 30 days) and chronic phase has been correlated with poor motor outcomes, but it is unclear whether FA values obtained within the acute stroke phase (here defined as 80 hours after onset) can predict later outcome. METHODS: Fifty-eight patients underwent an assessment of motor impairment in the acute phase and at 3 months using the upper extremity Fugl-Meyer assessment. FA values, obtained within 80 hours after stroke onset, were determined in 2 regions of interest: cerebral peduncle and a stretch of the CST caudal to each stroke lesion (nearest-5-slices). RESULTS: The FA laterality index for the cerebral peduncle-regions of interest was a poor predictor of 3-month outcome (R(2)=0.044; P=0.137), whereas the slope over the FA laterality index of the nearest-5-slices showed a relatively weak but significant prediction (R(2)=0.11; P=0.022) with the affected side having lower FA values. Initial upper extremity Fugl-Meyer (R(2)=0.69; P<0.001) and the weighted CST lesion load (R(2)=0.71; P<0.001) were strong predictors of 3-month outcome. In multivariate analyses, controlling for initial upper extremity Fugl-Meyer, weighted CST lesion load, and days-of-therapy, neither the FA laterality index of the cerebral peduncle nor the slope over the FA laterality index of the nearest-5-slices significantly contributed to the prediction of 86% of the variance in the upper extremity Fugl-Meyer at 3 months. CONCLUSIONS: FA reductions of the CST can be detected near the ischemic lesion in the acute stroke phase, but offer minimal predictive value to motor outcomes at 3 months.

Does stroke location predict walk speed response to gait rehabilitation?

OBJECTIVES: Recovery of independent ambulation after stroke is a major goal. However, which rehabilitation regimen best benefits each individual is unknown and decisions are currently made on a subjective basis. Predictors of response to specific therapies would guide the type of therapy most appropriate for each patient. Although lesion topography is a strong predictor of upper limb response, walking involves more distributed functions. Earlier studies that assessed the cortico-spinal tract (CST) were negative, suggesting other structures may be important. EXPERIMENTAL DESIGN: The relationship between lesion topography and response of walking speed to standard rehabilitation was assessed in 50 adult-onset patients using both volumetric measurement of CST lesion load and voxel-based lesion-symptom mapping (VLSM) to assess non-CST structures. Two functional mobility scales, the functional ambulation category (FAC) and the modified rivermead mobility index (MRMI) were also administered. Performance measures were obtained both at entry into the study (3-42 days post-stroke) and at the end of a 6-week course of therapy. Baseline score, age, time since stroke onset and white matter hyperintensities score were included as nuisance covariates in regression models. PRINCIPAL OBSERVATIONS: CST damage independently predicted response to therapy for FAC and MRMI, but not for walk speed. However, using VLSM the latter was predicted by damage to the putamen, insula, external capsule and neighbouring white matter. CONCLUSIONS: Walk speed response to rehabilitation was affected by damage involving the putamen and neighbouring structures but not the CST, while the latter had modest but significant impact on everyday functions of general mobility and gait. Hum Brain Mapp 37:689-703, 2016. © 2015 Wiley Periodicals, Inc.

Corticospinal tract lesion load: An imaging biomarker for stroke motor outcomes.

OBJECTIVE: The aim of this work was to investigate whether an imaging measure of corticospinal tract (CST) injury in the acute phase can predict motor outcome at 3 months in comparison to clinical assessment of initial motor impairment. METHODS: A two-site prospective cohort study followed up a group of first-ever ischemic stroke patients using the Upper-Extremity Fugl-Meyer (UE-FM) Scale to measure motor impairment in the acute phase and at 3 months. A weighted CST lesion load (wCST-LL) was calculated by overlaying the patient's lesion map on magnetic resonance imaging with a probabilistic CST constructed from healthy control subjects. Regression models were fit to assess the predictive value of wCST-LL and compared with initial motor impairment. RESULTS: Seventy-six patients (37 from cohort 1 and 39 from cohort 2) completed the study. wCST-LL as well as assessment of motor impairment (UE-FM) in the acute phase correlated with motor impairment (UE-FM) at 3 months in both cohort 1 (R(2) = 0.69 vs. R(2) = 0.67; p = 0.43) and cohort 2 (R(2) = 0.69 vs. R(2) = 0.62; p = 0.25). In the severely impaired subgroup (defined as UE-FM ≤ 10 at baseline), wCST-LL correlated with outcomes significantly better than clinical assessment (R(2) = 0.47 vs. R(2) = 0.11; p = 0.03). In the nonseverely impaired subgroup, stroke patients recovered approximately 70% of their maximal recovery potential. All stroke patients in both cohorts had poor motor outcomes at 3 months (defined as UE-FM ≤ 25) when wCST-LL was ≥ 7.0 cc (positive predictive value was 100%). INTERPRETATION: wCST-LL, an imaging biomarker determined in the acute phase, can predict poststroke motor outcomes at 3 months, especially in patients with severe impairment at baseline.

A comparative study of fractional anisotropy measures and ICH score in predicting functional outcomes after intracerebral hemorrhage.

BACKGROUND: Improved prognostication during the acute phase of intracerebral hemorrhage (ICH) could influence goals of care. We investigated the utility of diffusion tensor imaging (DTI)-derived data obtained during the acute phase of ICH in predicting outcome, compared with the ICH score. METHODS: We measured fractional anisotropy (FA) values in 5 slices below the level of the lesion on the affected and unaffected corticospinal tracts (CST) and in the cerebral peduncles (CPs) in 32 patients with supratentorial ICH who had DTI MRI within 4 days after ictus. We calculated the FA ratio (rFA = FAaffected side/FAunaffected side), and examined the value of the ICH score and rFA in predicting functional outcome assessed by modified Ranking Scale (mRS) at follow-up, using ROC analyses. RESULTS: The rFA values at the CPs level, but not the 5 slices below the lesion, were significantly lower in the group with poor functional outcome (defined as mRS > 2) than in those with good functional outcome (0.96 ± 0.14 vs. 0.99 ± 0.08, p = 0.025). The ICH score had greater areas under ROC curve in predicting functional outcome compared to the mean rFA (AUC 0.74 vs. 0.44; p = 0.01 for mRS > 2; and 0.84 vs. 0.40; p < 0.001 for mRS > 3). CONCLUSIONS: The prognostic value of the ICH score surpassed that of DTI-derived data during the acute phase of ICH in this cohort of patients. Prospective and larger studies are needed to validate our findings and to assess the prognostic role of various DTI-derived measures at different times following ICH.

Rac1 and Nectin3 are essential for PCP-directed axon guidance in the peripheral auditory system.

Our sense of hearing is critically dependent on the spiral ganglion neurons (SGNs) that connect the sound receptors in the organ of Corti (OC) to the cochlear nuclei of the hindbrain. Type I SGNs innervate inner hair cells (IHCs) to transmit sound signals, while type II SGNs (SGNIIs) innervate outer hair cells (OHCs) to detect moderate-to-intense sound. During development, SGNII afferents make a characteristic 90-degree turn toward the base of the cochlea and innervate multiple OHCs. It has been shown that the Planar Cell Polarity (PCP) pathway acts non-autonomously to mediate environmental cues in the cochlear epithelium for SGNII afferent turning towards the base. However, the underlying mechanisms are unknown. Here, we present evidence that PCP signaling regulates multiple downstream effectors to influence cell adhesion and the cytoskeleton in cochlear supporting cells (SCs), which serve as intermediate targets of SGNII afferents. We show that the core PCP gene Vangl2 regulates the localization of the small GTPase Rac1 and the cell adhesion molecule Nectin3 at SC-SC junctions through which SGNII afferents travel. Through in vivo genetic analysis, we also show that loss of Rac1 or Nectin3 partially phenocopied SGNII peripheral afferent turning defects in Vangl2 mutants, and that Rac1 plays a non-autonomous role in this process in part by regulating PCP protein localization at the SC-SC junctions. Additionally, epistasis analysis indicates that Nectin3 and Rac1 likely act in the same genetic pathway to control SGNII afferent turning. Together, these experiments identify Nectin3 and Rac1 as novel regulators of PCP-directed SGNII axon guidance in the cochlea.

Predictors of Blood Transfusion in Patients Undergoing Lumbar Spinal Fusion.

OBJECTIVE: To determine risk factors for perioperative blood transfusion after lumbar fusion surgery. METHODS: After institutional review board approval, a retrospective cohort study of adult patients who underwent lumbar fusion at a single, urban tertiary academic center was retrospectively retrieved. Our primary outcome, blood transfusion, was collected via chart query. A receiver operating characteristic curve was used to evaluate the regression model. A P-value < 0.05 was considered statistically significant. RESULTS: Of the 3,842 patients, 282 (7.3%) required a blood transfusion. For patients undergoing posterolateral decompression and fusion, predictors of transfusion included age (P < 0.001) and more levels fused (P < 0.001). A higher preoperative hemoglobin level (P < 0.001) and revision surgery (P = 0.005) were protective of blood transfusion. For patients undergoing transforaminal lumbar interbody fusion, greater Elixhauser comorbidity index (P < 0.001), longer operative time (P = 0.040), and more levels fused (P = 0.030) were independent predictors of the need for blood transfusion. Patients with a higher body mass index (P = 0.012) and preoperative hemoglobin level (P < 0.001) had a reduced likelihood of receiving a transfusion. For circumferential fusion, greater age (P = 0.006) and longer operative times (P = 0.015) were independent predictors of blood transfusion, while a higher preoperative hemoglobin level (P < 0.001) and male sex (P = 0.002) were protective. CONCLUSIONS: Our analysis identified older age, lower body mass index, greater Elixhauser comorbidity index, longer operative duration, more levels fused, and lower preoperative hemoglobin levels as independent predictors of requiring a blood transfusion following lumbar spinal fusion. Different surgical approaches were not found to be associated with transfusion.

Creation of a Risk Calculator for Predicting New-Onset Cardiac Arrhythmias in Patients Undergoing Lumbar Fusion.

INTRODUCTION: As an increasing number of lumbar fusion procedures are being conducted at specialty hospitals and surgery centers, appropriate patient selection and risk stratification is critical to minimizing patient transfers. Postoperative cardiac arrhythmia has been linked to worse patient outcomes and is a common cause of patient transfer. Therefore, we created a risk calculator to predict a patient's likelihood of developing a new-onset postoperative cardiac arrhythmia after lumbar spinal fusion, which may improve preoperative facility selection. METHODS: A retrospective review was conducted of patients who undergoing lumbar fusion from 2017 to 2021 at a single academic center. Patients were excluded if they had any medical history of a cardiac arrhythmia. Multivariable regression was conducted to determine independent predictors of inpatient arrhythmias. The final regression was applied to a bootstrap to validate an arrhythmia prediction model. A risk calculator was created to determine a patient's risk of new-onset cardiac arrhythmia. RESULTS: A total of 1,622 patients were included, with 45 patients developing a new-onset postoperative arrhythmia. Age (OR = 1.05; 95% CI, 1.02 to 1.09; P = 0.003), history of beta-blocker use (OR = 2.01; 95% CI, 1.08 to 3.72; P = 0.027), and levels fused (OR = 1.59; 95% CI, 1.20 to 2.00; P = 0.001) were all independent predictors of having a new-onset inpatient arrhythmia. This multivariable regression produced an area under the curve of 0.742. The final regression was applied to a bootstrap prediction modeling technique to create a risk calculator including the male sex, age, body mass index, beta-blocker use, and levels fused (OR = 1.04, [CI = 1.03 to 1.06]) that produced an area under the curve of 0.733. CONCLUSION: A patient's likelihood of developing postoperative cardiac arrhythmias may be predicted by comorbid conditions and demographic factors including age, sex, body mass index, and beta-blocker use. Knowledge of these risk factors may improve appropriate selection of an outpatient surgical center or orthopaedic specialty hospital versus an inpatient hospital for lumbar fusions.

Patient-Reported Outcomes Following Anterior and Posterior Surgical Approaches for Multilevel Cervical Myelopathy.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: To compare health-related quality of life (HRQoL) outcomes between approach techniques for the treatment of multilevel degenerative cervical myelopathy (DCM). SUMMARY OF BACKGROUND DATA: Both anterior and posterior approaches for the surgical treatment of cervical myelopathy are successful techniques in the treatment of myelopathy. However, the optimal treatment has yet to be determined, especially for multilevel disease, as the different approaches have separate complication profiles and potentially different impacts on HRQoL metrics. MATERIALS AND METHODS: Retrospective review of a prospectively managed single institution database of patient-reported outcome measures after 3 and 4-level anterior cervical discectomy and fusion (ACDF) and posterior cervical decompression and fusion (PCDF) for DCM. The electronic medical record was reviewed for patient baseline characteristics and surgical outcomes whereas preoperative radiographs were analyzed for baseline cervical lordosis and sagittal balance. Bivariate and multivariate statistical analyses were performed to compare the two groups. RESULTS: We identified 153 patients treated by ACDF and 43 patients treated by PCDF. Patients in the ACDF cohort were younger (60.1 ± 9.8 vs . 65.8 ± 6.9 yr; P < 0.001), had a lower overall comorbidity burden (Charlson Comorbidity Index: 2.25 ± 1.61 vs . 3.07 ± 1.64; P = 0.002), and were more likely to have a 3-level fusion (79.7% vs . 30.2%; P < 0.001), myeloradiculopathy (42.5% vs . 23.3%; P = 0.034), and cervical kyphosis (25.7% vs . 7.69%; P = 0.027). Patients undergoing an ACDF had significantly more improvement in their neck disability index after surgery (-14.28 vs . -3.02; P = 0.001), and this relationship was maintained on multivariate analysis with PCDF being independently associated with a worse neck disability index (+8.83; P = 0.025). Patients undergoing an ACDF also experienced more improvement in visual analog score neck pain after surgery (-2.94 vs . -1.47; P = 0.025) by bivariate analysis. CONCLUSIONS: Our data suggest that patients undergoing an ACDF or PCDF for multilevel DCM have similar outcomes after surgery.

Reasons for transfer and subsequent outcomes among patients undergoing elective spine surgery at an orthopedic specialty hospital.

Objective: To evaluate the reasons for transfer as well as the 90-day outcomes of patients who were transferred from a high-volume orthopedic specialty hospital (OSH) following elective spine surgery. Materials and Methods: All patients admitted to a single OSH for elective spine surgery from 2014 to 2021 were retrospectively identified. Ninety-day complications, readmissions, revisions, and mortality events were collected and a 3:1 propensity match was conducted. Results: Thirty-five (1.5%) of 2351 spine patients were transferred, most commonly for arrhythmia (n = 7; 20%). Thirty-three transferred patients were matched to 99 who were not transferred, and groups had similar rates of complications (18.2% vs. 10.1%; P = 0.228), readmissions (3.0% vs. 4.0%; P = 1.000), and mortality (6.1% vs. 0%; P = 0.061). Conclusion: Overall, this study demonstrates a low transfer rate following spine surgery. Risk factors should continue to be optimized in order to decrease patient risks in the postoperative period at an OSH.

Prostate cancer extracellular vesicle digital scoring assay - a rapid noninvasive approach for quantification of disease-relevant mRNAs.

Optimizing outcomes in prostate cancer (PCa) requires precision in characterization of disease status. This effort was directed at developing a PCa extracellular vesicle (EV) Digital Scoring Assay (DSA) for detecting metastasis and monitoring progression of PCa. PCa EV DSA is comprised of an EV purification device (i.e., EV Click Chip) and reverse-transcription droplet digital PCR that quantifies 11 PCa-relevant mRNA in purified PCa-derived EVs. A Met score was computed for each plasma sample based on the expression of the 11-gene panel using the weighted Z score method. Under optimized conditions, the EV Click Chips outperformed the ultracentrifugation or precipitation method of purifying PCa-derived EVs from artificial plasma samples. Using PCa EV DSA, the Met score distinguished metastatic (n = 20) from localized PCa (n = 20) with an area under the receiver operating characteristic curve of 0.88 (95% CI:0.78-0.98). Furthermore, longitudinal analysis of three PCa patients showed the dynamics of the Met scores reflected clinical behavior even when disease was undetectable by imaging. Overall, a sensitive PCa EV DSA was developed to identify metastatic PCa and reveal dynamic disease states noninvasively. This assay may complement current imaging tools and blood-based tests for timely detection of metastatic progression that can improve care for PCa patients.