Patient-Reported Outcome Measurement Information System Depression and Anxiety in Elective Knee Surgery Patients.

Mental health has been shown to play an important role in patient-reported outcomes (PRO); however, there is a general lack of literature describing patient-reported outcome measurement information system (PROMIS) depression and anxiety computer adaptive tests in elective knee surgery patients. The purpose of our study was to assess the prevalence of depression and anxiety symptoms before and after elective knee surgery and to determine whether these symptoms influence postoperative functional outcomes. An institutional review board-approved prospective orthopaedic registry was retrospectively queried for patients undergoing elective knee surgery from June 2015 to November 2018. Electronic surveys collecting patient demographic information and PROs were administered pre- and postoperatively. Of the 663 patients that completed baseline questionnaires, 466 completed 2-year follow-up (70.3%). PROs included PROMIS depression, PROMIS anxiety, International Knee Documentation Committee Subjective Knee Form (IKDC), and PROMIS physical function (PF). Wilcoxon rank sum and Spearman's rank order correlation were utilized to determine associations between variables. Multivariable analysis was used to control for confounding variables. Average PROMIS depression and anxiety scores significantly improved 2 years after surgery. PROMIS depression and anxiety scores significantly correlated with each other. PROMIS depression and anxiety scores significantly correlated with PROMIS PF and IKDC scores. After controlling for confounders on multivariable analysis, worse 2-year PROMIS anxiety was predictive of less functional improvement and worse 2-year PF and IKDC, while worse 2-year PROMIS depression was predictive of less improvement in IKDC. This study confirms the important relationship between mental health and functional outcomes. Given that psychiatric comorbidities are potentially modifiable with treatment, proper recognition could potentially lead to better orthopaedic outcomes. In addition, the prevalence of depression and anxiety symptoms postoperatively, as documented by PROMIS computer adaptive tests, may act as a barrier to achieving optimal functional outcomes after elective knee surgery. LEVEL OF EVIDENCE: Level III.

CD24-Fc suppression of immune related adverse events in a therapeutic cancer vaccine model of murine neuroblastoma.

Introduction: The combination of Myc-suppressed whole tumor cells with checkpoint inhibitors targeting CTLA-4 and PD-L1 generates a potent therapeutic cancer vaccine in a mouse neuroblastoma model. As immunotherapies translate from pre-clinical to clinical trials, the potential immune-related adverse events (irAEs) associated with induction of potent immunity must be addressed. The CD24-Siglec 10/G interaction is an innate checkpoint that abrogates inflammatory responses to molecules released by damaged cells, but its role in cancer immunology is not well defined. We investigate irAEs of an effective whole cell neuroblastoma vaccine and subsequently the effect of CD24-Fc, a CD24 and Fc fusion protein, on both the vaccine efficacy and induced irAEs in a mouse neuroblastoma model. Methods: To test whether the whole tumor cell vaccination leads to autoimmune responses in other organ systems we harvested lung, heart, kidney and colon from naïve mice (n=3), unvaccinated tumor only mice (n=3), and vaccinated mice with CD24 Fc (n=12) or human IgG-Fc control (n=12) after tumor inoculation and vaccination therapy at day 30. The Immune cell infiltrates and immunogenic pathway signatures in different organ systems were investigated using NanoString Autoimmune Profiling arrays. Nanostring RNA transcript results were validated with immunohistochemistry staining. Results: The whole tumor cell vaccine combined with immune checkpoint therapy triggers occult organ specific immune cell infiltrates, primarily in cardiac tissue and to a lesser extent in the renal and lung tissue, but not in the colon. CD24-Fc administration with vaccination partially impedes anti-tumor immunity but delaying CD24-Fc administration after initial vaccination reverses this effect. CD24-Fc treatment also ameliorates the autoimmune response induced by effective tumor vaccination in the heart. Discussion: This study illustrates that the combination of Myc suppressed whole tumor cell vaccination with checkpoint inhibitors is an effective therapy, but occult immune infiltrates are induced in several organ systems in a mouse neuroblastoma model. The systemic administration of CD24-Fc suppresses autoimmune tissue responses, but appropriate timing of administration is critical for maintaining efficacy of the therapeutic vaccine.

Extracellular Vesicles as Drug Delivery System for Treatment of Neurodegenerative Disorders: Optimization of the Cell Source.

Extracellular vesicles (EVs) represent a next generation drug delivery system that combines nanoparticle size with extraordinary ability to cross biological barriers, reduced immunogenicity, and low offsite toxicity profiles. A successful application of this natural way of delivering biological compounds requires deep understanding EVs intrinsic properties inherited from their parent cells. Herein, we evaluated EVs released by cells of different origin, with respect to drug delivery to the brain for treatment of neurodegenerative disorders. The morphology, size, and zeta potential of EVs secreted by primary macrophages (mEVs), neurons (nEVs), and astrocytes (aEVs) were examined by nanoparticle NTA, DLS, cryoTEM, and AFM. Spherical nanoparticles with average size 110-130 nm and zeta potential around -20 mV were identified for all EVs types. mEVs showed the highest levels of tetraspanins and integrins compared to nEVs and aEVs, suggesting superior adhesion and targeting to the inflamed tissues by mEVs. Strikingly, aEVs were preferentially taken up by neuronal cells in vitro, followed by mEVs and nEVs. Nevertheless, the brain accumulation levels of mEVs in a transgenic mouse model of Parkinson's disease were significantly higher than those of nEVs or aEVs. Therefore, mEVs were suggested as the most promising nanocarrier system for drug delivery to the brain.

Single cell RNA sequencing of AML initiating cells reveals RNA-based evolution during disease progression.

The prognosis of most patients with AML is poor due to frequent disease relapse. The cause of relapse is thought to be from the persistence of leukemia initiating cells (LIC's) following treatment. Here we assessed RNA based changes in LICs from matched patient diagnosis and relapse samples using single-cell RNA sequencing. Previous studies on AML progression have focused on genetic changes at the DNA mutation level mostly in bulk AML cells and demonstrated the existence of DNA clonal evolution. Here we identified in LICs that the phenomenon of RNA clonal evolution occurs during AML progression. Despite the presence of vast transcriptional heterogeneity at the single cell level, pathway analysis identified common signaling networks involving metabolism, apoptosis and chemokine signaling that evolved during AML progression and become a signature of relapse samples. A subset of this gene signature was validated at the protein level in LICs by flow cytometry from an independent AML cohort and functional studies were performed to demonstrate co-targeting BCL2 and CXCR4 signaling may help overcome therapeutic challenges with AML heterogeneity. It is hoped this work will facilitate a greater understanding of AML relapse leading to improved prognostic biomarkers and therapeutic strategies to target LIC's.

Mitochondrial DNA Content Is Linked to Cardiovascular Disease Patient Phenotypes.

Background We sought to determine whether mitochondrial DNA (mtDNA) content can be used as markers for 12 key phenotypes among cardiovascular disease patients, and whether these markers are valid across patients with diverse ancestries. Methods and Results DNA was collected from the peripheral blood of 996 cardiovascular disease patients at the Cleveland Clinic. The mtDNA copy number and DNA-level variation were assessed from whole-genome sequence. Patients were also ascertained retrospectively for histories of 10 clinical events, as well as for maximum stenosis and extent of disease at baseline. Self-reported race and maternal ancestry inferred from mtDNA sequence were recorded. MtDNA copy number and overall mtDNA rare variant load were significantly lower in patients with histories of various adverse clinical events, and mtDNA copy number was inversely correlated with extent of disease. Strong associations were also found between absence of rare variants in the genes MT-ATP6 and MT-COII and patient histories of hyperlipidemia and myocardial infarction, respectively. Importantly, associations were not ancestry dependent. Conclusions This study provides evidence that mtDNA copy number in circulation is associated with a variety of cardiovascular disease patient phenotypes. Results also suggest a protective role for some rare inherited mtDNA variants. Overall, the study supports the potential of mtDNA content and abundance as biomarkers in heart disease, in a manner that is valid across diverse ancestries.

Extracellular Vesicle-Based Therapeutics: Preclinical and Clinical Investigations.

Drug nanoformulations hold remarkable promise for the efficient delivery of therapeutics to a disease site. Unfortunately, artificial nanocarriers, mostly liposomes and polymeric nanoparticles, show limited applications due to the unfavorable pharmacokinetics and rapid clearance from the blood circulation by the reticuloendothelial system (RES). Besides, many of them have high cytotoxicity, low biodegradability, and the inability to cross biological barriers, including the blood brain barrier. Extracellular vesicles (EVs) are novel candidates for drug delivery systems with high bioavailability, exceptional biocompatibility, and low immunogenicity. They provide a means for intercellular communication and the transmission of bioactive compounds to targeted tissues, cells, and organs. These features have made them increasingly attractive as a therapeutic platform in recent years. However, there are many obstacles to designing EV-based therapeutics. In this review, we will outline the main hurdles and limitations for therapeutic and clinical applications of drug loaded EV formulations and describe various attempts to solve these problems.

Clear Cell Meningioma: A Clinicopathologic Study of a Rare Meningioma Subtype in 35 Patients.

OBJECTIVE: Clear cell meningioma (CCM) is a rare histologic variant, accounting for only 0.2%-0.8% of all meningiomas. Given their relative infrequency, few cases have been reported. We have presented one of the largest series of patients with intracranial CCM and reported the treatments and outcomes of these patients. METHODS: Patients with histologically proven CCM from 2003 to 2018 were identified for inclusion in the present study. Relevant clinical and radiographic data were obtained via retrospective review and analyzed. Kaplan-Meier and Cox proportional hazards analyses were used to compare overall and progression-free survival. RESULTS: A total of 35 patients had undergone surgical resection for CCM, including 18 women and 17 men, with a mean age of 59.3 years. Gross total resection was achieved in 22 patients (62.9%), and 11 patients (31.4%) had received adjuvant postoperative radiotherapy. Tumors recurred in 17 patients (48.6%), with a mean time to recurrence of 31.3 months. The mean postoperative follow-up was 66.3 months. On multivariable analysis, adjuvant radiotherapy and gross total tumor resection were both independently associated with prolonged progression-free survival (P < 0.033), although not with overall survival (P >0.274). CONCLUSIONS: The data from the present series of 35 patients with CCM have shown distinct contrasts to previous series, with an older mean age and a nearly 1:1 male/female ratio. Although gross total resection and adjuvant postoperative radiotherapy were both independently associated with longer progression-free survival for patients with CCM, tumor recurrence has remained a challenge in the treatment of these patients.

Cost-effectiveness analysis of chromosomal microarray as a primary test for prenatal diagnosis in Hong Kong.

BACKGROUND: Chromosomal microarray (CMA) has been shown to be cost-effective over karyotyping in invasive prenatal diagnosis for pregnancies with fetal ultrasound anomalies. Yet, information regarding preceding and subsequent tests must be considered as a whole before the true cost-effectiveness can emerge. Currently in Hong Kong, karyotyping is offered free as the standard prenatal test while genome-wide array comparative genome hybridization (aCGH), a form of CMA, is self-financed. A new algorithm was proposed to use aCGH following quantitative fluorescent polymerase chain reaction (QF-PCR) as primary test instead of karyotyping. This study aims to evaluate the cost-effectiveness of the proposed algorithm versus the current algorithm for prenatal diagnosis in Hong Kong. METHODS: Between November 2014 and February 2016, 129 pregnant women who required invasive prenatal diagnosis at two public hospitals in Hong Kong were prospectively recruited. The proposed algorithm was performed for all participants in this demonstration study. For the cost-effectiveness analysis, cost and outcome (diagnostic rate) data were compared with that of a hypothetical scenario representing the current algorithm. Further analysis was performed to incorporate women's willingness-to-pay for the aCGH test. Impact of government subsidies on the aCGH test was explored as a sensitivity analysis. RESULTS: The proposed algorithm dominated the current algorithm for prenatal diagnosis. Both algorithms were equally effective but the proposed algorithm was significantly cheaper (p ≤ 0.05). Taking into account women's willingness-to-pay for an aCGH test, the proposed algorithm was more effective and less costly than the current algorithm. When the government subsidy reaches 100%, the maximum number of diagnoses could be made. CONCLUSION: By switching to the proposed algorithm, cost saving can be achieved whilst maximizing the diagnostic rate for invasive prenatal diagnosis. It is recommended to implement aCGH as a primary test following QF-PCR to replace the majority of karyotyping for prenatal diagnosis in Hong Kong.

Relationship Between Sever Disease and Skeletal Maturity.

BACKGROUND: Sever disease is a common condition in active, growing children. This condition presents as pain in the heel and is thought to be an overuse condition of the calcaneal apophysis. There are currently no defined radiographic diagnostic criteria for evaluation of Sever disease, with radiographs generally showing normal appearance of the calcaneal apophysis. A better understanding of the relationship of Sever disease and skeletal maturity may allow for improved interpretation of radiographs when trying to diagnose this condition. METHODS: ICD-9 code 732.5 was used to search for patients diagnosed with Sever disease from 2007 to 2015 at a single hospital. For every patient with Sever disease with available calcaneal imaging within 40 days of diagnosis, heel x-rays were staged for calcaneal maturity score using a previously described calcaneal skeletal maturity assessment system. Controls matched by age, race, and sex were evaluated for calcaneal stage to compare with the Sever patients. RESULTS: The chart review yielded 78 patients diagnosed with Sever disease by the orthopaedic attending, 39 of which have x-rays around the time of diagnosis. Calcaneal scores averaged 2.2±0.8 for all patients, 2.1±0.9 for male individuals, and 2.3±0.8 for female individuals. The average age for male individuals was 10.4±1.9 years and for female individuals, 9.2±2.2 years. The ages of diagnosis were similar for patients with and without x-rays. Twenty-two of 39 patients with Sever disease were calcaneal stage 2, and 37 of 39 were stages 1, 2, or 3. We calculated the absolute difference from stage 2 for the Sever and control groups. Mean difference from stage 2 was 0.51±0.68 for the Sever patients and 0.95±0.79 for control patients (P=0.01). CONCLUSION: Sever disease occurs in a very narrow range of skeletal maturity, as measured by the calcaneal skeletal maturity assessment system and our observations with chronological age. When compared with age-matched and race-matched controls, stage 2 was seen more frequently in the Sever patients. If a child is not within calcaneal stages 1, 2, or 3, then a different diagnosis should be considered. LEVEL OF EVIDENCE: Level III-retrospective case-control study.

Macrophage-Derived Extracellular Vesicles as Drug Delivery Systems for Triple Negative Breast Cancer (TNBC) Therapy.

Efficient targeted delivery of anticancer agents to TNBC cells remains one of the greatest challenges to developing therapies. The lack of tumor-specific markers, aggressive nature of the tumor, and unique propensity to recur and metastasize make TNBC tumors more difficult to treat than other subtypes. We propose to exploit natural ability of macrophages to target cancer cells by means of extracellular vesicles (EVs) as drug delivery vehicles for chemotherapeutic agents, paclitaxel (PTX) and doxorubicin (Dox). We demonstrated earlier that macrophage-derived EVs loaded with PTX (EV-PTX) and Dox (EV-Dox) target cancer cells and exhibited high anticancer efficacy in a mouse model of pulmonary metastases. Herein, we report a manufacture and characterization of novel EV-based drug formulations using different loading procedures that were optimized by varying pH, temperature, and sonication conditions. Selected EV-based formulations showed a high drug loading, efficient accumulation in TNBC cells in vitro, and pronounced anti-proliferation effect. Drug-loaded EVs target TNBC in vivo, including the orthotopic mouse T11 tumors in immune competent BALB/C mice, and human MDA-MB-231 tumors in athymic nu/nu mice, and abolished tumor growth. Overall, EV-based formulations can provide a novel solution to a currently unmet clinical need and reduce the morbidity and mortality of TNBC patients. Graphical Abstract Macrophage-derived extracellular vesicles (EVs) for targeted drug delivery to TNBC tumors. Chemotherapeutics with different water solubility (Dox or PTX, i.e. hydrophilic or hydrophobic drugs, respectively) were loaded into macrophage-derived EVs through parental cells (Dox), or into naïve EVs (Dox or PTX), and their antitumor efficacy was demonstrated in mouse orthotopic TNBC model.

Experience of chromosomal microarray applied in prenatal and postnatal settings in Hong Kong.

Chromosomal microarray (CMA) is recommended as a first tier investigation for patients with developmental delay (DD), intellectual disability (ID), autistic spectrum disorder (ASD), and multiple congenital anomalies (MCA). It is widely used in the prenatal and postnatal settings for detection of chromosomal aberrations. This is a retrospective review of all array comparative genomic hybridization (aCGH/ array CGH) findings ascertained in two major prenatal and postnatal genetic diagnostic centers in Hong Kong from June 2012 to December 2017. Medical records were reviewed for cases with pathogenic and variants of uncertain clinical significance (VUS). Classification of copy number variants (CNVs) was based on current knowledge and experience by August 2018. The aims of this review are to study the diagnostic yield of array CGH application in prenatal and postnatal settings in Hong Kong and to describe the spectrum of abnormalities found. Prenatal indications included abnormal ultrasound findings, positive Down syndrome screening, abnormal noninvasive prenatal test results, advanced maternal age and family history of chromosomal or genetic abnormalities. Postnatal indications included unexplained DD, ID, ASD, and MCA. A total of 1,261 prenatal subjects and 3,096 postnatal patients were reviewed. The prenatal diagnostic yield of pathogenic CNV and VUS (excluding those detectable by karyotype) was 3.5%. The postnatal diagnostic yield of pathogenic CNV was 15.2%. The detection rates for well-defined microdeletion and microduplication syndromes were 4.6% in prenatal and 6.1% (1 in 16 index patients) in postnatal cases, respectively. Chromosomes 15, 16, and 22 accounted for over 21 and 25% of pathogenic CNVs detected in prenatal and postnatal cohorts, respectively. This review provides the first large scale overview of genomic imbalance of mostly Chinese patients in prenatal and postnatal settings.

Applicability of the Calcaneal Apophysis Ossification Staging System to the Modern Pediatric Population.

BACKGROUND: The calcaneal apophysis ossification staging system is a novel method for assessing skeletal maturity. However, it was created using the same historic patient population that was used to create the Greulich and Pyle atlas of the hand and wrist, predominantly white children. It is unclear if the calcaneal apophysis ossification staging system is still applicable to the modern pediatric population and to children of other races. METHODS: We retrospectively studied 1327 benign lateral foot x-rays from modern white and black children. Calcaneal stage was determined and age, race, and sex were collected for each patient. A 2-tailed Student t test was used to compare between cohorts the differences in age for each calcaneal stage. RESULTS: Mean age was 11.55±4.39 years. Modern white females graded as stage 3 and 4 were significantly delayed in their bone age (stage 3 P<0.002; stage 4 P<0.003) when compared with their historic counterparts. Skeletal maturity was consistent between modern and historic white males for stages 1 to 4. Modern black females graded as stage 1 to 4 were significantly advanced in their skeletal age when compared with modern white females (stage 1 P<0.038; stage 2 P<0.005; stage 3 P<0.002; stage 4 P<0.002). Modern black males graded as stages 1, 3, and 4 were also significantly advanced in their bone age when compared with their modern white counterparts (stage 1 P<0.003; stage 3 P<0.012; stage 4 P<0.029). CONCLUSIONS: Modern white females mature more slowly in the later stages when compared with their historic counterparts. No significant difference is seen between modern and historic white males. Modern black females and males were skeletally advanced compared with modern white females and males. We have shown that the calcaneal ossification staging system can be used to assess for skeletal maturity in the modern pediatric population with only mild corrections for white females and more significant adjustments for black females and males. LEVEL OF EVIDENCE: Level III-retrospective chart review.

The Association Between Body Mass Index and the Prevalence, Severity, and Frequency of Low Back Pain: Data From the Osteoarthritis Initiative.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: To determine whether there is an association between body mass index (BMI) and the prevalence, severity, and frequency of low back pain and identify other potential patient risk factors for the development of low back pain. SUMMARY OF BACKGROUND DATA: Many studies have implicated that a high BMI is a risk factor for low back pain. However, few studies have examined the association between increased BMI and the prevalence, severity, and frequency of low back pain. METHODS: Data from the Osteoarthritis Initiative, a multicenter, prospective study of knee osteoarthritis, were used to conduct this study, which included 4796 patients. BMI was categorized according to the World Health Organization classification and the prevalence, severity, and frequency of low back pain were assessed. Logistic regression was performed to identify additional patient risk factors associated with low back pain. RESULTS: The prevalence of low back pain was found to be significantly higher in patients with an elevated BMI compared to those with normal or underweight BMI and demonstrated a stepwise increase with each BMI category. Approximately 47.4% of patients with normal or underweight BMI complained of low back pain compared with 72.8% of morbidly obese patients (P < 0.0001). No association was seen between BMI and the frequency or severity of low back pain episodes. Osteoarthritis of the back and depression were patient variables found to be associated with all three measures (prevalence, severity, and frequency) of low back pain. CONCLUSION: Elevated BMI is strongly associated with an increased prevalence of low back pain. Depression and osteoarthritis of the back are associated with the prevalence, severity, and frequency of low back pain. LEVEL OF EVIDENCE: 3.

Micromechanisms of fatigue crack growth in polycarbonate polyurethane: Time dependent and hydration effects.

Polycarbonate polyurethane has cartilage-like, hygroscopic, and elastomeric properties that make it an attractive material for orthopedic joint replacement application. However, little data exists on the cyclic loading and fracture behavior of polycarbonate polyurethane. This study investigates the mechanisms of fatigue crack growth in polycarbonate polyurethane with respect to time dependent effects and conditioning. We studied two commercially available polycarbonate polyurethanes, Bionate® 75D and 80A. Tension testing was performed on specimens at variable time points after being removed from hydration and variable strain rates. Fatigue crack propagation characterized three aspects of loading. Study 1 investigated the impact of continuous loading (24h/day) versus intermittent loading (8-10h/day) allowing for relaxation overnight. Study 2 evaluated the effect of frequency and study 3 examined the impact of hydration on the fatigue crack propagation in polycarbonate polyurethane. Samples loaded intermittently failed instantaneously and prematurely upon reloading while samples loaded continuously sustained longer stable cracks. Crack growth for samples tested at 2 and 5Hz was largely planar with little crack deflection. However, samples tested at 10Hz showed high degrees of crack tip deflection and multiple crack fronts. Crack growth in hydrated samples proceeded with much greater ductile crack mouth opening displacement than dry samples. An understanding of the failure mechanisms of this polymer is important to assess the long-term structural integrity of this material for use in load-bearing orthopedic implant applications.

Relationship Between Nutritional Factors and Hip Bone Density in Individuals with Chronic Stroke.

The aim of this study was to investigate the relationship between dietary habits and hip bone health in community-dwelling individuals with chronic stroke. The usual dietary intake of 94 individuals with chronic stroke (30 women, mean age: 59.0 years) was assessed by a 3-day food record within a single week. Dual-energy X-ray absorptiometry was used to measure bone mineral density (BMD) at both hips. The results showed that low hip bone mass was found in 59 and 50 of the participants on the affected and unaffected side, respectively. The mean hip BMD was also significantly lower on the affected side than the unaffected side (P < 0.001). The intake of total fat, carbohydrates, calcium, magnesium, iron, zinc, fiber, folic acid, vitamin B1, B2, B3, B6, C, and K was significantly lower than the respective recommended daily intake values (P < 0.05). Multiple regression analyses revealed that after adjusting for the effects of age, sex, body mass index, post-stroke duration, side of paresis, motor impairment, physical activity level, walking endurance, total calories intake, and total number of medications, intake of protein, fiber, and magnesium remained significantly associated with hip T score on the affected side, accounting for 4.2, 4.4, and 3.2% of the variance, respectively. On the other hand, intake of protein and fiber was independently associated with hip T score on the unaffected side, explaining 2.7 and 5.2% of the variance, respectively. The results highlighted the potential relevance of diet modification in maintaining bone health post stroke, which would require further study.

Axial and appendicular body proportions for evaluation of limb and trunk asymmetry.

Background and purpose - When children with irregular body proportions or asymmetric limbs present, it may be unclear where the pathology is located. An improved understanding of the clinical ratio between upper extremity, lower extremity, and spine length may help elucidate whether there is disproportion between the trunk and limbs, and whether there is a reduction deficit of the shorter limb rather than hypertrophy of the longer limb. Patients and methods - We used the Brush Foundation study of child growth and development, which was a prospective, longitudinal study of healthy children between the 1930s and the 1950s, and we collected serial clinical measurements for 290 children at 3,326 visits. Children ranged from 2 to 20 years of age during the study period. Linear and quadratic regression were used to construct nomographs and 95% prediction intervals for anthropometric body proportions. Results - The maximum anterior superior iliac spine height to sitting height ratio occurred at 12.4 years in females and at 14.17 years in males. Overall, the ratio of arm length to sitting height was 0.76 (SD 0.06), the ratio of arm length to anterior superior iliac spine height was 0.76 (SD 0.03), and the ratio of anterior superior iliac spine height to sitting height was 0.98 (SD 0.13). When comparing ratios between arm length, anterior superior iliac spine height, and sitting height, the smallest variance between appendicular proportions was found in the arm length to anterior superior iliac spine height ratio. Interpretation - We recommend comparisons between total arm length and anterior superior iliac spine height to distinguish limb reduction deficits from hemi-hypertrophy, with sitting height being used only if combined upper and lower extremity discrepancy is noted.

Does Tobacco Use Attenuate Benefits of Early Decompression in Patients With Cervical Myelopathy?

STUDY DESIGN: A retrospective cohort. OBJECTIVE: This study investigates the interplay between duration of preoperative symptoms and smoking status with respect to postoperative outcomes in patients with cervical spondylotic myelopathy (CSM). SUMMARY OF BACKGROUND DATA: Many studies have established the harms of smoking and several have identified the benefits of early decompression in patients with cervical myelopathy, but to our knowledge, none have assessed the relationship between these two variables. METHODS: The medical records of all 212 patients operated on by the senior author between March 2005 and July 2012 were reviewed. Inclusion criteria were the diagnosis of CSM with a Nurick score, surgical intervention, and at least 2 years of follow-up. Patients were categorized according to smoking status and quantification of tobacco use by packs per day and pack-years, and duration of symptoms according to thresholds of 6, 12, or 24 months. Age, sex, preoperative Nurick score, duration of preoperative symptoms, duration of follow-up, procedure performed, prior surgery, number of levels operated on, diabetes status, ethanol use, and signal change on preoperative magnetic resonance imaging were also recorded for ordered logistical regression analysis. RESULTS: One hundred twenty-five patients met all criteria. Eighty patients were smokers and 45 were nonsmokers. The median change in Nurick score for nonsmokers was 2 compared with 1 in smokers. Nonsmokers had a statistically significant likelihood of decreased change in Nurick score for symptom duration of greater than 24 months (odds ratio = 0.06, P = 0.0025). Smokers did not show a significant difference in the change in Nurick score for any threshold of symptom duration. CONCLUSION: Increased duration of symptoms significantly affects outcomes in surgical decompression of CSM. A history of cigarette use may attenuate the benefit of early decompression and results in lower improvement in Nurick score regardless of symptom duration. LEVEL OF EVIDENCE: 3.

MYCN controls an alternative RNA splicing program in high-risk metastatic neuroblastoma.

The molecular mechanisms underlying the aggressive behavior of MYCN driven neuroblastoma (NBL) is under intense investigation; however, little is known about the impact of this family of transcription factors on the splicing program. Here we used high-throughput RNA sequencing to systematically study the expression of RNA isoforms in stage 4 MYCN-amplified NBL, an aggressive subtype of metastatic NBL. We show that MYCN-amplified NBL tumors display a distinct gene splicing pattern affecting multiple cancer hallmark functions. Six splicing factors displayed unique differential expression patterns in MYCN-amplified tumors and cell lines, and the binding motifs for some of these splicing factors are significantly enriched in differentially-spliced genes. Direct binding of MYCN to promoter regions of the splicing factors PTBP1 and HNRNPA1 detected by ChIP-seq demonstrates that MYCN controls the splicing pattern by direct regulation of the expression of these key splicing factors. Furthermore, high expression of PTBP1 and HNRNPA1 was significantly associated with poor overall survival of stage4 NBL patients (p ≤ 0.05). Knocking down PTBP1, HNRNPA1 and their downstream target PKM2, an isoform of pro-tumor-growth, result in repressed growth of NBL cells. Therefore, our study reveals a novel role of MYCN in controlling global splicing program through regulation of splicing factors in addition to its well-known role in the transcription program. These findings suggest a therapeutically potential to target the key splicing factors or gene isoforms in high-risk NBL with MYCN-amplification.