ICD-10 diagnosis codes in electronic health records do not adequately capture fracture complexity for proximal humerus fractures.

BACKGROUND: The ability to do comparative effectiveness research (CER) for proximal humerus fractures (PHF) using data in electronic health record (EHR) systems and administrative claims databases was enhanced by the 10th revision of the International Classification of Diseases (ICD-10), which expanded the diagnosis codes for PHF to describe fracture complexity including displacement and the number of fracture parts. However, these expanded codes only enhance secondary use of data for research if the codes selected and recorded correctly reflect the fracture complexity. The objective of this project was to assess the accuracy of ICD-10 diagnosis codes documented during routine clinical practice for secondary use of EHR data. METHODS: A sample of patients with PHFs treated by orthopedic providers across a large, regional health care system between January 1, 2016, and December 31, 2018, were retrospectively identified from the EHR. Four fellowship-trained orthopedic surgeons reviewed patient radiographs and recorded the Neer Classification characteristics of displacement, number of parts, and fracture location(s). The fracture characteristics were then reviewed by a trained coder, and the most clinically appropriate ICD-10 diagnosis code based on the number of fracture parts was assigned. We assessed congruence between ICD-10 codes documented in the EHR and radiograph-validated codes, and assessed sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for EHR-documented ICD-10 codes. RESULTS: There were 761 patients with unilateral, closed PHF who met study inclusion criteria. On average, patients were 67 years of age and 77% were female. Based on radiograph review, 37% were 1-part fractures, 42% were 2-part, 11% were 3-part, and 10% were 4-part fractures. Of the EHR diagnosis codes recorded during clinical practice, 59% were "unspecified" fracture diagnosis codes that did not identify the number of fracture parts. Examination of fracture codes revealed PPV was highest for 1-part (PPV = 0.66, 95% confidence interval [CI] 0.60-0.72) and 4-part fractures (PPV = 0.67, 95% CI 0.13-1.00). CONCLUSIONS: Current diagnosis coding practices do not adequately capture the fracture complexity needed to conduct subgroup analysis for PHF. Conclusions drawn from population studies or large databases using ICD-10 codes for PHF classification should be interpreted within this limitation. Future studies are warranted to improve diagnostic coding to support large observational studies using EHR and administrative claims data.

Can the Femoro-Epiphyseal Acetabular Roof (FEAR) Index Be Used to Distinguish Dysplasia from Impingement?

BACKGROUND: Classifying hips with structural deformity on the spectrum from impingement to dysplasia is often subjective and frequently inexact. Currently used radiographic measures may inaccurately predict a hip's morphological stability in borderline hips. A recently described radiographic measure, the Femoro-Epiphyseal Acetabular Roof (FEAR) index, has demonstrated an ability to predict stability in the borderline hip. This measure is attractive to clinicians because procedures can be used on the basis of a hip's pathomechanics. This study was designed to further validate and characterize the FEAR index in a skeletally immature population, in hips with dysplasia/femoroacetabular impingement (FAI), and in asymptomatic hips. QUESTIONS/PURPOSES: (1) What are the characteristics of the FEAR index in children and how does the index change with skeletal maturation? (2) How does the FEAR index correlate with clinical diagnosis and surgical treatment in a large cohort of symptomatic hips and asymptomatic controls? (3) How does the FEAR index correlate with clinical diagnosis in the borderline hip (lateral center-edge angle [LCEA] 20°-25°) group? METHODS: A total of 220 participants with symptomatic investigational hips with a clinical diagnosis of dysplasia or FAI between January 2008 and January 2018 were retrospectively collected from the senior author's practice. Investigational hips were excluded if they had any femoral head abnormalities preventing LCEA measurement (for example, Perthes disease), Tönnis osteoarthritis grade greater than 1, prior hip surgery, or prior femoral osteotomy. In the 220 participants, 395 hips met inclusion criteria. Once exclusion criteria were applied, 15 hips were excluded due to prior hip surgery or prior femoral osteotomy, and 12 hips were excluded due to femoral head deformity. A single hip was then randomly selected from each participant, resulting in 206 investigational hips with a mean age of 13 ± 3 years. Between January 2017 and December 2017, 70 asymptomatic control participants were retrospectively collected from the senior author's institutional trauma database. Control hips were included if the AP pelvis film had the coccyx centered over the pubic symphysis and within 1 to 3 cm of the superior aspect of the symphysis. Control hips were excluded if there was any fracture to the pelvis or ipsilateral femur or the participant had prior hip/pelvis surgery. After exclusion criteria were applied, 16 hips were excluded due to fracture. One hip was then randomly selected from each participant, resulting in 65 control hips with a mean age of 16 ± 8 years. Standardized standing AP pelvis radiographs were used to measure the FEAR index, LCEA, and Tönnis angle in the investigational cohort. Standardized false-profile radiographs were used to measure the anterior center-edge angle (ACEA) in the investigational cohort. Two blinded investigators measured the FEAR index with an intraclass correlation coefficient of 0.92 [95% CI 0.84 to 0.96]. Question 1 was answered by comparing the above radiographic measures in age subgroups (childhood: younger than 10 years; adolescence: 10 to 14 years old; maturity: older than 14 years) of dysplastic, FAI, and control hips. Question 2 was answered by comparing the radiographic measures in all dysplastic, FAI, control hips, and a subgroup of operatively or nonoperatively managed dysplasia and FAI hips. Question 3 was answered by comparing the radiographic measures in borderline (LCEA 20°-25°) dysplastic, FAI, and control hips. RESULTS: The FEAR index was lower in older dysplastic of hips (younger than 10 years, 6° ± 9°; 10 to 14 years, 4° ± 10°; older than 14 years, 5° ± 9°; p < 0.001) and control hips (younger than 10 years, -6° ± 5°; 10 to 14 years, -15° ± 4°; older than 14 years, -16° ± 7°; p < 0.001). The diagnosis and age groups were independently correlated with the FEAR index (p < 0.001). The relationship between the FEAR index and diagnosis remained consistent in each age group (p = 0.11). The FEAR index was higher in all dysplastic hips (mean 5° ± 10°) than in asymptomatic controls (mean -13° ± 7°; p < 0.001) and FAI hips (mean -10° ± 11°; p < 0.001). Using -1.3° as a cutoff for FAI/control hips and dysplastic hips, 81% (112 of 139) of hips with values below this threshold were FAI/control, and 89% (117 of 132) of hips with values above -1.3° were dysplastic. The receiver operator characteristics area under the curve (ROC-AUC) was 0.91. Similarly, the FEAR index was higher in borderline dysplastic hips than in both asymptomatic borderline controls (p < 0.001) and borderline FAI hips (p < 0.001). Eighty-nine percent (33 of 37) of hips with values below this threshold were FAI/control, and 90% (37 of 41) of hips with values above -1.3° were dysplastic. The ROC-AUC for borderline hips was 0.86. CONCLUSION: The FEAR index was associated with the diagnosis of hip dysplasia and FAI in a patient cohort with a wide age range and with varying degrees of acetabular deformity. Specifically, a FEAR index greater than -1.3° is associated with a dysplastic hip and a FEAR index less than -1.3° is associated with a hip displaying FAI. Using this reliable, developmentally based radiographic measure may help hip preservation surgeons establish a correct diagnosis and more appropriately guide treatment. LEVEL OF EVIDENCE LEVEL: III, diagnostic study.

The three major types of CRISPR-Cas systems function independently in CRISPR RNA biogenesis in Streptococcus thermophilus.

CRISPR-Cas systems are small RNA-based immune systems that protect prokaryotes from invaders such as viruses and plasmids. We have investigated the features and biogenesis of the CRISPR (cr)RNAs in Streptococcus thermophilus (Sth) strain DGCC7710, which possesses four different CRISPR-Cas systems including representatives from the three major types of CRISPR-Cas systems. Our results indicate that the crRNAs from each CRISPR locus are specifically processed into divergent crRNA species by Cas proteins (and non-coding RNAs) associated with the respective locus. We find that the Csm Type III-A and Cse Type I-E crRNAs are specifically processed by Cas6 and Cse3 (Cas6e), respectively, and retain an 8-nucleotide CRISPR repeat sequence tag 5' of the invader-targeting sequence. The Cse Type I-E crRNAs also retain a 21-nucleotide 3' repeat tag. The crRNAs from the two Csn Type II-A systems in Sth consist of a 5'-truncated targeting sequence and a 3' tag; however, these are distinct in size between the two. Moreover, the Csn1 (Cas9) protein associated with one Csn locus functions specifically in the production of crRNAs from that locus. Our findings indicate that multiple CRISPR-Cas systems can function independently in crRNA biogenesis within a given organism - an important consideration in engineering coexisting CRISPR-Cas pathways.

Corticosteroid injection prior to surgery had no effect on 2-year outcomes following arthroscopic rotator cuff repair.

Background: Corticosteroid injections (CSIs) can be an effective nonsurgical treatment for patients with rotator cuff tears. Recent large database studies have raised concern that CSI may result in a higher reoperation rate, increased infection risk, and worse outcome after arthroscopic rotator cuff repair (ARCR). The purpose of this study was to evaluate the reoperation rate, incidence of postoperative infection, and two-year outcomes of patients undergoing ARCR with and without the use of preoperative CSI. Methods: An institutional database generated from fellowship-trained orthopedic sports surgeons was retrospectively queried for patients who underwent ARCR with a minimum of two-year follow-up. Inclusion criteria consisted of 1) primary full-thickness rotator cuff tear and 2) preoperative and minimum two-year patient-reported outcome measures (PROMs). Of the 219 patients identified, 134 patients had preoperative subacromial CSI administered within one year of ARCR. Reoperation rate, number of injections, Visual Analog Scale, American Shoulder and Elbow Surgeons Score, Single Assessment Numeric Evaluation, and Veterans Rand 12-Item Health Survey Physical Component Score/Mental Component Score were compared between groups at six months, one year, and two years. Chi-square and t-tests were used to compare baseline differences, postoperative infections, and reoperations. A repeated measures Analyses of Covariance was used to measure differences between PROMs at each time point. Simple Analyses of Covariance were used for the two-year sub-analyses for patients receiving CSI within 90 days of surgery and if multiple preoperative CSI had been given (α ≤ 0.05). Results: There were no significant demographic differences between groups (P > .05). Preoperative use of subacromial CSI within one year prior to ARCR did not increase reoperation rate (P = .85) or impact PROMs at any timepoint. There were two reoperations during the study period in the CSI group (2 lysis of adhesions). No infections occurred in either cohort. No differences were found if injections were performed within 90 days of surgery or if more than one CSI was administered within the year prior to surgery (P > .05). Conclusion: Our results show that preoperative CSI prior to primary ARCR did not increase risk of reoperation, infection, or influence PROMs with a minimum follow-up of 2 years.

Post-translational modification of amyloid a protein in patients with AA amyloidosis.

AA amyloidosis is a disease caused by extracellular deposition of insoluble ß-pleated sheet fibrils composed of amyloid A (AA) protein, an amino (N)-terminal fragment of serum amyloid A (SAA). The deposits disrupt tissue structure and compromise organ function. Although the disease is systemic, deposition in kidney glomeruli is the most common manifestation. The leading cause of AA amyloidosis is sustained or recurrent inflammation accompanied by elevated levels of SAA. Factors determining the conversion of SAA to AA amyloid fibrils have yet to be fully resolved. Herein, we present liquid chromatography tandem-mass spectrometry (LC-MS/MS) analysis of AA proteins purified from eight patients with AA amyloidosis. For the first time, post-translational modifications (PTM), including carbamylation, acetylation and oxidation, were identified on AA peptides; all eight samples showed some degree of PTM. The amyloid in 6 samples comprised peptides derived from SAA1 with few or none from SAA2, while the other two samples contained both SAA1- and SAA2-derived peptides. N-terminal AA peptides beginning with Arg1 as well as AA peptides starting with Ser2 were present in five of the eight samples, while all or nearly all of the N-terminal peptides in the other three samples lacked Arg1. These data demonstrate that multiple species of AA amyloid proteins can comprise the subunits in amyloid fibrils and raise the possibility that PTM may play a role in fibrillogenesis.

Masking effect of high IQ on the Rey Auditory Verbal Learning Test in an adult sample with attention deficit/hyperactivity disorder.

OBJECTIVE: High intelligence (IQ) adults with attention-deficit/hyperactivity disorder (ADHD) often perform better on neuropsychological tests relative to average IQ adults with ADHD, despite commensurate functional impairment. This study compared adults with ADHD and high versus average IQ on the Rey Auditory Verbal Learning Test (RAVLT) to specifically assess this proposed masking effect of IQ on verbal learning/memory performance among those undergoing neuropsychological evaluation. METHOD: RAVLT performance between patients with ADHD and average versus high Test of Premorbid Function-estimated IQ were compared. Latent growth curve modeling (LGCM) evaluated learning acquisition across trials. RESULTS: RAVLT total learning, immediate, and delayed free recall performances were significantly better in the high IQ relative to the average IQ group. LGCM showed similar quadradic growth trajectories for both IQ groups. Both groups reported equivalent symptom severity and functional complaints in childhood and adulthood. CONCLUSIONS: Adults with ADHD and high IQ performed normally on a verbal learning/memory test compared to adults with average IQ, who scored 0.5-1.0 standard deviations below the mean. These results suggest a masking of performance-based memory deficits in the context of higher IQ in adults with ADHD, supporting growing evidence that higher IQ masks neurocognitive deficits during the assessment of adults with ADHD.

Anatomic Considerations in the Lateral Transpsoas Interbody Fusion: The Impact of Age, Sex, BMI, and Scoliosis.

STUDY DESIGN: This is a retrospective case series. OBJECTIVE: Define the anatomic variations and the risk factors for such within the operative corridor of the transpsoas lateral interbody fusion. SUMMARY OF BACKGROUND DATA: The lateral interbody fusion approach has recently been associated with devastating complications such as injury to the lumbosacral plexus, surrounding vasculature, and bowel. A more comprehensive understanding of anatomic structures in relation to this approach using preoperative imaging would help surgeons identify high-risk patients potentially minimizing these complications. MATERIALS AND METHODS: Age-sex distributed, naive lumbar spine magnetic resonance imagings (n=180) were used to identify the corridor for the lateral lumbar interbody approach using axial images. Bilateral measurements were taken from L1-S1 to determine the locations of critical vascular, intraperitoneal, and muscular structures. In addition, a subcohort of scoliosis patients (n=39) with a Cobb angle >10 degrees were identified and compared. RESULTS: Right-sided vascular anatomy was significantly more variant than left (9.9% vs. 5.7%; P=0.001). There were 9 instances of "at-risk" vasculature on the right side compared with 0 on the left (P=0.004). Age increased vascular anatomy variance bilaterally, particularly in the more caudal levels (P≤0.001). A "rising-psoas sign" was observed in 26.1% of patients. Bowel was identified within the corridor in 30.5% of patients and correlated positively with body mass index (P<0.001). Scoliosis increased variant anatomy of left-sided vasculature at L2-3/L3-4. Nearly all variant anatomy in this group was found on the convex side of the curvature (94.2%). CONCLUSIONS: Given the risks and complications associated with this approach, careful planning must be taken with an understanding of vulnerable anatomic structures. Our analysis suggests that approaching the intervertebral space from the patient's left may reduce the risk of encountering critical vascular structures. Similarly, in the setting of scoliosis, an approach toward the concave side may have a more predictable course for surrounding anatomy. LEVEL OF EVIDENCE: Level 3-study.

Environmental Factors Impacting Bone-Relevant Chemokines.

Chemokines play an important role in normal bone physiology and the pathophysiology of many bone diseases. The recent increased focus on the individual roles of this class of proteins in the context of bone has shown that members of the two major chemokine subfamilies-CC and CXC-support or promote the formation of new bone and the remodeling of existing bone in response to a myriad of stimuli. These chemotactic molecules are crucial in orchestrating appropriate cellular homing, osteoblastogenesis, and osteoclastogenesis during normal bone repair. Bone healing is a complex cascade of carefully regulated processes, including inflammation, progenitor cell recruitment, differentiation, and remodeling. The extensive role of chemokines in these processes and the known links between environmental contaminants and chemokine expression/activity leaves ample opportunity for disruption of bone healing by environmental factors. However, despite increased clinical awareness, the potential impact of many of these environmental factors on bone-related chemokines is still ill defined. A great deal of focus has been placed on environmental exposure to various endocrine disruptors (bisphenol A, phthalate esters, etc.), volatile organic compounds, dioxins, and heavy metals, though mainly in other tissues. Awareness of the impact of other less well-studied bone toxicants, such as fluoride, mold and fungal toxins, asbestos, and chlorine, is also reviewed. In many cases, the literature on these toxins in osteogenic models is lacking. However, research focused on their effects in other tissues and cell lines provides clues for where future resources could be best utilized. This review aims to serve as a current and exhaustive resource detailing the known links between several classes of high-interest environmental pollutants and their interaction with the chemokines relevant to bone healing.

Sulfated glycopeptide nanostructures for multipotent protein activation.

Biological systems have evolved to utilize numerous proteins with capacity to bind polysaccharides for the purpose of optimizing their function. A well-known subset of these proteins with binding domains for the highly diverse sulfated polysaccharides are important growth factors involved in biological development and tissue repair. We report here on supramolecular sulfated glycopeptide nanostructures, which display a trisulfated monosaccharide on their surfaces and bind five critical proteins with different polysaccharide-binding domains. Binding does not disrupt the filamentous shape of the nanostructures or their internal ß-sheet backbone, but must involve accessible adaptive configurations to interact with such different proteins. The glycopeptide nanostructures amplified signalling of bone morphogenetic protein 2 significantly more than the natural sulfated polysaccharide heparin, and promoted regeneration of bone in the spine with a protein dose that is 100-fold lower than that required in the animal model. These highly bioactive nanostructures may enable many therapies in the future involving proteins.