Clinical implications and molecular features of extracellular matrix networks in soft tissue sarcomas.

PURPOSE: The landscape of extracellular matrix (ECM) alterations in soft tissue sarcomas (STS) remains poorly characterised. We aimed to investigate the tumour ECM and adhesion signalling networks present in STS and their clinical implications. EXPERIMENTAL DESIGN: Proteomic and clinical data from 321 patients across 11 histological subtypes were analysed to define ECM and integrin adhesion networks. Subgroup analysis was performed in leiomyosarcomas (LMS), dedifferentiated liposarcomas (DDLPS) and undifferentiated pleiomorphic sarcomas (UPS). RESULTS: This analysis defined subtype-specific ECM profiles including enrichment of basement membrane proteins in LMS and ECM proteases in UPS. Across the cohort, we identified three distinct co-regulated ECM networks which are associated with tumour malignancy grade and histological subtype. Comparative analysis of LMS cell line and patient proteomic data identified the LCP1 cytoskeletal protein as a prognostic factor in LMS. Characterisation of ECM network events in DDLPS revealed three subtypes with distinct oncogenic signalling pathways and survival outcomes. Evaluation of the DDLPS subtype with the poorest prognosis nominates ECM remodelling proteins as candidate anti-stromal therapeutic targets. Finally, we define a proteoglycan signature which is an independent prognostic factor for overall survival in DDLPS and UPS. CONCLUSIONS: STS comprise heterogeneous ECM signalling networks and matrix-specific features have utility for risk stratification and therapy selection which could in future guide precision medicine in these rare cancers.

Proteomic features of soft tissue tumours in adolescents and young adults.

BACKGROUND: Adolescents and young adult (AYA) patients with soft tissue tumours including sarcomas are an underserved group with disparities in treatment outcomes. METHODS: To define the molecular features between AYA and older adult (OA) patients, we analysed the proteomic profiles of a large cohort of soft tissue tumours across 10 histological subtypes (AYA n = 66, OA n = 243), and also analysed publicly available functional genomic data from soft tissue tumour cell lines (AYA n = 5, OA n = 8). RESULTS: Biological hallmarks analysis demonstrates that OA tumours are significantly enriched in MYC targets compared to AYA tumours. By comparing the patient-level proteomic data with functional genomic profiles from sarcoma cell lines, we show that the mRNA splicing pathway is an intrinsic vulnerability in cell lines from OA patients and that components of the spliceosome complex are independent prognostic factors for metastasis free survival in AYA patients. CONCLUSIONS: Our study highlights the importance of performing age-specific molecular profiling studies to identify risk stratification tools and targeted agents tailored for the clinical management of AYA patients.

Soft tissue tumours are cancers that develop in the connective and supporting tissues of the body, such as muscle or fat. These tumours arise in patients across the entire age range. However, improvements in survival outcomes in adolescent and young adult (AYA) patients have lagged behind outcomes in older adults (OA) and children. To better understand the biology of AYA patients with soft tissue tumours, we analysed protein profiles across 10 different types. We identified biological differences between AYA and OA patients and report an age-specific signature that can potentially be used to help predict which AYA patients are more likely to have aggressive cancers that will spread to other parts of the body. Our study highlights the importance of performing age-specific studies to identify new tools to predict patient outcomes and potentially find more suitable treatments.

SARS-CoV-2 Viral Replication Persists in the Human Lung for Several Weeks after Symptom Onset.

Rationale: In the upper respiratory tract, replicating (culturable) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is recoverable for ∼4-8 days after symptom onset, but there is a paucity of data about the frequency and duration of replicating virus in the lower respiratory tract (i.e., the human lung).Objectives: We undertook lung tissue sampling (needle biopsy) shortly after death in 42 mechanically ventilated decedents during the Beta and Delta waves. An independent group of 18 ambulatory patients served as a control group.Methods: Lung biopsy cores from decedents underwent viral culture, histopathological analysis, electron microscopy, transcriptomic profiling, and immunohistochemistry.Measurements and Main Results: Thirty-eight percent (16 of 42) of mechanically ventilated decedents had culturable virus in the lung for a median of 15 days (persisting for up to 4 wk) after symptom onset. Lung viral culture positivity was not associated with comorbidities or steroid use. Delta but not Beta variant lung culture positivity was associated with accelerated death and secondary bacterial infection (P < 0.05). Nasopharyngeal culture was negative in 23.1% (6 of 26) of decedents despite lung culture positivity. This hitherto undescribed biophenotype of lung-specific persisting viral replication was associated with an enhanced transcriptomic pulmonary proinflammatory response but with concurrent viral culture positivity.Conclusions: Concurrent rather than sequential active viral replication continues to drive a heightened proinflammatory response in the human lung beyond the second week of illness and was associated with variant-specific increased mortality and morbidity. These findings have potential implications for the design of interventional strategies and clinical management of patients with severe coronavirus disease (COVID-19).

Effects of Voice Pitch on Social Perceptions Vary With Relational Mobility and Homicide Rate.

Fundamental frequency ( fo) is the most perceptually salient vocal acoustic parameter, yet little is known about how its perceptual influence varies across societies. We examined how fo affects key social perceptions and how socioecological variables modulate these effects in 2,647 adult listeners sampled from 44 locations across 22 nations. Low male fo increased men's perceptions of formidability and prestige, especially in societies with higher homicide rates and greater relational mobility in which male intrasexual competition may be more intense and rapid identification of high-status competitors may be exigent. High female fo increased women's perceptions of flirtatiousness where relational mobility was lower and threats to mating relationships may be greater. These results indicate that the influence of fo on social perceptions depends on socioecological variables, including those related to competition for status and mates.

Nanophytomedicines as Therapeutic Agents for Parkinson's Disease.

Phytochemicals are promising therapeutics for various neurodegenerative disorders, including Parkinson's disease (PD). However, their efficacy, pharmacokinetic properties, and penetration across the blood-brain barrier can be improved using delivery systems such as nanoparticles. We reviewed recently published work in which nanoparticles were used to deliver phytochemicals toward PD treatment. The studies show that nanoparticles not only improve the pharmacological effect of the phytochemicals but also enable targeting to the brain and crossing of the blood-brain barrier. Various ligands were added to the nanoparticles to improve blood-brain barrier transportation. The promising findings from the published studies reveal that more research into nanophytomedicine approaches as therapeutic targets for PD is warranted, especially since they have the potential to protect against key features of PD, including α-synuclein aggregation, mitochondrial dysfunction, and dopaminergic neuronal death. Furthermore, future directions should involve smart designs to tailor nanoparticles for improved therapeutic delivery by modifying their features, such as architecture, surface and material properties, targeting ligands, and responsiveness.

The proteomic landscape of soft tissue sarcomas.

Soft tissue sarcomas (STS) are rare and diverse mesenchymal cancers with limited treatment options. Here we undertake comprehensive proteomic profiling of tumour specimens from 321 STS patients representing 11 histological subtypes. Within leiomyosarcomas, we identify three proteomic subtypes with distinct myogenesis and immune features, anatomical site distribution and survival outcomes. Characterisation of undifferentiated pleomorphic sarcomas and dedifferentiated liposarcomas with low infiltrating CD3 + T-lymphocyte levels nominates the complement cascade as a candidate immunotherapeutic target. Comparative analysis of proteomic and transcriptomic profiles highlights the proteomic-specific features for optimal risk stratification in angiosarcomas. Finally, we define functional signatures termed Sarcoma Proteomic Modules which transcend histological subtype classification and show that a vesicle transport protein signature is an independent prognostic factor for distant metastasis. Our study highlights the utility of proteomics for identifying molecular subgroups with implications for risk stratification and therapy selection and provides a rich resource for future sarcoma research.

Age and CRP Associated With Improved Tissue Pathogen Identification in Children With Blood Culture Negative Osteomyelitis: Results From the CORTICES Multicenter Database.

BACKGROUND: Acute hematogenous osteomyelitis (AHO) is a relatively common condition in children, and identifying the offending pathogen with blood or tissue cultures aids in diagnosis and medical management while reducing treatment failure. Recent 2021 AHO clinical practice guidelines from the Pediatric Infectious Disease Society recommend obtaining routine tissue cultures, particularly in cases with negative blood cultures. The purpose of this study was to identify variables associated with positive tissue cultures when blood cultures are negative. METHODS: Children with AHO from 18 pediatric medical centers throughout the United States through the Children's ORthopaedic Trauma and Infection Consortium for Evidence-based Study were evaluated for predictors of positive tissue cultures when blood cultures were negative. Cutoffs of predictors were determined with associated sensitivity and specificity. RESULTS: One thousand three children with AHO were included, and in 688/1003 (68.6%) patients, both blood cultures and tissue cultures were obtained. In patients with negative blood cultures (n=385), tissue was positive in 267/385 (69.4%). In multivariate analysis, age ( P <0.001) and C-reactive protein (CRP) ( P =0.004) were independent predictors. With age >3.1 years and CRP >4.1 mg/dL as factors, the sensitivity of obtaining a positive tissue culture when blood cultures were negative was 87.3% (80.9-92.2%) compared with 7.1% (4.4-10.9%) if neither of these factors was present. There was a lower ratio of methicillin-resistant Staphylococcus aureus in blood culture-negative patients who had a positive tissue culture 48/188 (25.5%), compared with patients who had both positive blood and tissue cultures 108/220 (49.1%). CONCLUSION: AHO patients with CRP ≤ 4.1 mg/dL and age under 3.1 years are unlikely to have clinical value from tissue biopsy that exceeds the morbidity associated with this intervention. In patients with CRP > 4.1 mg/dL and age over 3.1 years, obtaining a tissue specimen may add value; however, it is important to note that effective empiric antibiotic coverage may limit the utility of positive tissue cultures in AHO. LEVEL OF EVIDENCE: Level III-Retrospective comparative study.

Metagenomic next-generation sequencing in osteoarticular infections with a focus on pediatrics: current concepts and clinical applications.

Osteoarticular infections (OAI) are a significant cause of morbidity and mortality. Cultures and serology are some of the gold standards for identifying infection but are often unable to provide a timely diagnosis or a diagnosis at all. Genetic testing offers capabilities that other modalities lack. Polymerase chain reaction has multiple versions with various costs and turnaround times. This technology has become implemented in multiple pediatric center OAI diagnostic protocols. There is sufficient literature documenting effectiveness in certain clinical situations, especially with fastidious organism diagnosis, but significant limitation still exists. Metagenomic next-generation sequencing is an unbiased or hypothesis-free modality with the capability to detect the genetic material of bacteria, viruses, parasites, fungi, and humans from a single sample. Potential benefits include pathogen identification unaffected by antimicrobial administration, detection of fastidious organisms more quickly, delineation of pathogens in polymicrobial infections, antimicrobial susceptibility, and avoidance of invasive procedures. It is a resource-intensive modality with little standardization of the complex processes. Appropriate use and definitive clinical impact have yet to be determined.

Postoperative Urinary Retention after Pediatric Orthopedic Surgery.

Purpose: This study aims to describe the incidence of postoperative urinary retention among pediatric patients undergoing orthopedic surgery and identify risk factors. Methods: The Pediatric Health Information System was used to identify children aged 1−18 years who underwent orthopedic surgery. Collected from each patient's record were demographic information, principal procedure during hospitalization, the presence of neurologic/neuromuscular conditions and other complex chronic medical conditions, the total postoperative length of stay, and the presence of postoperative urinary retention. Results: The overall incidence of postoperative urinary retention was 0.38%. Children with complex chronic neuromuscular conditions (OR 11.54 (95% CI 9.60−13.88), p = < 0.001) and complex chronic non-neuromuscular medical conditions (OR 5.07 (95% CI 4.11−6.25), p ≤ 0.001) had a substantially increased incidence of urinary retention. Surgeries on the spine (OR 3.98 (95% CI 3.28−4.82, p ≤ 0.001) and femur/hip (OR 3.63 (95% CI 3.03−4.36), p ≤ 0.001) were also associated with an increased incidence. Conclusions: Children with complex chronic neuromuscular conditions have a substantially increased risk of experiencing postoperative urinary retention. Complex chronic non-neuromuscular medical conditions and surgeries to the spine, hip, and femur also carry a notably increased risk.

Survey of healthcare professionals' knowledge, attitudes and practices regarding spontaneous intracranial hypotension.

Objective: To assess the knowledge, attitudes and practices of healthcare professionals regarding the diagnosis and management of spontaneous intracranial hypotension (SIH). Methods: We performed a cross-sectional, web-based survey of multiple healthcare professional groups in the UK from June to August 2021. There were 227 respondents to the survey, including 62 general practitioners, 39 emergency medicine physicians, 38 neurologists, 35 radiologists, 20 neurosurgeons, 18 anaesthetists and 15 headache nurse specialists. The majority of the respondents were at the consultant level and all worked in the UK National Health Service. Results: Few general practitioners or emergency medicine physicians had ever been involved in the care of a patient with SIH or received teaching about SIH. Only 3 of 62 (4.8%) general practitioners and 1 of 39 (2.5%) emergency medicine physicians were confident in recognising the symptoms of SIH. Most neurologists were confident in recognising SIH and performed MRI of the brain as a first-line investigation, although there was variability in the urgency of the request, whether contrast was given or MRI of the spine organised at the same time. Most said they never or rarely performed lumbar puncture for diagnosis of SIH. Most neuroradiologists, but few general radiologists, were confident in interpreting imaging of patients with suspected SIH. Lack of access to epidural blood patching, personnel able to perform myelography, and established management pathways were identified by many respondents as barriers to the treatment of SIH. Conclusions: We have identified a lack of awareness of SIH among non-specialists, several barriers to optimal treatment of SIH and a variation in current management pathways. The results highlight the need for education of healthcare professionals about SIH and the development of clinical practice guidelines to enable delivery of optimal and equitable care for patients with SIH.

The modified Kocher criteria for septic hip: Does it apply to the knee?

Background: Pediatric septic arthritis is a surgical emergency and timely diagnosis prevents serious complications. To differentiate between septic hip and transient synovitis, the predictive value of four original Kocher criteria (fever, inability to bear weight, elevated serum white blood cell count, and elevated erythrocyte sedimentation rate) plus Caird's addition of elevated C-reactive protein have been studied, termed the modified Kocher criteria. These criteria have not been tested extensively on septic knee. This study tested the utility of the modified Kocher criteria in predicting septic knee while validating it for septic hip. Methods: A retrospective chart review was conducted of pediatric patients evaluated at a single institution for irritable hip or knee between 2009 and 2018. Patients who underwent arthrocentesis were included and the modified Kocher criteria were applied to all. Results: One hundred fifty-five patients (96 hips and 59 knees) were identified. One hundred four (67.1%) patients had septic arthritis with 44/59 (74.6%) of knees and 60/96 (62.5%) of hips. The strongest predictors for septic hip and knee were elevated C-reactive protein (odds ratio = 26.9, p < 0.0001) and refusal to bear weight (odds ratio = 14.5, p < 0.0001), respectively. For hips, 5/5 criteria produced a 100% positive predictive value for septic arthritis. For knees, the combination of inability to bear weight and elevated C-reactive protein had a positive predictive value of 89.7%. Conclusion: While all five of the modified Kocher criteria are not predictive of pediatric septic knee, the combination of two specific factors (inability to bear weight and elevated C-reactive protein) is strongly predictive. This study validates previous work that the modified Kocher criteria are predictive of septic hip. Level of evidence: level III.

The Cancer Genome Atlas: Impact and Future Directions in Sarcoma.

Sarcomas are rare and heterogeneous malignancies. Owing to their low prevalence and limited capacity to conduct large-scale clinical trials, understanding the molecular mechanisms of sarcomagenesis has become important in determining appropriate treatment. The Cancer Genome Atlas soft tissue sarcoma (STS) project (TCGA-SARC) was the largest and most comprehensive attempt to profile the genomics of multiple STS subtypes. TCGA-SARC made huge contributions to disease understanding. Since the publication of TCGA-SARC, numerous studies have used molecular profiling to assess STS biology. Herein molecular profiling studies in STS are reviewed and future directions with regard to omics profiling in STS research are discussed.

Pancreatic ductal adenocarcinoma cells employ integrin α6ß4 to form hemidesmosomes and regulate cell proliferation.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis due to its aggressive progression, late detection and lack of druggable driver mutations, which often combine to result in unsuitability for surgical intervention. Together with activating mutations of the small GTPase KRas, which are found in over 90% of PDAC tumours, a contributory factor for PDAC tumour progression is formation of a rigid extracellular matrix (ECM) and associated desmoplasia. This response leads to aberrant integrin signalling, and accelerated proliferation and invasion. To identify the integrin adhesion systems that operate in PDAC, we analysed a range of pancreatic ductal epithelial cell models using 2D, 3D and organoid culture systems. Proteomic analysis of isolated integrin receptor complexes from human pancreatic ductal epithelial (HPDE) cells predominantly identified integrin α6ß4 and hemidesmosome components, rather than classical focal adhesion components. Electron microscopy, together with immunofluorescence, confirmed the formation of hemidesmosomes by HPDE cells, both in 2D and 3D culture systems. Similar results were obtained for the human PDAC cell line, SUIT-2. Analysis of HPDE cell secreted proteins and cell-derived matrices (CDM) demonstrated that HPDE cells secrete a range of laminin subunits and form a hemidesmosome-specific, laminin 332-enriched ECM. Expression of mutant KRas (G12V) did not affect hemidesmosome composition or formation by HPDE cells. Cell-ECM contacts formed by mouse and human PDAC organoids were also assessed by electron microscopy. Organoids generated from both the PDAC KPC mouse model and human patient-derived PDAC tissue displayed features of acinar-ductal cell polarity, and hemidesmosomes were visible proximal to prominent basement membranes. Furthermore, electron microscopy identified hemidesmosomes in normal human pancreas. Depletion of integrin ß4 reduced cell proliferation in both SUIT-2 and HPDE cells, reduced the number of SUIT-2 cells in S-phase, and induced G1 cell cycle arrest, suggesting a requirement for α6ß4-mediated adhesion for cell cycle progression and growth. Taken together, these data suggest that laminin-binding adhesion mechanisms in general, and hemidesmosome-mediated adhesion in particular, may be under-appreciated in the context of PDAC. Proteomic data are available via ProteomeXchange with the identifiers PXD027803, PXD027823 and PXD027827.

Clinical Scores Predict Acute and Chronic Complications in Pediatric Osteomyelitis: An External Validation.

BACKGROUND: Pediatric acute hematogenous osteomyelitis (AHO) outcomes are highly dependent on the disease severity. Recently, the A-SCORE and C-SCORE, were proposed as predictors of an acute complicated course and chronic morbidity, respectively. The purpose of this study was to externally validate the A-SCORE and C-SCORE at a single institution. METHODS: This IRB-approved retrospective chart review included AHO patients admitted at a tertiary referral hospital between October 1, 2015 and December 31, 2019. The inclusion criteria were ages 0 to 18 and clinical response to treatment. The exclusion criteria were immunocompromised status or penetrating inoculation. RESULTS: The A-SCORE demonstrated an area under the receiver operator curve (ROC area) of >86% with regards to all acute complications. It also demonstrated sensitivities >85% and specificities >92% at the cut-off of 4 (Youden index) for all acute complications. The C-SCORE demonstrated an ROC area of 100% with regards to chronic osteomyelitis. It also demonstrated sensitivities >70% and specificities >93% for the chronic morbidity variables seen in our population at the cut-off of 3 (Youden index.). CONCLUSIONS: These novel composite clinical scores, in combination with clinical judgment, could help guide early care decisions. The A-SCORE and C-SCORE are useful risk stratification tools in the management of pediatric AHO and in predicting acute complicated courses or chronic sequelae of AHO, respectively. These scoring systems, if integrated into standardized pediatric AHO guidelines, can allow clinicians to stratify the AHO population and guide clinical decision making. LEVEL OF EVIDENCE: Level III (prognostic study, retrospective chart review).

Practice Variation in the Surgical Management of Children With Acute Hematogenous Osteomyelitis.

INTRODUCTION: The surgical indications to manage children with acute hematogenous osteomyelitis (AHO) remain poorly defined. The purpose of this study was to identify if practice pattern variation exists in the surgical management of pediatric AHO among tertiary pediatric medical centers across the United States. A secondary purpose was to evaluate variables that may impact the rate of surgical intervention among these institutions. METHODS: Children with AHO were retrospectively analyzed between January 1, 2010, and December 31, 2016, from 18 pediatric medical centers throughout the United States. The rates of surgery were identified. Admission vitals, labs, weight-bearing status, length of stay, and readmission rates were compared between those who did and did not undergo surgery. Multivariate regression and classification and regression tree analyses were performed to identify the variables that were associated with surgical intervention. RESULTS: Of the 1003 children identified with AHO in this retrospective, multicenter database, 619/1003 (62%) were treated surgically. Multivariate analysis revealed institution, inability to ambulate, presence of multifocal infection, elevated admission C-reactive protein, increased admission platelet count, and location of the osteomyelitis were significant predictors of surgery (P<0.01). Patients who underwent surgery were more than twice as likely to have a recurrence or readmission and stayed a median of 2 days longer than those who did not have surgery. In the classification and regression tree analysis, 2 distinct patterns of surgical intervention were identified based on institution, with 12 institutions operating in most cases (72%), regardless of clinical factors. A second cohort of 6 institutions operated less routinely, with 47% receiving surgery overall. At these 6 institutions, patients without multifocal infection only received surgery 26% of the time, which increased to 74% with multifocal infection and admission erythrocyte sedimentation rate >37.5 mm/h. CONCLUSIONS: This study is the first to objectively identify significant differences in the rates of surgical management of pediatric AHO across the United States. Variation in the surgical management of AHO appears to be driven primarily based on institutional practice. Twelve institutions operated on 72% of patients, regardless of the severity of disease, indicating that the institution custom or dogma may drive the surgical indications. Six institutions relied more on clinical judgment with significant variability in rates of surgical intervention (26% vs. 74%), depending on the severity of the disease. Surgical intervention is associated with increased recurrence, readmission, and hospital length of stay. As a result of these findings, it is essential to prospectively study the appropriate surgical indications and measure the outcomes in children with pediatric AHO. LEVEL OF EVIDENCE: Level III.

Patient experience of diagnosis and management of spontaneous intracranial hypotension: a cross-sectional online survey.

OBJECTIVES: To present the results of a survey of patients with spontaneous intracranial hypotension (SIH) secondary to spinal cerebrospinal fluid (CSF) leak, documenting the patient experience of its diagnosis and management as well as quantifying its impact on quality of life. DESIGN: A cross-sectional anonymous online survey was designed in conjunction with the CSF Leak Association patient charity. The survey included questions on diagnosis, investigations and treatments received, as well as validated disability and quality of life questionnaires. PARTICIPANTS: Sixty-four patients with a confirmed diagnosis of SIH who were receiving treatment within the UK were included in the analysis. The mean age was 42.8 years, 94% were female and 43 had ongoing symptoms of SIH. RESULTS: Patients who presented to their general practitioner with symptoms of SIH were seen an average three times before being referred to a specialist, and in just under half of patients, the diagnosis was not made by the first specialist they saw. There was variability in which investigations were performed and how urgently they were organised. The mean EuroQol (EQ-5D-5L) Visual Analogue Scale score was 36.4/100 and median Headache Impact Test-6 score was 68/78 (very severe impact). More than half of the respondents reported that they had to amend work duties due to SIH, more than a quarter reported that they had lost their job and two-thirds reported that their condition had affected their financial health. Only 23.4% of patients felt that they had received enough help and advice to manage their pain due to SIH. CONCLUSIONS: SIH is a highly disabling disorder, affecting multiple domains, including pain, mobility, activities of daily living, financial circumstances and employment. Diagnostic delay and misdiagnosis are common, and currently there is a lack of consistency in the investigation and management of SIH in the UK.

A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids.

Experimental in vitro models that capture pathophysiological characteristics of human tumours are essential for basic and translational cancer biology. Here, we describe a fully synthetic hydrogel extracellular matrix designed to elicit key phenotypic traits of the pancreatic environment in culture. To enable the growth of normal and cancerous pancreatic organoids from genetically engineered murine models and human patients, essential adhesive cues were empirically defined and replicated in the hydrogel scaffold, revealing a functional role of laminin-integrin α3/α6 signalling in establishment and survival of pancreatic organoids. Altered tissue stiffness-a hallmark of pancreatic cancer-was recapitulated in culture by adjusting the hydrogel properties to engage mechano-sensing pathways and alter organoid growth. Pancreatic stromal cells were readily incorporated into the hydrogels and replicated phenotypic traits characteristic of the tumour environment in vivo. This model therefore recapitulates a pathologically remodelled tumour microenvironment for studies of normal and pancreatic cancer cells in vitro.

Motion laboratory gait analysis and orthopedic resident education: preliminary results.

Gait analysis in the pediatric and adult orthopedic patient populations can adjunct the diagnosis and treatment of a multitude of musculoskeletal conditions. Understanding of normal and abnormal gait biomechanics is an important aspect of orthopedic residency; yet, there is great variability in the time residency programs dedicate to gait analysis education. The purpose of this study was to investigate if formal gait analysis education during residency improves an orthopedic resident's understanding of normal and pathologic gait. Five residency programs consisting of 81 resident subjects were surveyed at the beginning of the 2016-2017 academic year. The residents were divided into those with formal gait analysis education (group A) and those without (group B). Each resident was sent an online survey with 11 questions from former orthopedic in-training exams (OITE) regarding gait pattern analysis. The average number of correct questions was compared between the two groups with Student's t-test. Fifty-three of the 81 surveys sent out were completed. There were 23 subjects in group A and 30 in group B. All five programs and all postgraduate years (PGYs) were represented (PGY1: 10, PGY2: 12, PGY3: 12, PGY4: 6, PGY5 12). The average score for all residents was 5.6 out of 11 correct (51%). The residents from group A averaged a significantly higher score (6.3) than group B (5.0) (P = 0.017). Understanding gait biomechanics is a critical skill for orthopedic surgeons, and residency training often lacks sufficient training in their curriculum. A good understanding of gait analysis allows orthopedic surgeons to analyze gait disturbances and develop patient-specific treatment plans in adult and pediatric populations. This study found improved knowledge of gait patterns amongst orthopedic residents with formal education. Even though the residents with formal education fared better than their counterparts, the overall percent correct was still low (51%). Evidence: Level 3: Prospective Cohort Study.

Use of Metagenomic Next-Generation Sequencing to Identify Pathogens in Pediatric Osteoarticular Infections.

BACKGROUND: Osteoarticular infections (OAIs) are frequently encountered in children. Treatment may be guided by isolation of a pathogen; however, operative cultures are often negative. Metagenomic next-generation sequencing (mNGS) allows for broad and sensitive pathogen detection that is culture-independent. We sought to evaluate the diagnostic utility of mNGS in comparison to culture and usual care testing to detect pathogens in acute osteomyelitis and/or septic arthritis in children. METHODS: This was a single-site study to evaluate the use of mNGS in comparison to culture to detect pathogens in acute pediatric osteomyelitis and/or septic arthritis. Subjects admitted to a tertiary children's hospital with suspected OAI were eligible for enrollment. We excluded subjects with bone or joint surgery within 30 days of admission or with chronic osteomyelitis. Operative samples were obtained at the surgeon's discretion per standard care (fluid or tissue) and based on imaging and operative findings. We compared mNGS to culture and usual care testing (culture and polymerase chain reaction [PCR]) from the same site. RESULTS: We recruited 42 subjects over the enrollment period. mNGS of the operative samples identified a pathogen in 26 subjects compared to 19 subjects in whom culture identified a pathogen. In 4 subjects, mNGS identified a pathogen where combined usual care testing (culture and PCR) was negative. Positive predictive agreement and negative predictive agreement both were 93.0% for mNGS. CONCLUSIONS: In this single-site prospective study of pediatric OAI, we demonstrated the diagnostic utility of mNGS testing in comparison to culture and usual care (culture and PCR) from operative specimens.

Characteristics of Medical Professional Liability Claims in Pediatric Orthopedics.

OBJECTIVES: Medical malpractice is burdensome to the U.S. healthcare system. The following is an epidemiological analysis of the closed medical professional liability (MPL) claims in pediatric orthopedics using data maintained by the Physician Insurers Association of America. METHODS: The Physician Insurers Association of America registry of MPL claims from 1985 to 2013 for all specialties included 286,021 closed claims in the United States. All closed MPL claims for orthopedic surgery in patients younger than 18 years were retrospectively reviewed (N = 2,671). The error categories, result of the claim, the most common procedures, severity of injury, and the most common presenting and resultant medical conditions were reported with the paid-to-close ratios, average indemnity payment, and average cost of litigation. The pediatric orthopedic population was compared with all orthopedics. The data were adjusted for inflation and trended for the 29-year period. RESULTS: Of the 2671 pediatric orthopedic claims, 881 resulted in a payment and the average indemnity was U.S. $317,574 with adjustment for inflation - significantly higher than for all of orthopedics at U.S. $268,817 (P = 0.0013). The paid-to-close ratio was 33.0%, compared with 28.7% for all of orthopedics (P = 0.023). CONCLUSIONS: Costs to defend individual medical malpractice claims and the average indemnity payment per claim have both increased over time, and pediatric (versus adult) orthopedic claims are more likely to result in payment and result in a higher payment. Knowledge of the details of liability claims should assist practicing general and pediatric orthopedic surgeons in improving patient safety and quality of care, reducing patient injury, and reducing the incidence of MPL claims.