Personalized, parcel-guided non-invasive transcranial magnetic stimulation for the treatment of post-concussive syndrome: safety and proof of concept.

OBJECTIVE: To determine the safety and proof of concept of a parcel-guided, repetitive Transcranial Magnetic Stimulation (rTMS) in patients who develop a heterogeneous array of symptoms, known collectively as post-concussive syndrome (PCS), following traumatic brain injury (TBI). METHODS: We performed a retrospective review of off-label, individualized, parcel-guided rTMS in 19 patients from December 2020 to May 2023. Patients had at least one instance of mild, moderate, or severe TBI and developed symptoms not present prior to injury. rTMS targets were identified based on machine learning connectomic software using functional connectivity anomaly matrices compared to healthy controls. EuroQol (EQ-5D), as a measurement of quality of life, and additional questionnaires dependent on individual's symptoms were submitted prior to, after, and during follow-up from rTMS. RESULTS: Nineteen patients showed improvement in EQ-5D and Rivermead Post Concussion Symptoms Questionnaires - 3 after treatment and follow-up. For nine patients who developed depression, five (55%) attained response and remission based on the Beck Depression Inventory after treatment. Eight of ten patients with anxiety had a clinically significant reduction in Generalized Anxiety Disorder-7 scores during follow-up. CONCLUSION: Parcel-guided rTMS is safe and may be effective in reducing PCS symptoms following TBI and should incite further controlled studies.

Targeting the NLRP3 inflammasome reduces inflammation in hidradenitis suppurativa skin.

BACKGROUND: Treatment for the debilitating disease hidradenitis suppurativa (HS) is inadequate in many patients. Despite an incidence of approximately 1%, HS is often under-recognized and underdiagnosed, and is associated with a high morbidity and poor quality of life. OBJECTIVES: To gain a better understanding of the pathogenesis of HS, in order to design new therapeutic strategies. METHODS: We employed single-cell RNA sequencing to analyse gene expression in immune cells isolated from involved HS skin vs. healthy skin. Flow cytometry was used to quantify the absolute numbers of the main immune populations. The secretion of inflammatory mediators from skin explant cultures was measured using multiplex and enzyme-linked immunosorbent assays. RESULTS: Single-cell RNA sequencing analysis identified a significant enrichment in the frequency of plasma cells, T helper (Th) 17 cells and dendritic cell subsets in HS skin, and the immune transcriptome was distinct and more heterogeneous than healthy skin. Flow cytometry revealed significantly increased numbers of T cells, B cells, neutrophils, dermal macrophages and dendritic cells in HS skin. Genes and pathways associated with Th17 cells, interleukin (IL)-17, IL-1ß and the NLRP3 inflammasome were enhanced in HS skin, particularly in samples with a high inflammatory load. Inflammasome constituent genes principally mapped to Langerhans cells and a subpopulation of dendritic cells. The secretome of HS skin explants contained significantly increased concentrations of inflammatory mediators, including IL-1ß and IL-17A, and culture with an NLRP3 inflammasome inhibitor significantly reduced the secretion of these, as well as other, key mediators of inflammation. CONCLUSIONS: These data provide a rationale for targeting the NLRP3 inflammasome in HS using small-molecule inhibitors that are currently being tested for other indications.

Factors that influence whether patients with acute coronary syndromes undergo cardiac catheterisation.

OBJECTIVE: To determine whether the availability of invasive coronary angiography at the hospital of presentation influences catheterisation rates for patients with acute coronary syndrome (ACS), and whether presenting to a catheterisation-capable hospital is associated with better outcomes for patients with ACS. DESIGN, SETTING: Retrospective cohort study; analysis of Cooperative National Registry of Acute Coronary Events (CONCORDANCE) data. SETTING, PARTICIPANTS: Adults admitted with ACS to 43 Australian hospitals (including 31 catheterisation-capable hospitals), February 2009 - October 2018. MAIN OUTCOME MEASURES: Major adverse cardiovascular events (myocardial infarction, stroke, congestive heart failure, cardiogenic shock, cardiovascular death) and all-cause deaths in hospital and by six and 12- or 24-month follow-up. RESULTS: The proportion of women among the 5637 patients who presented to catheterisation-capable hospitals was smaller than for the 2608 patients who presented to hospitals without catheterisation facilities (28% v 33%); the proportion of patients diagnosed with ST elevation myocardial infarction was larger (32% v 20%). The proportions of patients who underwent catheterisation (81% v 70%) or percutaneous coronary intervention (49% v 35%) were larger for those who presented to catheterisation-capable hospitals. The baseline characteristics of patients who underwent catheterisation were similar for both presentation hospital categories, as were rates of major adverse cardiovascular events and all-cause death in hospital and by 6- and 12- or 24-month follow-up. CONCLUSIONS: Although a larger proportion of patients who presented to catheterisation-capable hospitals underwent catheterisation, patients with similar characteristics were selected for the procedure, independent of the hospital of presentation. Major outcomes for patients were also similar, suggesting equitable management of patients with ACS across Australia.

Research and Practice of AI Ethics: A Case Study Approach Juxtaposing Academic Discourse with Organisational Reality.

This study investigates the ethical use of Big Data and Artificial Intelligence (AI) technologies (BD + AI)-using an empirical approach. The paper categorises the current literature and presents a multi-case study of 'on-the-ground' ethical issues that uses qualitative tools to analyse findings from ten targeted case-studies from a range of domains. The analysis coalesces identified singular ethical issues, (from the literature), into clusters to offer a comparison with the proposed classification in the literature. The results show that despite the variety of different social domains, fields, and applications of AI, there is overlap and correlation between the organisations' ethical concerns. This more detailed understanding of ethics in AI + BD is required to ensure that the multitude of suggested ways of addressing them can be targeted and succeed in mitigating the pertinent ethical issues that are often discussed in the literature.

In AI We Trust: Ethics, Artificial Intelligence, and Reliability.

One of the main difficulties in assessing artificial intelligence (AI) is the tendency for people to anthropomorphise it. This becomes particularly problematic when we attach human moral activities to AI. For example, the European Commission's High-level Expert Group on AI (HLEG) have adopted the position that we should establish a relationship of trust with AI and should cultivate trustworthy AI (HLEG AI Ethics guidelines for trustworthy AI, 2019, p. 35). Trust is one of the most important and defining activities in human relationships, so proposing that AI should be trusted, is a very serious claim. This paper will show that AI cannot be something that has the capacity to be trusted according to the most prevalent definitions of trust because it does not possess emotive states or can be held responsible for their actions-requirements of the affective and normative accounts of trust. While AI meets all of the requirements of the rational account of trust, it will be shown that this is not actually a type of trust at all, but is instead, a form of reliance. Ultimately, even complex machines such as AI should not be viewed as trustworthy as this undermines the value of interpersonal trust, anthropomorphises AI, and diverts responsibility from those developing and using them.

The Future of Transportation: Ethical, Legal, Social and Economic Impacts of Self-driving Vehicles in the Year 2025.

Self-driving vehicles (SDVs) offer great potential to improve efficiency on roads, reduce traffic accidents, increase productivity, and minimise our environmental impact in the process. However, they have also seen resistance from different groups claiming that they are unsafe, pose a risk of being hacked, will threaten jobs, and increase environmental pollution from increased driving as a result of their convenience. In order to reap the benefits of SDVs, while avoiding some of the many pitfalls, it is important to effectively determine what challenges we will face in the future and what steps need to be taken now to avoid them. The approach taken in this paper is the construction of a likely future (the year 2025), through the process of a policy scenario methodology, if we continue certain trajectories over the coming years. The purpose of this is to articulate issues we currently face and the construction of a foresight analysis of how these may develop in the next 6 years. It will highlight many of the key facilitators and inhibitors behind this change and the societal impacts caused as a result. This paper will synthesise the wide range of ethical, legal, social and economic impacts that may result from SDV use and implementation by 2025, such as issues of autonomy, privacy, liability, security, data protection, and safety. It will conclude with providing steps that we need to take to avoid these pitfalls, while ensuring we reap the benefits that SDVs bring.

Using the Health Belief Model to Analyze Instagram Posts about Zika for Public Health Communications.

We analyzed Instagram posts about Zika by using the Health Belief Model. We found a high presence of threat messages, yet little engagement with these posts. Public health professionals should focus on posting messages to increase self-efficacy and benefits of protective behavior, especially when a vaccine becomes available.

Cardiac implanted electronic devices and MRI safety in 2018-the state of play.

Traditionally, the presence of cardiac implanted electronic devices (CIEDs) was a contra-indication to magnetic resonance (MR) imaging. Professional groups from around the world are releasing updated guidelines for the imaging of MR-conditional and legacy CIEDs, reflecting increasing evidence that this can be performed safely when strict protocols are followed. KEY POINTS: • The presence of a pacemaker or automatic implanted cardioverter defibrillator is no longer an absolute contraindication to magnetic resonance imaging. • Strict protocols enable diagnostic quality images to be obtained with minimal risk. • Close collaboration among radiologists, cardiologists and device manufacturer representatives is required.

Human rights-based approach to unintentional injury prevention.

Unintentional injury remains an important global public health issue, and efforts to address it are often hampered by a lack of visibility, leadership, funding, infrastructure, capacity and evidence of effective solutions. The growing support for a socioecological model and a systems approach to prevention-along with the acknowledgement that injury prevention can be a byproduct of salutogenic design and activities-has increased opportunities to integrate unintentional injury prevention into other health promotion and disease prevention agendas. It has also helped to integrate it into the broader human development agenda through the Sustainable Development Goals. This growing support provides new opportunities to use a human rights-based approach to address the issue. The human rights-based approach is based on the idea that all members of society have social, economic and cultural rights and that governments are responsible and accountable for upholding those rights. It incorporates a systems approach, addresses inequity and places an emphasis on the most vulnerable corners of humanity. It also leverages legal statutes and provides organisations with the opportunity to build existing international goals and benchmarks into their monitoring efforts. This paper describes the approach and highlights how it can leverage attention and investment to address current challenges for unintentional injury.

An Observational Study of the Factor Xa Inhibitors Rivaroxaban and Apixaban as Reported to Eight Poison Centers.

STUDY OBJECTIVE: Rivaroxaban and apixaban are part of a new group of oral anticoagulants targeting factor Xa and approved by the Food and Drug Administration in 2011 and 2012. These oral anticoagulants are administered at fixed daily doses, without the need for laboratory-guided adjustments. There are limited data available on supratherapeutic doses or overdose of the oral Xa inhibitors. This study characterizes the clinical effect in patients exposed to rivaroxaban and apixaban. METHODS: A retrospective study collected data from 8 regional poison centers covering 9 states. Cases were initially identified by a search of the poison centers' databases for case mentions involving a human exposure to Xarelto, rivaroxaban, Eliquis, or apixaban. Inclusion criteria included single-substance exposure. Exclusion criteria were animal exposure, polysubstance exposure, or information call. Data for the study were collected by individual chart review, including case narratives, and compiled into a single data set. RESULTS: There were 223 patients: 124 (56%) were female patients, mean age was 60 years, and 20 were children younger than 12 years (9%). One hundred ninety-eight patients ingested rivaroxaban (89%) and 25 ingested apixaban (11%). Dose was reported in 182 rivaroxaban patients, with a mean dose of 64.5 mg (range 15 to 1,200 mg), and in 21 apixaban patients, with a mean dose of 9.6 mg (range 2.5 to 20 mg). For rivaroxaban, prothrombin time was measured in 49 patients (25%) and elevated in 7; partial thromboplastin time, measured in 49 (25%) and elevated in 5; and international normalized ratio, measured in 61 (31%) and elevated in 13. For apixaban, prothrombin time was measured in 6 patients (24%) and elevated in none; partial thromboplastin time, measure in 6 (24%) and elevated in none; and international normalized ratio, measured in 5 patients (20%) and elevated in none. Bleeding was reported in 15 patients (7%): 11 rivaroxaban and 4 apixaban. The site of bleeding was gastrointestinal (8), oral (2), nose (1), bruising (1), urine (1), and subdural (1). The subdural bleeding occurred after fall and head injury. All cases with bleeding involved long-term ingestions. Coagulation test results were normal in most patients with bleeding: prothrombin time 5 of 6 (83%), partial thromboplastin time 5 of 6 (83%), and international normalized ratio 5 of 9 (55%). Blood products were used in 7 rivaroxaban patients (1 suicide) and 3 apixaban patients. No bleeding or altered coagulation test results occurred in children, which all involved a one-time ingestion. All 12 suicide attempts involved rivaroxaban: altered coagulation test results occurred for 5 patients (42%), no bleeding occurred in any suicide attempt patient, 1 patient was treated with fresh frozen plasma (international normalized ratio 12.47), and dose by patient history did not predict risk of altered coagulation or bleeding. Two rivaroxaban patients experienced elevation of hepatic transaminase levels greater than 1,000 U/L. CONCLUSION: Bleeding after Xa inhibitor ingestion as a single agent is uncommon. Prothrombin time, partial thromboplastin time, or international normalized ratio may be elevated in a minority of cases but appears unreliable to measure risk of bleeding. Massive acute ingestion in suicide attempt may result in significant anticoagulation. Single exploratory ingestion by children was not associated with toxicity.

Hip Strength Deficits in Patients With Symptomatic Femoroacetabular Impingement and Labral Tears.

PURPOSE: To determine the prevalence of hip strength deficits in a consecutive cohort of patients with unilateral femoroacetabular impingement (FAI) compared with the asymptomatic contralateral hip. METHODS: Fifty consecutive patients undergoing hip arthroscopy for symptomatic FAI underwent preoperative hip strength dynamometer measurements and were included in the study. Manual isometric hip strength measurements were performed with a handheld dynamometer and included measurements of various hip strengths (flexion, extension, adduction, abduction, internal rotation, and external rotation). Weakness greater than or equal to 10% for any given measurement was defined as a strength deficit in this study. Clinical data including age, gender, size of labral tear, and preoperative outcome scores were recorded. Outcome scores included the modified Harris Hip Score and Short Form 12 Physical Component. RESULTS: The mean age of patients in the study was 32.0 years (range, 18.1 to 49.8 years). There were 32 male and 18 female patients. Hip abduction strength deficits were seen in 46% of patients and flexion strength deficits in 42% of patients. An 8% decrease in strength of the involved hip was seen in flexion, and an 8.7% decrease was seen in abduction. Patients with hip flexion strength deficits had a loss of function (mean modified Harris Hip Score, 57.8 v 66.1; P = .021) and larger labral tears (mean, 39 mm v 28 mm; P = .003). Hip flexion strength deficits correlated with loss of hip flexion (r = 0.373, P = .008). CONCLUSIONS: Hip strength deficits were common in patients presenting with unilateral symptomatic FAI and occurred most commonly in hip abduction and flexion. Strength deficits in hip flexion were associated with decreased function, loss of motion, and larger labral tears in patients with FAI and labral tears. LEVEL OF EVIDENCE: Level IV, prognostic case series.

Interprofessional education as a method to address health needs in a Hispanic community setting: A pilot study.

The Hispanic population in and around Richmond, Virginia, USA, has grown rapidly since 2000. The Richmond City Latino Needs Assessment emphasized this growth and also reported concerns regarding healthcare access. Schools of medicine, pharmacy, and nursing at Virginia Commonwealth University have partnered together with community organizations to develop and implement an interprofessional student service learning pilot program to meet community needs and provide an opportunity for enhanced learning. Community events allowed students to work on interprofessional teams to provide healthcare screenings and education to the Hispanic community. The program was evaluated by the use of a community service survey. Results indicated improved perceptions of student comfort with working with diverse patients, working on teams, and patient-centered care, as well as statistically significant improvements in student understanding of health care access and barriers, community needs, and social determinants of health. Results suggest that this community-based service-learning interprofessional experience was critical in student learning.

IL-21 receptor is required for the systemic accumulation of activated B and T lymphocytes in MRL/MpJ-Fas(lpr/lpr)/J mice.

MRL/MpJ-Fas(lpr/lpr)/J (MRL(lpr)) mice develop lupus-like disease manifestations in an IL-21-dependent manner. IL-21 is a pleiotropic cytokine that can influence the activation, differentiation, and expansion of B and T cell effector subsets. Notably, autoreactive CD4(+) T and B cells spontaneously accumulate in MRL(lpr) mice and mediate disease pathogenesis. We sought to identify the particular lymphocyte effector subsets regulated by IL-21 in the context of systemic autoimmunity and, thus, generated MRL(lpr) mice deficient in IL-21R (MRL(lpr).IL-21R(-/-)). Lymphadenopathy and splenomegaly, which are characteristic traits of the MRL(lpr) model were significantly reduced in the absence of IL-21R, suggesting that immune activation was likewise decreased. Indeed, spontaneous germinal center formation and plasma cell accumulation were absent in IL-21R-deficient MRL(lpr) mice. Correspondingly, we observed a significant reduction in autoantibody titers. Activated CD4(+) CD44(+) CD62L(lo) T cells also failed to accumulate, and CD4(+) Th cell differentiation was impaired, as evidenced by a significant reduction in CD4(+) T cells that produced the pronephritogenic cytokine IFN-γ. T extrafollicular helper cells are a recently described subset of activated CD4(+) T cells that function as the primary inducers of autoantibody production in MRL(lpr) mice. Importantly, we demonstrated that T extrafollicular helper cells are dependent on IL-21R for their generation. Together, our data highlighted the novel observation that IL-21 is a critical regulator of multiple pathogenic B and T cell effector subsets in MRL(lpr) mice.

Creation of Three-dimensional Anatomic Models in Pediatric Surgical Patients Using Cross-sectional Imaging: A Demonstration of Low-cost Methods and Applications.

BACKGROUND: Pediatric surgery patients often present with complex congenital anomalies or other conditions requiring deep understanding of their intricate anatomy. Commercial applications and services exist for the conversion of cross-sectional imaging data into three-dimensional (3D) models for education and preoperative planning. However, the associated costs and lack of familiarity may discourage their use in centers with limited resources. The purpose of this report is to present a low-cost, reproducible method for generating 3D images to visualize patient anatomy. METHODS: De-identified DICOM files were obtained from the hospital PACS system in preparation for assorted pediatric surgical procedures. Using open-source visualization software, variations in anatomic structures were examined using volume rendering and segmentation techniques. Images were further refined using available editing tools or artificial intelligence-assisted software extensions. RESULTS: Using the described techniques we were able to obtain excellent visualization of desired structures and associated anatomic variations. Once structures were selected and modeled in 3D (segmentation), they could be exported as one of several 3D object file formats. These could then be retained for 3D printing, visualization in virtual reality, or as an anatomic reference during the perioperative period. Models may also be imported into commercial gaming engines for rendering under optimal lighting conditions and with enhanced detail. CONCLUSION: Pediatric surgeons are frequently tasked with the treatment of patients with complex and rare anomalies. Visualization and preoperative planning can be assisted by advanced imaging software at minimal to no cost, thereby facilitating enhanced understanding of these conditions in resource-limited environments. LEVEL OF EVIDENCE: V, Case Series, Description of Technique.

Cervical Collar-Associated Pressure Injury in Pediatric Trauma Patients: A Western Pediatric Surgery Research Consortium Study.

BACKGROUND: Healthcare-associated pressure injuries (HAPI) are known to be associated with medical devices and are preventable. Cervical spine immobilization is commonly utilized in injured children prior to clinical clearance or for treatment of an unstable cervical spinal injury. The frequency of HAPI has been quantified in adults with cervical spine immobilization but has not been well-described in children. The aim of this study was to describe characteristics of children who developed HAPI associated with cervical immobilization. METHODS: We analyzed a retrospective cohort of children (0-18 years) who developed a stage two or greater cervical HAPI. This cohort was drawn from an overall sample of 49,218 registry patients treated over a five-year period (2017-2021) at ten pediatric trauma centers. Patient demographics, injury characteristics, and cervical immobilization were tabulated to describe the population. RESULTS: The cohort included 32 children with stage two or greater cervical HAPI. The median age was 5 years (IQR 2-13) and 78% (n = 25) were admitted to the intensive care unit. The median (IQR) time to diagnosis of HAPI was 11 (7-21) days post-injury. The majority of cervical HAPI (78%, 25/32) occurred in children requiring immobilization for cervical injuries, with only four children developing HAPI after wearing a prophylactic cervical collar in the absence of a cervical spine injury. CONCLUSION: Advanced-stage HAPI associated with cervical collar use in pediatric trauma patients is rare and usually occurs in patients with cervical spine injuries requiring immobilization for treatment. More expedient cervical spine clearance with MRI is unlikely to substantially reduce cervical HAPI in injured children. LEVEL OF EVIDENCE: Level III (Epidemiologic and Prognostic).

The use and timing of angioembolization in pediatric blunt liver and spleen injury.

BACKGROUND: Nonoperative management (NOM) is the standard of care for the management of blunt liver and spleen injuries (BLSI) in the stable pediatric patient. Angiography with embolization (AE) is used as an adjunctive therapy in the management of adult BLSI patients, but it is rarely used in the pediatric population. In this planned secondary analysis, we describe the current utilization patterns of AE in the management of pediatric BLSI. METHODS: After obtaining IRB approval at each center, cohort data was collected prospectively for children admitted with BLSI confirmed on CT at 10 Level I pediatric trauma centers (PTCs) throughout the United States from April 2013 to January 2016. All patients who underwent angiography with or without embolization for a BLSI were included in this analysis. Data collected included patient demographics, injury details, organ injured and grade of injury, CT finding specifics such as contrast blush, complications, failure of NOM, time to angiography and techniques for embolization. RESULTS: Data were collected for 1004 pediatric patients treated for BLSI over the study period, 30 (3.0%) of which underwent angiography with or without embolization for BLSI. Ten of the patients who underwent angiography for BLSI failed NOM. For patients with embolized splenic injuries, splenic salvage was 100%. Four of the nine patients undergoing embolization of the liver ultimately required an operative intervention, but only one patient required hepatorrhaphy and no patient required hepatectomy after AE. Few angiography studies were obtained early during hospitalization for BLSI, with only one patient undergoing angiography within 1 hour of arrival at the PTC, and 7 within 3 hours. CONCLUSION: Angioembolization is rarely used in the management of BLSI in pediatric trauma patients with blunt abdominal trauma and is generally used in a delayed fashion. However, when implemented, angioembolization is associated with 100% splenic salvage for splenic injuries. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Outcomes of Extracorporeal Life Support Utilization for Pediatric Patients With COVID-19 Infections.

Outcomes of pediatric patients who received extracorporeal life support (ECLS) for COVID-19 remain poorly described. The aim of this multi-institutional retrospective observational study was to evaluate these outcomes and assess for prognostic factors associated with in-hospital mortality. Seventy-nine patients at 14 pediatric centers across the United States who received ECLS support for COVID-19 infections between January 2020 and July 2022 were included for analysis. Data were extracted from the electronic medical record. The median age was 14.5 years (interquartile range [IQR]: 2-17 years). Most patients were female (54.4%) and had at least one pre-existing comorbidity (84.8%), such as obesity (44.3%, median body mass index percentile: 97% [IQR: 67.5-99.0%]). Venovenous (VV) ECLS was initiated in 50.6% of patients. Median duration of ECLS was 12 days (IQR: 6.0-22.5 days) with a mean duration from admission to ECLS initiation of 5.2 ± 6.3 days. Survival to hospital discharge was 54.4%. Neurological deficits were reported in 16.3% of survivors. Nonsurvivors were of older age (13.3 ± 6.2 years vs. 9.3 ± 7.7 years, p = 0.012), more likely to receive renal replacement therapy (63.9% vs. 30.2%, p = 0.003), demonstrated longer durations from admission to ECLS initiation (7.0 ± 8.1 days vs. 3.7 ± 3.8 days, p = 0.030), and had higher rates of ECLS-related complications (91.7% vs. 69.8%, p = 0.016) than survivors. Pediatric patients with COVID-19 who received ECLS demonstrated substantial morbidity and further investigation is warranted to optimize management strategies.

The Sensitivity of Limited-Sequence MRI in Identifying Pediatric Cervical Spine Injury: A Western Pediatric Surgery Research Consortium Multicenter Retrospective Cohort Study.

INTRODUCTION: Clinical clearance of a child's cervical spine after trauma is often challenging due to impaired mental status or an unreliable neurologic examination. Magnetic resonance imaging (MRI) is the gold standard for excluding ligamentous injury in children but is constrained by long image acquisition times and frequent need for anesthesia. Limited-sequence MRI (LSMRI) is used in evaluating the evolution of traumatic brain injury and may also be useful for cervical spine clearance while potentially avoiding the need for anesthesia. The purpose of this study was to assess the sensitivity and negative predictive value of LSMRI as compared to gold standard full-sequence MRI as a screening tool to rule out clinically significant ligamentous cervical spine injury. METHODS: We conducted a ten-center, five-year retrospective cohort study (2017-2021) of all children (0-18y) with a cervical spine MRI after blunt trauma. MRI images were re-reviewed by a study pediatric radiologist at each site to determine if the presence of an injury could be identified on limited sequences alone. Unstable cervical spine injury was determined by study neurosurgeon review at each site. RESULTS: We identified 2,663 children less than 18 years of age who underwent an MRI of the cervical spine with 1,008 injuries detected on full-sequence studies. The sensitivity and negative predictive value of LSMRI were both >99% for detecting any injury and 100% for detecting any unstable injury. Young children (age < 5 years) were more likely to be electively intubated or sedated for cervical spine MRI. CONCLUSION: LSMRI is reliably detects clinically significant ligamentous injury in children after blunt trauma. To decrease anesthesia use and minimize MRI time, trauma centers should develop LSMRI screening protocols for children without a reliable neurologic exam. LEVEL OF EVIDENCE: 2 (Diagnostic Tests or Criteria).

Biophysical and mechanistic insights into novel allosteric inhibitor of spleen tyrosine kinase.

Extracellular stimulation of the B cell receptor or mast cell FcεRI receptor activates a cascade of protein kinases, ultimately leading to antigenic or inflammation immune responses, respectively. Syk is a soluble kinase responsible for transmission of the receptor activation signal from the membrane to cytosolic targets. Control of Syk function is, therefore, critical to the human antigenic and inflammation immune response, and an inhibitor of Syk could provide therapy for autoimmune or inflammation diseases. We report here a novel allosteric Syk inhibitor, X1, that is noncompetitive against ATP (K(i) 4 ± 1 µM) and substrate peptide (K(i) 5 ± 1 µM), and competitive against activation of Syk by its upstream regulatory kinase LynB (K(i) 4 ± 1 µM). The inhibition mechanism was interrogated using a combination of structural, biophysical, and kinetic methods, which suggest the compound inhibits Syk by reinforcing the natural regulatory interactions between the SH2 and kinase domains. This novel mode of inhibition provides a new opportunity to improve the selectivity profile of Syk inhibitors for the development of safer drug candidates.