Mapping the evidence of the effects of environmental factors on the prevalence of antibiotic resistance in the non-built environment: Protocol for a systematic evidence map.

BACKGROUND: Human, animal, and environmental health are increasingly threatened by the emergence and spread of antibiotic resistance. Inappropriate use of antibiotic treatments commonly contributes to this threat, but it is also becoming apparent that multiple, interconnected environmental factors can play a significant role. Thus, a One Health approach is required for a comprehensive understanding of the environmental dimensions of antibiotic resistance and inform science-based decisions and actions. The broad and multidisciplinary nature of the problem poses several open questions drawing upon a wide heterogeneous range of studies. OBJECTIVE: This study seeks to collect and catalogue the evidence of the potential effects of environmental factors on the abundance or detection of antibiotic resistance determinants in the outdoor environment, i.e., antibiotic resistant bacteria and mobile genetic elements carrying antibiotic resistance genes, and the effect on those caused by local environmental conditions of either natural or anthropogenic origin. METHODS: Here, we describe the protocol for a systematic evidence map to address this, which will be performed in adherence to best practice guidelines. We will search the literature from 1990 to present, using the following electronic databases: MEDLINE, Embase, and the Web of Science Core Collection as well as the grey literature. We shall include full-text, scientific articles published in English. Reviewers will work in pairs to screen title, abstract and keywords first and then full-text documents. Data extraction will adhere to a code book purposely designed. Risk of bias assessment will not be conducted as part of this SEM. We will combine tables, graphs, and other suitable visualisation techniques to compile a database i) of studies investigating the factors associated with the prevalence of antibiotic resistance in the environment and ii) map the distribution, network, cross-disciplinarity, impact and trends in the literature.

Portable Differential Detection of CTX-M ESBL Gene Variants, blaCTX-M-1 and blaCTX-M-15, from Escherichia coli Isolates and Animal Fecal Samples Using Loop-Primer Endonuclease Cleavage Loop-Mediated Isothermal Amplification.

Cefotaximase-Munich (CTX-M) extended-spectrum beta-lactamase (ESBL) enzymes produced by Enterobacteriaceae confer resistance to clinically relevant third-generation cephalosporins. CTX-M group 1 variants, CTX-M-1 and CTX-M-15, are the leading ESBL-producing Enterobacteriaceae associated with animal and human infection, respectively, and are an increasing antimicrobial resistance (AMR) global health concern. The blaCTX-M-1 and blaCTX-M-15 genes encoding these variants have an approximate nucleotide sequence similarity of 98.7%, making effective differential diagnostic monitoring difficult. Loop-primer endonuclease cleavage loop-mediated isothermal amplification (LEC-LAMP) enables rapid real-time multiplex pathogen detection with single-base specificity and portable on-site testing. We have developed an internally controlled multiplex CTX-M-1/15 LEC-LAMP assay for the differential detection of blaCTX-M-1 and blaCTX-M-15. Assay analytical specificity was established using a panel of human, animal, and environmental Escherichia coli isolates positive for blaCTX-M-1 (n = 18), blaCTX-M-15 (n = 35), and other closely related blaCTX-Ms (n = 38) from Ireland, Germany, and Portugal, with analytical sensitivity determined using probit regression analysis. Animal fecal sample testing using the CTX-M-1/15 LEC-LAMP assay in combination with a rapid DNA extraction protocol was carried out on porcine fecal samples previously confirmed to be PCR-positive for E. coli blaCTX-M. Portable instrumentation was used to further analyze each fecal sample and demonstrate the on-site testing capabilities of the LEC-LAMP assay with the rapid DNA extraction protocol. The CTX-M-1/15 LEC-LAMP assay demonstrated complete analytical specificity for the differential detection of both variants with sensitive low-level detection of 8.5 and 9.8 copies per reaction for blaCTX-M-1 and blaCTX-M-15, respectively, and E. coli blaCTX-M-1 was identified in all blaCTX-M positive porcine fecal samples tested. IMPORTANCE CTX-M ESBL-producing E. coli is an increasing AMR public health issue with the transmission between animals and humans via zoonotic pathogens now a major area of interest. Accurate and timely identification of ESBL-expressing E. coli CTX-M variants is essential for disease monitoring, targeted antibiotic treatment and infection control. This study details the first report of portable diagnostics technology for the rapid differential detection of CTX-M AMR markers blaCTX-M-1 and blaCTX-M-15, facilitating improved identification and surveillance of these closely related variants. Further application of this portable internally controlled multiplex CTX-M-1/15 LEC-LAMP assay will provide new information on the transmission and prevalence of these CTX-M ESBL alleles. Furthermore, this transferable diagnostic technology can be applied to other new and emerging relevant AMR markers of interest providing more efficient and specific portable pathogen detection for improved epidemiological surveillance.

Use and Cost Analysis of Comprehensive Respiratory Panel Testing in a Pediatric Emergency Department.

OBJECTIVES: Fever and respiratory infections are among the leading causes of pediatric emergency department visits and hospitalizations. Although typically self-resolving, clinicians may perform diagnostic tests to determine microbial etiologies of these illnesses. Although comprehensive respiratory viral panels can quickly identify causative organisms, cost to the hospital and patient may be significant. The objective of this study was to analyze the financial impact of comprehensive respiratory viral panel use in relation to associated clinical outcomes. METHODS: This study was a single-center, retrospective chart review of pediatric emergency department patients who were evaluated between October 1, 2016, and April 30, 2018, with International Classification of Diseases, Tenth Revision (ICD-10) code diagnoses of acute upper respiratory infection, fever unspecified, and/or bronchiolitis. Our primary outcome was the effect of comprehensive respiratory viral panel testing and results on the total health care charge to patients. Secondary outcomes were the effect of comprehensive respiratory viral panel testing and results on emergency department length of stay and antimicrobial use. RESULTS: A total of 5766 visits were included for primary analysis, with 229 (4%) undergoing comprehensive respiratory viral panel testing. Of these, 163 had a positive result (71%) for at least 1 organism. The total cost was significantly higher in the group that underwent comprehensive respiratory viral panel testing ($643.39 [$534.18-$741.15] vs $295.15 [$249.72-$353.92]; P < 0.001). There was no decrease in emergency department length of stay or significant change in antimicrobial use associated with comprehensive respiratory viral panel use. CONCLUSIONS: This study demonstrates that the utilization of comprehensive respiratory viral panels in pediatric emergency department patients with bronchiolitis, unspecified fever, and/or acute upper respiratory infection adds significant cost to patient care without a decrease in their length of stay or antimicrobial use. Further studies are needed to determine the appropriate targeted use of comprehensive respiratory viral panels.

Rectified Classifier Chains for Prediction of Antibiotic Resistance From Multi-Labelled Data With Missing Labels.

Predicting Antimicrobial Resistance (AMR) from genomic data has important implications for human and animal healthcare, and especially given its potential for more rapid diagnostics and informed treatment choices. With the recent advances in sequencing technologies, applying machine learning techniques for AMR prediction have indicated promising results. Despite this, there are shortcomings in the literature concerning methodologies suitable for multi-drug AMR prediction and especially where samples with missing labels exist. To address this shortcoming, we introduce a Rectified Classifier Chain (RCC) method for predicting multi-drug resistance. This RCC method was tested using annotated features of genomics sequences and compared with similar multi-label classification methodologies. We found that applying the eXtreme Gradient Boosting (XGBoost) base model to our RCC model outperformed the second-best model, XGBoost based binary relevance model, by 3.3% in Hamming accuracy and 7.8% in F1-score. Additionally, we note that in the literature machine learning models applied to AMR prediction typically are unsuitable for identifying biomarkers informative of their decisions; in this study, we show that biomarkers contributing to AMR prediction can also be identified using the proposed RCC method. We expect this can facilitate genome annotation and pave the path towards identifying new biomarkers indicative of AMR.

Compatibility of calcium chloride with milrinone, epinephrine, vasopressin, and heparin via in vitro testing and simulated Y-site administration.

PURPOSE: The purpose of this study is to evaluate calcium chloride (CaCl) compatibility with commercially available and extemporaneously compounded milrinone, vasopressin, epinephrine, and heparin. This report describes 2 clinical scenarios in which patients experienced intravenous catheter precipitation when receiving multiple continuous infusions, including CaCl, and the results of an in vitro simulation of those scenarios. The hypothesis was that one or a combination of the medications would precipitate with CaCl. METHODS: CaCl compatibility was tested in 3 stages to simulate clinical situations where line precipitation occurred. Multiple tests were conducted in each stage to determine if precipitation had occurred, including visual assessment, absorbance measurement at 650 nm, and pH measurement. First, milrinone, vasopressin, epinephrine, and heparin were mixed pairwise with CaCl in a test tube. Second, the medications were mixed in different combinations deemed likely to precipitate. Finally, 5 medications were infused via simulated Y-site administration. Incompatibility was defined as observed crystals, haziness, or turbidity upon visual inspection or absorbance of greater than 0.01 absorbance unit (AU). All solutions were tested at time 0 and at 20, 60, 240, and 1,440 minutes. RESULTS: Across all tests, only a commercially available formulation of heparin 2 units/mL in 0.9% sodium chloride injection precipitated with CaCl, alone or in combination with other medications. Upon further review, it was found that this specific formulation of heparin contained a monohydrate and dibasic sodium phosphate buffer. CONCLUSION: CaCl only precipitated with a commercially available heparin formulation that contained a phosphate buffer. CaCl was deemed to be compatible with all other medications and formulations tested.

Keyhole Approaches Applied to Clipping of Acutely Ruptured Intracerebral Aneurysms-A Technical Note and Case Series.

BACKGROUND: Evolution of keyhole techniques in aneurysm surgery allows for definitive surgical management of aneurysmal pathology with little disruption of normal surrounding tissue. While experienced vascular neurosurgeons are increasingly applying keyhole techniques to unruptured aneurysms, experience with ruptured aneurysms is limited. OBJECTIVE: We sought to explore technical nuances and present operative outcomes for our series of 40 consecutive patients presenting with ruptured intracerebral aneurysms treated with surgical clipping via a keyhole approach. METHODS: This study is a consecutive, single-surgeon, single-center retrospective case series of aneurysms clipped with keyhole approaches at Helen Joseph Hospital in Johannesburg, South Africa. Patients presenting with subarachnoid hemorrhage were worked up exclusively with computed tomography. On the basis of vessel location and unique anatomic features, aneurysms were clipped through one of these approaches: minipterional, supraorbital, or keyhole interhemispheric. Operative details were assessed on retrospective file review, and patient outcomes were assessed on clinic follow-up. RESULTS: A minipterional approach was used for 55% of cases, the supraorbital approach in 30% of cases, and the mini-interhemispheric approach in 15% of cases. The intraoperative aneurysm rupture rate was 26.2%. Complete aneurysm occlusion was achieved in 97.4% with none of the 40 cases requiring conversion of a keyhole to a larger craniotomy. A good outcome was achieved for 72.5% of patients (modified Rankin Scale score ≤2). For patients presenting with World Federation of Neurological Surgeons grade I to III subarachnoid hemorrhage, 92.9% achieved a good outcome. CONCLUSIONS: The present series supports the concept that sound technical execution of keyhole approaches, even in the setting of acutely ruptured cerebral aneurysms, is a viable option for clipping of intracranial aneurysms.

Optimization of Vancomycin Dosing to Achieve Target Area Under the Curve in Pediatrics.

OBJECTIVE: Vancomycin dosing requirements to achieve a target area under curve/minimum inhibitory concentration (AUC/MIC) of 400 to 600 mg•hr/L have not been established in pediatrics. Dose modeling studies and recent guidelines suggest dosing higher than historical recommendations. This study examines dosing requirements to achieve target AUC/MIC in human pediatric patients. METHODS: This retrospective study includes 77 patients, aged 1 month to 18 years, at a single center, who received at least 2 days of intravenous vancomycin with a pharmacokinetic monitoring note and calculated AUC/MIC. Dosing to achieve target AUC/MIC was evaluated by age and indication. Nephrotoxicity was also assessed. RESULTS: The mean dose required to achieve target AUC/MIC for all patients was 67.7 mg/kg/day. Adjusting for age, the mean dose required to achieve target AUC/MIC of 400 to 600 mg•hr/L was found to be statistically significantly different among 3 age cohorts: 1 month to 5 years, 6 to 12 years, and 13 to 18 years [F(2,74) = 15.32, p < 0.001], with mean requirements of 79 ± 14.1, 65.6 ± 21.1, and 53.9 ± 17.1 mg/kg/day, respectively. Dosing requirements were also found to be statistically significantly different across indications [F(6,70) = 4.84, p < 0.001]. Acute kidney injury was identified in 5 patients (6.5%). CONCLUSIONS: The vancomycin dose required to achieve target AUC/MIC in pediatrics was significantly higher in younger pediatric patients and ranged from 53.9 to 79 mg/kg/day, confirming recent guideline recommendations. Doses can be further adjusted for indication. Nephrotoxicity rates remain low compared with historical rates with single trough monitoring.

Comparison of the predictive value of area under the curve versus maximum serum concentration of intravenous tobramycin in cystic fibrosis patients treated for an acute pulmonary exacerbation.

OBJECTIVES: The primary objective of this study was to compare the therapeutic predictive value of area under the curve (AUC24 ) versus maximum concentration (Cmax ) in cystic fibrosis (CF) patients receiving intravenous (IV) tobramycin for a Pseudomonas aeruginosa (PsA) acute pulmonary exacerbation (APE). Acute kidney injury (AKI) incidence and the relationship between time undetectable and efficacy were also assessed. METHODS: A retrospective review was conducted in patients aged at least 1 month with a diagnosis of CF receiving IV tobramycin for treatment of a PsA APE and admitted to the University of Kentucky between August 2015 and August 2019. Patients were excluded if they had no growth of PsA on sputum culture or if two postdose tobramycin levels were not obtained following a dose adjustment of ≥20%. RESULTS: A total of 44 pediatric and 107 adult patient encounters met inclusion criteria. In patients with therapeutic success (n = 91), 75.8% had an AUC24 ≥80% and 80.3% had a Cmax ≥8 times the highest PsA minimal inhibitory concentration. There was a significant correlation between AUC24 and Cmax (r[149] = 0.727; p < 0.001). AKI incidence was significantly higher in patients receiving IV tobramycin dosed multiple times daily versus at least every 24 h (χ2 [1, 151] = 3.9; p = 0.047). CONCLUSIONS: The results of this study indicate that both AUC24 and Cmax serve as relatively accurate predictors of tobramycin efficacy. Additionally, given the significant increase in incidence of AKI, multidaily dosing of IV tobramycin should be avoided in pediatric and adult patients with CF.

Supervised Learning With First-to-Spike Decoding in Multilayer Spiking Neural Networks.

Experimental studies support the notion of spike-based neuronal information processing in the brain, with neural circuits exhibiting a wide range of temporally-based coding strategies to rapidly and efficiently represent sensory stimuli. Accordingly, it would be desirable to apply spike-based computation to tackling real-world challenges, and in particular transferring such theory to neuromorphic systems for low-power embedded applications. Motivated by this, we propose a new supervised learning method that can train multilayer spiking neural networks to solve classification problems based on a rapid, first-to-spike decoding strategy. The proposed learning rule supports multiple spikes fired by stochastic hidden neurons, and yet is stable by relying on first-spike responses generated by a deterministic output layer. In addition to this, we also explore several distinct, spike-based encoding strategies in order to form compact representations of presented input data. We demonstrate the classification performance of the learning rule as applied to several benchmark datasets, including MNIST. The learning rule is capable of generalizing from the data, and is successful even when used with constrained network architectures containing few input and hidden layer neurons. Furthermore, we highlight a novel encoding strategy, termed "scanline encoding," that can transform image data into compact spatiotemporal patterns for subsequent network processing. Designing constrained, but optimized, network structures and performing input dimensionality reduction has strong implications for neuromorphic applications.

Pharmacist Survey: Pharmacist Perception of Vancomycin Area Under the Curve Therapeutic Drug Monitoring.

BACKGROUND: Evidence suggests the standard vancomycin trough goal of 15 to 20 mg/L for serious Staphylococcus aureus infections is associated with acute kidney injury, whereas appropriate monitoring of 24-hour area under the curve (AUC) may decrease nephrotoxicity. As a result, institutions have transitioned to AUC monitoring, the predictive pharmacokinetic/pharmacodynamic parameter of vancomycin to improve safety outcomes. However, this method may require increased pharmacist time and effort. Pharmacist perception of the practice change is largely unknown and warrants investigation. METHODS: An electronic survey was disseminated via e-mail to pharmacists 5 months post-AUC implementation. Items of interest were focused on pharmacist perception, including quantity of patients monitored using AUC, justification of the practice change, differences in efficacy and safety, and changes in monitoring time requirements. RESULTS: The pharmacist survey was distributed to 196 pharmacists and 84 responded (43% response rate). Eighty-one pharmacists had monitored patients using AUC methods. Sixty-nine percent of these respondents perceived the change to result in increased or slightly increased patient safety, 27% described no difference, and 4% stated safety was decreased or slightly decreased. Forty-two percent perceived the transition to result in increased or slightly increased efficacy, while 48% noted no difference and 10% responded that efficacy was decreased or slightly decreased. Pharmacists stated the creation of an institutional calculator decreased the time required to calculate AUC. CONCLUSION: After the change to AUC monitoring, pharmacists perceived improvements in safety outcomes while efficacy was at least similar if not increased.

Evaluation of Two Fosphenytoin Loading Dose Regimens and Monitoring in Infants and Neonates Less Than Six Months of Age.

OBJECTIVES: The objectives of the study were to compare the free serum concentrations after different fosphenytoin loading dose strategies in patients younger than 6 months old and to investigate the frequency of seizure cessation following a loading dose of fosphenytoin. METHODS: This retrospective cohort study included neonates and infants admitted to a 150-bed children's hospital between August 1, 2014, and February 1, 2018. Patients were included if they were younger than 6 months old and had a postload free phenytoin serum concentration collected during the specified time frame. Patients were identified through a database query screening for the inclusion criteria. Patients were separated into 2 groups with the 15 mg/kg group as per protocol and the 20 mg/kg group as noted in common practice. Data collection included demographic information, fosphenytoin dose, time of administration of the fosphenytoin loading dose, time of sampling, free phenytoin serum concentration results, concomitant antiepileptic agents, albumin serum concentration, and total bilirubin serum concentration. RESULTS: Forty-one patients were included for analysis, 12 in the 15 mg/kg group and 29 in the 20 mg/kg group. The average free phenytoin concentration after the loading dose was 2.45 ± 0.54 mg/L in the 15 mg/kg group and 2.52 ± 0.66 mg/L in the 20 mg/kg group. Seizure cessation after the fosphenytoin loading dose was achieved in 3 of 12 (25%) patients in the 15 mg/kg group and in 13 of 29 (45%) patients in the 20 mg/kg group (p = 0.305). CONCLUSIONS: The study demonstrates that a traditional range of fosphenytoin loading dose (15-20 mg/kg) led to elevated postloading dose free phenytoin serum concentrations in the majority of patients with a seizure cessation rate of approximately 39%. The question remains as to what the optimal dose and target concentration should be in this patient population to achieve the best efficacy without risking associated toxicities.

Incidence of nephrotoxicity with prolonged aminoglycoside exposure in patients with cystic fibrosis.

Cystic fibrosis (CF) patients, with Pseudomonas aeruginosa infection, often require repeated aminoglycoside courses for the management of acute pulmonary exacerbations (APEs). Acute kidney injury (AKI) due to aminoglycosides has been reported; little data exist regarding long-term nephrotoxicity with repeated exposure. The objective of this study was to describe the incidence of acute and chronic nephrotoxicity due to cumulative intravenous (IV) aminoglycoside exposure. This is a retrospective, observational study of pediatric and adult CF patients admitted to an academic medical center between January 1, 2006 and October 1, 2018 for APE management. Patients were eligible for inclusion if they received at least five courses of an IV aminoglycoside for at least 7 days each. Cumulative weight-based aminoglycoside dose was reported in milligrams per kilogram. For each admission, baseline and highest serum creatinine were collected to assess the incidence of AKI. The baseline and final estimated glomerular filtration rate (eGFR) were calculated to assess long-term effects on renal function. Sixty-six patients, representing greater than 700 courses, were included in the final analysis. The median cumulative weight-based aminoglycoside dose was 1183 mg/kg of tobramycin or tobramycin equivalent. Twenty percent of courses resulted in AKI; 86% were Stage 1. A repeated measure multivariate model showed colistin, piperacillin/tazobactam, vancomycin, and age were significant AKI risk factors. There was no correlation between cumulative aminoglycoside dose and change in eGFR. AKI from IV aminoglycoside exposure occurred in 20% of courses. Cumulative exposure to IV aminoglycosides in APE management was not correlated with long-term renal dysfunction.

Characterization of Admission Medication Reconciliations Performed by Pharmacists in a Pediatric Institution: Resource Allocation.

BACKGROUND: Compared with adults, children may be at greater risk of medication errors and potential adverse effects. The American Academy of Pediatrics recommends developing mechanisms for proactively identifying patients at risk for medication-related adverse events and failed reconciliation. This study's primary purpose was to evaluate pediatric patients admitted to identify risk factors requiring pharmacist intervention during medication reconciliation (MedRec). METHODS: This prospective study included pediatric patients admitted during the study time frame until the target population of 500 patient encounters was achieved. During each admission, pharmacy staff completed a medication history, after which a pediatric pharmacist completed a MedRec, as is standard hospital practice. The primary outcome was identification of factors for high-risk transitions of care during pediatric admissions based on the need for pharmacist interventions during the MedRec process. RESULTS: In total, 331 interventions were made for 127 patients (median 2; range, 1-12). Of the 331 interventions, 196 (59.2%) were classified as being of moderate or significant severity. Although patients with at least 2 home medications were significantly more likely to require any intervention (p < 0.0001), patients with 5 or more home medications were more likely to have a significant intervention. CONCLUSION: Identifying patients with home medications could allow for focused efforts to intervene. Also, patients admitted to the PICU or those with cardiology- or endocrinology-related diagnoses should be prioritized for MedRec process, because of the likelihood of requiring multiple home medications. This strategy should be tailored to individual pediatric institutions based on internal quality control assessments and available resources.

Vancomycin Area Under the Curve Dosing and Monitoring at an Academic Medical Center: Transition Strategies and Lessons Learned.

Due to the inconsistent correlation of vancomycin trough concentrations with 24-hour area under the curve (AUC) and a desire to reduce rates of vancomycin-associated acute kidney injury, an institutional guideline was implemented by the Antimicrobial Stewardship Team in September 2017 to monitor vancomycin using AUC. Three stages were utilized to organize the process: preparation, implementation, and evaluation. The preparation stage was used to present literature to key stakeholders, and pharmacy meetings focused on the development of a dosing and monitoring guideline. Along with institution-wide education, the implementation stage included information technology development and support. The evaluation stage was comprised of quality improvement and clinical research. Future plans include dissemination of the results and analyses. Numerous lessons were learned due to barriers experienced during the process, but the transition was successful.

Effect of timing on endovascular therapy and exploratory laparotomy outcome in acute mesenteric ischemia.

BACKGROUND: Abdominal exploration followed by vascular bypass has been the standard of care for acute mesenteric ischemia (AMI), but there is increasing use of endovascular treatment with selective exploratory laparotomy. METHODS: We performed a retrospective review of patients diagnosed with AMI who underwent mesenteric artery angioplasty or stenting at a single institution from 2010-2017. Patients were divided into 3 groups: those who did not undergo exploratory laparotomy; those who received endovascular treatment before laparotomy (post-reperfusion laparotomy group); and those who had endovascular treatment after laparotomy (pre-reperfusion laparotomy group). RESULTS: Patients who did not undergo exploratory laparotomy showed 85.7% (12/14) survival, compared with 63.6% (7/11) in the post-reperfusion group and 25.0% (2/8) in the pre-reperfusion group, P=0.077). Time to reperfusion was significant (P=0.009) in predicting survival for patients who underwent exploratory laparotomy. CONCLUSION: Emergent endovascular treatment prior to laparotomy seems to be associated with a higher survival.

Management and prognosis of acute traumatic cervical central cord syndrome: systematic review and Spinal Cord Society-Spine Trauma Study Group position statement.

PURPOSE: Spinal Cord Society (SCS) and Spine Trauma Study Group (STSG) established a panel tasked with reviewing management and prognosis of acute traumatic cervical central cord syndrome (ATCCS) and recommend a consensus statement for its management. METHODS: A systematic review was performed according to the PRISMA 2009 guidelines. Delphi method was used to identify key research questions and achieve consensus. PubMed, Scopus and Google Scholar were searched for corresponding keywords. The initial search retrieved 770 articles of which 37 articles dealing with management, timing of surgery, complications or prognosis of ATCCS were identified. The literature review and draft position statements were compiled and circulated to panel members. The draft was modified incorporating relevant suggestions to reach consensus. RESULTS: Out of 37 studies, 15 were regarding management strategy, ten regarding timing of surgery and 12 regarding prognosis of ATCCS. CONCLUSION: There is reasonable evidence that patients with ATCCS secondary to vertebral fracture, dislocation, traumatic disc herniation or instability have better outcomes with early surgery (< 24 h). In patients of ATCCS secondary to extension injury in stenotic cervical canal without fracture/fracture dislocation/traumatic disc herniation/instability, there is requirement of high-quality prospective randomized controlled trials to resolve controversy regarding early surgery versus conservative management and delayed surgery if recovery plateaus or if there is a neurological deterioration. Until such time decision on surgery and its timing should be left to the judgment of physician, deliberating on pros and cons relevant to the particular patient and involving the well-informed patient and relatives in decision making. These slides can be retrieved under Electronic Supplementary Material.

The Immune Contexture Associates with the Genomic Landscape in Lung Adenomatous Premalignancy.

Epithelial cells in the field of lung injury can give rise to distinct premalignant lesions that may bear unique genetic aberrations. A subset of these lesions may escape immune surveillance and progress to invasive cancer; however, the mutational landscape that may predict progression has not been determined. Knowledge of premalignant lesion composition and the associated microenvironment is critical for understanding tumorigenesis and the development of effective preventive and interception strategies. To identify somatic mutations and the extent of immune cell infiltration in adenomatous premalignancy and associated lung adenocarcinomas, we sequenced exomes from 41 lung cancer resection specimens, including 89 premalignant atypical adenomatous hyperplasia lesions, 15 adenocarcinomas in situ, and 55 invasive adenocarcinomas and their adjacent normal lung tissues. We defined nonsynonymous somatic mutations occurring in both premalignancy and the associated tumor as progression-associated mutations whose predicted neoantigens were highly correlated with infiltration of CD8+ and CD4+ T cells as well as upregulation of PD-L1 in premalignant lesions, suggesting the presence of an adaptive immune response to these neoantigens. Each patient had a unique repertoire of somatic mutations and associated neoantigens. Collectively, these results provide evidence for mutational heterogeneity, pathway dysregulation, and immune recognition in pulmonary premalignancy.Significance: These findings identify progression-associated somatic mutations, oncogenic pathways, and association between the mutational landscape and adaptive immune responses in adenomatous premalignancy.See related commentary by Merrick, p. 4811.

Survey of the Current Use of Dexmedetomidine and Management of Withdrawal Symptoms in Critically Ill Children.

OBJECTIVES: Dexmedetomidine use for sedation in the pediatric intensive care units (PICUs) has increased since its initial US Food and Drug Administration (FDA) approval in adults. However, there is limited evidence to direct providers regarding current usage, dosing, and monitoring for withdrawal symptoms in pediatric patients. This study sought to determine the utilization of dexmedetomidine and management of dexmedetomidine withdrawal symptoms among PICU physicians. METHODS: A questionnaire survey was distributed to all members of the American Academy of Pediatrics Section on Critical Care. It assessed the practice site demographics, indication, dosing, and duration of dexmedetomidine infusion, unit protocol, and strategies for management of dexmedetomidine withdrawal. RESULTS: A total of 147 surveys (21.1%) were returned and analyzed. The reported uses for dexmedetomidine were as a primary sedative (59.9%), adjunctive agent for sedation (82.3%), and adjunctive agent to assist weaning sedation (62.6%) or from mechanical ventilation (70.1%). One hundred twenty-nine respondents (87.8%) had concerns over dexmedetomidine withdrawal, with 59 respondents becoming concerned after 120 hours of infusion (45.7%). Most respondents reported managing dexmedetomidine withdrawal symptoms via a regimented wean and initiation of clonidine (81%). Units with >1000 admissions per year were more likely to have a protocol related to dexmedetomidine use (p = 0.021). Units with >1000 admissions per year reported using clonidine for withdrawal at a higher rate, whereas units with ≤1000 admissions per year used a systematic wean of dexmedetomidine (p = 0.014). CONCLUSIONS: Dexmedetomidine use in the PICU is varied among pediatric intensive care physicians. Intensivists have withdrawal concerns after dexmedetomidine discontinuation, and the primary management of this withdrawal phenomenon is the initiation of clonidine with a regimented dexmedetomidine wean.