Implementing human factors in anaesthesia: guidance for clinicians, departments and hospitals: Guidelines from the Difficult Airway Society and the Association of Anaesthetists: Guidelines from the Difficult Airway Society and the Association of Anaesthetists.

Human factors is an evidence-based scientific discipline used in safety critical industries to improve safety and worker well-being. The implementation of human factors strategies in anaesthesia has the potential to reduce the reliance on exceptional personal and team performance to provide safe and high-quality patient care. To encourage the adoption of human factors science in anaesthesia, the Difficult Airway Society and the Association of Anaesthetists established a Working Party, including anaesthetists and operating theatre team members with human factors expertise and/or interest, plus a human factors scientist, an industrial psychologist and an experimental psychologist/implementation scientist. A three-stage Delphi process was used to formulate a set of 12 recommendations: these are described using a 'hierarchy of controls' model and classified into design, barriers, mitigations and education and training strategies. Although most anaesthetic knowledge of human factors concerns non-technical skills, such as teamwork and communication, human factors is a broad-based scientific discipline with many other additional aspects that are just as important. Indeed, the human factors strategies most likely to have the greatest impact are those related to the design of safe working environments, equipment and systems. While our recommendations are primarily provided for anaesthetists and the teams they work with, there are likely to be lessons for others working in healthcare beyond the speciality of anaesthesia.

Human factors in anaesthesia: a narrative review.

Healthcare relies on high levels of human performance, as described by the 'human as the hero' concept. However, human performance varies and is recognised to fall in high-pressure situations, meaning that it is not a reliable method of ensuring safety. Other safety-critical industries embed human factors principles into all aspects of their organisations to improve safety and reduce reliance on exceptional human performance; there is potential to do the same in anaesthesia. Human factors is a broad-based scientific discipline which aims to make it as easy as possible for workers to do things correctly. The human factors strategies most likely to be effective are those which 'design out' the chance of an error or adverse event occurring. When errors or adverse events do happen, barriers are in place to trap them and reduce the risk of progression to patient and/or worker harm. If errors or adverse events are not trapped by these barriers, mitigations are in place to minimise the consequences. Non-technical skills form an important part of human factors barriers and mitigation strategies and include: situation awareness; decision-making; task management; and team working. Human factors principles are not a substitute for proper investment and appropriate staffing levels. Although applying human factors science has the potential to save money in the long term, its proper implementation may require investment before reward can be reaped. This narrative review describes what is known about human factors in anaesthesia to date.

Intra-Areal Visual Topography in Primate Brains Mapped with Probabilistic Tractography of Diffusion-Weighted Imaging.

Noninvasive diffusion-weighted magnetic resonance imaging (dMRI) can be used to map the neural connectivity between distinct areas in the intact brain, but the standard resolution achieved fundamentally limits the sensitivity of such maps. We investigated the sensitivity and specificity of high-resolution postmortem dMRI and probabilistic tractography in rhesus macaque brains to produce retinotopic maps of the lateral geniculate nucleus (LGN) and extrastriate cortical visual area V5/MT based on their topographic connections with the previously established functional retinotopic map of primary visual cortex (V1). We also replicated the differential connectivity of magnocellular and parvocellular LGN compartments with V1 across visual field positions. Predicted topographic maps based on dMRI data largely matched the established retinotopy of both LGN and V5/MT. Furthermore, tractography based on in vivo dMRI data from the same macaque brains acquired at standard field strength (3T) yielded comparable topographic maps in many cases. We conclude that tractography based on dMRI is sensitive enough to reveal the intrinsic organization of ordered connections between topographically organized neural structures and their resultant functional organization.

Regional analgesia for lower leg trauma and the risk of acute compartment syndrome: Guideline from the Association of Anaesthetists.

Pain resulting from lower leg injuries and consequent surgery can be severe. There is a range of opinion on the use of regional analgesia and its capacity to obscure the symptoms and signs of acute compartment syndrome. We offer a multi-professional, consensus opinion based on an objective review of case reports and case series. The available literature suggested that the use of neuraxial or peripheral regional techniques that result in dense blocks of long duration that significantly exceed the duration of surgery should be avoided. The literature review also suggested that single-shot or continuous peripheral nerve blocks using lower concentrations of local anaesthetic drugs without adjuncts are not associated with delays in diagnosis provided post-injury and postoperative surveillance is appropriate and effective. Post-injury and postoperative ward observations and surveillance should be able to identify the signs and symptoms of acute compartment syndrome. These observations should be made at set frequencies by healthcare staff trained in the pathology and recognition of acute compartment syndrome. The use of objective scoring charts is recommended by the Working Party. Where possible, patients at risk of acute compartment syndrome should be given a full explanation of the choice of analgesic techniques and should provide verbal consent to their chosen technique, which should be documented. Although the patient has the right to refuse any form of treatment, such as the analgesic technique offered or the surgical procedure proposed, neither the surgeon nor the anaesthetist has the right to veto a treatment recommended by the other.

Using RNA Sequencing to Characterize the Tumor Microenvironment.

RNA sequencing (RNA-seq) is an integral tool in immunogenomics, allowing for interrogation of the transcriptome of a tumor and its microenvironment. Analytical methods to deconstruct the genomics data can then be applied to infer gene expression patterns associated with the presence of various immunocyte populations. High quality RNA-seq is possible from formalin-fixed, paraffin-embedded (FFPE), fresh-frozen, and fresh tissue, with a wide variety of sequencing library preparation methods, sequencing platforms, and downstream bioinformatics analyses currently available. Selection of an appropriate library preparation method is largely determined by tissue type, quality of RNA, and quantity of RNA. Downstream of sequencing, many analyses can be applied to the data, including differential gene expression analysis, immune gene signature analysis, gene pathway analysis, T/B-cell receptor inference, HLA inference, and viral transcript quantification. In this chapter, we will describe our workflow for RNA-seq from bulk tissue to evaluable data, including extraction of RNA, library preparation methods, sequencing of libraries, alignment and quality assurance of data, and initial downstream analyses of RNA-seq data to extract relevant immunogenomics features. Systems biology methods that draw additional insights by integrating these features are covered further in Chapters 28 - 30 .

White matter changes in the perforant path area in patients with amyotrophic lateral sclerosis.

OBJECTIVE: The aim of this study was to test the hypothesis that white matter degeneration of the perforant path - as part of the Papez circuit - is a key feature of amyotrophic lateral sclerosis (ALS), even in the absence of frontotemporal dementia (FTD) or deposition of pTDP-43 inclusions in hippocampal granule cells. METHODS: We used diffusion Magnetic Resonance Imaging (dMRI), polarized light imaging (PLI) and immunohistochemical analysis of post mortem hippocampus specimens from controls (n = 5) and ALS patients (n = 14) to study white matter degeneration in the perforant path. RESULTS: diffusion Magnetic Resonance Imaging demonstrated a decrease in fractional anisotropy (P = 0.01) and an increase in mean diffusivity (P = 0.01) in the perforant path in ALS compared to controls. PLI-myelin density was lower in ALS (P = 0.05) and correlated with fractional anisotropy (r = 0.52, P = 0.03). These results were confirmed by immunohistochemistry; both myelin (proteolipid protein, P = 0.03) and neurofilaments (SMI-312, P = 0.02) were lower in ALS. Two out of the fourteen ALS cases showed pTDP-43 pathology in the dentate gyrus, but with comparable myelination levels in the perforant path to other ALS cases. CONCLUSION: We conclude that degeneration of the perforant path occurs in ALS patients and that this may occur before, or independent of, pTDP-43 aggregation in the dentate gyrus of the hippocampus. Future research should focus on correlating the degree of cognitive decline to the amount of white matter atrophy in the perforant path.

Microstructural imaging of the human brain with a 'super-scanner': 10 key advantages of ultra-strong gradients for diffusion MRI.

The key component of a microstructural diffusion MRI 'super-scanner' is a dedicated high-strength gradient system that enables stronger diffusion weightings per unit time compared to conventional gradient designs. This can, in turn, drastically shorten the time needed for diffusion encoding, increase the signal-to-noise ratio, and facilitate measurements at shorter diffusion times. This review, written from the perspective of the UK National Facility for In Vivo MR Imaging of Human Tissue Microstructure, an initiative to establish a shared 300 mT/m-gradient facility amongst the microstructural imaging community, describes ten advantages of ultra-strong gradients for microstructural imaging. Specifically, we will discuss how the increase of the accessible measurement space compared to a lower-gradient systems (in terms of Δ, b-value, and TE) can accelerate developments in the areas of 1) axon diameter distribution mapping; 2) microstructural parameter estimation; 3) mapping micro-vs macroscopic anisotropy features with gradient waveforms beyond a single pair of pulsed-gradients; 4) multi-contrast experiments, e.g. diffusion-relaxometry; 5) tractography and high-resolution imaging in vivo and 6) post mortem; 7) diffusion-weighted spectroscopy of metabolites other than water; 8) tumour characterisation; 9) functional diffusion MRI; and 10) quality enhancement of images acquired on lower-gradient systems. We finally discuss practical barriers in the use of ultra-strong gradients, and provide an outlook on the next generation of 'super-scanners'.

PEAR: PEriodic and ApeRiodic signal separation for fast FMRI.

Undersampling of functional MRI (fMRI) data leads to increased temporal resolution, as it allows shorter acquisition time per frame. High quality reconstruction of fMRI data from undersampled measurements requires proper modeling of the fMRI data. Recent publications suggest that the fMRI signal is a superposition of periodic and aperiodic signals. In this paper we develop an fMRI reconstruction approach based on this modeling. The fMRI data is assumed to be composed of two components: a component that holds a sum of periodic signals which is sparse in the temporal Fourier domain and an component that holds the remaining imaging information (consisting of the background and aperiodic signals) which has low rank. Data reconstruction is done by solving a constrained problem that enforces a fixed, moderate rank on one of the components, and a limited number of temporal frequencies on the other. Our approach is coined PEAR - PEriodic and ApeRiodic signal separation for fast fMRI. Experimental results are based on fMRI reconstruction using realistic timecourses. Evaluation was performed both quantitatively and visually versus ground truth. Results demonstrate PEAR's improvement in estimating the realistic timecourses versus state-of-the-art approaches at acceleration ratio of R=16.6.

A comparison of electronic and manual fracture risk assessment tools in screening elderly male US veterans at risk for osteoporosis.

This study compares four screening tools in their ability to predict osteoporosis. We found that there was no significant difference between the tools. These results provide support for the use of automated screening tools which work in conjunction with the electronic medical record and help improve screening rates for osteoporosis. INTRODUCTION: The purpose of this study is to compare the performance of four fracture risk assessment tools (FRATs) in identifying osteoporosis by bone mineral density (BMD) T-score: Veterans Affairs Fracture Absolute Risk Assessment Tool (VA-FARA), World Health Organization's Fracture Risk Assessment Tool (FRAX), electronic FRAX (e-FRAX), and Osteoporosis Self-Assessment Screening Tool (OST). METHODS: We performed a cross-sectional analysis of all patients enrolled in the VA Salt Lake City bone health team (BHT) who had completed a DXA scan between February 1, 2012, and February 1, 2013. DXA scan results were obtained by chart abstraction. For calculation of FRAX, osteoporosis risk factors were obtained from a screening questionnaire completed prior to DXA. For VA-FARA and e-FRAX, risk factors were derived from the electronic medical record (EMR). Clinical risk scores were calculated and compared against the gold standard of DXA-based osteoporosis. Sensitivity, specificity, and predictive values were calculated. Receiver operator characteristic (ROC) curves were plotted, and areas under the curve (AUC) were compared. RESULTS: A cohort of 463 patients met eligibility criteria (mean age 80.4 years). One hundred twelve patients (24%) had osteoporosis as defined by DXA T-score ≤-2.5. Sensitivity, specificity, and predictive values were calculated. ROC statistics were compared and did not reach statistical significance difference between FRATs in identifying DXA-based osteoporosis. CONCLUSIONS: Our study suggests that all FRATs tested perform similarly in identifying osteoporosis among elderly, primarily Caucasian, male veterans. If these electronic screening methods perform similarly for fracture outcomes, they could replace manual FRAX and thus improve efficiency in identifying individuals who should be sent for DXA scan.

Individual Differences in the Alignment of Structural and Functional Markers of the V5/MT Complex in Primates.

Extrastriate visual area V5/MT in primates is defined both structurally by myeloarchitecture and functionally by distinct responses to visual motion. Myelination is directly identifiable from postmortem histology but also indirectly by image contrast with structural magnetic resonance imaging (sMRI). First, we compared the identification of V5/MT using both sMRI and histology in Rhesus macaques. A section-by-section comparison of histological slices with in vivo and postmortem sMRI for the same block of cortical tissue showed precise correspondence in localizing heavy myelination for V5/MT and neighboring MST. Thus, sMRI in macaques accurately locates histologically defined myelin within areas known to be motion selective. Second, we investigated the functionally homologous human motion complex (hMT+) using high-resolution in vivo imaging. Humans showed considerable intersubject variability in hMT+ location, when defined with myelin-weighted sMRI signals to reveal structure. When comparing sMRI markers to functional MRI in response to moving stimuli, a region of high myelin signal was generally located within the hMT+ complex. However, there were considerable differences in the alignment of structural and functional markers between individuals. Our results suggest that variation in area identification for hMT+ based on structural and functional markers reflects individual differences in human regional brain architecture.

Dentatorubrothalamic tract localization with postmortem MR diffusion tractography compared to histological 3D reconstruction.

Diffusion-weighted imaging (DWI) tractography is a technique with great potential to characterize the in vivo anatomical position and integrity of white matter tracts. Tractography, however, remains an estimation of white matter tracts, and false-positive and false-negative rates are not available. The goal of the present study was to compare postmortem tractography of the dentatorubrothalamic tract (DRTT) by its 3D histological reconstruction, to estimate the reliability of the tractography algorithm in this specific tract. Recent studies have shown that the cerebellum is involved in cognitive, language and emotional functions besides its role in motor control. However, the exact working mechanism of the cerebellum is still to be elucidated. As the DRTT is the main output tract it is of special interest for the neuroscience and clinical community. A postmortem human brain specimen was scanned on a 7T MRI scanner using a diffusion-weighted steady-state free precession sequence. Tractography was performed with PROBTRACKX. The specimen was subsequently serially sectioned and stained for myelin using a modified Heidenhain-Woelke staining. Image registration permitted the 3D reconstruction of the histological sections and comparison with MRI. The spatial concordance between the two modalities was evaluated using ROC analysis and a similarity index (SI). ROC curves showed a high sensitivity and specificity in general. Highest measures were observed in the superior cerebellar peduncle with an SI of 0.72. Less overlap was found in the decussation of the DRTT at the level of the mesencephalon. The study demonstrates high spatial accuracy of postmortem probabilistic tractography of the DRTT when compared to a 3D histological reconstruction. This gives hopeful prospect for studying structure-function correlations in patients with cerebellar disorders using tractography of the DRTT.

Dependence of ß3-adrenergic signaling on the adipokine leptin in cardiac myocytes.

ß3-Adrenergic receptors (ß3ARs) negatively regulate ß-adrenergic signaling via nitric oxide and are dependent on the adipokine leptin for normal expression in adipocytes, thus making ß3AR an attractive candidate for cross-talk with leptin in the heart. Accordingly, we tested the hypothesis that cardiac ß3AR expression and function are dependent on leptin and are severely diminished in leptin-deficient ob/ob mice. Using isolated cardiac myocyte physiology studies, we found that ß3AR function was significantly diminished in ob/ob myocytes and in wild-type myocytes treated with leptin antagonist. This finding was supported by quantitative PCR demonstrating markedly decreased ß3AR mRNA levels in ob/ob mice. Both ß3AR mRNA and function were restored in ob/ob mice after in vivo leptin repletion. We propose that diminished ß3AR signaling may be the critical element to explain the direct effects of leptin on the myocardium and suggest that this work reveals a key feature in the role of leptin in obesity-related cardiac hypertrophy and heart failure.

The danger of systematic bias in group-level FMRI-lag-based causality estimation.

Schippers, Renken and Keysers (NeuroImage, 2011) present a simulation of multi-subject lag-based causality estimation. We fully agree that single-subject evaluations (e.g., Smith et al., 2011) need to be revisited in the context of multi-subject studies, and Schippers' paper is a good example, including detailed multi-level simulation and cross-subject statistical modelling. The authors conclude that "the average chance to find a significant Granger causality effect when no actual influence is present in the data stays well below the p-level imposed on the second level statistics" and that "when the analyses reveal a significant directed influence, this direction was accurate in the vast majority of the cases". Unfortunately, we believe that the general meaning that may be taken from these statements is not supported by the paper's results, as there may in reality be a systematic (group-average) difference in haemodynamic delay between two brain areas. While many statements in the paper (e.g., the final two sentences) do refer to this problem, we fear that the overriding message that many readers may take from the paper could cause misunderstanding.

Social network size affects neural circuits in macaques.

It has been suggested that variation in brain structure correlates with the sizes of individuals' social networks. Whether variation in social network size causes variation in brain structure, however, is unknown. To address this question, we neuroimaged 23 monkeys that had been living in social groups set to different sizes. Subject comparison revealed that living in larger groups caused increases in gray matter in mid-superior temporal sulcus and rostral prefrontal cortex and increased coupling of activity in frontal and temporal cortex. Social network size, therefore, contributes to changes both in brain structure and function. The changes have potential implications for an animal's success in a social context; gray matter differences in similar areas were also correlated with each animal's dominance within its social network.

Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study.

Recent whole-genome sequencing efforts led to the identification of IDH1(R132) mutations in acute myeloid leukemia (AML) patients. We studied the prevalence and clinical implications of IDH1 genomic alterations in pediatric and adult AML. Diagnostic DNA from 531 AML patients treated on Children's Oncology Group trial COG-AAML03P1 (N=257), and Southwest Oncology Group trials SWOG-9031, SWOG-9333 and SWOG-9500 (N=274), were tested for IDH1 mutations. Codon R132 mutations were absent in the pediatric cohort, but were found in 12 of 274 adult patients (4.4%, 95% CI 2.3-7.5). IDH1(R132) mutations occurred most commonly in patients with normal karyotype, and those with FLT3/ITD and NPMc mutations. Patients with IDH1(R132) mutations trended toward higher median diagnostic white blood cell counts (59.2 x 10(9) vs 29.1 x 10(9) per liter, P=0.19) than those without mutations, but the two groups did not differ significantly in age, bone marrow blast percentage, overall survival or relapse-free survival. Eleven patients (2.1%) harbored a novel V71I sequence alteration, which was found to be a germ-line polymorphism. IDH1 mutations were not detected in pediatric AML, and are uncommon in adult AML.

Haemophilia A: patients' knowledge level of treatment and sources of treatment-related information.

There are minimal or no data regarding the extent of patient and/or parent/legal guardian/caregiver knowledge about haemophilia A and its treatment, their sources for this information, or their preferred methods of communication. A pilot study using a survey instrument developed by haemophilia nurse coordinators was conducted at a national meeting to obtain information on these topics. A total of 187 surveys were completed. More than 80% of respondents reported high and high-medium knowledge levels about how haemophilia A is inherited, types of bleeding, identifying and treating bleeding emergencies, prophylaxis and on-demand treatment, travel and vacation planning and guidelines for exercise and sports activities. However, a lower proportion of respondents (<65%) reported high and high-medium knowledge levels for drug-related topics. The majority of respondents (>55%) consistently ranked healthcare providers as the most useful source of information for most topics related to haemophilia A. This pilot survey of well-informed respondents identified deficits in knowledge regarding factor concentrates for the treatment of haemophilia A and highlights the need for healthcare providers to provide more information about factor concentrates, insurance coverage for treatments, and community and educational resources. Additional study is necessary to determine the extent of knowledge deficits and how best to address them in the haemophilia A population as a whole. Other areas of study needed are whether information deficits and delivery of information vary by age or by other factors.

Implantable central venous access device procedures in haemophilia patients without an inhibitor: systematic review of the literature and institutional experience.

Elective surgical procedures involving central venous access devices (CVADs) in patients with haemophilia are often necessary for adequate factor delivery but there are few data regarding haemostatic coverage and acute complication rates accompanying these procedures. To describe experience with CVAD insertion, revision and removal in young haemophilia patients at our institution and in the literature and to assess acute complications following CVAD procedures. PubMed, Medline and Cochrane databases were searched for articles, which included a description of factor coverage during CVAD procedures. A retrospective review of our comprehensive haemophilia database identified patients undergoing CVAD placement, revision and removal between January 1993 and August 2005. Manual and electronic searches of the published literature yielded 14 articles, which met inclusion criteria. Peri-operative factor administration varied greatly among the reports. Mean acute infection and haematoma rates were 8% and 12.5% respectively. A retrospective review identified 49 CVAD placements, revisions, or removals meeting inclusion criteria. Most patients received outpatient bolus factor replacement to achieve a level of 100% preoperatively, immediately postoperatively and on postoperative days 1, 2, 3, 5 and 7. Thirty-six procedures were performed without hospitalization. Ten patients developed 11 (22%) minor haematomas postoperatively. Major haemorrhage, acute infection, or pneumothorax was not encountered. Few published data exist regarding haemostatic coverage and complications following CVAD procedures. Our institutional experience using a consistent management approach was favourable. Further studies are required to define optimal haemostatic coverage during minor surgical procedures in haemophilia.

Short-term oral corticosteroid therapy for acute haemarthrosis in haemophilia patients with high-titre inhibitors.

Treatment of acute bleeding events is unsatisfactory in patients with haemophilia and high-titre factor VIII (FVIII) inhibitors. In order to determine whether short-term corticosteroid therapy enhances resolution of the signs and symptoms of acute haemarthrosis, we performed a randomized, double-blind, placebo-controlled study in children with FVIII deficiency and high-titre inhibitors receiving Factor Eight Inhibitor Bypass Activity (FEIBA) for acute haemorrhagic events. At each haemarthrosis, patients were randomized to receive either prednisolone 2 mg kg(-1) day(-1) or placebo-divided t.i.d. for 2 days (six doses) in addition to FEIBA. The primary endpoint was the number of subsequent doses of FEIBA required. The effect of the study medication was also assessed subjectively by patients or parents, by physical examination and by repeated haemorrhages into the joint. During the study period, seven patients were enrolled with 45 evaluable events, 24 treated with prednisolone and 21 with placebo. An average of 2.08 and 1.86 doses of FEIBA were infused in the prednisolone- and placebo-treated patients, respectively. By Wilcoxon Rank Sum Test, there was no statistically significant difference in number of additional infusions of FEIBA or duration of symptoms between the corticosteroid and placebo arms. We conclude that there is no significant benefit of a 2-day course of oral corticosteroids as adjunctive therapy for haemarthrosis in patients with haemophilia and a high-titre inhibitor.

Nuclear medicine technologists and unauthorized self-injections.

An Office of Investigation (OI) investigation by the U.S. Nuclear Regulatory Commission (NRC) determined that, on three separate occasions over the past 10 years, technologists in one licensed nuclear medicine program were injected with radiopharmaceuticals without Authorized User knowledge or approval. The most recent instance, the one that precipitated the investigation, was discovered by the licensee and self-reported to the NRC; the other two instances were discovered during the OI investigation and came as a complete surprise to the licensee. In a mediated Alternative Dispute Resolution (ADR) involving the licensee, a professional, independent mediator and representatives of the NRC, an agreement was worked out whereby the licensee would admit to the violations and work with the NRC to inform other licensees that this is not an acceptable practice and that there are additional precautions that licensees can and should take to assure that such violations do not happen on their watch.