Machine and deep learning models for accurate detection of ischemia and scar with myocardial blood flow positron emission tomography imaging.

BACKGROUND: Quantification of myocardial blood flow (MBF) is used for the noninvasive diagnosis of patients with coronary artery disease (CAD). This study compared traditional statistics, machine learning, and deep learning techniques in their ability to diagnose disease using only the rest and stress MBF values. METHODS: This study included 3245 rest and stress rubidium-82 positron emission tomography (PET) studies and matching diagnostic labels from perfusion reports. Standard logistic regression, lasso logistic regression, support vector machine, random forest, multilayer perceptron, and dense U-Net were compared for per-patient detection and per-vessel localization of scars and ischemia. RESULTS: Receiver-operator characteristic area under the curve (AUC) of machine learning models was significantly higher than those of traditional statistics models for per-patient detection of disease (0.92-0.95 vs. 0.87) but not for per-vessel localization of ischemia or scar. Random forest showed the highest AUC = 0.95 among the different models compared. On the final hold-out set for generalizability, random forest showed an AUC of 0.92 for detection and 0.89 for localization of perfusion abnormalities. CONCLUSIONS: For per-vessel localization, simple models trained on segmental data performed similarly to a convolutional neural network trained on polar-map data, highlighting the need to justify the use of complex predictive algorithms through comparison with simpler methods.

Follicular (Infundibular-Tricholemmal) Squamous Cell Carcinoma: A New WHO Entity. Clinicopathological Features in 103 Cases, Including Follow-Up and Implications for Patient Management.

AIMS: Cutaneous follicular (infundibular-tricholemmal) squamous cell carcinoma (FSCC) is a new World Health Organization entity. We present the largest series of published cases, summarizing clinical data, diagnostic criteria, differential diagnosis, and implications for patient management. METHODS: Cases were identified from 2004 to 2011. Inclusion criteria included discrete attachment(s) of the tumor to the overlying epidermis via follicular infundibula, tricholemmal keratinization, and cellular pleomorphism. Keratoacanthoma and lesions with adjacent bowenoid epidermal dysplasia were excluded. RESULTS: One hundred three cases of FSCC identified. 48.5% demonstrated completely circumscript borders ( in situ for practical purposes), 12.6% uncertain for invasion (overwhelmingly pushing borders), and only 38.8% as clearly invasive. Follicular mucin in acantholytic spaces within tumor epithelium was a distinctive finding in 57.2% of cases. Clinical data indicated predominance in elderly (median 78.5 years) men (70.4%), with preferential head and neck location (81.6%). Many were clinically suspected as squamous cell carcinoma (48.5%). However, a significant minority were clinically diagnosed as basal cell carcinoma (40.8%). This may reflect that FSCC commonly presented as a papule or nodule (51.3%). By contrast, keratoacanthoma was less frequently suggested (17.2%) and still fewer lesions were suspected to be actinic keratosis/Bowen's disease (13.6%). Follow-up in 82 cases (median 26.5 months, range 3-144) identified 5 (6.1%) local recurrences. There was no instance of metastasis in the subgroup of lesions with completely circumscript borders. Three of 45 (6.7%) patients, with follow-up, considered to have tumors with invasive pushing, and/or infiltrative borders developed lymph node metastases. CONCLUSIONS: FSCC is identified as a common skin cancer, incorporating historical entities, such as infundibular carcinoma and tricholemmal carcinoma, with readily identifiable histologic features. Correct diagnosis has implications for patient management; a significant subgroup of lesions show completely circumscript borders that are considered in situ for practical purposes.

Mapping Processes in the Emergency Department Using the Functional Resonance Analysis Method.

Emergency departments (EDs) are dynamic, complex, and demanding environments. Introducing changes that lead to improvements in EDs can be challenging owing to the high staff turnover and mix, high patient volume with different needs, and being the front door to the hospital for the sickest patients. Quality improvement is a methodology applied routinely in EDs to instigate change to improve several outcomes such as waiting times, time to definitive treatment, and patient safety. Introducing the changes needed to transform the system in this way is seldom straightforward with the risk of "not seeing the forest for the trees" when attempting to change the system. In this article, we demonstrate how the functional resonance analysis method can be used to capture the experiences and perceptions of frontline staff to identify the key functions in the system (the trees), to understand the interactions and dependencies between them to make up the ED ecosystem ("the forest") and to support quality improvement planning, identifying priorities and patient safety risks.

Complexity for complexity-How advanced modeling may limit its applicability for decision-makers.

As today's engineering systems have become increasingly sophisticated, assessing the efficacy of their safety-critical systems has become much more challenging. The more classical methods of "failure" analysis by decomposition into components related by logic trees, such as fault and event trees, root cause analysis, and failure mode and effects analysis lead to models that do not necessarily behave like the real systems they are meant to represent. These models need to display similar emergent and unpredictable behaviors to sociotechnical systems in the real world. The question then arises as to whether a return to a simpler whole system model is necessary to understand better the behavior of real systems and to build confidence in the results. This question is more prescient when one considers that the causal chain in many serious accidents is not as deep-rooted as is sometimes claimed. If these more obvious causes are not taken away, why would the more intricate scenarios that emanate from more sophisticated models be acted upon. The paper highlights the advantages of modeling and analyzing these "normal" deviations from ideality, so called weak signals, versus just system failures and near misses as well as catastrophes. In this paper we explore this question.

The ethical dilemmas of risky decisions.

Even in a pandemic there seem to be inherent conflicts of interest between the individual and societal consequences of remedial actions and strategies. Actions taken in the sole interests of patients, as required by the Hippocratic oath, can have broadly inconvenient economic implications for the State. ("Average" benefits for a population can impose individual inconveniences for the vulnerable.). Understandably these decisions are not normally made explicitly and transparently by governments. This leads to seemingly illogical and inhumane strategies which are not understood and hence mistrusted and often ignored by the public. Vaccination sentiments on social media are often an unwanted symptom of this dilemma. This article outlines and discusses a number of examples of such situations with a focus on ethical aspects. It concludes that each case must be considered individually as to the issues that need to be weighed in these difficult decisions; and that there are no clear and universally acceptable ethical solutions. What can be learned from the COVID-19 crisis is that short term utilitarianism has consequences that in the eyes of the population are unacceptable. This lesson seems equally valid for cost benefit evaluations regarding other risks, such as from hazardous industries, flood defenses, and air transport. Decisionmakers and politicians can learn that persuasion only goes so far. In the end the people appear to prioritize in terms of deontology.

Adaptations to practice and resilience in a paediatric major trauma centre during a mass casualty incident.

BACKGROUND: Innovation and human adaptation in the face of unfolding catastrophe is the cornerstone of an effective systemwide response. Capturing, analysing, and disseminating this is fundamental in developing resilience for future events. The aim of this study was to understand the characteristics of adaptations to practice early in a paediatric major trauma centre during a mass casualty incident. METHODS: A qualitative interview study of 40 healthcare staff at a paediatric major trauma centre in the immediate aftermath of a terrorist bombing was conducted. An inductive thematic analysis approach was used, followed by a deductive analysis of the identified adaptations informed by constructs of resilience engineering. RESULTS: Five themes of adaptations to practice that enhanced the resilient performance of the hospital were identified: teamworking; psychologically supporting patients, families, and staff; reconfiguring infrastructure; working around the hospital electronic systems; and maintaining hospital safety. Examples of resilience potential in terms of respond, monitor, anticipate, and learn are presented. CONCLUSIONS: Our study shows how adaptations to practice sustained the resilient performance of a paediatric major trauma centre during a mass casualty incident. Rapid, early capture of these data during a mass casualty incident provides key insights into enhancing future emergency preparedness, response, and resilience planning.

Beacon-Based Remote Measurement of Social Behavior in ASD Clinical Trials: A Technical Feasibility Assessment.

In this work, we propose a Bluetooth low energy (BLE) beacon-based algorithm to enable remote measurement of the social behavior of the participants of an observational Autism Spectrum Disorder (ASD) clinical trial (NCT03611075). We have developed a mobile application for a smartphone and a smartwatch to collect beacon signals from BLE beacon sensors as well as to store information about the participants' household rooms. Our goal is to collect beacon information about the time the participants spent in different rooms of their household to infer sociability information. We applied the same technology and setup in an internal experiment with healthy volunteers to evaluate the accuracy of the proposed algorithm in 10 different home setups, and we observed an average accuracy of 97.2%. Moreover, we show that it is feasible for the clinical study participants/caregivers to set up the BLE beacon sensors in their homes without any technical help, with 96% of them setting up the technology on the first day of data collection. Next, we present results from one-week location data from study participants collected through the proposed technology. Finally, we provide a list of good practice guidelines for optimally applying beacon technology for indoor location monitoring. The proposed algorithm enables us to estimate time spent in different rooms of a household that can pave the development of objective sociability features and eventually support decisions regarding drug efficacy in ASD.

Neural basis of induced phantom limb pain relief.

OBJECTIVE: Phantom limb pain (PLP) is notoriously difficult to treat, partly due to an incomplete understanding of PLP-related disease mechanisms. Noninvasive brain stimulation (NIBS) is used to modulate plasticity in various neuropathological diseases, including chronic pain. Although NIBS can alleviate neuropathic pain (including PLP), both disease and treatment mechanisms remain tenuous. Insight into the mechanisms underlying both PLP and NIBS-induced PLP relief is needed for future implementation of such treatment and generalization to related conditions. METHODS: We used a within-participants, double-blind, and sham-controlled design to alleviate PLP via task-concurrent NIBS over the primary sensorimotor missing hand cortex (S1/M1). To specifically influence missing hand signal processing, amputees performed phantom hand movements during anodal transcranial direct current stimulation. Brain activity was monitored using neuroimaging during and after NIBS. PLP ratings were obtained throughout the week after stimulation. RESULTS: A single session of intervention NIBS significantly relieved PLP, with effects lasting at least 1 week. PLP relief associated with reduced activity in the S1/M1 missing hand cortex after stimulation. Critically, PLP relief and reduced S1/M1 activity correlated with preceding activity changes during stimulation in the mid- and posterior insula and secondary somatosensory cortex (S2). INTERPRETATION: The observed correlation between PLP relief and decreased S1/M1 activity confirms our previous findings linking PLP with increased S1/M1 activity. Our results further highlight the driving role of the mid- and posterior insula, as well as S2, in modulating PLP. Lastly, our novel PLP intervention using task-concurrent NIBS opens new avenues for developing treatment for PLP and related pain conditions. ANN NEUROL 2019;85:59-73.

Dragons, black swans and decisions.

Since Nassim Taleb coined black swan as an event that occurred as a complete surprise for everybody, the metaphor of the black swan has been applied to a much wider variety of events. Black swan events now comprise events that are a surprise for some but not for others, events that have a low likelihood, events that were not believed to be possible but still proved to be possible, events that were dismissed as being too improbable to worry about but happened anyway. For a decision maker the black swan problem is choosing where to put effort to prevent, or mitigate events for which there are warnings, or for which the possibility has been put forward. Does the fact that there are thousands of books written about fire breathing dragons warrant the development of an Anti-Dragon Defense Shield? The black swan may have been a surprise for Willem de Vlamingh in 1697, it was not a surprise for the inhabitants of Australia, for which the appearance of tall white humans was their "black swan event". In this paper we explore the options available to decision makers when confronted with the various sorts of swan (or dragon) events.

Evolution of white matter tract microstructure across the life span.

The human brain undergoes dramatic structural change over the life span. In a large imaging cohort of 801 individuals aged 7-84 years, we applied quantitative relaxometry and diffusion microstructure imaging in combination with diffusion tractography to investigate tissue property dynamics across the human life span. Significant nonlinear aging effects were consistently observed across tracts and tissue measures. The age at which white matter (WM) fascicles attain peak maturation varies substantially across tissue measurements and tracts. These observations of heterochronicity and spatial heterogeneity of tract maturation highlight the importance of using multiple tissue measurements to investigate each region of the WM. Our data further provide additional quantitative evidence in support of the last-in-first-out retrogenesis hypothesis of aging, demonstrating a strong correlational relationship between peak maturational timing and the extent of quadratic measurement differences across the life span for the most myelin sensitive measures. These findings present an important baseline from which to assess divergence from normative aging trends in developmental and degenerative disorders, and to further investigate the mechanisms connecting WM microstructure to cognition.

Artificial limb representation in amputees.

The human brain contains multiple hand-selective areas, in both the sensorimotor and visual systems. Could our brain repurpose neural resources, originally developed for supporting hand function, to represent and control artificial limbs? We studied individuals with congenital or acquired hand-loss (hereafter one-handers) using functional MRI. We show that the more one-handers use an artificial limb (prosthesis) in their everyday life, the stronger visual hand-selective areas in the lateral occipitotemporal cortex respond to prosthesis images. This was found even when one-handers were presented with images of active prostheses that share the functionality of the hand but not necessarily its visual features (e.g. a 'hook' prosthesis). Further, we show that daily prosthesis usage determines large-scale inter-network communication across hand-selective areas. This was demonstrated by increased resting state functional connectivity between visual and sensorimotor hand-selective areas, proportional to the intensiveness of everyday prosthesis usage. Further analysis revealed a 3-fold coupling between prosthesis activity, visuomotor connectivity and usage, suggesting a possible role for the motor system in shaping use-dependent representation in visual hand-selective areas, and/or vice versa. Moreover, able-bodied control participants who routinely observe prosthesis usage (albeit less intensively than the prosthesis users) showed significantly weaker associations between degree of prosthesis observation and visual cortex activity or connectivity. Together, our findings suggest that altered daily motor behaviour facilitates prosthesis-related visual processing and shapes communication across hand-selective areas. This neurophysiological substrate for prosthesis embodiment may inspire rehabilitation approaches to improve usage of existing substitutionary devices and aid implementation of future assistive and augmentative technologies.

Simultaneous estimation of population receptive field and hemodynamic parameters from single point BOLD responses using Metropolis-Hastings sampling.

We introduce a new approach to Bayesian pRF model estimation using Markov Chain Monte Carlo (MCMC) sampling for simultaneous estimation of pRF and hemodynamic parameters. To obtain high performance on commonly accessible hardware we present a novel heuristic consisting of interpolation between precomputed responses for predetermined stimuli and a large cross-section of receptive field parameters. We investigate the validity of the proposed approach with respect to MCMC convergence, tuning and biases. We compare different combinations of pRF - Compressive Spatial Summation (CSS), Dumoulin-Wandell (DW) and hemodynamic (5-parameter and 3-parameter Balloon-Windkessel) models within our framework with and without the usage of the new heuristic. We evaluate estimation consistency and log probability across models. We perform as well a comparison of one model with and without lookup table within the RStan framework using its No-U-Turn Sampler. We present accelerated computation of whole-ROI parameters for one subject. Finally, we discuss risks and limitations associated with the usage of the new heuristic as well as the means of resolving them. We found that the new algorithm is a valid sampling approach to joint pRF/hemodynamic parameter estimation and that it exhibits very high performance.

Networks of myelin covariance.

Networks of anatomical covariance have been widely used to study connectivity patterns in both normal and pathological brains based on the concurrent changes of morphometric measures (i.e., cortical thickness) between brain structures across subjects (Evans, ). However, the existence of networks of microstructural changes within brain tissue has been largely unexplored so far. In this article, we studied in vivo the concurrent myelination processes among brain anatomical structures that gathered together emerge to form nonrandom networks. We name these "networks of myelin covariance" (Myelin-Nets). The Myelin-Nets were built from quantitative Magnetization Transfer data-an in-vivo magnetic resonance imaging (MRI) marker of myelin content. The synchronicity of the variations in myelin content between anatomical regions was measured by computing the Pearson's correlation coefficient. We were especially interested in elucidating the effect of age on the topological organization of the Myelin-Nets. We therefore selected two age groups: Young-Age (20-31 years old) and Old-Age (60-71 years old) and a pool of participants from 48 to 87 years old for a Myelin-Nets aging trajectory study. We found that the topological organization of the Myelin-Nets is strongly shaped by aging processes. The global myelin correlation strength, between homologous regions and locally in different brain lobes, showed a significant dependence on age. Interestingly, we also showed that the aging process modulates the resilience of the Myelin-Nets to damage of principal network structures. In summary, this work sheds light on the organizational principles driving myelination and myelin degeneration in brain gray matter and how such patterns are modulated by aging.

Enzyme Function Initiative-Enzyme Similarity Tool (EFI-EST): A web tool for generating protein sequence similarity networks.

The Enzyme Function Initiative, an NIH/NIGMS-supported Large-Scale Collaborative Project (EFI; U54GM093342; http://enzymefunction.org/), is focused on devising and disseminating bioinformatics and computational tools as well as experimental strategies for the prediction and assignment of functions (in vitro activities and in vivo physiological/metabolic roles) to uncharacterized enzymes discovered in genome projects. Protein sequence similarity networks (SSNs) are visually powerful tools for analyzing sequence relationships in protein families (H.J. Atkinson, J.H. Morris, T.E. Ferrin, and P.C. Babbitt, PLoS One 2009, 4, e4345). However, the members of the biological/biomedical community have not had access to the capability to generate SSNs for their "favorite" protein families. In this article we announce the EFI-EST (Enzyme Function Initiative-Enzyme Similarity Tool) web tool (http://efi.igb.illinois.edu/efi-est/) that is available without cost for the automated generation of SSNs by the community. The tool can create SSNs for the "closest neighbors" of a user-supplied protein sequence from the UniProt database (Option A) or of members of any user-supplied Pfam and/or InterPro family (Option B). We provide an introduction to SSNs, a description of EFI-EST, and a demonstration of the use of EFI-EST to explore sequence-function space in the OMP decarboxylase superfamily (PF00215). This article is designed as a tutorial that will allow members of the community to use the EFI-EST web tool for exploring sequence/function space in protein families.

Reassessing cortical reorganization in the primary sensorimotor cortex following arm amputation.

The role of cortical activity in generating and abolishing chronic pain is increasingly emphasized in the clinical community. Perhaps the most striking example of this is the maladaptive plasticity theory, according to which phantom pain arises from remapping of cortically neighbouring representations (lower face) into the territory of the missing hand following amputation. This theory has been extended to a wide range of chronic pain conditions, such as complex regional pain syndrome. Yet, despite its growing popularity, the evidence to support the maladaptive plasticity theory is largely based on correlations between pain ratings and oftentimes crude measurements of cortical reorganization, with little consideration of potential contributions of other clinical factors, such as adaptive behaviour, in driving the identified brain plasticity. Here, we used a physiologically meaningful measurement of cortical reorganization to reassess its relationship to phantom pain in upper limb amputees. We identified small yet consistent shifts in lip representation contralateral to the missing hand towards, but not invading, the hand area. However, we were unable to identify any statistical relationship between cortical reorganization and phantom sensations or pain either with this measurement or with the traditional Euclidian distance measurement. Instead, we demonstrate that other factors may contribute to the observed remapping. Further research that reassesses more broadly the relationship between cortical reorganization and chronic pain is warranted.

Network-level reorganisation of functional connectivity following arm amputation.

One of the most striking demonstrations of plasticity in the adult human brain follows peripheral injury, such as amputation. In the primary sensorimotor cortex, arm amputation results in massive local remapping of the missing hands' cortical territory. However, little is known about the consequences of sensorimotor deprivation on global brain organisation. Here, we used resting-state fMRI to identify large-scale reorganisation beyond the primary sensorimotor cortex in arm amputees, compared with two-handed controls. Specifically, we characterised changes in functional connectivity between the cortical territory of the missing hand in the primary sensorimotor cortex ('missing hand cortex') and two networks of interest: the sensorimotor network, which is typically strongly associated with the hand cortex, and the default mode network (DMN), which is normally dissociated from it. Functional connectivity values between the missing hand cortex and the sensorimotor network were reduced in amputees, and connectivity was weaker in individuals amputated for longer periods. Lower levels of functional coupling between the missing hand cortex and the sensorimotor network were also associated with emerged coupling of this cortex with the DMN. Our results demonstrate that plasticity following arm amputation is not restricted to local remapping occurring within the sensorimotor homunculus of the missing hand but rather produces a cascade of cortical reorganisation at a network-level scale. These findings may provide a new framework for understanding how local deprivation following amputation could elicit complex perceptual experiences of phantom sensations, such as phantom pain.

Development of a real-time PCR Assay for identification of Coccidioides immitis by use of the BD Max system.

Rapid real-time PCR (RT-PCR) can be performed in a community hospital setting to identify Coccidioides species using the new Becton Dickinson molecular instrument BD Max. Following sample preparation, DNA extraction and PCR were performed on the BD Max using the BD Max extraction kit ExK-DNA-1 test strip and a master mix prepared by BioGX (Birmingham, AL). Sample preparation took 2 h, and testing on the BD Max took an additional 2 h. Method sensitivity and specificity were evaluated along with the limits of detection to confirm that this convenient method would provide medically useful information. Using serial dilutions, the lower limit of detection was determined to be 1 CFU/µl. Testing with this method was validated using samples from various body sites, including bronchial alveolar lavage (BAL) fluid; sputum and lung tissue samples; and pleural and spinal fluids. Safety protocols were established, and specimen preparation processes were developed for the various types of specimens. The range for the cycle threshold (CT) indicating adequate fluorescent signal to signify a positive result was established along with the acceptable range for the internal standard. Positive controls run with each batch were prepared by spiking a pooled BAL fluid specimen with a known dilution of Coccidioides immitis organism. Our experience with testing >330 patient samples shows that clinically relevant information can be available within 4 h using an RT-PCR method on the BD Max to identify Coccidioides spp., with sensitivity equivalent to culture.

Sensory ganglionopathy with livedoid vasculopathy controlled by immunotherapy.

INTRODUCTION: Livedoid vasculopathy is a rare dermatological condition characterized by painful ulceration, atrophic scarring, and persistent livedo reticularis. The pathogenesis is unclear. METHODS: We report a patient with biopsy-proven livedoid vasculopathy who developed a progressive sensory ganglionopathy with profound sensory ataxia. Serial nerve conduction assessments were undertaken. RESULTS: Combined treatment with prednisolone and mycophenolate mofetil failed to control the ganglionopathy. After addition of rituximab, both symptoms and nerve conduction studies showed stabilization. CONCLUSIONS: Sensory ganglionopathies associated with autoimmune and inflammatory conditions may be characterized by a sub-population of "sick" dorsal root ganglia that can be rescued with aggressive immunotherapy.

Oral Ulceration in Newly Diagnosed Leukaemic Patient with Undiagnosed Sweet's Syndrome.

Sweet's syndrome is a relatively rare but important skin condition which can affect the oral cavity. Awareness of this reactive condition is important for dentists who work in hospitals, where it is most likely to present. This report summarizes one such case and aims to introduce the reader to Sweet's syndrome.

Connectomic approaches before the connectome.

Connectome is a term with a short history but a long past. Since the origins of neuroscience the concept of a 'map of neural connections' has been a constant inspiring idea for those who believed the brain as the organ of intellect. A myriad of proto-connectome maps have been produced throughout the centuries, each one reflecting the theory and method of investigation that prevailed at the time. Even contemporary definitions of the connectome rest upon the formulation of a neuronal theory that has been proposed over a hundred years ago. So, what is new? In this article we attempt to trace the development of certain anatomical and physiological concepts at the origins of modern definitions of the connectome. We argue that compared to previous attempts current connectomic approaches benefit from a wealth of imaging methods that in part could justify the enthusiasm for finally succeeding in achieving the goal. One of the unique advantages of contemporary approaches is the possibility of using quantitative methods to define measures of connectivity where structure, function and behaviour are integrated and correlated. We also argue that many contemporary maps are inaccurate surrogates of the true anatomy and a comprehensive connectome of the human brain remains a far distant point in the history to come.