The truth Hertz-synchronization of electroencephalogram signals with physiological waveforms recorded in an intensive care unit.

Objective.The ability to synchronize continuous electroencephalogram (cEEG) signals with physiological waveforms such as electrocardiogram (ECG), invasive pressures, photoplethysmography and other signals can provide meaningful insights regarding coupling between brain activity and other physiological subsystems. Aligning these datasets is a particularly challenging problem because device clocks handle time differently and synchronization protocols may be undocumented or proprietary.Approach.We used an ensemble-based model to detect the timestamps of heartbeat artefacts from ECG waveforms recorded from inpatient bedside monitors and from cEEG signals acquired using a different device. Vectors of inter-beat intervals were matched between both datasets and robust linear regression was applied to measure the relative time offset between the two datasets as a function of time.Main Results.The timing error between the two unsynchronized datasets ranged between -84 s and +33 s (mean 0.77 s, median 4.31 s, IQR25-4.79 s, IQR75 11.38s). Application of our method improved the relative alignment to within ± 5ms for more than 61% of the dataset. The mean clock drift between the two datasets was 418.3 parts per million (ppm) (median 414.6 ppm, IQR25 411.0 ppm, IQR75 425.6 ppm). A signal quality index was generated that described the quality of alignment for each cEEG study as a function of time.Significance.We developed and tested a method to retrospectively time-align two clinical waveform datasets acquired from different devices using a common signal. The method was applied to 33,911h of signals collected in a paediatric critical care unit over six years, demonstrating that the method can be applied to long-term recordings collected under clinical conditions. The method can account for unknown clock drift rates and the presence of discontinuities caused by clock resynchronization events.

Analyzing Continuous Physiologic Data to Find Hemodynamic Signatures Associated With New Brain Injury After Congenital Heart Surgery.

Continuous data capture technology is becoming more common. Establishing analytic approaches for continuous data could aid in understanding the relationship between physiology and clinical outcomes. OBJECTIVES: Our objective was to design a retrospective analysis for continuous physiologic measurements and their relationship with new brain injury over time after cardiac surgery. DESIGN SETTING AND PARTICIPANTS: Retrospective cohort study in the Cardiac Critical Care Unit at the Hospital for Sick Children in patients after repair of transposition of the great arteries (TGA) or single ventricle (SV) lesions. MAIN OUTCOMES AND MEASURES: Continuously acquired physiologic measurements for up to 72 hours after cardiac surgery were analyzed for association with new brain injury by MRI. Distributions of heart rate (HR), systolic blood pressure (BP), and oxygen saturation (Spo2) for SV and TGA were analyzed graphically and with descriptive statistics over postoperative time for data-driven variable selection. Mixed-effects regression analyses characterized relationships between HR, BP, and Spo2 and new brain injury over time while accounting for variation between patients, measurement heterogeneity, and missingness. RESULTS: Seventy-seven patients (60 TGA; 17 SV) were included. New brain injury was seen in 26 (34%). In SV patients, with and without new brain injury, respectively, in the first 24 hours after cardiac surgery, the median (interquartile range) HR was 172.0 beats/min (bpm) (169.7-176.0 bpm) versus 159.6 bpm (145.0-167.0 bpm); systolic BP 74.8 (67.9-78.5 mm Hg) versus 68.9 mm Hg (61.6-70.9 mm Hg). Higher postoperative HR (parameter estimate, 19.4; 95% CI, 7.8-31; p = 0.003 and BP, 8.6; 1.3-15.8; p = 0.024) were associated with new brain injury in SV patients. The strength of this relationship decreased with time. CONCLUSIONS AND RELEVANCE: Retrospective analysis of continuous physiologic measurements can provide insight into changes in postoperative physiology over time and their relationship with new brain injury. This technique could be applied to assess relationships between physiologic data and many patient interventions or outcomes.

Timing errors and temporal uncertainty in clinical databases-A narrative review.

A firm concept of time is essential for establishing causality in a clinical setting. Review of critical incidents and generation of study hypotheses require a robust understanding of the sequence of events but conducting such work can be problematic when timestamps are recorded by independent and unsynchronized clocks. Most clinical models implicitly assume that timestamps have been measured accurately and precisely, but this custom will need to be re-evaluated if our algorithms and models are to make meaningful use of higher frequency physiological data sources. In this narrative review we explore factors that can result in timestamps being erroneously recorded in a clinical setting, with particular focus on systems that may be present in a critical care unit. We discuss how clocks, medical devices, data storage systems, algorithmic effects, human factors, and other external systems may affect the accuracy and precision of recorded timestamps. The concept of temporal uncertainty is introduced, and a holistic approach to timing accuracy, precision, and uncertainty is proposed. This quantitative approach to modeling temporal uncertainty provides a basis to achieve enhanced model generalizability and improved analytical outcomes.

An integration engineering framework for machine learning in healthcare.

Background and Objectives: Machine Learning offers opportunities to improve patient outcomes, team performance, and reduce healthcare costs. Yet only a small fraction of all Machine Learning models for health care have been successfully integrated into the clinical space. There are no current guidelines for clinical model integration, leading to waste, unnecessary costs, patient harm, and decreases in efficiency when improperly implemented. Systems engineering is widely used in industry to achieve an integrated system of systems through an interprofessional collaborative approach to system design, development, and integration. We propose a framework based on systems engineering to guide the development and integration of Machine Learning models in healthcare. Methods: Applied systems engineering, software engineering and health care Machine Learning software development practices were reviewed and critically appraised to establish an understanding of limitations and challenges within these domains. Principles of systems engineering were used to develop solutions to address the identified problems. The framework was then harmonized with the Machine Learning software development process to create a systems engineering-based Machine Learning software development approach in the healthcare domain. Results: We present an integration framework for healthcare Artificial Intelligence that considers the entirety of this system of systems. Our proposed framework utilizes a combined software and integration engineering approach and consists of four phases: (1) Inception, (2) Preparation, (3) Development, and (4) Integration. During each phase, we present specific elements for consideration in each of the three domains of integration: The Human, The Technical System, and The Environment. There are also elements that are considered in the interactions between these domains. Conclusion: Clinical models are technical systems that need to be integrated into the existing system of systems in health care. A systems engineering approach to integration ensures appropriate elements are considered at each stage of model design to facilitate model integration. Our proposed framework is based on principles of systems engineering and can serve as a guide for model development, increasing the likelihood of successful Machine Learning translation and integration.

GPN-1/glypican and UNC-52/perlecan do not appear to function in BMP signaling to pattern the C. elegans postembryonic mesoderm.

Heparan sulfate proteoglycans (HSPGs) are diverse macromolecules consisting of a protein core modified with glycosaminoglycan (GAG) chains. HSPGs, including glypicans and perlecans, have been implicated in shaping the extracellular matrix (ECM) to affect growth factor signaling. Here, we tested if GPN-1/glypicanor UNC-52/perlecan plays a role in the bone morphogenetic protein (BMP) signaling pathway in patterning the C. elegans postembryonic mesoderm. Using the suppression of sma-9(0) (Susm)assay, we found that animals carrying mutant alleles of gpn-1 or unc-52 do not exhibit any Susm phenotype. We also tested and found that the two glypicans GPN-1 and LON-2 do not share functional redundancy in the BMP pathway. Our results suggest that GPN-1/glypican and UNC-52/perlecan do not play a major role in the C. elegans BMP pathway, at least in patterning of the postembryonic mesoderm.

A practical approach to storage and retrieval of high-frequency physiological signals.

OBJECTIVE: Storage of physiological waveform data for retrospective analysis presents significant challenges. Resultant data can be very large, and therefore becomes expensive to store and complicated to manage. Traditional database approaches are not appropriate for large scale storage of physiological waveforms. Our goal was to apply modern time series compression and indexing techniques to the problem of physiological waveform storage and retrieval. APPROACH: We deployed a vendor-agnostic data collection system and developed domain-specific compression approaches that allowed long term storage of physiological waveform data and other associated clinical and medical device data. The database (called AtriumDB) also facilitates rapid retrieval of retrospective data for high-performance computing and machine learning applications. MAIN RESULTS: A prototype system has been recording data in a 42-bed pediatric critical care unit at The Hospital for Sick Children in Toronto, Ontario since February 2016. As of December 2019, the database contains over 720,000 patient-hours of data collected from over 5300 patients, all with complete waveform capture. One year of full resolution physiological waveform storage from this 42-bed unit can be losslessly compressed and stored in less than 300 GB of disk space. Retrospective data can be delivered to analytical applications at a rate of up to 50 million time-value pairs per second. SIGNIFICANCE: Stored data are not pre-processed or filtered. Having access to a large retrospective dataset with realistic artefacts lends itself to the process of anomaly discovery and understanding. Retrospective data can be replayed to simulate a realistic streaming data environment where analytical tools can be rapidly tested at scale.

CXCL14 suppresses human papillomavirus-associated head and neck cancer through antigen-specific CD8+ T-cell responses by upregulating MHC-I expression.

Evasion of the host immune responses is critical for both persistent human papillomavirus (HPV) infection and associated cancer progression. We have previously shown that expression of the homeostatic chemokine CXCL14 is significantly downregulated by the HPV oncoprotein E7 during cancer progression. Restoration of CXCL14 expression in HPV-positive head and neck cancer (HNC) cells dramatically suppresses tumor growth and increases survival through an immune-dependent mechanism in mice. Although CXCL14 recruits natural killer (NK) and T cells to the tumor microenvironment, the mechanism by which CXCL14 mediates tumor suppression through NK and/or T cells remained undefined. Here we report that CD8+ T cells are required for CXCL14-mediated tumor suppression. Using a CD8+ T-cell receptor transgenic model, we show that the CXCL14-mediated antitumor CD8+ T-cell responses require antigen specificity. Interestingly, CXCL14 expression restores major histocompatibility complex class I (MHC-I) expression on HPV-positive HNC cells downregulated by HPV, and knockdown of MHC-I expression in HNC cells results in loss of tumor suppression even with CXCL14 expression. These results suggest that CXCL14 enacts antitumor immunity through restoration of MHC-I expression on tumor cells and promoting antigen-specific CD8+ T-cell responses to suppress HPV-positive HNC.

Temporal Variability in the Sampling of Vital Sign Data Limits the Accuracy of Patient State Estimation.

OBJECTIVES: Physiologic signals are typically measured continuously in the critical care unit, but only recorded at intermittent time intervals in the patient health record. Low frequency data collection may not accurately reflect the variability and complexity of these signals or the patient's clinical state. We aimed to characterize how increasing the temporal window size of observation from seconds to hours modifies the measured variability and complexity of basic vital signs. DESIGN: Retrospective analysis of signal data acquired between April 1, 2013, and September 30, 2015. SETTING: Critical care unit at The Hospital for Sick Children, Toronto. PATIENTS: Seven hundred forty-seven patients less than or equal to 18 years old (63,814,869 data values), within seven diagnostic/surgical groups. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Measures of variability (SD and the absolute differences) and signal complexity (multiscale sample entropy and detrended fluctuation analysis [expressed as the scaling component α]) were calculated for systolic blood pressure, heart rate, and oxygen saturation. The variability of all vital signs increases as the window size increases from seconds to hours at the patient and diagnostic/surgical group level. Significant differences in the magnitude of variability for all time scales within and between groups was demonstrated (p < 0.0001). Variability correlated negatively with patient age for heart rate and oxygen saturation, but positively with systolic blood pressure. Changes in variability and complexity of heart rate and systolic blood pressure from time of admission to discharge were found. CONCLUSIONS: In critically ill children, the temporal variability of physiologic signals supports higher frequency data capture, and this variability should be accounted for in models of patient state estimation.

THE ENVIRONMENTAL AND SAFETY PERFORMANCE OF GAS UTILITIES IN THE UNITED STATES.

The performance of energy service providers has important environmental and safety consequences in local communities. This paper uses a novel dataset compiled from operator reports and infrastructure monitoring data obtained from three different US federal agencies to assess the performance of retail gas utilities nationwide in terms of addressing gas leaks and minimizing leak volumes. Our panel data set includes yearly observations for 727 retail gas utilities from 2009 to 2017. We show that safety hazards and environmental costs of gas leaks are widespread across providers that vary in terms of ownership, size, and region. We then use series of Bayesian hierarchical models to regress four outcome variables--hazardous leaks, end-year unfixed leaks, total gas volume leaked, and significant incidents--on infrastructure conditions, regional service context, and socio-economic service population characteristics. Unlike what is observed in other critical infrastructure cases such as drinking water, socioeconomic conditions are not strongly predictive of service outcomes. Public utilities exhibit better environmental performance on average, and no difference in maintenance backlogs. Because the environmental costs of poor performance--primarily in terms of methane greenhouse gas emissions--are predominantly social, policy tools such as consolidation and privatization are unlikely to improve environmental outcomes.

Benign oral mucosal lesions: Clinical and pathological findings.

A diverse spectrum of benign oral mucosal lesions exists, presenting as either isolated oral findings or in association with dermatologic conditions. Oral lesions can closely resemble one another; therefore, it is important for clinicians to be able to recognize their distinctive features, to be able to recognize benign versus malignant disease, and to recognize when obtaining a biopsy specimen is warranted. The first article in this continuing medical education series reviews oral anatomy, the clinical attributes of several benign lesions of the oral cavity, and appropriate management and therapeutic modalities.

Premalignant and malignant oral mucosal lesions: Clinical and pathological findings.

The second article in this continuing medical education series discusses the clinical and histopathologic features of common premalignant and malignant lesions of the oral cavity. It is imperative for dermatologists to be able to appropriately recognize suspicious lesions, determine the need to obtain a biopsy specimen, counsel, and refer patients presenting with premalignant or malignant conditions. Given the higher rates of mortality and morbidity of oral mucosal malignancies because of late diagnosis, appropriate treatment with multidisciplinary care in a timely manner is essential to patients with these neoplasms.

Assessment of biologically aggressive, recurrent glandular odontogenic cysts for mastermind-like 2 (MAML2) rearrangements: histopathologic and fluorescent in situ hybridization (FISH) findings in 11 cases.

BACKGROUND: Glandular odontogenic cyst (GOC) demonstrates a significant predilection toward localized biologic aggressiveness and recurrence. GOC shares certain histopathologic features with intraosseous mucoepidermoid carcinoma (IMEC). The current investigation evaluates a group of recurrent, biologically aggressive GOCs to determine whether any cases demonstrated unique histologic features or mastermind-like2 (MAML2) rearrangements common to IMEC. METHODS: Microscopic slides from 11 previously diagnosed GOCs were stained with hematoxylin and eosin and assessed by 2 study participants for 10 classic histopathologic features required to establish a diagnosis of GOC. Cases were evaluated utilizing break-apart fluorescent in situ hybridization (FISH) analysis for the presence of MAML2 gene rearrangements. Clinical and demographic data on all patients were recorded. RESULTS: The mean age for patients included in the study was 55.27 years with a range of 36 to 72 years. The most common presenting symptom was a jaw expansion, and all cysts presented initially as a unilocular or multilocular radiolucency. Cysts displayed a minimum of 6 of 10 histologic parameters necessary for a diagnosis of GOC. One case demonstrated MAML2 rearrangements by FISH. That case also showed marked ciliation of cyst-lining epithelial cells and extensive mucous-secreting goblet cell proliferation. CONCLUSION: Findings in the current study are in concert with previous investigations, and although this study finds only limited molecular evidence to support the premise that recurrent biologically aggressive GOCs are a precursor to IMEC, detection of MAML2 rearrangements in 1 case suggests that such a theoretic transition, while rare, is possible.

Distributions and Behavior of Vital Signs in Critically Ill Children by Admission Diagnosis.

OBJECTIVES: Define the distributions of heart rate and intraarterial blood pressure in children at admission to an ICU based on admission diagnosis and examine trends in these physiologic signs over 72 hours from admission (or to discharge if earlier). DESIGN: A retrospective analysis of continuously acquired signals. SETTING: A quaternary and primary referral children's hospital with a general PICU and cardiac critical care unit. PATIENTS: One thousand two hundred eighty-nine patients less than 18 years old were analyzed. Data from individual patient admissions were divided into 19 groups by primary admission diagnosis or surgical procedure. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Distributions at admission are dependent on patient age and admission diagnosis (p < 10(-6)). Heart rate decreases over time, whereas arterial blood pressure is relatively stable, with differences seen in the directions and magnitude of these trends when analyzed by diagnosis group (p < 10(-6)). Multiple linear regression analysis shows that patient age, diagnosis group, and physiologic vital sign value at admission explain 50-63% of the variation observed for that physiologic signal at 72 hours (or at discharge if earlier) with admission value having the greatest influence. Furthermore, the variance of either heart rate or arterial blood pressure for the individual patient is smaller than the variance measured at the level of the group of patients with the same diagnosis. CONCLUSIONS: This is the first study reporting distributions of continuously measured physiologic variables and trends in their behavior according to admission diagnosis in critically ill children. Differences detected between and within diagnostic groups may aid in earlier recognition of outliers as well as allowing refinement of patient monitoring strategies.

Heart Rate and Blood Pressure Centile Curves and Distributions by Age of Hospitalized Critically Ill Children.

Heart rate (HR) and blood pressure (BP) form the basis for monitoring the physiological state of patients. Although norms have been published for healthy and hospitalized children, little is known about their distributions in critically ill children. The objective of this study was to report the distributions of these basic physiological variables in hospitalized critically ill children. Continuous data from bedside monitors were collected and stored at 5-s intervals from 3,677 subjects aged 0-18 years admitted over a period of 30 months to the pediatric and cardiac intensive care units at a large quaternary children's hospital. Approximately 1.13 billion values served to estimate age-specific distributions for these two basic physiological variables: HR and intra-arterial BP. Centile curves were derived from the sample distributions and compared to common reference ranges. Properties such as kurtosis and skewness of these distributions are described. In comparison to previously published reference ranges, we show that children in these settings exhibit markedly higher HRs than their healthy counterparts or children hospitalized on in-patient wards. We also compared commonly used published estimates of hypotension in children (e.g., the PALS guidelines) to the values we derived from critically ill children. This is a first study reporting the distributions of basic physiological variables in children in the pediatric intensive care settings, and the percentiles derived may serve as useful references for bedside clinicians and clinical trials.

Suppression of Antitumor Immune Responses by Human Papillomavirus through Epigenetic Downregulation of CXCL14.

UNLABELLED: High-risk human papillomaviruses (HPVs) are causally associated with multiple human cancers. Previous studies have shown that the HPV oncoprotein E7 induces immune suppression; however, the underlying mechanisms remain unknown. To understand the mechanisms by which HPV deregulates host immune responses in the tumor microenvironment, we analyzed gene expression changes of all known chemokines and their receptors using our global gene expression data sets from human HPV-positive and -negative head/neck cancer and cervical tissue specimens in different disease stages. We report that, while many proinflammatory chemokines increase expression throughout cancer progression, CXCL14 is dramatically downregulated in HPV-positive cancers. HPV suppression of CXCL14 is dependent on E7 and associated with DNA hypermethylation in the CXCL14 promoter. Using in vivo mouse models, we revealed that restoration of Cxcl14 expression in HPV-positive mouse oropharyngeal carcinoma cells clears tumors in immunocompetent syngeneic mice, but not in Rag1-deficient mice. Further, Cxcl14 reexpression significantly increases natural killer (NK), CD4(+) T, and CD8(+) T cell infiltration into the tumor-draining lymph nodes in vivo In vitro transwell migration assays show that Cxcl14 reexpression induces chemotaxis of NK, CD4(+) T, and CD8(+) T cells. These results suggest that CXCL14 downregulation by HPV plays an important role in suppression of antitumor immune responses. Our findings provide a new mechanistic understanding of virus-induced immune evasion that contributes to cancer progression. IMPORTANCE: Human papillomaviruses (HPVs) are causally associated with more than 5% of all human cancers. During decades of cancer progression, HPV persists, evading host surveillance. However, little is known about the immune evasion mechanisms driven by HPV. Here we report that the chemokine CXCL14 is significantly downregulated in HPV-positive head/neck and cervical cancers. Using patient tissue specimens and cultured keratinocytes, we found that CXCL14 downregulation is linked to CXCL14 promoter hypermethylation induced by the HPV oncoprotein E7. Restoration of Cxcl14 expression in HPV-positive cancer cells clears tumors in immunocompetent syngeneic mice, but not in immunodeficient mice. Mice with Cxcl14 reexpression show dramatically increased natural killer and T cells in the tumor-draining lymph nodes. These results suggest that epigenetic downregulation of CXCL14 by HPV plays an important role in suppressing antitumor immune responses. Our findings may offer novel insights to develop preventive and therapeutic tools for restoring antitumor immune responses in HPV-infected individuals.

Remote, real-time monitoring and analysis of vital signs of neonatal graduate infants.

This paper presents a system for the remote monitoring of a newborn infant's physiological data outside the Neonatal Intensive Care Unit. By providing a simple means for parents to enable monitoring, and physicians a simple mobile application to monitor live and historical physiological information, this system provides the insight once only possible in an Intensive Care Unit. The system utilizes a variety of connectivity means such as Wi-Fi and 3G to facilitate the communication between a multitude of industry standard vital sign monitor and a remote server. A system trial monitoring an infant to simulate neonatal graduate monitoring has determined the system was able to successfully transmit 99.99% of data generated from the vital sign monitor.

The Berkeley Rudimentary Vision Test.

PURPOSE: Very poor visual acuity often cannot be measured with letter charts even at close viewing distances. The Berkeley Rudimentary Vision Test (BRVT) was developed as a simple test to extend the range of visual acuity measurement beyond the limits of letter charts by systematically simplifying the visual task and using close viewing distances to achieve large angular sizes. The test has three pairs of hinged cards, 25 cm square. One card-pair has four single tumbling E (STE) optotypes at sizes 100 M, 63 M, 40 M, and 25 M. Another card-pair has four grating acuity (GA) targets at sizes 200 M, 125 M, 80 M, and 50 M. The third card-pair has a test of white field projection (WFP) and a test of black white discrimination (BWD). As a demonstration of feasibility, a population of subjects with severe visual impairment was tested with the BRVT. METHODS: Adults with severe visual impairments from a wide variety of causes were recruited from three different rehabilitation programs. Vision measurements were made on 54 eyes from 37 subjects; test administration times were measured. RESULTS: For this population, letter chart visual acuity could be measured on 24 eyes. Measurements of visual acuity for STE targets were made for 18 eyes and with GA targets, for two eyes. Five eyes had WFP, and one had BWD. Four had light perception only. The median testing time with the BRVT was 2.5 min. DISCUSSION: The BRVT extends the range of visual acuity up to logMAR = 2.60 (20/8000) for STEs, to logMAR = 2.90 (20/16,000) for gratings and includes the WFP and BWD tests. CONCLUSIONS: The BRVT is a simple and efficient test of spatial vision that, with 13 increments, extends the range of measurement from the limits of the letter chart up to light perception.

Oral manifestations of smokeless tobacco use.

Smokeless tobacco (SLT) has been smoked, chewed, and inhaled in various forms for hundreds of years. The primary oral, mucosal, and hard tissue changes associated with SLT use include SLT keratosis (STK); gingival inflammation, periodontal inflammation, and alveolar bone damage; and dental caries, tooth abrasion, and dysplasia and oral squamous cell carcinoma (SCC). Some high-risk STKs are human papillomavirus associated, and the highest level of transition of STK to dysplasia or oral SCC appears to be in those lesions that have a diffuse velvety or papillary texture clinically. There is minimal risk for oral cancer associated with SLT use.