Prediction of MET Overexpression in Lung Adenocarcinoma from Hematoxylin and Eosin Images.

Mesenchymal epithelial transition (MET) protein overexpression is a targetable event in non-small cell lung cancer and is the subject of active drug development. Challenges in identifying patients for these therapies include lack of access to validated testing, such as standardized immunohistochemistry assessment, and consumption of valuable tissue for a single gene/protein assay. Development of prescreening algorithms using routinely available digitized hematoxylin and eosin (H&E)-stained slides to predict MET overexpression could promote testing for those who will benefit most. Recent literature reports a positive correlation between MET protein overexpression and RNA expression. In this work, a large database of matched H&E slides and RNA expression data were leveraged to train a weakly supervised model to predict MET RNA overexpression directly from H&E images. This model was evaluated on an independent holdout test set of 300 overexpressed and 289 normal patients, demonstrating a receiver operating characteristic area under curve of 0.70 (95th percentile interval: 0.66 to 0.74) with stable performance characteristics across different patient clinical variables and robust to synthetic noise on the test set. These results suggest that H&E-based predictive models could be useful to prioritize patients for confirmatory testing of MET protein or MET gene expression status.

Artificial intelligence-augmented histopathologic review using image analysis to optimize DNA yield from formalin-fixed paraffin-embedded slides.

To achieve minimum DNA input requirements for next-generation sequencing (NGS), pathologists visually estimate macrodissection and slide count decisions. Unfortunately, misestimation may cause tissue waste and increased laboratory costs. We developed an artificial intelligence (AI)-augmented smart pathology review system (SmartPath) to empower pathologists with quantitative metrics for accurately determining tissue extraction parameters. SmartPath uses two deep learning architectures, a U-Net based network for cell segmentation and a multi-field-of-view convolutional network for tumor area segmentation, to extract features from digitized H&E-stained formalin-fixed paraffin-embedded slides. From the segmented tumor area, SmartPath suggests a macrodissection area. To predict DNA yield per slide, the extracted features from within the macrodissection area are correlated with known DNA yields to fit a regularized linear model (R = 0.85). Then, a pathologist-defined target yield divided by the predicted DNA yield per slide gives the number of slides to scrape. Following model development, an internal validation trial was conducted within the Tempus Labs molecular sequencing laboratory. We evaluated our system on 501 clinical colorectal cancer slides, where half received SmartPath-augmented review and half traditional pathologist review. The SmartPath cohort had 25% more DNA yields within a desired target range of 100-2000 ng. The number of extraction attempts was statistically unchanged between cohorts. The SmartPath system recommended fewer slides to scrape for large tissue sections, saving tissue in these cases. Conversely, SmartPath recommended more slides to scrape for samples with scant tissue sections, especially those with degraded DNA, helping prevent costly re-extraction due to insufficient extraction yield. A statistical analysis was performed to measure the impact of covariates on the results, offering insights on how to improve future applications of SmartPath. With these improvements, AI-augmented histopathologic review has the potential to decrease tissue waste, sequencing time, and laboratory costs by optimizing DNA yields, especially for samples with scant tissue and/or degraded DNA.

Benchmarking Transfer Entropy Methods for the Study of Linear and Nonlinear Cardio-Respiratory Interactions.

Transfer entropy (TE) has been used to identify and quantify interactions between physiological systems. Different methods exist to estimate TE, but there is no consensus about which one performs best in specific applications. In this study, five methods (linear, k-nearest neighbors, fixed-binning with ranking, kernel density estimation and adaptive partitioning) were compared. The comparison was made on three simulation models (linear, nonlinear and linear + nonlinear dynamics). From the simulations, it was found that the best method to quantify the different interactions was adaptive partitioning. This method was then applied on data from a polysomnography study, specifically on the ECG and the respiratory signals (nasal airflow and respiratory effort around the thorax). The hypothesis that the linear and nonlinear components of cardio-respiratory interactions during light and deep sleep change with the sleep stage, was tested. Significant differences, after performing surrogate analysis, indicate an increased TE during deep sleep. However, these differences were found to be dependent on the type of respiratory signal and sampling frequency. These results highlight the importance of selecting the appropriate signals, estimation method and surrogate analysis for the study of linear and nonlinear cardio-respiratory interactions.

The Effects of Primary Defect Characteristics on Reconstruction Type and Adjunctive Intervention in Mohs Micrographic Surgery: A Retrospective Review.

BACKGROUND: Cosmetic concerns following Mohs Micrographic surgery (MMS) are significant and may require adjunctive treatments for unsatisfactory appearance. OBJECTIVE: To determine factors associated with adjunctive cosmetic intervention for facial defects following MMS. METHODS AND MATERIALS: A retrospective review of 699 patients undergoing repair of facial defects after MMS from 2008-2018 was performed. Tumor types, defect sizes, patient demographics, repair methods, complications, and post-operative cosmetic interventions were examined. RESULTS: 666 Mohs cases and resultant defects were analyzed. The most common method of repair following MMS was primary closure (52.3%), and the most common post-operative intervention was steroid injection (18.3%). The lip subunit was more than twice as likely as other locations to be treated with steroid injections (P<.001). The lip subunit also had the highest frequency of scar revision (13%; P<0.001). Patients who had primary closure were less likely to require scar revision (P=0.003) or dermabrasion (P=0.042), and there was no significant association between skin graft repair and cosmetic intervention. CONCLUSIONS: Both defect subunit and closure type were independently associated with adjunctive cosmetic intervention following MMS. Defect size was not significantly associated with an adjunctive intervention in our study. Understanding the factors affecting the need for adjunctive cosmetic interventions may improve patient counseling prior to Mohs repair. J Drugs Dermatol. 2020;19(3): doi:10.36849/JDD.2020.4701.

Comparing Kadish, TNM, and the modified Dulguerov staging systems for esthesioneuroblastoma.

BACKGROUND: Esthesioneuroblastoma (ENB) is a rare neuroendocrine tumor. The purpose of this study was to compare the Kadish, tumor-node-metastasis (TNM), and Dulguerov's modified TNM staging in order to determine the impact of the stage on primary surgical treatment selection, margin status, and survival. METHODS: The National Cancer Database (NCDB) was used to identify patients diagnosed with ENB between 2004 to 2015. Patients were excluded based on the ability to properly stage their disease as well as the availability of treatment data. RESULTS: Eight-hundred eighty-three patients had sufficient data for analysis. On multivariate analysis, age and government insurance were associated with primary surgical treatment, whereas tumor stage, gender, race, hospital type and volume, and comorbidity score were not. Age, charlson-deyo comorbidity (CDCC) score, hospital volume, and nodal status were found to be predictors of survival. Multivariate-analysis controlling for stage failed to demonstrate clear survival differences between staging in both TNM and Kadish systems. T-stage and the presence of regional nodal metastasis were associated with an increased risk of positive margins on multivariate analysis. CONCLUSION: Although primary surgical management and positive margins can be predicted by certain patient and tumor factors, clinical staging systems for ENB poorly predict prognosis over a 10-year horizon.

Changes in autonomic regulation due to Kangaroo care remain unaffected by using a swaddling device.

AIM: To investigate the effects of a swaddling device known as the Hugsy (Hugsy, Eindhoven, the Netherlands) towards improving autonomic regulation. This device can be used both in the incubator and during Kangaroo care to absorb parental scent and warmth. After Kangaroo care, these stimuli can continue to be experienced by infants, while in the incubator. Additionally, a pre-recorded heartbeat sound can be played. METHOD: Autonomic regulation was compared in preterm infants before, during and after Kangaroo care with and without the use of a swaddling device in a within-subject study carried out in a level III neonatal intensive care unit. Descriptive statistics and effect sizes were calculated corresponding to changes in heart rate, respiratory rate, oxygen saturation, temperature and heart rate variability on intervention versus control days. RESULTS: In this study of 20 infants with a median (interquartile range) gestational age of 28.4 (27-29.9) weeks, Kangaroo care was associated with a decrease in heart rate, respiratory rate and heart rate variability on both intervention and control days. There were no differences between intervention and control days. CONCLUSION: The use of an alternative swaddling device aimed at facilitating Kangaroo care did not enhance autonomic regulation, as measured by vital signs and heart rate variability.

Pharma-Oncogenomics in the Era of Personal Genomics: A Quick Guide to Online Resources and Tools.

The past two decades have seen unprecedented advances in the field of oncogenomics. The ongoing characterization of neoplastic tissues through genomic techniques has transformed many aspects of cancer research, diagnosis, and treatment. However, identifying sequence variants with biological and clinical significance is a challenging endeavor. In order to accomplish this task, variants must be annotated and interpreted using various online resources. Data on protein structure, functional prediction, variant frequency in relevant populations, and multiple other factors have been compiled in useful databases for this purpose. Thus, understanding the available online resources for the annotation and interpretation of sequence variants is critical to aid molecular pathologists and researchers working in this space.

Features of Heart Rate Variability Capture Regulatory Changes During Kangaroo Care in Preterm Infants.

OBJECTIVE: To determine whether heart rate variability (HRV) can serve as a surrogate measure to track regulatory changes during kangaroo care, a period of parental coregulation distinct from regulation within the incubator. STUDY DESIGN: Nurses annotated the starting and ending times of kangaroo care for 3 months. The pre-kangaroo care, during-kangaroo care, and post-kangaroo care data were retrieved in infants with at least 10 accurately annotated kangaroo care sessions. Eight HRV features (5 in the time domain and 3 in the frequency domain) were used to visually and statistically compare the pre-kangaroo care and during-kangaroo care periods. Two of these features, capturing the percentage of heart rate decelerations and the extent of heart rate decelerations, were newly developed for preterm infants. RESULTS: A total of 191 kangaroo care sessions were investigated in 11 preterm infants. Despite clinically irrelevant changes in vital signs, 6 of the 8 HRV features (SD of normal-to-normal intervals, root mean square of the SD, percentage of consecutive normal-to-normal intervals that differ by >50 ms, SD of heart rate decelerations, high-frequency power, and low-frequency/high-frequency ratio) showed a visible and statistically significant difference (P <.01) between stable periods of kangaroo care and pre-kangaroo care. HRV was reduced during kangaroo care owing to a decrease in the extent of transient heart rate decelerations. CONCLUSION: HRV-based features may be clinically useful for capturing the dynamic changes in autonomic regulation in response to kangaroo care and other changes in environment and state.

Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control.

Virus-specific CD8+ T cells probably mediate control over HIV replication in rare individuals, termed long-term nonprogressors (LTNPs) or elite controllers. Despite extensive investigation, the mechanisms responsible for this control remain incompletely understood. We observed that HIV-specific CD8+ T cells of LTNPs persisted at higher frequencies than those of treated progressors with equally low amounts of HIV. Measured on a per-cell basis, HIV-specific CD8+ T cells of LTNPs efficiently eliminated primary autologous HIV-infected CD4+ T cells. This function required lytic granule loading of effectors and delivery of granzyme B to target cells. Defective cytotoxicity of progressor effectors could be restored after treatment with phorbol ester and calcium ionophore. These results establish an effector function and mechanism that clearly segregate with immunologic control of HIV. They also demonstrate that lytic granule contents of memory cells are a critical determinant of cytotoxicity that must be induced for maximal per-cell killing capacity.

Signatures of quantum phases in a dissipative system.

Lindbladian formalism, as tuned to dissipative and open systems, has been all-pervasive to interpret non-equilibrium steady states of quantum many-body systems. We study the fate of free fermionic and superconducting phases in a dissipative one-dimensional Kitaev model-where the bath acts both as a source and a sink of fermionic particles with different coupling rates. As a function of these two couplings, we investigate the steady state, its entanglement content, and its approach from varying initial states. Interestingly, we find that the steady state phase diagram retains decipherable signatures of ground state critical physics. We also show that early-time fidelity is a useful marker to find a subclass of phase transitions in such situations. Moreover, we show that the survival of critical signatures at late-times, strongly depend on the thermal nature of the steady state. This connection hints at a correspondence between quantum observables and classical magnetism in the steady state of such systems. Our work uncovers interesting connections between dissipative quantum many-body systems, thermalization of a classical spin and many-body quantum critical phenomena.

Modeling meibum secretion: Alternatives for obstructive Meibomian Gland Dysfunction (MGD).

PURPOSE: While changes in meibum quality are correlated with severity of meibomian gland dysfunction (MGD) and dry eye disease, little is known regarding the mechanics of meibum secretion. The purpose of this study was to develop a finite element model of meibum secretion and evaluate the effect of various factors that might impact meibum delivery to the ocular surface. METHODS: A finite element analysis in COMSOL 6.0 was used to simulate the flow of meibum within the gland's terminal excretory duct. Historical normal human meibum rheology data taken over the meibum melting range from fluid (35-40 °C) to solid (25-30 °C) were then used to calculate the minimum yield stress and plastic viscosity of meibum. The effects of meibum melting state, eyelid pressure and terminal duct diameter on meibum flow rates were then systematically investigated. RESULTS: The melting state of meibum from liquid to solid was associated with an increase in the minimum yield stress and plastic viscosity that caused an exponential decrease in meibum flow. Modeling also established that there was a linear correlation between meibum flow rate and eyelid pressure needed to express meibum and the 4th power of the terminal duct radius. CONCLUSIONS: Our results suggest that changes in the melting state of meibum from fluid to solid, as well as changes in the radius of the terminal excretory duct and the force exerted by the eyelid can lead to dramatic decreases in the flow of meibum. Together these findings suggest alternative mechanisms for meibomian gland obstruction.

Changes in Maternal Heart Rate Variability and Photoplethysmography Morphology after Corticosteroid Administration: A Prospective, Observational Study.

Background: Owing to the association between dysfunctional maternal autonomic regulation and pregnancy complications, assessing non-invasive features reflecting autonomic activity-e.g., heart rate variability (HRV) and the morphology of the photoplethysmography (PPG) pulse wave-may aid in tracking maternal health. However, women with early pregnancy complications typically receive medication, such as corticosteroids, and the effect of corticosteroids on maternal HRV and PPG pulse wave morphology is not well-researched. Methods: We performed a prospective, observational study assessing the effect of betamethasone (a commonly used corticosteroid) on non-invasively assessed features of autonomic regulation. Sixty-one women with an indication for betamethasone were enrolled and wore a wrist-worn PPG device for at least four days, from which five-minute measurements were selected for analysis. A baseline measurement was selected either before betamethasone administration or sufficiently thereafter (i.e., three days after the last injection). Furthermore, measurements were selected 24, 48, and 72 h after betamethasone administration. HRV features in the time domain and frequency domain and describing heart rate (HR) complexity were calculated, along with PPG morphology features. These features were compared between the different days. Results: Maternal HR was significantly higher and HRV features linked to parasympathetic activity were significantly lower 24 h after betamethasone administration. Features linked to sympathetic activity remained stable. Furthermore, based on the PPG morphology features, betamethasone appears to have a vasoconstrictive effect. Conclusions: Our results suggest that administering betamethasone affects maternal autonomic regulation and cardiovasculature. Researchers assessing maternal HRV in complicated pregnancies should schedule measurements before or sufficiently after corticosteroid administration.

Quantitative assessment of carotid ultrasound diameter measurements in the operating room: a comparable analysis of long-axis versus rotated and tilted orientation.

Objective. Carotid ultrasound (US) has been studied as a non-invasive alternative for hemodynamic monitoring. A long-axis (LA) view is traditionally employed but is difficult to maintain and operator experience may impact the diameter estimates, making it unsuitable for monitoring. Preliminary results show that a new, i.e. rotated and tilted (RT) view is more robust to motion and less operator-dependent. This study aimed to quantitatively assess common carotid diameter estimates obtained in a clinical setting from an RT view and compare those to corresponding estimates obtained using other views.Approach. Carotid US measurements were performed in 30 adult cardiac-surgery patients (26 males, 4 females) with short-axis (SA), LA, and RT probe orientations, the first being used as a reference for measuring the true vessel diameter. Per 30 s acquisition, the median and spread in diameter values were computed, the latter representing a measure of robustness, and were statistically compared between views.Main results. The median (IQR) over all the patients of the median diameter per 30 s acquisition was 7.15 (1.15) mm for the SA view, 7.03 (1.51) mm for the LA view, and 6.99 (1.72) mm for the RT view. The median spread in diameter values was 0.18 mm for the SA view, 0.16 mm for the LA view, and 0.18 mm for the RT view. There were no statistically significant differences between views in the median diameter values (p= 0.088) or spread (p= 0.122).Significance. The RT view results in comparable and equally robust median carotid diameter values compared to the reference. These findings open the path for future studies investigating the use of the RT view in new applications, such as in wearable ultrasound devices.

Development and validation of a deep learning-based microsatellite instability predictor from prostate cancer whole-slide images.

Microsatellite instability-high (MSI-H) is a tumor-agnostic biomarker for immune checkpoint inhibitor therapy. However, MSI status is not routinely tested in prostate cancer, in part due to low prevalence and assay cost. As such, prediction of MSI status from hematoxylin and eosin (H&E) stained whole-slide images (WSIs) could identify prostate cancer patients most likely to benefit from confirmatory testing to evaluate their eligibility for immunotherapy and need for Lynch syndrome testing. Prostate biopsies and surgical resections from prostate cancer patients referred to our institution were analyzed. MSI status was determined by next-generation sequencing. Patients sequenced before a cutoff date formed an algorithm development set (n = 4015, MSI-H 1.8%) and a paired validation set (n = 173, MSI-H 19.7%) that consisted of two serial sections from each sample, one stained and scanned internally and the other at an external site. Patients sequenced after the cutoff date formed a temporally independent validation set (n = 1350, MSI-H 2.3%). Attention-based multiple instance learning models were trained to predict MSI-H from H&E WSIs. The predictor achieved area under the receiver operating characteristic curve values of 0.78 (95% CI [0.69-0.86]), 0.72 (95% CI [0.63-0.81]), and 0.72 (95% CI [0.62-0.82]) on the internally prepared, externally prepared, and temporal validation sets, respectively, showing effective predictability and generalization to both external staining/scanning processes and temporally independent samples. While MSI-H status is significantly correlated with Gleason score, the model remained predictive within each Gleason score subgroup.

Diacylglycerol kinases: regulated controllers of T cell activation, function, and development.

Diacylglycerol kinases (DGKs) are a diverse family of enzymes that catalyze the conversion of diacylglycerol (DAG), a crucial second messenger of receptor-mediated signaling, to phosphatidic acid (PA). Both DAG and PA are bioactive molecules that regulate a wide set of intracellular signaling proteins involved in innate and adaptive immunity. Clear evidence points to a critical role for DGKs in modulating T cell activation, function, and development. More recently, studies have elucidated factors that control DGK function, suggesting an added complexity to how DGKs act during signaling. This review summarizes the available knowledge of the function and regulation of DGK isoforms in signal transduction with a particular focus on T lymphocytes.

Iridocorneal angle imaging of a human donor eye by spectral-domain optical coherence tomography.

Iridocorneal angle (ICA) details particularly the trabecular meshwork (TM), Schlemm's canal (SC), and collector channels (CCs) play crucial roles in the regulation of the aqueous outflow in the eyes and are closely associated with glaucoma. Current clinical gonioscopy imaging provides no depth information, and studies of 3D high-resolution optical coherence tomography (OCT) imaging of these structures are limited. We developed a custom-built spectral-domain (SD-) OCT imaging system to fully characterize the angle details. Imaging of a human cadaver eye reveals the visibility of details in the TM/SC/CC region via a 'crossline' scanning and a series of image processing. This shows that ICA imaging can be used for preoperative glaucoma inspections in the clinical setting with the proposed prototype.

Survival differences of low-grade versus high-grade head and neck pleomorphic dermal sarcomas and a review of a scalp case.

Objective: To examine survival by tumor grade of pleomorphic dermal sarcomas (PDS) of the head and neck (H&N) and review a scalp PDS case. Methods: Patients in the Surveillance, Epidemiology, and End Results (SEER) database were included from 1980 to 2016 based on a diagnosis of H&N PDS. Survival estimates were performed using Kaplan-Meier analysis. Additionally, a case of a grade III H&N PDS is presented. Results: Two hundred-seventy cases of PDS were identified. The mean age at diagnosis was 75.1 years (SD: 13.5). Two hundred-thirty-four (86.7%) patients were male. Eighty-seven percent of patients received surgery as a part of their care. The 5-year overall survival rates for grades I, II, III, and IV PDSs were 69%, 60%, 50%, and 42%, respectively (P = 0.03). Conclusions: H&N PDS occurs most commonly in older-age males. Surgical management is frequently a part of H&N PDS care. Survival rates significantly decline based on tumor grade.

Maternal cardiorespiratory coupling: differences between pregnant and nonpregnant women are further amplified by sleep-stage stratification.

Pregnancy complications are associated with abnormal maternal autonomic regulation. Subsequently, thoroughly understanding maternal autonomic regulation during healthy pregnancy may enable the earlier detection of complications, in turn allowing for the improved management thereof. Under healthy autonomic regulation, reciprocal interactions occur between the cardiac and respiratory systems, i.e., cardiorespiratory coupling (CRC). Here, we investigate, for the first time, the differences in CRC between healthy pregnant and nonpregnant women. We apply two algorithms, namely, synchrograms and bivariate phase-rectified signal averaging, to nighttime recordings of ECG and respiratory signals. We find that CRC is present in both groups. Significantly less (P < 0.01) cardiorespiratory synchronization occurs in pregnant women (11% vs. 15% in nonpregnant women). Moreover, there is a smaller response in the heart rate of pregnant women corresponding to respiratory inhalations and exhalations. In addition, we stratified these analyses by sleep stages. As each sleep stage is governed by different autonomic states, this stratification not only amplified some of the differences between groups but also brought out differences that remained hidden when analyzing the full-night recordings. Most notably, the known positive relationship between CRC and deep sleep is less prominent in pregnant women than in their nonpregnant counterparts. The decrease in CRC during healthy pregnancy may be attributable to decreased maternal parasympathetic activity, anatomical changes to the maternal respiratory system, and the increased physiological stress accompanying pregnancy. This work offers novel insight into the physiology of healthy pregnancy and forms part of the base knowledge needed to detect abnormalities in pregnancy.NEW & NOTEWORTHY We compare CRC, i.e., the reciprocal interaction between the cardiac and respiratory systems, between healthy pregnant and nonpregnant women for the first time. Although CRC is present in both groups, CRC is reduced during healthy pregnancy; there is less synchronization between maternal cardiac and respiratory activity and a smaller response in maternal heart rate to respiratory inhalations and exhalations. Stratifying this analysis by sleep stages reveals that differences are most prominent during deep sleep.

Changes in Maternal Heart Rate and Autonomic Regulation following the Antenatal Administration of Corticosteroids: A Secondary Analysis.

While the effect of antenatally administered corticosteroids on fetal heart rate (HR) and heart rate variability (HRV) is well established, little information is available on how these drugs affect maternal physiology. In this secondary analysis of a prospective, observational cohort study, we quantify how corticosteroids affect maternal HR and HRV, which serve as a proxy measure for autonomic regulation. Abdominal ECG measurements were recorded before and in the five days following the administration of betamethasone­a corticosteroid commonly used for fetal maturation­in 46 women with singleton pregnancies. Maternal HR and HRV were determined from these recordings and compared between these days. HRV was assessed with time- and frequency-domain features, as well as non-linear and complexity features. In the 24 h after betamethasone administration, maternal HR was significantly increased (p < 0.01) by approximately 10 beats per minute, while HRV features linked to parasympathetic activity and HR complexity were significantly decreased (p < 0.01 and p < 0.001, respectively). Within four days after the initial administration of betamethasone, HR decreases and HRV features increase again, indicating a diminishing effect of betamethasone a few days after administration. We conclude that betamethasone administration results in changes in maternal HR and HRV, despite the heterogeneity of the studied population. Therefore, its recent administration should be considered when evaluating these cardiovascular metrics.

Laryngectomy: Social media analysis of patient perception.

BACKGROUND: Social media continues to grow as a relevant information source for the lay public and medical professionals. METHODS: A search of posts on Facebook and Instagram was conducted using the hashtag #laryngectomy. Posts were categorized based upon perspective, media type, timeframe, topic, tone, and popularity. RESULTS: Final analysis included 929 Instagram posts and 355 Facebook posts. Most Facebook posts were made by companies (38%) and physicians (17%) with information (30%) and advertisements (22%) being common topics. Patients (40%) were the largest group of Instagram authors with lifestyle (39%) being the most common topic. Greater than 90% of posts were either neutral or positive in tone across both platforms. CONCLUSIONS: Patient perspective was most commonly represented on Instagram, whereas Facebook more commonly included posts by physicians and companies. The majority of posts carried a neutral or positive tone, which is consistent with positive quality of life patients have shown postoperatively.