A Novel Curriculum for Internal Medicine Residents to Care for High-Need, High-Cost Patients.

OBJECTIVES: High-need, high-cost (HNHC) patients represent a small proportion of patients in the US, but result in disproportionately higher healthcare utilization. Teaching Internal Medicine (IM) resident trainees to provide high value care for HNHC patients is critical. We sought to improve resident attitudes and increase clinical skills associated with treating HNHC patients by creating a curriculum that leveraged the UCLA Extensivist Program, a patient-centered medical home for HNHC patients. METHODS: We developed a curriculum for PGY-2 and PGY-3 IM residents centered on caring for HNHC patients over the course of 6, 4h sessions during 1 academic year. Participants completed pre- and post-intervention surveys assessing self-rated attitudes and skills associated with caring for an HNHC patient population. RESULTS: Twenty-one IM residents completed the curriculum and 41 were in the control group. There were no statistically significant differences in assessed attitudes and skills, but there were trends of improvement, including a decrease in participants who agreed or strongly agreed they felt overwhelmed when seeing patients for posthospital discharge follow up (45.0% pre- to 41.7% post-intervention) and an increase in participants who agreed or strongly agreed they have the skills to successfully transition HNHC patients between inpatient and ambulatory settings (20.0% pre- to 33.3% post-intervention). Participants reported better understanding of resources available to HNHC patients, effective coordination of transitions of care, and comprehensive assessment of social determinants of health. CONCLUSION: A curriculum to improve resident attitudes and skills associated with caring for HNHC patients was successfully implemented in an IM program at a large academic medical center. The curriculum may be adapted for other training programs; long-term training woven throughout training may be important to significantly improve resident education on how to care for HNHC patients.

Simulated resections and RNS placement can optimize post-operative seizure outcomes when guided by fast ripple networks.

In medication-resistant epilepsy, the objective of epilepsy surgery is to render a patient seizure free with a resection/ablation that is as small as possible to minimize morbidity. The standard of care in planning the margins of epilepsy surgery involves electroclinical delineation of the seizure onset zone (SOZ) in the epilepsy monitoring unit (EMU) by an expert epileptologist, and incorporation of neuroimaging findings from MRI, PET, SPECT, and MEG modalities. Resecting cortical tissue generating high-frequency oscillations (HFOs) has been investigated as a more efficacious alternative to targeting the SOZ. In this study, we used support vector machines (SVMs) to compare the resection volumes of actual resections, defined using the clinical standard of care, with virtual resections of fast ripple (FR 350-600 Hz) networks. Cross-validation of the SVM that labeled patients as seizure free or not seizure free using FR metrics as factors demonstrated an accuracy of 0.78. In all the patients rendered seizure free after surgery, we found that the virtual resection, defined using FR generator sites with highest rate and greatest autonomy, was larger than the actual resection. In the patients who experienced seizures after the actual resection, a virtual resection that included the SOZ and other FR generating regions rendered half of these patients virtually seizure free. We also examined patients implanted with the responsive neurostimulator system (RNS) and virtually targeted the RNS stimulation contacts proximal to sites generating FR. We used the simulations to investigate if the likelihood of a RNS super response (>90% seizure reduction) would be increased.

Demographics of Youth With Newly Diagnosed Acute/Recent HIV Infection in Adolescent Trials Network 147: Early Treatment of Acute HIV Infection.

PURPOSE: Gay, bisexual, and other cisgender men who have sex with men, and racial minority youth are at elevated risk of acquiring HIV infection. The Adolescent Trials Network 147 recruited youth with acute/recent HIV-infection for early antiretroviral treatment. The cohort make-up is described here. METHODS: Treatment-naïve, recently identified HIV + youth, aged 12-24 years, from Los Angeles and New Orleans were recruited from community centers, clinics, social media, and a high-risk seronegative cohort (n = 1,727, the Adolescent Trials Network 149) using point-of-care assays. Acute HIV infection was determined by Fiebig staging. HIV RNA viral load (VL) and CD4 cell counts, along with demographic and behavioral data were assessed at enrollment. RESULTS: Between July 2017 and July 2021, 103 newly diagnosed youth were enrolled, initiating antiretroviral treatment within a week. Mean age was 20.8 years (standard deviation: 2.4); 90.3% identified as cis male, 83.5% were single or in casual relationships, 71.8% were gay, bisexual, and other cisgender men who have sex with men; 60.2% were Black. One-fourth (24.3%) reported homelessness ever; 10.7% within last 4 months. At enrollment, median plasma VL was 37,313 HIV RNA copies/ml (interquartile range: 5,849-126,162) and median CD4 count 445.5 cells/mm3 (interquartile range: 357-613). 40% of youth reported acute retroviral symptoms before or at enrollment. Acutely infected, seroconverting youth had the highest VL. Sexually transmitted coinfections were present at enrollment in 56% of the cohort, with syphilis being most frequent (39%). DISCUSSION: Early identification and treatment of HIV can increase positive HIV outcomes. A high sexually transmitted infection burden was present in recently HIV-infected youth. Acute retroviral symptoms were not reported by most participants, demonstrating that broad universal HIV screening is needed for identification of recent infection in youth.

Near-Peer Supervision in Primary Care: Bringing Teaching Teams From the Wards to the Clinic.

Background: Teaching near-peers yields numerous benefits to residents. Opportunities for near-peer teaching are typically restricted to hospital settings. Little is known about the educational potential of outpatient near-peer teaching. Objective: To describe Primary Care Teaching (PC Teach), a novel outpatient near-peer teaching experience for residents in a large, urban, internal medicine residency program; characterize its feasibility and acceptability; and evaluate changes in residents' self-reported confidence in outpatient teaching and attitudes toward teaching and primary care/outpatient medicine. Methods: In 2020-2021, following a didactic workshop, 43 postgraduate year 3 (PGY-3) residents at continuity clinics assigned to PC Teach completed a series of half-day sessions acting as preceptor to interns under attending supervision. Worksheets facilitated post-session feedback for residents and interns. Eighteen PGY-3s at nonparticipating clinics, who also completed the workshop, served as controls. We assessed process measures for feasibility and acceptability and analyzed resident attitudes using pre-post surveys. Results: Participating residents completed 2 to 8 sessions each. Post-intervention scores for confidence in outpatient teaching and attitudes toward teaching were greater, relative to pre-intervention group means, for intervention residents (median pre-post changes +0.60 [IQR 0.26, 1.26] and +0.46 [-0.04, 0.46], respectively) vs controls (-0.15 [-0.48, 0.85] and -0.36 [-0.86, 0.39]; between-group differences +0.75 [P=.03] and +0.82 [P=.02]). Changes in attitudes toward primary care/outpatient medicine did not differ significantly between intervention and control groups (+0.43 [-0.07, 0.68] and 0.04 [-0.58, 0.42]; between-group difference +0.39 [P=.12]). In multivariable analyses, odds of gains in confidence in outpatient teaching remained significantly larger for intervention residents vs controls. Conclusions: Implementing PC Teach with existing resources was feasible and acceptable, with program flexibility highlighted as a strength. Resident participation was associated with greater confidence in outpatient teaching.

Early Postoperative Volume Overload is a Predictor of 1-Year Post-Transplant Mortality in Pediatric Heart Transplant Recipients.

Fluid restriction and diuretic management are mainstays in the postoperative management of cardiac patients, at risk of volume overload and its deleterious effects on primary cardiac function and multi-organ systems. The importance of fluid homeostasis is further emphasized among orthotopic heart transplant recipients (OHT). We sought to investigate the relationship between postoperative volume overload, mortality, and allograft dysfunction among pediatric OHT recipients within 1-year of transplantation. This is a retrospective cohort study from a single pediatric OHT center. Children under 21 years undergoing cardiac transplantation between 2010 and 2018 were included. Cumulative fluid overload (cFO) was assessed as percent fluid accumulation adjusted for preoperative body weight. Greater than 10% cFO defined those with postoperative cFO and a comparison of postoperative cFO vs. no postoperative cFO (< 5%) is reported. 102 pediatric OHT recipients were included. Early cFO at 72 h post-OHT occurred in 14% and overall cFO at 1-week post-OHT occurred in 23% of patients. Risk factors for cFO included younger age, lower weight, and postoperative ECMO. Early cFO was associated with postoperative mortality at 1-year, OR 8.6 (95% CI 1.4, 51.6), p = 0.04, independent of age and weight. There was no significant relationship between cFO and allograft dysfunction, measured by rates of clinical rejection and cardiopulmonary filling pressures within 1-year of transplant. Early postoperative volume overload is prevalent and associated with increased risk of death at 1-year among pediatric OHT recipients. It may be an important postoperative marker of transplant survival, and this relationship warrants further clinical investigation.

Volumetric Assessment of the Anterior Digastric Muscles: A Deeper Understanding of the Volumetric Changes With Aging.

BACKGROUND: Targeting the deeper, subplatysmal structures in the neck has recently grown in popularity. In particular, interventions targeting the "bulky" anterior digastric (AD) muscle have been described with excellent results. However, much remains to be understood about the deep anatomy of the neck and the age-associated changes of the AD. OBJECTIVES: The aim of this study was to examine the relationship between AD volume and age. METHODS: This retrospective study calculated the AD volume from MRI segmentation in subjects between the ages of 20 to 92 years, scans of whom had previously been recorded. Those with compromised imaging due to pathology or artifact were excluded. Subjects were divided into 4 age-defined cohorts for clinical applicability. RESULTS: This study included 129 patients (male n = 64) with a mean age of 52.3. The AD volume of the reference group was 3.2 cm3. A linear decrease in muscle volume was observed with age compared with the reference group: 2.95 cm3 in the 45- to 54-year-old cohort (P = 0.3), 2.7 cm3 in the 55- to 64-year-old cohort (P = 0.05), and 2.45 cm3 in the >65-year-old cohort (P < 0.001). Male sex (P = 0.0001) and laterality (P = 0.003) were associated with significantly larger volumes. Overweight and obese BMI classification was not associated with a significantly different volume than normal or underweight subjects (P = 0.067). CONCLUSIONS: The study findings suggest an age-associated reduction in AD volume. Gender and laterality significantly affected volume, whereas BMI did not. Although the results do not support the theory of muscular hypertrophy with aging, they reveal that the perceived bulkiness may be due to changes in the surrounding anatomy affecting the morphology of the AD and subsequent blunting of the cervicomental angle.

HCC EV ECG score: An extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma.

BACKGROUND AND AIMS: The sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC. APPROACH AND RESULTS: Tissue microarray was used to evaluate four potential HCC-associated protein markers. An HCC EV surface protein assay, composed of covalent chemistry-mediated HCC EV purification and real-time immuno-polymerase chain reaction readouts, was developed and optimized for quantifying subpopulations of EVs. An HCC EV ECG score, calculated from the readouts of three HCC EV subpopulations ( E pCAM + CD63 + , C D147 + CD63 + , and G PC3 + CD63 + HCC EVs), was established for detecting early-stage HCC. A phase 2 biomarker study was conducted to evaluate the performance of ECG score in a training cohort ( n  = 106) and an independent validation cohort ( n  = 72).Overall, 99.7% of tissue microarray stained positive for at least one of the four HCC-associated protein markers (EpCAM, CD147, GPC3, and ASGPR1) that were subsequently validated in HCC EVs. In the training cohort, HCC EV ECG score demonstrated an area under the receiver operating curve (AUROC) of 0.95 (95% confidence interval [CI], 0.90-0.99) for distinguishing early-stage HCC from cirrhosis with a sensitivity of 91% and a specificity of 90%. The AUROCs of the HCC EV ECG score remained excellent in the validation cohort (0.93; 95% CI, 0.87-0.99) and in the subgroups by etiology (viral: 0.95; 95% CI, 0.90-1.00; nonviral: 0.94; 95% CI, 0.88-0.99). CONCLUSION: HCC EV ECG score demonstrated great potential for detecting early-stage HCC. It could augment current surveillance methods and improve patients' outcomes.

Characterizing physiological high-frequency oscillations using deep learning.

Objective.Intracranially-recorded interictal high-frequency oscillations (HFOs) have been proposed as a promising spatial biomarker of the epileptogenic zone. However, HFOs can also be recorded in the healthy brain regions, which complicates the interpretation of HFOs. The present study aimed to characterize salient features of physiological HFOs using deep learning (DL).Approach.We studied children with neocortical epilepsy who underwent intracranial strip/grid evaluation. Time-series EEG data were transformed into DL training inputs. The eloquent cortex (EC) was defined by functional cortical mapping and used as a DL label. Morphological characteristics of HFOs obtained from EC (ecHFOs) were distilled and interpreted through a novel weakly supervised DL model.Main results.A total of 63 379 interictal intracranially-recorded HFOs from 18 children were analyzed. The ecHFOs had lower amplitude throughout the 80-500 Hz frequency band around the HFO onset and also had a lower signal amplitude in the low frequency band throughout a one-second time window than non-ecHFOs, resembling a bell-shaped template in the time-frequency map. A minority of ecHFOs were HFOs with spikes (22.9%). Such morphological characteristics were confirmed to influence DL model prediction via perturbation analyses. Using the resection ratio (removed HFOs/detected HFOs) of non-ecHFOs, the prediction of postoperative seizure outcomes improved compared to using uncorrected HFOs (area under the ROC curve of 0.82, increased from 0.76).Significance.We characterized salient features of physiological HFOs using a DL algorithm. Our results suggested that this DL-based HFO classification, once trained, might help separate physiological from pathological HFOs, and efficiently guide surgical resection using HFOs.

Peripheral CRF-R1/CRF-R2 antagonist, astressin C, induces a long-lasting blockade of acute stress-related visceral pain in male and female rats.

Peptide CRF antagonists injected peripherally alleviate stress-induced visceral hypersensitivity (SIVH) to colorectal distension (CRD) in rodents. Here we further evaluated the dose and time-dependent inhibitory activity of several long-acting peptide CRF receptor antagonists related to astressin on SIVH, focusing on astressin C (AstC), which previously showed high efficacy on stress-related alterations of HPA axis and gut secretomotor functions. Male and female Sprague-Dawley rats pretreated subcutaneously (SC) with AstC were injected intraperitoneally (IP) with CRF 15 min later. The visceromotor responses (VMR) to graded phasic CRD (10, 20, 40 and 60 mmHg) were monitored at basal, 15 min and up to 1-8 days after pretreatment. Two other astressin analogs, hexanoyl-astressin D (Hex-AstD) and [CαMeVal19,32]-AstC, were also tested. The response to IP CRF was sex-dependent with female rats requiring a higher dose to exhibit visceral hyperalgesia. Pretreatment with AstC (30-1000 µg/kg) resulted in a dose-related inhibition of IP CRF-induced SIVH and diarrhea in both sexes. The highest dose prevented SIVH and diarrhea up to 5-7 days after a single SC injection and was lost on day 7 (females) and day 8 (males) but reinstated after a second injection of AstC on day 8 or 9 respectively. [CαMeVal19,32]-AstC and Hex-AstD (1000 µg/kg in males) also prevented SIVH. These data show the potent long-lasting anti-hyperalgesic effect of AstC in an acute model of SIVH in both male and female rats. This highlights the potential of long-acting peripheral CRF antagonists to treat stress-sensitive irritable bowel syndrome.

Admission Source Is Associated With the Risk of Rapid Response Team Activation in a Children's Hospital.

OBJECTIVE: To evaluate source of admission to a children's hospital as a predictor of rapid response team (RRT) activation, both in the first 48 hours of admission and over the entire hospitalization. METHODS: Retrospective cohort study of all patients admitted to the pediatric ward between March 1, 2013 and December 31, 2015. Source of admission was categorized as from the emergency department, transfer from another hospital facility, admission following a planned surgery, direct admission planned in advance, or unplanned direct admission. Information was collected including whether or not the patient had a RRT activation and survival to discharge. A Fisher's exact test was used to assess the association between source of admission and risk of rapid response. RESULTS: Of 8083 admissions included in the study, 194 had at least one RRT event. The odds of having an RRT was significantly associated with source of admission (P < .001). Using admission from the emergency department as a reference group, planned elective admissions (odds ratio [OR] 0.27; P < .001) and admissions following planned surgery (OR 0.07; P < .001) were significantly associated with reduced odds of having at least one RRT activation during the admission. Planned elective admissions also demonstrated reduced odds of RRT in the first 48 hours of hospitalization (OR 0.14; P = .002). Source of admission was also associated with survival to discharge (P < .05). CONCLUSION: Source of admission is associated with likelihood of RRT activation as well as with survival to discharge and should be considered by providers when assessing inpatient risk of decompensation.

Tooth-Specific Streptococcus mutans Distribution and Associated Microbiome.

Dental caries is multifactorial and polymicrobial in nature and remains one of the most common oral diseases. While caries research has focused on Streptococcus mutans as the main etiological pathogen, its impact at the tooth level is not fully understood. In this cross-sectional study, the levels and distribution of S. mutans in the posterior teeth at different dentition stages were investigated along with the corresponding tooth-specific microbiome. Occlusal plaque samples of 87 individual posterior teeth were collected from thirty children in three dentition stages (primary, mixed, and permanent). The S. mutans levels in the occlusal plaque of individual posterior teeth were quantified with qPCR, and those with preferential colonization were selected for tooth-specific microbiome analysis using 16S rRNA sequencing. Results: Quantification of S. mutans levels in the occlusal plaque confirmed the preferential colonization on the first primary and permanent molars. These teeth were selected for further tooth-specific microbiome sequencing, as they also displayed high caries experience. There were significant differences in the relative abundance of the four most abundant genera: Neisseria, Streptococcus, Rothia, and Veillonella. Furthermore, the tooth-level caries experience was correlated with a reduction in the microbiome diversity. Analyzing the different tooth-associated microbial communities, distinct tooth-specific core microbiomes were identified. Conclusions: Our findings suggest that caries susceptibility at the tooth level, depending on tooth type and dentition stage, is influenced by individual species as well as plaque community.

Age-Related Changes in the Submandibular Gland: An Imaging Study of Gland Ptosis Versus Volume.

BACKGROUND: Debate surrounding the morphological evolution of the submandibular gland (SMG) with aging, and the uncertain influence of patient demographics, has led to hesitancy about incorporating targeted interventions of the SMG into clinical practice. OBJECTIVES: The aim of this study was to determine whether SMG ptosis, hypertrophy, or both is the primary etiology behind the increase in submandibular volume with age. METHODS: MRI segmentation was used to calculate the total and inframandibular (IM) volume and height of the SMG. Adult subjects with previous MRIs of the head and neck were used for analysis. Those with pathology or artifact compromising the SMG were excluded. Subjects were divided into 4 age-defined cohorts, for clinical applicability. RESULTS: The study included 129 patients (65 females; 64 males) with a mean age of 52.3 years (range, 20-85 years). No significant change in total SMG volume was observed between the reference group and all cohorts. The IM-SMG volume of the reference cohort was 5.77 cm3. All 3 cohorts had a greater IM-SMG volume than the reference group. The 45- to 54-year cohort had a mean volume of 6.7 cm3 (P = 0.4), the 55- to 64-year cohort, 7.5 cm3 (P = 0.01), and the ≥65-year cohort, 7.2 cm3 (P = 0.01). Male sex and overweight or obese BMI were associated with significantly larger total and IM-SMG volumes. CONCLUSIONS: The novel finding of a significantly larger IM-SMG volume with no change in total volume provides evidence for SMG ptosis rather than hypertrophy as a significant contributor to age-related submandibular fullness. The lack of any significant difference in total volume or height with aging emphasizes the role of glandular descent.

Oncologic Outcomes of Multi-Institutional Minimally Invasive Inguinal Lymph Node Dissection for Melanoma Compared with Open Inguinal Dissection in the Second Multicenter Selective Lymphadenectomy Trial (MSLT-II).

BACKGROUND: Minimally invasive inguinal lymphadenectomy (MILND) is safe and feasible, but limited data exist regarding oncologic outcomes. METHODS: This study performed a multi-institutional retrospective cohort analysis of consecutive MILND performed for melanoma between January 2009 and June 2016. The open ILND (OILND) comparative cohort comprised patients enrolled in the second Multicenter Selective Lymphadenectomy Trial (MSLT-II) between December 2004 and March 2014.The pre-defined primary end point was the same-basin regional nodal recurrence, calculated using properties of binomial distribution. Time to events was calculated using the Kaplan-Meier method. The secondary end points were overall survival, progression-free survival, melanoma-specific survival (MSS), and distant metastasis-free survival (DMFS). RESULTS: For all the patients undergoing MILND, the same-basin regional recurrence rate was 4.4 % (10/228; 95 % confidence interval [CI], 2.1-7.9 %): 8.2 % (4/49) for clinical nodal disease and 3.4 % (6/179) for patients with a positive sentinel lymph node (SLN) as the indication. For the 288 patients enrolled in MSLT-II who underwent OILND for a positive SLN, 17 (5.9 %) had regional node recurrence as their first event. After controlling for ulceration, positive LN count and positive non-SLNs at the time of lymphadenectomy, no difference in OS, PFS, MSS or DMFS was observed for patients with a positive SLN who underwent MILND versus OILND. CONCLUSION: This large multi-institutional experience supports the oncologic safety of MILND for melanoma. The outcomes in this large multi-institutional experience of MILND compared favorably with those for an OILND population during similar periods, supporting the oncologic safety of MILND for melanoma.

Sentinel lymph node melanoma metastases: Assessment of tumor burden for clinical prediction of outcome in the first Multicenter Selective Lymphadenectomy Trial (MSLT-I).

PURPOSE: As clinical management decisions in patients with Stage III melanoma have become more complex, precise pathologic characterization of sentinel lymph node (SLN) metastases has become critical to guide management. The extent of SLN involvement correlates with risk of adverse outcomes, but reported methods of disease quantification vary. We examined SLN metastases from patients participating in an international clinical trial and compared several methods of tumor burden quantification. METHODS: SLNs from 146 node-positive patients in the first Multicenter Selective Lymphadenectomy Trial (MSLT-I) were centrally-reviewed and characterized by number of tumor-positive nodes, percent nodal area tumor replacement, maximum dimension of largest metastasis, tumor penetrative depth, number of tumor foci, metastasis microanatomic location, and extracapsular extension. These data were analyzed for correlation with non-SLN metastasis and melanoma-specific survival (MSS). RESULTS: The median number of tumor-involved SLNs was 1. The median maximum metastasis dimension was 1.11 mm. Median SLN area involvement was 1.5%. Tumor burden measures were highly correlated with each other. Factors associated with non-SLN metastasis by univariable analysis were primary tumor ulceration and extent of metastases. Tumor thickness, ulceration, non-SLN metastasis and multiple measures of SLN tumor burden were significantly related to MSS on univariable analysis. After multivariable adjustment, number of involved SLNs (p = 0.05) and percent nodal area tumor replacement (p = 0.02) were independent predictors of MSS. CONCLUSION: Central review of MSLT-I pathology indicates that primary tumor and SLN tumor characteristics predict non-SLN metastasis and MSS. Percent nodal involvement was more powerfully prognostic than the more commonly used maximum dimension of largest metastasis.

Refining epileptogenic high-frequency oscillations using deep learning: a reverse engineering approach.

Intracranially recorded interictal high-frequency oscillations have been proposed as a promising spatial biomarker of the epileptogenic zone. However, its visual verification is time-consuming and exhibits poor inter-rater reliability. Furthermore, no method is currently available to distinguish high-frequency oscillations generated from the epileptogenic zone (epileptogenic high-frequency oscillations) from those generated from other areas (non-epileptogenic high-frequency oscillations). To address these issues, we constructed a deep learning-based algorithm using chronic intracranial EEG data via subdural grids from 19 children with medication-resistant neocortical epilepsy to: (i) replicate human expert annotation of artefacts and high-frequency oscillations with or without spikes, and (ii) discover epileptogenic high-frequency oscillations by designing a novel weakly supervised model. The 'purification power' of deep learning is then used to automatically relabel the high-frequency oscillations to distill epileptogenic high-frequency oscillations. Using 12 958 annotated high-frequency oscillation events from 19 patients, the model achieved 96.3% accuracy on artefact detection (F1 score = 96.8%) and 86.5% accuracy on classifying high-frequency oscillations with or without spikes (F1 score = 80.8%) using patient-wise cross-validation. Based on the algorithm trained from 84 602 high-frequency oscillation events from nine patients who achieved seizure-freedom after resection, the majority of such discovered epileptogenic high-frequency oscillations were found to be ones with spikes (78.6%, P < 0.001). While the resection ratio of detected high-frequency oscillations (number of resected events/number of detected events) did not correlate significantly with post-operative seizure freedom (the area under the curve = 0.76, P = 0.06), the resection ratio of epileptogenic high-frequency oscillations positively correlated with post-operative seizure freedom (the area under the curve = 0.87, P = 0.01). We discovered that epileptogenic high-frequency oscillations had a higher signal intensity associated with ripple (80-250 Hz) and fast ripple (250-500 Hz) bands at the high-frequency oscillation onset and with a lower frequency band throughout the event time window (the inverted T-shaped), compared to non-epileptogenic high-frequency oscillations. We then designed perturbations on the input of the trained model for non-epileptogenic high-frequency oscillations to determine the model's decision-making logic. The model confidence significantly increased towards epileptogenic high-frequency oscillations by the artificial introduction of the inverted T-shaped signal template (mean probability increase: 0.285, P < 0.001), and by the artificial insertion of spike-like signals into the time domain (mean probability increase: 0.452, P < 0.001). With this deep learning-based framework, we reliably replicated high-frequency oscillation classification tasks by human experts. Using a reverse engineering technique, we distinguished epileptogenic high-frequency oscillations from others and identified its salient features that aligned with current knowledge.

Automated preprocessing and phase-amplitude coupling analysis of scalp EEG discriminates infantile spasms from controls during wakefulness.

OBJECTIVE: Delta-gamma phase-amplitude coupling in EEG is useful for localizing epileptic sources and to evaluate severity in children with infantile spasms. We (1) develop an automated EEG preprocessing pipeline to clean data using artifact subspace reconstruction (ASR) and independent component (IC) analysis (ICA) and (2) evaluate delta-gamma modulation index (MI) as a method to distinguish children with epileptic spasms (cases) from normal controls during sleep and awake. METHODS: Using 400 scalp EEG datasets (200 sleep, 200 awake) from 100 subjects, we calculated MI after applying high-pass and line-noise filters (Clean 0), and after ASR followed by either conservative (Clean 1) or stringent (Clean 2) artifactual IC rejection. Classification of cases and controls using MI was evaluated with Receiver Operating Characteristics (ROC) to obtain area under curve (AUC). RESULTS: The artifact rejection algorithm reduced raw signal variance by 29-45% and 38-60% for Clean 1 and Clean 2, respectively. MI derived from sleep data, with or without preprocessing, robustly classified the groups (all AUC > 0.98). In contrast, group classification using MI derived from awake data was successful only after Clean 2 (AUC = 0.85). CONCLUSIONS: We have developed an automated EEG preprocessing pipeline to perform artifact rejection and quantify delta-gamma modulation index.

Circulating trophoblast cell clusters for early detection of placenta accreta spectrum disorders.

Placenta accreta spectrum (PAS) is a high-risk obstetrical condition associated with significant morbidity and mortality. Current clinical screening modalities for PAS are not always conclusive. Here, we report a nanostructure-embedded microchip that efficiently enriches both single and clustered circulating trophoblasts (cTBs) from maternal blood for detecting PAS. We discover a uniquely high prevalence of cTB-clusters in PAS and subsequently optimize the device to preserve the intactness of these clusters. Our feasibility study on the enumeration of cTBs and cTB-clusters from 168 pregnant women demonstrates excellent diagnostic performance for distinguishing PAS from non-PAS. A logistic regression model is constructed using a training cohort and then cross-validated and tested using an independent cohort. The combined cTB assay achieves an Area Under ROC Curve of 0.942 (throughout gestation) and 0.924 (early gestation) for distinguishing PAS from non-PAS. Our assay holds the potential to improve current diagnostic modalities for the early detection of PAS.

Thrombomodulin is associated with increased mortality and organ failure in mechanically ventilated children with acute respiratory failure: biomarker analysis from a multicenter randomized controlled trial.

BACKGROUND: Acute respiratory failure (ARF) can progress to acute respiratory distress syndrome and death. Biomarkers may allow for risk stratification and prognostic enrichment in ARF. Thrombomodulin (TM) is a transmembrane antithrombotic mediator expressed in endothelial cells. It is cleaved into its soluble form (sTM) during inflammation and vascular injury. Levels of sTM correlate with inflammation and end organ dysfunction. METHODS: This was a prospective observational study of 432 patients aged 2 weeks-17 years requiring invasive mechanical ventilation. It was ancillary to the multicenter clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE). After consent, patients had up to 3 plasma samples collected at 24-h intervals within 5 days after intubation. sTM was assayed by ELISA. The Hazard ratio (HR) for 90-day mortality was determined by Cox regression. Mixed effect models (MEM) were used to test for association with extrapulmonary multiorgan failure (MOF) and oxygenation index (OI). Age, race, sex and PRISM-III scores were used as confounding variables for multivariable analyses. RESULTS: sTM values ranged from 16.6 to 670.9 ng/ml within 5 days after intubation. Higher sTM was associated with increased 90-day mortality (n = 432, adjusted HR = 1.003, p = 0.02) and worse OI in the first 5 days after intubation (n = 252, Estimate = 0.02, p < 0.01). Both initial and slope of sTM were associated with increased extrapulmonary MOF in unadjusted and adjusted analyses (Intercept, Estimate = 0.003, p < 0.0001; and slope, Estimate = 0.01, p = 0.0009, n = 386). CONCLUSIONS: Plasma sTM is associated with mortality, severity of hypoxic respiratory failure and worsening extrapulmonary MOF in children with ARF. This suggests a role of vascular injury in the pathogenesis of ARF and provides potential applicability towards targeted therapies. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT00814099 . In healthy lung endothelium, thrombomodulin (TM) recruits thrombin to activate Protein-C (PC/APC), that inhibits plasminogen activator-1 (PAI-1) and thrombosis. In inflamed and damaged endothelium, TM is cleaved into its soluble form (sTM), precluding its usual regulation of thrombosis. In this study, we measured plasma sTM levels in pediatric patients with respiratory failure and found that sTM correlated with mortality and other clinical markers of poor outcomes.