Acetylcholine Engages Distinct Amygdala Microcircuits to Gate Internal Theta Rhythm.

Acetylcholine (ACh) is released from basal forebrain cholinergic neurons in response to salient stimuli and engages brain states supporting attention and memory. These high ACh states are associated with theta oscillations, which synchronize neuronal ensembles. Theta oscillations in the basolateral amygdala (BLA) in both humans and rodents have been shown to underlie emotional memory, yet their mechanism remains unclear. Here, using brain slice electrophysiology in male and female mice, we show large ACh stimuli evoke prolonged theta oscillations in BLA local field potentials that depend upon M3 muscarinic receptor activation of cholecystokinin (CCK) interneurons (INs) without the need for external glutamate signaling. Somatostatin (SOM) INs inhibit CCK INs and are themselves inhibited by ACh, providing a functional SOM→CCK IN circuit connection gating BLA theta. Parvalbumin (PV) INs, which can drive BLA oscillations in baseline states, are not involved in the generation of ACh-induced theta, highlighting that ACh induces a cellular switch in the control of BLA oscillatory activity and establishes an internally BLA-driven theta oscillation through CCK INs. Theta activity is more readily evoked in BLA over the cortex or hippocampus, suggesting preferential activation of the BLA during high ACh states. These data reveal a SOM→CCK IN circuit in the BLA that gates internal theta oscillations and suggest a mechanism by which salient stimuli acting through ACh switch the BLA into a network state enabling emotional memory.

Differential Regulation of Prelimbic and Thalamic Transmission to the Basolateral Amygdala by Acetylcholine Receptors.

The amygdalar anterior basolateral nucleus (BLa) plays a vital role in emotional behaviors. This region receives dense cholinergic projections from basal forebrain which are critical in regulating neuronal activity in BLa. Cholinergic signaling in BLa has also been shown to modulate afferent glutamatergic inputs to this region. However, these studies, which have used cholinergic agonists or prolonged optogenetic stimulation of cholinergic fibers, may not reflect the effect of physiological acetylcholine release in the BLa. To better understand these effects of acetylcholine, we have used electrophysiology and optogenetics in male and female mouse brain slices to examine cholinergic regulation of afferent BLa input from cortex and midline thalamic nuclei. Phasic ACh release evoked by single pulse stimulation of cholinergic terminals had a biphasic effect on transmission at cortical input, producing rapid nicotinic receptor-mediated facilitation followed by slower mAChR-mediated depression. In contrast, at this same input, sustained ACh elevation through application of the cholinesterase inhibitor physostigmine suppressed glutamatergic transmission through mAChRs only. This suppression was not observed at midline thalamic nuclei inputs to BLa. In agreement with this pathway specificity, the mAChR agonist, muscarine more potently suppressed transmission at inputs from prelimbic cortex than thalamus. Muscarinic inhibition at prelimbic cortex input required presynaptic M4 mAChRs, while at thalamic input it depended on M3 mAChR-mediated stimulation of retrograde endocannabinoid signaling. Muscarinic inhibition at both pathways was frequency-dependent, allowing only high-frequency activity to pass. These findings demonstrate complex cholinergic regulation of afferent input to BLa that is pathway-specific and frequency-dependent.SIGNIFICANCE STATEMENT Cholinergic modulation of the basolateral amygdala regulates formation of emotional memories, but the underlying mechanisms are not well understood. Here, we show, using mouse brain slices, that ACh differentially regulates afferent transmission to the BLa from cortex and midline thalamic nuclei. Fast, phasic ACh release from a single optical stimulation biphasically regulates glutamatergic transmission at cortical inputs through nicotinic and muscarinic receptors, suggesting that cholinergic neuromodulation can serve precise, computational roles in the BLa. In contrast, sustained ACh elevation regulates cortical input through muscarinic receptors only. This muscarinic regulation is pathway-specific with cortical input inhibited more strongly than midline thalamic nuclei input. Specific targeting of these cholinergic receptors may thus provide a therapeutic strategy to bias amygdalar processing and regulate emotional memory.

Guideline-compliant adjuvant chemotherapy for resected high risk oral cavity cancer: Homefield advantage.

PURPOSE: Factors that are associated with failure to receive guideline-compliant adjuvant chemotherapy after resection of high-risk oral cavity cancer are understudied. Here, we performed a retrospective cohort study of surgically treated patients with oral cavity squamous cell carcinoma to determine rates of guideline-compliant adjuvant chemotherapy and to examine patient factors associated with receiving guideline-compliant chemotherapy. STUDY DESIGN: Retrospective cohort. SETTING: Two tertiary care referral centers. METHODS: Patients with resected high-risk oral cavity squamous cell carcinoma and known adjuvant therapy details were included. Extranodal extension or positive margins were considered high-risk features for which adjuvant chemoradiation was indicated. Patient factors were examined to determine associations with receiving on-guidelines treatment. Univariable and multivariable logistic regression were used to determine significance of associations. RESULTS: 75 patients were included. 36 (48 %) patients received guideline-compliant cisplatin. In total, 39 (52 %) patients did not receive guideline-compliant chemotherapy. On multivariable analysis, meeting with a university medical oncologist was significantly associated with the receipt of guideline-compliant cisplatin (OR 6.38, 95 % CI 2.26-20.0, p < 0.001). CONCLUSION: Adherence to on-guidelines treatment can be difficult to achieve in patients with advanced stage head and neck cancer. Meeting with university medical oncology is associated with an increased chance of receiving guideline-compliant chemotherapy.

COVID-19 impact on facial trauma: Insights from Mississippi's only level 1 trauma center.

PURPOSE: Our primary aim was to understand and describe the impact of COVID-19 on the incidence and etiology of facial trauma in the state of Mississippi. METHODS: Retrospective review of facial trauma-related Emergency Department encounters in Mississippi from March 11, 2019 to March 10, 2021, divided into three time periods using the state of Mississippi's Governor's Office Executive Orders. Chi-square tests and segmented linear regressions were used for analysis. RESULTS: Patients presenting with facial trauma were typically male, 18-44 years old, and lived in urban zip codes. Insurance payors significantly differed across time periods. There were no significant differences in self-inflicted assault or accidental injury between the 3 time periods, with pre- and pandemic patients more likely to be self-pay while patients during recovery being more likely to have private insurance. During the pandemic, facial trauma from a family member, partner or spouse, or other person in the household significantly increased. CONCLUSION: Similar accidental facial trauma trends may reflect lower adherence to social distancing guidelines. The increase in facial trauma perpetrated by family members is consistent with reported increases in domestic violence during the pandemic. While overall facial trauma demographic patterns did not change significantly during the COVID-19 pandemic, there were notable changes in the etiology and insurance payor of facial trauma cases. LAY SUMMARY: The COVID-19 pandemic impacted healthcare systems worldwide, and our study seeks to understand how the pandemic affected incidence of facial trauma.

Evaluation of the CARES Skills Framework as a Peer Support Model in the Paramedic Undergraduate Curriculum: Facilitating Challenging Discussions in a Safe Environment.

OBJECTIVE: Infant or child death is reported as being the most distressing type of case paramedics attend. Student paramedics also identify supporting bereaved families as an area associated with low confidence. This study evaluated the CARES skills framework (Connect to emotion, Attention training, Reflective listening, Empathy, Support help seeking) as a peer support model to encourage student paramedics to talk about grief and death related to infants and children. METHOD: A convenience sample of first-year paramedic students (target n = 154) was recruited from a single Australian regional university. A modified nominal group technique method was used following a student debriefing session designed to identify problems, generate solutions, and make decisions regarding the efficacy of the CARES skills framework. RESULTS: Of 154 eligible participants, 141 participated (92% response rate). Peer social support normalized students' emotions related to death and dying. Although naming emotions was challenging, students reported that the CARES model facilitated a safe environment to talk about death and dying. Students reported feeling heard and connected to their peers during the exercise and an enhanced sense of belonging after the exercise. CONCLUSIONS: Findings contribute to evidence that suggests the CARES model is a useful mechanism to enhance peer social support in paramedic students.

A systematic review on inequalities in accessing and using community-based social care in dementia.

OBJECTIVES: To evaluate and synthesize the evidence base on barriers and facilitators to accessing and using community-based social care in dementia. DESIGN: Mixed-methods systematic review. SETTING: Community-based social care (such as day care, respite care, paid home care, and peer support groups). PARTICIPANTS: People living with dementia and unpaid carers. MEASUREMENTS: Seven databases were searched in March 2022, including English and German evidence published from 2000 focusing on inequalities in community-based social care for dementia across the globe. Titles and abstracts were screened by two reviewers, with all full texts screened by two reviewers also. Study quality was assessed using QualSyst. RESULTS: From 3,904 screened records, 39 papers were included. The majority of studies were qualitative, with 23 countries represented. Barriers and facilitators could be categorized into the following five categories/themes: situational, psychological, interpersonal, structural, and cultural. Barriers were notably more prominent than facilitators and were multifaceted, with many factors hindering or facilitating access to social care linked together. CONCLUSIONS: People with dementia and carers experience significant barriers in accessing care in the community, and a varied approach on multiple levels is required to address systemic and individual-level barriers to enable more equitable access to care for all.

OpenABM-Covid19-An agent-based model for non-pharmaceutical interventions against COVID-19 including contact tracing.

SARS-CoV-2 has spread across the world, causing high mortality and unprecedented restrictions on social and economic activity. Policymakers are assessing how best to navigate through the ongoing epidemic, with computational models being used to predict the spread of infection and assess the impact of public health measures. Here, we present OpenABM-Covid19: an agent-based simulation of the epidemic including detailed age-stratification and realistic social networks. By default the model is parameterised to UK demographics and calibrated to the UK epidemic, however, it can easily be re-parameterised for other countries. OpenABM-Covid19 can evaluate non-pharmaceutical interventions, including both manual and digital contact tracing, and vaccination programmes. It can simulate a population of 1 million people in seconds per day, allowing parameter sweeps and formal statistical model-based inference. The code is open-source and has been developed by teams both inside and outside academia, with an emphasis on formal testing, documentation, modularity and transparency. A key feature of OpenABM-Covid19 are its Python and R interfaces, which has allowed scientists and policymakers to simulate dynamic packages of interventions and help compare options to suppress the COVID-19 epidemic.

COVID-19 mortality prediction in the intensive care unit with deep learning based on longitudinal chest X-rays and clinical data.

OBJECTIVES: We aimed to develop deep learning models using longitudinal chest X-rays (CXRs) and clinical data to predict in-hospital mortality of COVID-19 patients in the intensive care unit (ICU). METHODS: Six hundred fifty-four patients (212 deceased, 442 alive, 5645 total CXRs) were identified across two institutions. Imaging and clinical data from one institution were used to train five longitudinal transformer-based networks applying five-fold cross-validation. The models were tested on data from the other institution, and pairwise comparisons were used to determine the best-performing models. RESULTS: A higher proportion of deceased patients had elevated white blood cell count, decreased absolute lymphocyte count, elevated creatine concentration, and incidence of cardiovascular and chronic kidney disease. A model based on pre-ICU CXRs achieved an AUC of 0.632 and an accuracy of 0.593, and a model based on ICU CXRs achieved an AUC of 0.697 and an accuracy of 0.657. A model based on all longitudinal CXRs (both pre-ICU and ICU) achieved an AUC of 0.702 and an accuracy of 0.694. A model based on clinical data alone achieved an AUC of 0.653 and an accuracy of 0.657. The addition of longitudinal imaging to clinical data in a combined model significantly improved performance, reaching an AUC of 0.727 (p = 0.039) and an accuracy of 0.732. CONCLUSIONS: The addition of longitudinal CXRs to clinical data significantly improves mortality prediction with deep learning for COVID-19 patients in the ICU. KEY POINTS: • Deep learning was used to predict mortality in COVID-19 ICU patients. • Serial radiographs and clinical data were used. • The models could inform clinical decision-making and resource allocation.

Medication adherence prediction through temporal modelling in cardiovascular disease management.

BACKGROUND: Chronic conditions place a considerable burden on modern healthcare systems. Within New Zealand and worldwide cardiovascular disease (CVD) affects a significant proportion of the population and it is the leading cause of death. Like other chronic diseases, the course of cardiovascular disease is usually prolonged and its management necessarily long-term. Despite being highly effective in reducing CVD risk, non-adherence to long-term medication continues to be a longstanding challenge in healthcare delivery. The study investigates the benefits of integrating patient history and assesses the contribution of explicitly temporal models to medication adherence prediction in the context of lipid-lowering therapy. METHODS: Data from a CVD risk assessment tool is linked to routinely collected national and regional data sets including pharmaceutical dispensing, hospitalisation, lab test results and deaths. The study extracts a sub-cohort from 564,180 patients who had primary CVD risk assessment for analysis. Based on community pharmaceutical dispensing record, proportion of days covered (PDC) [Formula: see text] 80 is used as the threshold for adherence. Two years (8 quarters) of patient history before their CVD risk assessment is used as the observation window to predict patient adherence in the subsequent 5 years (20 quarters). The predictive performance of temporal deep learning models long short-term memory (LSTM) and simple recurrent neural networks (Simple RNN) are compared against non-temporal models multilayer perceptron (MLP), ridge classifier (RC) and logistic regression (LR). Further, the study investigates the effect of lengthening the observation window on the task of adherence prediction. RESULTS: Temporal models that use sequential data outperform non-temporal models, with LSTM producing the best predictive performance achieving a ROC AUC of 0.805. A performance gap is observed between models that can discover non-linear interactions between predictor variables and their linear counter parts, with neural network (NN) based models significantly outperforming linear models. Additionally, the predictive advantage of temporal models become more pronounced when the length of the observation window is increased. CONCLUSION: The findings of the study provide evidence that using deep temporal models to integrate patient history in adherence prediction is advantageous. In particular, the RNN architecture LSTM significantly outperforms all other model comparators.

Resilience and post-traumatic growth in the transition to motherhood during the COVID-19 pandemic: A qualitative exploratory study.

Most perinatal research relating to COVID-19 focuses on its negative impact on maternal and parental mental health. Currently, there are limited data on how to optimise positive health during the pandemic. We aimed to bridge this knowledge gap by exploring how women have adapted to becoming a new parent during the pandemic and to identify elements of resilience and growth within their narratives. Mothers of infants under the age of 4 months were recruited as part of a wider UK mixed-methods study. Semi-structured interviews with 20 mothers elicited data about how COVID-19 had influenced their transition to parent a new infant, and if and how they adapted during the pandemic, what strategies they used, and if and how these had been effective. Directed qualitative content analysis was undertaken, and pre-existing theoretical frameworks of resilience and post-traumatic growth (PTG) were used to analyse and interpret the data set. The findings show evidence of a range of resilience and PTG concepts experienced during the pandemic in this cohort. Salient resilience themes included personal (active coping, reflective functioning, and meaning-making), relational (social support, partner relationships, and family relationships), and contextual (health and social connectedness) factors. There was also evidence of PTG in terms of the potential for new work-related and leisure opportunities, and women developing wider and more meaningful connections with others. Although further research is needed, and with individuals from diverse socioeconomic backgrounds, these findings emphasise the significance of social support and connectivity as vital to positive mental health. Opportunities to increase digital innovations to connect and support new parents should be maximised to buffer the negative impacts of further social distancing and crisis situations.

Evaluation of Electrospun PCL-PLGA for Sustained Delivery of Kartogenin.

In this study, kartogenin was incorporated into an electrospun blend of polycaprolactone and poly(lactic-co-glycolic acid) (1:1) to determine the feasibility of this system for sustained drug delivery. Kartogenin is a small-molecule drug that could enhance the outcome of microfracture, a cartilage restoration procedure, by selectively stimulating chondrogenic differentiation of endogenous bone marrow mesenchymal stem cells. Experimental results showed that kartogenin did not affect the electrospinnability of the polymer blend, and it had negligible effects on fiber morphology and scaffold mechanical properties. The loading efficiency of kartogenin into electrospun membranes was nearly 100%, and no evidence of chemical reaction between kartogenin and the polymers was detected by Fourier transform infrared spectroscopy. Analysis of the released drug using high-performance liquid chromatography-photodiode array detection indicated an abundance of kartogenin and only a small amount of its major hydrolysis product. Kartogenin displayed a typical biphasic release profile, with approximately 30% being released within 24 h followed by a much slower, constant rate of release up to 28 days. Although additional development is needed to tune the release kinetics and address issues common to electrospun scaffolds (e.g., high fiber density), the results of this study demonstrated that a scaffold electrospun from biodegradable synthetic polymers is a suitable kartogenin delivery vehicle.

Environmentally Relevant Iron Oxide Nanoparticles Produce Limited Acute Pulmonary Effects in Rats at Realistic Exposure Levels.

Iron is typically the dominant metal in the ultrafine fraction of airborne particulate matter. Various studies have investigated the toxicity of inhaled nano-sized iron oxide particles (FeOxNPs) but their results have been contradictory, with some indicating no or minor effects and others finding effects including oxidative stress and inflammation. Most studies, however, did not use materials reflecting the characteristics of FeOxNPs present in the environment. We, therefore, analysed the potential toxicity of FeOxNPs of different forms (Fe3O4, α-Fe2O3 and γ-Fe2O3) reflecting the characteristics of high iron content nano-sized particles sampled from the environment, both individually and in a mixture (FeOx-mix). A preliminary in vitro study indicated Fe3O4 and FeOx-mix were more cytotoxic than either form of Fe2O3 in human bronchial epithelial cells (BEAS-2B). Follow-up in vitro (0.003, 0.03, 0.3 µg/mL, 24 h) and in vivo (Sprague-Dawley rats, nose-only exposure, 50 µg/m3 and 500 µg/m3, 3 h/d × 3 d) studies therefore focused on these materials. Experiments in vitro explored responses at the molecular level via multi-omics analyses at concentrations below those at which significant cytotoxicity was evident to avoid detection of responses secondary to toxicity. Inhalation experiments used aerosol concentrations chosen to produce similar levels of particle deposition on the airway surface as were delivered in vitro. These were markedly higher than environmental concentrations. No clinical signs of toxicity were seen nor effects on BALF cell counts or LDH levels. There were also no significant changes in transcriptomic or metabolomic responses in lung or BEAS-2B cells to suggest adverse effects.

Equine pregnancy-specific glycoprotein CEACAM49 secreted by endometrial cup cells activates TGFB.

In early equine pregnancy, a highly invasive trophoblast cell subpopulation, the chorionic girdle cells, invade the endometrium and form endometrial cups (EC). These cells express classical MHC molecules, thereby stimulating a humoral and cellular immune response, resulting in a massive accumulation of maternal CD4+ and CD8+ T cells around the EC. Nevertheless, no immediate destruction of endometrial cups by maternal lymphoid cells occurs, presumably due to immune tolerance. Although the environment of EC is rich in TGFB and in FOXP3+, CD4+ T cells, the mechanisms leading to tolerance have not been elucidated. Recently, we discovered that equine trophoblast cells secrete pregnancy-specific glycoproteins (PSGs). Since human and murine PSGs activate latent TGFB, we hypothesized that equine PSGs may have a similar activity. We performed plasmon surface resonance experiments to show that equine PSG CEACAM49 can directly bind to the latency-associated peptide (LAP) of both TGFB1 and TGFB2. We then found that the binding of CEACAM49 leads to the activation of TGFB1 as determined by both ELISA and cell-based assays. Furthermore, the activation of TGFB is a unique function of PSGs within the human CEA family, because CEACAM1, 3, 5, 6, 8 do not activate this cytokine. This finding further strengthens the classification of CEACAM49 as an equine PSG. Based on our results, we hypothesize that activation of latent TGFB in the EC environment by equine PSGs secreted by invasive trophoblast cells, could contribute to the generation of regulatory T cells (Tregs) to maintain immune tolerance.

Recombinant Pregnancy-Specific Glycoprotein 1 Has a Protective Role in a Murine Model of Acute Graft-versus-Host Disease.

Acute graft-versus-host disease (aGVHD) is an immune-mediated reaction that can occur after hematopoietic stem cell transplantation in which donor T cells recognize the host antigens as foreign, destroying host tissues. Establishment of a tolerogenic immune environment while preserving the immune response to infectious agents is required for successful bone marrow transplantation. Pregnancy-specific glycoprotein 1 (PSG1), which is secreted by the human placenta into the maternal circulation throughout pregnancy, likely plays a role in maintaining immunotolerance to prevent rejection of the fetus by the maternal immune system. We have previously shown that PSG1 activates the latent form of transforming growth factor ß1 (TGF-ß), a cytokine essential for the differentiation of tolerance-inducing CD4+FoxP3+ regulatory T cells (Tregs). Consistent with this observation, treatment of naïve murine T cells with PSG1 resulted in a significant increase in FoxP3+ cells that was blocked by a TGF-ß receptor I inhibitor. We also show here that PSG1 can increase the availability of active TGF-ß in vivo. As the role of CD4+FoxP3+ cells in the prevention of aGVHD is well established, we tested whether PSG1 has beneficial effects in a murine aGHVD transplantation model. PSG1-treated mice had reduced numbers of tissue-infiltrating inflammatory CD3+ T cells and had increased expression of FoxP3 in T cells compared with vehicle-treated mice. In addition, administration of PSG1 significantly inhibited aGVHD-associated weight loss and mortality. On the other hand, administration of PSG1 was less effective in managing aGVHD in the presence of an alloimmune reaction against a malignancy in a graft-versus-leukemia experimental model. Combined, this data strongly suggests that PSG1 could be a promising treatment option for patients with aGVHD following bone marrow transplantation for a nonmalignant condition, such as an autoimmune disorder or a genetic immunodeficiency.

Activation of latent transforming growth factor-ß1, a conserved function for pregnancy-specific beta 1-glycoproteins.

STUDY QUESTION: Do all 10 human pregnancy-specific beta 1-glycoproteins (PSGs) and murine PSG23 activate latent transforming growth factor-ß1 (TGF-ß1)? SUMMARY ANSWER: All human PSGs and murine PSG23 activated latent TGF-ß1. WHAT IS KNOWN ALREADY: Two of the 10 members of the PSG1 family, PSG1 and PSG9, were previously shown to activate the soluble small latent complex of TGF-ß1, a cytokine with potent immune suppressive functions. STUDY DESIGN, SIZE, DURATION: Recombinant PSGs were generated and tested for their ability to activate the small latent complex of TGF-ß1 in a cell-free ELISA-based assay and in a bioassay. In addition, we tested the ability of PSG1 and PSG4 to activate latent TGF-ß bound to the extracellular matrix (ECM) or on the membranes of the Jurkat human T-cell line. PARTICIPANTS/MATERIALS, SETTING, METHODS: Recombinant PSGs were generated by transient transfection and purified with a His-Trap column followed by gel filtration chromatography. The purified PSGs were compared to vehicle (PBS) used as control for their ability to activate the small latent complex of TGF-ß1. The concentration of active TGF-ß was measured in an ELISA using the TGF-ß receptor II as capture and a bioassay using transformed mink epithelial cells that express luciferase in response to active TGF-ß. The specificity of the signal was confirmed using a TGF-ß receptor inhibitor. We also measured the binding kinetics of some human PSGs for the latent-associated peptide (LAP) of TGF-ß using surface plasmon resonance and determined whether PSG1 and PSG4 could activate the large latent complex of TGF-ß1 bound to the ECM and latent TGF-ß1 bound to the cell membrane. All experiments were performed in triplicate wells and repeated three times. MAIN RESULTS AND THE ROLE OF CHANCE: All human PSGs activated the small latent complex of TGF-ß1 (P < 0.05 vs. control) and showed similar affinities (KD) for LAP. Despite the lack of sequence conservation with its human counterparts, the ability to activate latent TGF-ß1 was shared by a member of the murine PSG family. We found that PSG1 and PSG4 activated the latent TGF-ß stored in the ECM (P < 0.01) but did not activate latent TGF-ß1 bound to glycoprotein A repetitions predominant (GARP) on the surface of Jurkat T cells. LIMITATIONS, REASONS FOR CAUTION: The affinity of the interaction of LAP and PSGs was calculated using recombinant proteins, which may differ from the native proteins in their post-translational modifications. We also utilized a truncated form of murine PSG23 rather than the full-length protein. For the studies testing the ability of PSGs to activate membrane-bound TGF-ß1, we utilized the T-cell line Jurkat and Jurkat cells expressing GARP rather than primary T regulatory cells. All the studies were performed in vitro. WIDER IMPLICATIONS OF THE FINDINGS: Here, we show that all human PSGs activate TGF-ß1 and that this function is conserved in at least one member of the rodent PSG family. In vivo PSGs could potentially increase the availability of active TGF-ß1 from the soluble and matrix-bound latent forms of the cytokine contributing to the establishment of a tolerogenic environment during pregnancy. LARGE-SCALE DATA: None. STUDY FUNDING/COMPETING INTEREST(S): The research was supported by a grant from the Collaborative Health Initiative Research Program (CHIRP). No conflicts of interests are declared by the authors.

Rapid 12-lead automated localization method: Comparison to electrocardiographic imaging (ECGI) in patient-specific geometry.

BACKGROUND: Rapid accurate localization of the site of ventricular activation origin during catheter ablation for ventricular arrhythmias could facilitate the procedure. Electrocardiographic imaging (ECGI) using large lead sets can localize the origin of ventricular activation. We have developed an automated method to identify sites of early ventricular activation in real time using the 12-lead ECG. We aim to compare the localization accuracy of ECGI and the automated method, identifying pacing sites/VT exit based on a patient-specific model. METHODS: A patient undergoing ablation of VT on the left-ventricular endocardium and epicardium had 120-lead body-surface potential mapping (BSPM) recorded during the procedure. (1) ECGI methodology: The L1-norm regularization was employed to reconstruct epicardial potentials based on patient-specific geometry for localizing endocardial ventricular activation origin. We used the BSPM data corresponding to known endocardial pacing sites and a VT exit site identified by 3D contact mapping to analyze them offline. (2) The automatedmethod: location coordinates of pacing sites together with the time integral of the first 120 ms of the QRS complex of 3 ECG predictors (leads III, V2 and V6) were used to calculate patient-specific regression coefficients to predict the location of unknown sites of ventricular activation origin ("target" sites). Localization error was quantified over all pacing sites in millimeters by comparing the calculated location and the known reference location. RESULTS: Localization was tested for 14 endocardial pacing sites and 1 epicardial VT exit site. For 14 endocardial pacing sites the mean localization error of the automated method was significantly lower than that of the ECGI (8.9 vs. 24.9 mm, p < 0.01), when 10 training pacing sites are used. Emulation of a clinical procedure demonstrated that the automated method achieved localization error of <5 mm for the VT-exit site; while the ECGI approach approximately correlates with the site of VT exit from the scar within a distance of 18.4 mm. CONCLUSIONS: The automated method using only 3 ECGs shows promise to localize the origin of ventricular activation as tested by pacing, and the VT-exit site and compares favourably to inverse solution calculation, avoiding cumbersome lead sets. As 12-lead ECG data is acquired by current 3D mapping systems, it is conceivable that the algorithm could be directly incorporated into a mapping system. Further validation in a prospective cohort study is needed to confirm and extend observations reported in this study.

Criteria for ECG detection of acute myocardial ischemia: Sensitivity versus specificity.

BACKGROUND: Criteria for electrocardiographic detection of acute myocardial ischemia recommended by the Consensus Document of ESC/ACCF/AHA/WHF consist of two parts: The ST elevation myocardial infarction (STEMI) criteria based on ST elevation (ST↑) in 10 pairs of contiguous leads and the other on ST depression (ST↓) in the same 10 contiguous pairs. Our aim was to assess sensitivity (SE) and specificity (SP) of these criteria-and to seek their possible improvements-in three databases of 12­lead ECGs. METHODS: We used (1) STAFF III data of controlled ischemic episodes recorded from 99 patients (pts) during percutaneous coronary intervention (PCI) involving either left anterior descending (LAD) coronary artery, right coronary artery (RCA), or left circumflex (LCx) coronary artery. (2) Data from the University of Glasgow for 58 pts with acute myocardial infarction (AMI) and 58 pts without AMI, as confirmed by MRI. (3) Data from Lund University retrieved from a centralized ECG management system for 100 pts with various pathological ST changes-other than acute coronary occlusion-including ventricular pre-excitation, acute pericarditis, early repolarization syndrome, left ventricular hypertrophy, and left bundle branch block. ST measurements at J-point in ECGs of all 315 pts were obtained automatically on the averaged beat with manual review and the recommended criteria as well as their proposed modifications, were applied. Performance measures included SE, SP, positive predictive value (PPV), and benefit-to-harm ratio (BHR), defined as the ratio of true-positive vs. false-positive detections. RESULTS: We found that the SE of widely-used STEMI criteria can be indeed improved by the additional ST↓ criteria, but at the cost of markedly decreased SP. In contrast, using ST↑ in only 3 additional contiguous pairs of leads (STEMI13) can boost SE without any loss of SP. In the STAFF III database, SE/SP/PPV were 56/98/97% for the STEMI, 79/79/79% for the STEMI with added ST↓ and 67/97/96% for the STEMI13. In the Glasgow database, corresponding SE/SP/PPV were 43/98/96%, 84/90/89%, and 55/98/97%. For the Lund database, SP was 56% for the STEMI, 24% for the STEMI with ST↓, and 56% for the STEMI13. CONCLUSION: Current recommended criteria for detecting acute myocardial ischemia, involving ST↓, boost SE of widely-used STEMI criteria, at the cost of SP. To keep the SP high, we propose either the adjustment of threshold for the added ST↓ criteria or a selective use of ST↓ only in contiguous leads V2 and V3 plus ST↑ in lead pairs (aVL, -III) and (III, -aVL).

Microstructure-based knowledge systems for capturing process-structure evolution linkages.

This paper reviews and advances a data science framework for capturing and communicating critical information regarding the evolution of material structure in spatiotemporal multiscale simulations. This approach is called the MKS (Materials Knowledge Systems) framework, and was previously applied successfully for capturing mainly the microstructure-property linkages in spatial multiscale simulations. This paper generalizes this framework by allowing the introduction of different basis functions, and explores their potential benefits in establishing the desired process-structure-property (PSP) linkages. These new developments are demonstrated using a Cahn-Hilliard simulation as an example case study, where structure evolution was predicted three orders of magnitude faster than an optimized numerical integration algorithm. This study suggests that the MKS localization framework provides an alternate method to learn the underlying embedded physics in a numerical model expressed through Green's function based influence kernels rather than differential equations, and potentially offers significant computational advantages in problems where numerical integration schemes are challenging to optimize. With this extension, we have now established a comprehensive framework for capturing PSP linkages for multiscale materials modeling and simulations in both space and time.