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Ionic liquids (ILs) and deep eutectic solvents (DESs) have tremendous potential for reactive capture and conversion (RCC) of CO2 due to their wide electrochemical stability window, low volatility, and high CO2 solubility. There is environmental and economic interest in the direct utilization of the captured CO2 using electrified and modular processes that forgo the thermal- or pressure-swing regeneration steps to concentrate CO2, eliminating the need to compress, transport, or store the gas. The conventional electrochemical conversion of CO2 with aqueous electrolytes presents limited CO2 solubility and high energy requirement to achieve industrially relevant products. Additionally, aqueous systems have competitive hydrogen evolution. In the past decade, there has been significant progress toward the design of ILs and DESs, and their composites to separate CO2 from dilute streams. In parallel, but not necessarily in synergy, there have been studies focused on a few select ILs and DESs for electrochemical reduction of CO2, often diluting them with aqueous or non-aqueous solvents. The resulting electrode–electrolyte interfaces present a complex speciation for RCC. In this review, we describe how the ILs and DESs are tuned for RCC and specifically address the CO2 chemisorption and electroreduction mechanisms. Critical bulk and interfacial properties of ILs and DESs are discussed in the context of RCC, and the potential of these electrolytes are presented through a techno-economic evaluation. [ABSTRACT FROM AUTHOR]

Nonalcoholic steatohepatitis (NASH) and alcoholic hepatitis (AH) affect a large part of the general population worldwide. Dysregulation of lipid metabolism and alcohol toxicity drive disease progression by the activation of hepatic stellate cells and the capillarization of liver sinusoidal endothelial cells. Collagen deposition, along with sinusoidal remodeling, alters sinusoid structure, resulting in hepatic inflammation, portal hypertension, liver failure, and other complications. Efforts were made to develop treatments for NASH and AH. However, the success of such treatments is limited and unpredictable. We report a strategy for NASH and AH treatment involving the induction of integrin αvβ3-mediated cell apoptosis using a rationally designed protein (ProAgio). Integrin αvβ3 is highly expressed in activated hepatic stellate cells (αHSCs), the angiogenic endothelium, and capillarized liver sinusoidal endothelial cells (caLSECs). ProAgio induces the apoptosis of these disease-driving cells, therefore decreasing collagen fibril, reversing sinusoid remodeling, and reducing immune cell infiltration. The reversal of sinusoid remodeling reduces the expression of leukocyte adhesion molecules on LSECs, thus decreasing leukocyte infiltration/activation in the diseased liver. Our studies present a novel and effective approach for NASH and AH treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Yuan et al. present a strategy to modulate tumor immunity by simultaneously depleting CAFs and tumor angiogenic vessels using a rationally designed protein that induces integrin αvβ3-expressing cell apoptosis. The study offers a unique opportunity for the enhancement of cancer immunotherapies, especially for patients with a tumor of dense stroma and high angiogenesis. Fibrotic stroma and angiogenic tumor vessels play an important role in modulating tumor immunity. We previously reported a rationally designed protein (ProAgio) that targets integrin αvβ3 at a novel site. ProAgio induces the apoptosis of cells that express high levels of the integrin. Both activated cancer-associated fibroblasts (CAFs) and angiogenic endothelial cells (aECs) in tumors express high levels of integrin αvβ3. ProAgio simultaneously and specifically induces apoptosis in CAFs and aECs in tumors. We provide evidence here that the depletion of CAFs and the elimination of leaky tumor angiogenic vessels by ProAgio alter tumor immunity. ProAgio reduces CD4+ Treg and Myeloid-derived suppressor cells (MDSCs), increases CD8+ T-cells, and increases the M1/M2 macrophage ratio in the tumor. The depletion of dense fibrotic stroma (CAFs) by ProAgio decreases the Programmed Death Ligand 1 (PDL-1) levels in the stroma areas surrounding the tumors, and thus strongly increases the delivery of anti-PDL-1 antibody to the target cancer cells. The impact of ProAgio on tumor immunity provides strong synergistical effects of checkpoint inhibitors on lung cancer treatment. [ABSTRACT FROM AUTHOR]

Introduction: Chronic obstructive pulmonary disease (COPD) is currently listed as the 3rd leading cause of death in the United States. Accumulating data shows the association between COPD occurrence and the usage of electronic nicotine delivery systems (ENDS) in patients. However, the underlying pathogenesis mechanisms of COPD have not been fully understood. Methods: In the current study, bENaC-overexpressing mice (bENaC mice) were subjected to whole-body ENDS exposure. COPD related features including emphysema, mucus accumulation, inflammation and fibrosis are examined by tissue staining, FACS analysis, cytokine measurement. Cell death and ferroptosis of alveolar epithelial cells were further evaluated by multiple assays including staining, FACS analysis and lipidomics. Results: ENDS-exposed mice displayed enhanced emphysema and mucus accumulation, suggesting that ENDS exposure promotes COPD features. ENDS exposure also increased immune cell number infiltration in bronchoalveolar lavage and levels of multiple COPD-related cytokines in the lungs, including CCL2, IL-4, IL-13, IL-10, M-CSF, and TNF-α. Moreover, we observed increased fibrosis in ENDS-exposed mice, as evidenced by elevated collagen deposition and a-SMA+ myofibroblast accumulation. By investigating possible mechanisms for how ENDS promoted COPD, we demonstrated that ENDS exposure induced cell death of alveolar epithelial cells, evidenced by TUNEL staining and Annexin V/PI FACS analysis. Furthermore, we identified that ENDS exposure caused lipid dysregulations, including TAGs (9 species) and phospholipids (34 species). As most of these lipid species are highly associated with ferroptosis, we confirmed ENDS also enhanced ferroptosis marker CD71 in both type I and type II alveolar epithelial cells. Discussion: Overall, our data revealed that ENDS exposure exacerbates features of COPD in bENaC mice including emphysema, mucus accumulation, abnormal lung inflammation, and fibrosis, which involves the effect of COPD development by inducing ferroptosis in the lung. [ABSTRACT FROM AUTHOR]

The analysis of extensive electronic health records (EHR) datasets often calls for automated solutions, with machine learning (ML) techniques, including deep learning (DL), taking a lead role. One common task involves categorizing EHR data into predefined groups. However, the vulnerability of EHRs to noise and errors stemming from data collection processes, as well as potential human labeling errors, poses a significant risk. This risk is particularly prominent during the training of DL models, where the possibility of overfitting to noisy labels can have serious repercussions in healthcare. Despite the well-documented existence of label noise in EHR data, few studies have tackled this challenge within the EHR domain. Our work addresses this gap by adapting computer vision (CV) algorithms to mitigate the impact of label noise in DL models trained on EHR data. Notably, it remains uncertain whether CV methods, when applied to the EHR domain, will prove effective, given the substantial divergence between the two domains. We present empirical evidence demonstrating that these methods, whether used individually or in combination, can substantially enhance model performance when applied to EHR data, especially in the presence of noisy/incorrect labels. We validate our methods and underscore their practical utility in real-world EHR data, specifically in the context of COVID-19 diagnosis. Our study highlights the effectiveness of CV methods in the EHR domain, making a valuable contribution to the advancement of healthcare analytics and research. [ABSTRACT FROM AUTHOR]

Despite an abundance of support for culturally inclusive learning environments, there is little consensus regarding how to change educational contexts to effectively and sustainably foster cultural inclusion. To address this gap, we report findings from a research-practice partnership that leveraged the Culture Cycle Framework (CCF) to expand educators' praxis to include both independent and interdependent models of self. Most U.S. schools validate independent cultural models (i.e., those that prioritize individuality, uniqueness, and personal agency) and overlook interdependent models (i.e., those that prioritize connectedness, relationality, and collective well-being), which are more common among students from marginalized racial and socioeconomic backgrounds. Using a quasi-experimental longitudinal design, we trained school leadership to integrate ideas about cultural inclusion (i.e., validating the importance of both independent and interdependent cultural models) into school-wide flagship practices. We assessed downstream indicators of culture change by surveying teachers and students across the district and found that a) leadership-level training enhanced school-wide beliefs about cultural inclusion, b) teachers' endorsement of culturally inclusive beliefs predicted their use of culturally inclusive practices, and c) teachers' use of culturally inclusive practices predicted enhanced psychosocial and academic outcomes among students. This research represents a comprehensive culture change effort using the CCF and illustrates a means of fostering inclusion-focused educational culture change and assessing downstream consequences of culture change initiatives. [ABSTRACT FROM AUTHOR]

With the rapid growth of memory and computing power, datasets are becoming increasingly complex and imbalanced. This is especially severe in the context of clinical data, where there may be one rare event for many cases in the majority class. We introduce an imbalanced classification framework, based on reinforcement learning, for training extremely imbalanced data sets, and extend it for use in multi-class settings. We combine dueling and double deep Q-learning architectures, and formulate a custom reward function and episode-training procedure, specifically with the capability of handling multi-class imbalanced training. Using real-world clinical case studies, we demonstrate that our proposed framework outperforms current state-of-the-art imbalanced learning methods, achieving more fair and balanced classification, while also significantly improving the prediction of minority classes. [ABSTRACT FROM AUTHOR]

Background: Complete resection followed by adjuvant chemotherapy is the gold standard for patients with localized cholangiocarcinoma (CC) or gallbladder cancer (GBC). However, this is not always feasible, and recurrence rates remain high. Objectives: To understand the real-world proportions and reason for treatment failure in resected biliary tract cancers. Design and methods: We performed a retrospective population-based review of patients with GBC or CC [intrahepatic (IHCC) or extrahepatic (EHCC)] resected between 2005 and 2019 using the BC Cancer provincial database. A chart review was conducted to characterize demographics, treatments received and outcomes. Results: In total, 594 patients were identified of whom 416 (70%) had disease recurrence. Most GBCs (96%) were diagnosed incidentally, and repeat oncologic resection was performed in 45%. Adjuvant chemotherapy was received in 51% of patients diagnosed after 2017 (mostly capecitabine). Patient co-morbidities, disease progression and patient preference were the commonest reasons for not proceeding with adjuvant chemotherapy. One-third of patients did not complete all planned cycles. Median overall survival was significantly higher in those with complete (R0) versus incomplete (R1) resection [31.6 versus 18 months, hazard ratio (HR): 0.43, 95% confidence interval (CI): 0.35–0.53] and in those with versus without re-resection for GBC [29.4 versus 19 months, HR: 0.55, 95% CI: 0.41–0.73]. There was a trend towards improved survival with versus without adjuvant therapy (HR: 0.79, 95% CI: 0.61–1.02). Only 25% in the more contemporary cohort (2017–2019) had an R0 resection and completed adjuvant chemotherapy. Conclusion: Complete resection, including reresection for incidentally diagnosed GBCs, and adjuvant chemotherapy were associated with improved outcomes in this retrospective cohort, yet many patients were not able to complete these treatments. Neoadjuvant strategies may improve treatment delivery and ultimately, outcomes. [ABSTRACT FROM AUTHOR]

Current predictors of clinical outcomes after pulmonary thromboendarterectomy (PTE) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) are largely limited to preoperative clinical characteristics. N‐terminal‐pro‐brain natriuretic peptide (NT‐pro‐BNP), a biomarker of right ventricular dysfunction, has not yet been well described as one such predictor. From 2017 to 2021, 816 patients with CTEPH referred to the University of California, San Diego for PTE were reviewed for differences in NT‐pro‐BNP to predict preoperative characteristics and postoperative outcomes up to 30 days post‐PTE. For analysis, NT‐pro‐BNP was dichotomized to less than/equal to or greater than 1000 pg/mL based on the mean of the study population. Mean NT‐pro‐BNP was 1095.9 ±1783.4 pg/mL and median was 402.5 pg/mL (interquartile range: 119.5–1410.8). Of the 816 patients included, 250 had NT‐pro‐BNP > 1000 pg/mL. Those with NT‐pro‐BNP > 1000 pg/mL were significantly more likely to have worse preoperative functional class (III–IV) and worse preoperative hemodynamics. Patients with NT‐pro‐BNP > 1000 pg/mL also tended to have more postoperative complications including reperfusion pulmonary edema (22% vs. 5.1%, p < 0.001), airway hemorrhage (8.4% vs. 4.9%, p = 0.075), residual pulmonary hypertension (11.9% vs. 3.1%, p < 0.001), and 30‐day mortality (4.8% vs. 1.1%, p = 0.001). Even after adjusting for confounders, patients with NT‐pro‐BNP > 1000 pg/mL had a 2.48 times higher odds (95% confidence interval: 1.45–4.00) of reaching a combined endpoint that included the above complications. Preoperative NT‐pro‐BNP > 1000 pg/mL is a strong predictor of more severe preoperative hemodynamics and identifies patients at higher risk for postoperative complications. [ABSTRACT FROM AUTHOR]

Background: Cardiac dysfunction from pulmonary vascular disease causes characteristic findings on cardiopulmonary exercise testing (CPET). We tested the accuracy of CPET for detecting inadequate stroke volume (SV) augmentation during exercise, a pivotal manifestation of cardiac limitation in patients with pulmonary vascular disease. Methods: We reviewed patients with suspected pulmonary vascular disease in whom CPET and right heart catheterization (RHC) measurements were taken at rest and at anaerobic threshold (AT). We correlated CPET-determined O2·pulseAT/O2·pulserest with RHC-determined SVAT/SVrest. We evaluated the sensitivity and specificity of O2·pulseAT/O2·pulserest to detect SVAT/SVrest below the lower limit of normal (LLN). For comparison, we performed similar analyses comparing echocardiographically-measured peak tricuspid regurgitant velocity (TRVpeak) with SVAT/SVrest. Results: From July 2018 through February 2023, 83 simultaneous RHC and CPET were performed. Thirty-six studies measured O2·pulse and SV at rest and at AT. O2·pulseAT/O2·pulserest correlated highly with SVAT/SVrest (r = 0.72, 95% CI 0.52, 0.85; p < 0.0001), whereas TRVpeak did not (r = -0.09, 95% CI -0.47, 0.33; p = 0.69). The AUROC to detect SVAT/SVrest below the LLN was significantly higher for O2·pulseAT/O2·pulserest (0.92, SE 0.04; p = 0.0002) than for TRVpeak (0.69, SE 0.10; p = 0.12). O2·pulseAT/O2·pulserest of less than 2.6 was 92.6% sensitive (95% CI 76.6%, 98.7%) and 66.7% specific (95% CI 35.2%, 87.9%) for deficient SVAT/SVrest. Conclusions: CPET detected deficient SV augmentation more accurately than echocardiography. CPET-determined O2·pulseAT/O2·pulserest may have a prominent role for noninvasive screening of patients at risk for pulmonary vascular disease, such as patients with persistent dyspnea after pulmonary embolism. [ABSTRACT FROM AUTHOR]

Heart rate variability (HRV) is an important metric with a variety of applications in clinical situations such as cardiovascular diseases, diabetes mellitus, and mental health. HRV data can be potentially obtained from electrocardiography and photoplethysmography signals, then computational techniques such as signal filtering and data segmentation are used to process the sampled data for calculating HRV measures. However, uncertainties arising from data acquisition, computational models, and physiological factors can lead to degraded signal quality and affect HRV analysis. Therefore, it is crucial to address these uncertainties and develop advanced models for HRV analysis. Although several reviews of HRV analysis exist, they primarily focus on clinical applications, trends in HRV methods, or specific aspects of uncertainties such as measurement noise. This paper provides a comprehensive review of uncertainties in HRV analysis, quantifies their impacts, and outlines potential solutions. To the best of our knowledge, this is the first study that presents a holistic review of uncertainties in HRV methods and quantifies their impacts on HRV measures from an engineer's perspective. This review is essential for developing robust and reliable models, and could serve as a valuable future reference in the field, particularly for dealing with uncertainties in HRV analysis. [ABSTRACT FROM AUTHOR]

Innovations in digital health and machine learning are changing the path of clinical health and care. People from different geographical locations and cultural backgrounds can benefit from the mobility of wearable devices and smartphones to monitor their health ubiquitously. This paper focuses on reviewing the digital health and machine learning technologies used in gestational diabetes – a subtype of diabetes that occurs during pregnancy. This paper reviews sensor technologies used in blood glucose monitoring devices, digital health innovations and machine learning models for gestational diabetes monitoring and management, in clinical and commercial settings, and discusses future directions. Despite one in six mothers having gestational diabetes, digital health applications were underdeveloped, especially the techniques that can be deployed in clinical practice. There is an urgent need to (1) develop clinically interpretable machine learning methods for patients with gestational diabetes, assisting health professionals with treatment, monitoring, and risk stratification before, during and after their pregnancies; (2) adapt and develop clinically-proven devices for patient self-management of health and well-being at home settings (“virtual ward” and virtual consultation), thereby improving clinical outcomes by facilitating timely intervention; and (3) ensure innovations are affordable and sustainable for all women with different socioeconomic backgrounds and clinical resources. [ABSTRACT FROM AUTHOR]

Objective Maternal smoking is associated with as much as a 50% reduced risk of preeclampsia, despite increasing risk of other poor pregnancy outcomes that often co-occur with preeclampsia, such as preterm birth and fetal growth restriction. Researchers have long sought to understand whether this perplexing association is biologically based, or a result of noncausal mechanisms. We examined whether smoking-response genes modify the smoking-preeclampsia association to investigate potential biological explanations. Study Design We conducted a nested case–control study within the Norwegian Mother, Father and Child Birth Cohort (1999–2008) of 2,596 mother–child dyads. We used family-based log-linear Poisson regression to examine modification of the maternal smoking-preeclampsia relationship by maternal and fetal single nucleotide polymorphisms involved in cellular processes related to components of cigarette smoke (n = 1,915 with minor allele frequency ≥10%). We further investigated the influence of smoking cessation during pregnancy. Results Three polymorphisms showed overall (p < 0.001) multiplicative interaction between smoking and maternal genotype. For rs3765692 (TP73) and rs10770343 (PIK3C2G), protection associated with smoking was reduced with two maternal copies of the risk allele and was stronger in continuers than quitters (interaction p = 0.02 for both loci, based on testing 3-level smoking by 3-level genotype). For rs2278361 (APAF1) the inverse smoking-preeclampsia association was eliminated by the presence of a single risk allele, and again the trend was stronger in continuers than in quitters (interaction p = 0.01). Conclusion Evidence for gene–smoking interaction was limited, but differences by smoking cessation warrant further investigation. We demonstrate the potential utility of expanded dyad methods and gene–environment interaction analyses for outcomes with complex relationships between maternal and fetal genotypes and exposures. Key Points Maternal and fetal genotype may differentially influence preeclampsia. Smoking-related genes did not strongly modify smoking–preeclampsia association. Smoking cessation reduced strength of gene by smoking interactions. [ABSTRACT FROM AUTHOR]

Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by persistent organized thromboembolic obstruction of the pulmonary arteries from incompletely resolved pulmonary embolism. The treatment of choice is pulmonary thromboendarterectomy (PTE) surgery and all patients should be evaluated for operability candidacy. Despite advancements in PTE technique allowing more segmental–subsegmental surgeries, up to a third of patients with CTEPH may still be considered inoperable. Over the past decade, there have been increasing treatment options for these inoperable CTEPH patients. Balloon pulmonary angioplasty (BPA) is a percutaneous‐based interventional treatment option for select CTEPH cases. Early BPA experiences were plagued by high complication rates, but further refinements in technique and equipment pioneered by Japan led to the worldwide spread and adoption of BPA. Multiple centers have shown that patients experience significant improvements in hemodynamics, quality of life, exercise capacity, and survival with BPA treatment. There remain many questions on best practices, but BPA has evolved into a pivotal cornerstone of CTEPH treatment. [ABSTRACT FROM AUTHOR]

Chronic thromboembolic pulmonary hypertension (CTEPH) is a treatable form of pulmonary hypertension and right heart failure. CTEPH (group 4 pulmonary hypertension) is caused by persistent organized thromboembolic obstruction of the pulmonary arteries from incompletely resolved acute pulmonary embolism. CTEPH also may present without prior VTE history, which can contribute to its underrecognition. The true incidence of CTEPH is unclear, but is estimated to be approximately 3% after acute pulmonary embolism. V ˙ / Q ˙ scintigraphy is the best screening test for CTEPH, with CT scan imaging and other advanced imaging methods now playing a larger role in disease detection and confirmation. Perfusion defects on V ˙ / Q ˙ scintigraphy in the setting of pulmonary hypertension are suggestive of CTEPH, but pulmonary angiography and right heart catheterization are required for confirmation and treatment planning. CTEPH potentially is curative with pulmonary thromboendarterectomy surgery, with mortality rates of approximately 2% at expert centers. Advances in operative techniques are allowing more distal endarterectomies to be performed successfully with favorable outcomes. However, more than one-third of patients may be considered inoperable. Although these patients previously had minimal therapeutic options, effective treatments now are available with pharmacotherapy and balloon pulmonary angioplasty. Diagnosis of CTEPH should be considered in all patients with suspicion of pulmonary hypertension. Treatments for CTEPH have advanced with improvements in outcomes for both operable and inoperable patients. Therapy should be tailored based on multidisciplinary team evaluation to ensure optimal treatment response. [ABSTRACT FROM AUTHOR]

The dynamic interplay between teachers' beliefs and practices significantly impact the quality of instruction and the trajectory of talent development in young students. This case study explores the beliefs and practices of two elementary teachers instructing gifted ELs in mathematics. The constant comparison method was used to analyze data collected from classroom observations, semi-structured interviews, and field notes. Three factors were found to affect the (in)consistency between teachers' expressed beliefs and observed practices: compatibility among core and peripheral beliefs, knowledge about evidence-based practices, and classroom management skills. Students exhibit higher levels of participation, communication, and engagement in critical thinking skills when their teacher embraces constructive perspectives in teaching mathematics, demonstrates pedagogical expertise, and employs a proactive classroom management approach. Conversely, students encounter restricted opportunities to independently construct their own understanding of mathematics when their teacher holds maladaptive beliefs about teaching mathematics, has limited knowledge of evidence-based practices, and has an authoritarian classroom management style. These findings underscore the need for a new approach to professional development (PD) that encourages teachers to critically examine the connection between their beliefs and instructional practices and their impact on the student's mathematical talent development. [ABSTRACT FROM AUTHOR]

Machine learning is becoming increasingly prominent in healthcare. Although its benefits are clear, growing attention is being given to how these tools may exacerbate existing biases and disparities. In this study, we introduce an adversarial training framework that is capable of mitigating biases that may have been acquired through data collection. We demonstrate this proposed framework on the real-world task of rapidly predicting COVID-19, and focus on mitigating site-specific (hospital) and demographic (ethnicity) biases. Using the statistical definition of equalized odds, we show that adversarial training improves outcome fairness, while still achieving clinically-effective screening performances (negative predictive values >0.98). We compare our method to previous benchmarks, and perform prospective and external validation across four independent hospital cohorts. Our method can be generalized to any outcomes, models, and definitions of fairness. [ABSTRACT FROM AUTHOR]

Synaptic plasticity relies on rapid, yet spatially precise signaling to alter synaptic strength. Arc is a brain enriched protein that is rapidly expressed during learningrelated behaviors and is essential for regulating metabotropic glutamate receptormediated long-term depression (mGluR-LTD). We previously showed that disrupting the ubiquitination capacity of Arc enhances mGluR-LTD; however, the consequences of Arc ubiquitination on other mGluR-mediated signaling events is poorly characterized. Here we find that pharmacological activation of Group I mGluRs with S-3,5-dihydroxyphenylglycine (DHPG) increases Ca2C release from the endoplasmic reticulum (ER). Disrupting Arc ubiquitination on key amino acid residues enhances DHPG-induced ER-mediated Ca2C release. These alterations were observed in all neuronal subregions except secondary branchpoints. Deficits in Arc ubiquitination altered Arc self-assembly and enhanced its interaction with calcium/calmodulin-dependent protein kinase IIb (CaMKIIb) and constitutively active forms of CaMKII in HEK293 cells. Colocalization of Arc and CaMKII was altered in cultured hippocampal neurons, with the notable exception of secondary branchpoints. Finally, disruptions in Arc ubiquitination were found to increase Arc interaction with the integral ER protein Calnexin. These results suggest a previously unknown role for Arc ubiquitination in the fine tuning of ER-mediated Ca2C signaling that may support mGluR-LTD, which in turn, may regulate CaMKII and its interactions with Arc. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma, cancer of the biliary tract, is a rare malignancy with a poor prognosis. However, the incidence of cholangiocarcinoma is on the rise globally. Currently, complete surgical resection is the only curative treatment for localized disease while there is no cure for more advanced cholangiocarcinoma. In recent years, there have been several developments of adjuvant and palliative chemotherapies, especially with regards to targeted molecular therapies. Some of these treatments are now approved and funded in Canada. The purpose of the review is to provide a general overview of current cholangiocarcinoma systemic therapies, with a focus on Canadian standards of care. [ABSTRACT FROM AUTHOR]

Complete subglottic stenosis is often managed with surgical resection. However, involvement of the high subglottis can limit candidacy for open resection, and there are few treatment options for these patients. We refined an endoscopic approach that evolved into a tracheal rendezvous technique with T-tube placement as an alternative to open surgical resection. Here, we present our series, technique, and outcomes. A retrospective review was performed to identify patients who underwent endoscopic management of complete high subglottic stenosis at the University of California San Diego. The surgical technique was initially a two-step staged procedure and was subsequently revised to a single-stage procedure with stenosis ablation, dilation, and insertion of a T-tube, which was completed in one day. Patients were seen at regular follow-up intervals for reassessment. Five patients were identified with complete stenosis not amenable to surgical resection. The average age of the cohort was 44.8 years. The etiology of stenosis in all patients was related to prolonged intubation and tracheostomy, and the average length of stenosis was 19.6 mm. Stenosis resection was accomplished via laser ablation and balloon dilation, and the average T-tube length was 50.3 mm. All patients were discharged on postoperative day one. Two patients developed airway crusting within the T-tube and required emergency department visits. Decannulation was attempted in three patients, although failed in two. Tracheal rendezvous is a safe and effective procedure for patients with grade IV subglottic stenosis. This provides a feasible endoscopic alternative to patients who are not candidates for open surgical resection, ye are motivated to have phonatory capacity. [ABSTRACT FROM AUTHOR]

Background: During the COVID-19 pandemic, enforced social distancing initiatives have highlighted differences in social distancing practices and the resulting loneliness in various populations. The objective of this study was to examine how cancer history and social distancing practices relate to loneliness during COVID-19. Methods and findings: Participants from previous studies (N = 32,989) with permission to be re-contacted were invited to complete a survey online, by phone, or by mail between June and November 2020. Linear and logistic regression models were used to determine the associations between cancer history, social distancing, and loneliness. Results: Among the included participants (n = 5729), the average age was 56.7 years, 35.6% were male, 89.4% were White, and 54.9% had a cancer history (n = 3147). Individuals with a cancer history were more likely to not contact people outside of their household (49.0% vs. 41.9%, p<0.01), but were less likely to feel lonely (35.8% vs. 45.3%, p<0.0001) compared to those without a cancer history. Higher adherence to social distancing behaviors was associated with higher odds of loneliness among individuals with (OR = 1.27, 95% CI: 1.17-1.38) and without a cancer history (OR = 1.15, 95% CI: 1.06-1.25). Conclusions: Findings from this study can inform efforts to support the mental health of individuals susceptible to loneliness during the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

The present study compared ways of storytelling in Western and Asian literature. Content analysis was performed on Amazon.com and New York Times best-selling fictions and memoirs (N = 102) by Western and Asian authors. Although authors of the two cultural groups described similar numbers of event episodes per chapter, Western authors depicted the episodes in greater detail than Asian authors in both fictions and memoirs. Asian authors, on the other hand, described more frequently repeated events than Western authors in fictions. These findings highlight the important role of literature in reflecting as well as perpetuating cultural ways of storytelling. [ABSTRACT FROM AUTHOR]

A molecular cobalt CO2 hydrogenation catalyst was explored for electrocatalytic CO2 reduction under aqueous conditions. The resulting pH-dependent selectivity between H2 and HCO2− is rationalized with thermodynamic analysis and stoichiometric experiments. [ABSTRACT FROM AUTHOR]

The present study compared ways of storytelling in Western and Asian literature. Content analysis was performed on Amazon.com and New York Times best-selling fictions and memoirs (N = 102) by Western and Asian authors. Although authors of the two cultural groups described similar numbers of event episodes per chapter, Western authors depicted the episodes in greater detail than Asian authors in both fictions and memoirs. Asian authors, on the other hand, described more frequently repeated events than Western authors in fictions. These findings highlight the important role of literature in reflecting as well as perpetuating cultural ways of storytelling. [ABSTRACT FROM AUTHOR]

The management of pulmonary arterial hypertension (PAH) has become more complex in recent years because of increased pharmacotherapy options and longer patient survival with increasing numbers of comorbidities. As such, more opportunities exist for drug-drug interactions between PAH-targeted medications and medications potentially used to treat comorbid conditions. In this review, we provide an overview of pharmaceutical metabolism by cytochrome P450 and discuss important drug-drug interactions for the 14 Food and Drug Administration-approved medications for PAH in the nitric oxide (NO), endothelin, and prostacyclin pathways. Among the targets in the NO pathway (sildenafil, tadalafil, and riociguat), important interactions with nitrates, protease inhibitors, and other phosphodiesterase inhibitors can cause profound hypotension. In the endothelin pathway, bosentan is associated with more drug interactions via CYP3A4 inhibition; macitentan and ambrisentan have fewer interactions of note. Although the parenteral therapies in the prostacyclin pathway bypass significant liver metabolism and avoid drug interactions, selexipag and oral treprostinil may exhibit interactions with CYP2C8 inhibitors such as gemfibrozil and clopidogrel, which can raise drug levels. Finally, we provide a framework for identifying potential drug-drug interactions and avoiding errors. [ABSTRACT FROM AUTHOR]

The hypothalamic–pituitary–thyroid (HPT) axis is crucial in regulating thyroid hormone levels that contribute to the development and homeostasis of the human body. Current literature supports the presence of a local HPT axis equivalent within keratinocytes of the skin, with thyroid hormones playing a potential role in cancer progression. However, this remains to be seen within oral tissue cells. An electronic search of Scopus and PubMed/Medline databases was conducted to identify all original publications that reported data on the production or effects of HPT axis components in normal or malignant cells of the oral cavity. The search identified 221 studies, of which 14 were eligible. Eight studies were retrospective analyses of clinical samples, one study involved both in vivo and in vitro experiments, and the remaining five studies were conducted in vitro using cell lines. The search identified evidence of effects of HPT components on oral cancer cells. However, there were limited data for the production of HPT axis components by oral tissues. We conclude that a possible role of the local HPT axis equivalent in the oral mucosa may not be established at present. The gaps in knowledge identified in this scoping review, particularly regarding the production of HPT components by oral tissues, warrant further investigation. [ABSTRACT FROM AUTHOR]

Objective : Secondary procedures optimize outcomes following cleft lip and palate (CL/P) repair. We analyzed the association between race and the utilization and timing of revisionary/secondary cleft surgeries in the United States. Design : Primary CL/P repair, revisions, and secondary procedures—cleft rhinoplasty, speech surgery, and alveolar bone grafting (ABG)—performed from 2014–2018 were identified from the Pediatric National Surgical Quality Improvement Program (NSQIP) database. Utilization estimates were derived via univariable and multivariable logistic regression. A Kruskal-Wallis rank-sum test and multivariable linear regression were used to assess differences in timing for each procedure cohort. Main Outcome Measures : The primary outcome measures were the odds of a patient being a certain race/ethnicity, and the age at which patients of different race/ethnicity receive surgery. Results : There were 23 780 procedures analyzed. After controlling for sex, diagnosis, and functional status, there were significant differences in utilization estimates across procedure groups. Primarily, utilization was lowest in patient who were Black for cleft rhinoplasty (OR = 0.70, P =.023), ABG (OR = 0.44, P <.001) and speech surgery (OR = 0.57, P =.012), and highest in patients who were Asian patients in all surgery cohorts (OR 2.05-4.43). Timing of surgery also varied by race, although differences were minimal. Conclusions: Estimates of utilization and timing of secondary cleft procedures varied by race, particularly among patients who were Black (poor utilization) or Asian (high utilization). Further studies should identify the causes and implications of underutilized and/or delayed cleft care. [ABSTRACT FROM AUTHOR]

A central goal of physiological research is the understanding of cell-specific roles of disease-associated genes. Cre-mediated recombineering is the tool of choice for cell type–specific analysis of gene function in preclinical models. In the type 1 diabetes (T1D) research field, multiple lines of nonobese diabetic (NOD) mice have been engineered to express Cre recombinase in pancreatic β cells using insulin promoter fragments, but tissue promiscuity remains a concern. Constitutive Ins1 tm1.1(cre)Thor (Ins1 Cre) mice on the C57/bl6-J background have high β-cell specificity with no reported off-target effects. We explored whether NOD: Ins1 Cre mice could be used to investigate β-cell gene deletion in T1D disease modeling. We studied wild-type (Ins1 WT/WT), Ins1 heterozygous (Ins1 Cre/WT or Ins1 Neo/WT), and Ins1 null (Ins1 Cre/Neo) littermates on a NOD background. Female Ins1 Neo/WT mice exhibited significant protection from diabetes, with further near-complete protection in Ins1 Cre/WT mice. The effects of combined neomycin and Cre knockin in Ins1 Neo/Cre mice were not additive to the Cre knockin alone. In Ins1 Neo/Cre mice, protection from diabetes was associated with reduced insulitis at age 12 weeks. Collectively, these data confirm previous reports that loss of Ins1 alleles protects NOD mice from diabetes development and demonstrates, for the first time, that Cre itself may have additional protective effects. This has important implications for the experimental design and interpretation of preclinical T1D studies using β-cell-selective Cre in NOD mice. [ABSTRACT FROM AUTHOR]

Developing improved methods for CO2 capture and concentration (CCC) is essential to mitigating the impact of our current emissions and can lead to carbon net negative technologies. Electrochemical approaches for CCC can achieve much higher theoretical efficiencies compared to the thermal methods that have been more commonly pursued. The use of redox carriers, or molecular species that can bind and release CO2 depending on their oxidation state, is an increasingly popular approach as carrier properties can be tailored for different applications. The key requirements for stable and efficient redox carriers are discussed in the context of chemical scaling relationships and operational conditions. Computational and experimental approaches towards developing redox carriers with optimal properties are also described. [ABSTRACT FROM AUTHOR]

Chronic thromboembolic pulmonary hypertension (CTEPH) is the result of incompletely resolved pulmonary emboli (PE) that lead to chronic right heart failure. The two mechanical treatment options are pulmonary thromboendarterectomy (PTE) and balloon pulmonary angioplasty (BPA). There are no formal criteria for BPA patient selection and treatment decisions vary according to a center's experience with BPA and PTE. We performed a retrospective review of consecutive patients treated with PTE and BPA at UCSD from March 2015 to 2021. Clinical and hemodynamic data were collected. Patients were categorized according to the rationale for BPA. One hundred fifty three patients underwent 643 BPA sessions, and 1104 patients underwent PTE. Patients selected for PTE had worse baseline hemodynamics with mean pulmonary artery pressure 41.1 ± 11.7 versus 34.6 ± 11.2 mmHg, p < 0.001. 59% of patients selected for BPA had surgically inaccessible disease, 21% had residual CTEPH after PTE, 10% had a discordance between disease burden and symptoms/hemodynamics, 7% had comorbidities that prevented PTE and 3% refused PTE surgery. 28% of patients who underwent PTE had exclusively level III or IV disease based on surgical specimen. There were no BPA procedure-related mortalities and minor pulmonary vascular complication rates during BPA were 9.2%. The most common reason for BPA selection was surgically inaccessible disease followed by residual CTEPH after PTE. Almost one third of patients who underwent PTE had exclusively distal disease by surgical criteria and might have been directed to BPA at a less experienced surgical center. [ABSTRACT FROM AUTHOR]

Background For patients coinfected with hepatitis C virus (HCV) and hepatitis B virus (HBV), HCV treatment with direct-acting antivirals can lead to HBV reactivation. We evaluated HBV reactivation during ledipasvir/sofosbuvir treatment and 108-week follow-up. Methods In Taiwan, 111 patients with HCV genotype 1 or 2 and HBV received ledipasvir/sofosbuvir (90mg/400mg) once daily for 12 weeks. HBV virologic reactivation was defined as postbaseline increase in HBV DNA from either less than the lower limit of quantification (LLOQ, 20 IU/mL) to equal to or more than LLOQ or equal to or more than LLOQ to >1 log10 IU/mL. HBV clinical reactivation was HBV virologic reactivation with alanine aminotransferase (ALT) >2× upper limit of normal. Factors associated with development of HBV virologic or clinical reactivation were evaluated with logistic regression analysis. Results All patients (100%, 111/111) maintained HCV suppression through 108 weeks after treatment. HBV virologic reactivation occurred in 73% of patients (81/111). Clinical reactivation occurred in 9% (10/111). The majority of HBV virologic reactivations (86%, 70/81) occurred by follow-up week 12, whereas clinical reactivation was generally more delayed. Eight (7%, 8/111) initiated HBV therapy. In regression analyses, baseline HBV DNA and hepatitis B surface antigen (HBsAg) levels were associated with HBV virologic reactivation and baseline ALT and HBV DNA, and HBsAg levels were associated with HBV clinical reactivation. Conclusion Among HCV/HBV coinfected patients treated with direct-acting antivirals for HCV, HBV virologic reactivation occurred in a majority of patients during treatment and follow-up. In most patients, HBV virologic reactivation was asymptomatic; only a small proportion initiated HBV treatment. Notably, clinical reactivation may still occur >3 months after end of therapy. Clinical Trials Registration NCT02613871. [ABSTRACT FROM AUTHOR]

Patients with chronic thromboembolic pulmonary hypertension (CTEPH) require lifelong anticoagulant therapy. The safety and efficacy of direct oral anticoagulant (DOAC) in the chronic and transitional management of CTEPH has not been investigated. We performed a retrospective analysis of 405 consecutive pulmonary endarterectomy (PEA) cases at the University of California, San Diego, from July 2015 through July 2017. PEA specimen was reviewed for the presence of acute or subacute thrombotic material distinct from the expected chronic disease removed at the time of PEA by two investigators blinded to the patient information. Of 405 PEA cases, 166 patients (41.0%) were anticoagulated with one of three available DOACs; 239 (59.0%) presented on either oral vitamin‐K antagonist or chronic injectable therapy. There were no significant differences in baseline characteristics between DOAC and non‐DOAC groups. Evidence of recent thrombus was observed in 22 (13.3%) in the DOAC group versus 16 (6.7%) within the non‐DOAC group. The odds ratio of DOACs usage and evidence of recent thrombus was 2.34 (95% confidence interval: 1.1–5.0, p = 0.03) after adjusting for age, gender, race, body mass index, and history of antiphospholipid antibody syndrome. CTEPH patients referred for PEA while on DOAC therapy were twice as likely to have associated acute or subacute thrombi present at the time of surgery compared with those on more traditional, non‐DOAC anticoagulant therapies. This raises questions of the safety and efficacy of DOACs in the chronic management of CTEPH. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is often diagnosed during the last trimester of pregnancy, leaving only a short timeframe for intervention. However, appropriate assessment, management, and treatment have been shown to reduce the complications of GDM. This study introduces a machine learning-based stratification system for identifying patients at risk of exhibiting high blood glucose levels, based on daily blood glucose measurements and electronic health record (EHR) data from GDM patients. We internally trained and validated our model on a cohort of 1148 pregnancies at Oxford University Hospitals NHS Foundation Trust (OUH), and performed external validation on 709 patients from Royal Berkshire Hospital NHS Foundation Trust (RBH). We trained linear and non-linear tree-based regression models to predict the proportion of high-readings (readings above the UK's National Institute for Health and Care Excellence [NICE] guideline) a patient may exhibit in upcoming days, and found that XGBoost achieved the highest performance during internal validation (0.021 [CI 0.019–0.023], 0.482 [0.442–0.516], and 0.112 [0.109–0.116], for MSE, R2, MAE, respectively). The model also performed similarly during external validation, suggesting that our method is generalizable across different cohorts of GDM patients. [ABSTRACT FROM AUTHOR]

Aqueous direct air capture (DAC) is a key technology toward a carbon negative infrastructure. Developing sorbent molecules with water and oxygen tolerance and high CO2 binding capacity is therefore highly desired. We analyze the CO2 absorption chemistries on amines, alkoxides, and phenoxides with density functional theory calculations, and perform inverse molecular design of the optimal sorbent. The alkoxides and phenoxides are found to be more suitable for aqueous DAC than amines thanks to their water tolerance (lower pKa prevents protonation by water) and capture stoichiometry of 1:1 (2:1 for amines). All three molecular systems are found to generally obey the same linear scaling relationship (LSR) between pKCO2 and pKa, since both CO2 and proton are bonded to the nucleophilic (alkoxy or amine) binding site through a majorly s bonding orbital. Several high-performance alkoxides are proposed from the computational screening. Phenoxides have comparatively poorer correlation between pKCO2 and pKa, showing promise for optimization. We apply a genetic algorithm to search the chemical space of substituted phenoxides for the optimal sorbent. Several promising off-LSR candidates are discovered. The most promising one features bulky ortho substituents forcing the CO2 adduct into a perpendicular configuration with respect to the aromatic ring. In this configuration, the phenoxide binds CO2 and a proton using different molecular orbitals, thereby decoupling the pKCO2 and pKa. The pKCO2-pKa trend and off-LSR behaviors are then confirmed by experiments, validating the inverse molecular design framework. This work not only extensively studies the chemistry of the aqueous DAC, but also presents a transferrable computational workflow for understanding and optimization of other functional molecules. [ABSTRACT FROM AUTHOR]

As patient health information is highly regulated due to privacy concerns, most machine learning (ML)-based healthcare studies are unable to test on external patient cohorts, resulting in a gap between locally reported model performance and cross-site generalizability. Different approaches have been introduced for developing models across multiple clinical sites, however less attention has been given to adopting ready-made models in new settings. We introduce three methods to do this—(1) applying a ready-made model "as-is" (2); readjusting the decision threshold on the model's output using site-specific data and (3); finetuning the model using site-specific data via transfer learning. Using a case study of COVID-19 diagnosis across four NHS Hospital Trusts, we show that all methods achieve clinically-effective performances (NPV > 0.959), with transfer learning achieving the best results (mean AUROCs between 0.870 and 0.925). Our models demonstrate that site-specific customization improves predictive performance when compared to other ready-made approaches. [ABSTRACT FROM AUTHOR]

Background: This study evaluated clinical outcomes of a low barrier tele-buprenorphine bridge program for NYC residents with opioid use disorder (OUD) at 1 year during the coronavirus disease 2019 (COVID-19) pandemic. Methods and materials: This retrospective analysis of the NYC Health + Hospitals (NYC H + H) Virtual Buprenorphine Clinic registry assessed baseline demographic and clinical characteristics, rates of referrals to community treatment, and induction-related adverse events among city residents with OUD, from March 2020 to the end of March 2021. Results: The program enrolled 199 patients, of whom 62.3% were provided same-day visits (n = 124). Patients were enrolled in the program for a median of 14 days (range 0-130 days). Referrals sources included hospital and clinic staff (n = 83, 47.7%), word of mouth (n = 30, 17.2%), and correctional health or reentry services (n = 30, 17.2%). Induction-related adverse events were mostly limited to precipitated withdrawal symptoms (n = 21, 5%). Roughly half of patients were referred to community treatment (n = 109, 54.8%) and of those 51.4% (n = 56/109) completed at least one visit in community treatment. Discussion: Our experience indicates that a low threshold tele-buprenorphine bridge program in place of a safe and feasible approach to facilitating entry in community treatment for underserved people who use opioids in a large metropolitan area. [ABSTRACT FROM AUTHOR]

Over the past 20 years, despite significant advancements in pulmonary arterial hypertension (PAH) medical therapy, many patients require admission to the hospital and are at risk for in‐hospital cardiac arrest (IHCA). Prior data found poor survival in PAH patients after cardiac arrest. The purpose of this study was to explore post‐IHCA outcomes in PAH patients receiving advanced medical therapies. This is a single‐center retrospective study of PAH patients who underwent cardiopulmonary resuscitation for IHCA between July 2005 and May 2021. Patients were identified through an internal cardiac arrest database. Twenty six patients were included. Half of the cohort had idiopathic PAH, with 54% of patients on combination therapy, 27% on monotherapy, and 19% of patients on no therapy. Mean right atrial pressure, mean pulmonary artery pressure, cardiac index, and pulmonary vascular resistance were 13 ± 6 mmHg, 57 ± 13 mmHg, 2.0 ± 0.7 L/min/m², and 14.5 ± 7.6 Wood units, respectively. Most common etiology of cardiac arrest was circulatory collapse. Initial arrest rhythm in all but one patient was pulseless electrical activity. Six patients (23%) achieved return of spontaneous circulation (ROSC) and one patient (4%) survived to hospital discharge. Rates of ROSC and survival to discharge after IHCA are poor in patients with PAH. Even patients with mild hemodynamics had low likelihood of survival. In patients who are lung transplant candidates, there should be early consideration of extracorporeal support before cardiac arrest. [ABSTRACT FROM AUTHOR]

Nucleos(t)ide analogs are standard-of-care for the treatment of chronic hepatitis B and can effectively reduce hepatitis B virus (HBV) replication but rarely leads to cure. Nucleos(t)ide analogs do not directly eliminate the viral episome, therefore treatment cessation typically leads to rapid viral rebound. While treatment is effective, HBV DNA is still detectable (although not quantifiable) in the periphery of the majority of nucleos(t)ide analog treated HBV patients, even after prolonged treatment. Addressing whether the detectable HBV DNA represents infectious virus is a key unknown and has important implications for the development of a curative treatment for HBV. The minimum HBV genome equivalents required to establish infection in human liver chimeric mice was determined by titration of HBV patient sera and the infectivity in chimeric mice of serum from patients (n = 7) suppressed to the limit of detection on nucleos(t)ide analog therapy was evaluated. A minimum of 5 HBV genome equivalents were required to establish infection in the chimeric mice, confirming this model has sufficient sensitivity to determine whether serum from virally suppressed patients contains infectious virus. Strikingly, serum from 75% (n = 3 out of 4) of nucleos(t)ide-treated HBV patients with DNA that was detectable, but below the lower limit of quantitation, also established infection in the chimeric mice. These results demonstrate that infectious virus is still present in some HBV patients on suppressive nucleos(t)ide therapy. This residual virus may support viral persistence via continuous infection and explain the ongoing risk for HBV-related complications despite long-term suppression on therapy. Thus, additional treatment intensification may facilitate HBV cure. [ABSTRACT FROM AUTHOR]

Background: Hyperinsulinemia is independently associated with increased risk and mortality of pancreatic cancer. We recently reported that genetically reduced insulin production resulted in ~ 50% suppression of pancreatic intraepithelial neoplasia (PanIN) precancerous lesions in mice. However, only female mice remained normoglycemic, and only the gene dosage of the rodent-specific Ins1 alleles was tested in our previous model. Moreover, we did not delve into the molecular and cellular mechanisms associated with modulating hyperinsulinemia. Methods: We studied how reduced Ins2 gene dosage affects PanIN lesion development in both male and female Ptf1aCreER;KrasLSL-G12D mice lacking the rodent-specific Ins1 gene (Ins1-/-). We generated control mice having two alleles of the wild-type Ins2 gene (Ptf1aCreER;KrasLSL-G12D;Ins1-/-;Ins2+/+) and experimental mice having one allele of Ins2 gene (Ptf1aCreER;KrasLSL-G12D;Ins1-/-;Ins2+/-). We then performed thorough histopathological analyses and single-cell transcriptomics for both genotypes and sexes. Results: High-fat diet–induced hyperinsulinemia was transiently or modestly reduced in female and male mice, respectively, with only one allele of Ins2. This occurred without dramatically affecting glucose tolerance. Genetic reduction of insulin production resulted in mice with a tendency for less PanIN and acinar-to-ductal metaplasia (ADM) lesions. Using single-cell transcriptomics, we found hyperinsulinemia affected multiple cell types in the pancreas, with the most statistically significant effects on local immune cell types that were highly represented in our sampled cell population. Specifically, hyperinsulinemia modulated pathways associated with protein translation, MAPK-ERK signaling, and PI3K-AKT signaling, which were changed in epithelial cells and subsets of immune cells. Conclusions: These data suggest a potential role for the immune microenvironment in hyperinsulinemia-driven PanIN development. Together with our previous work, we propose that mild suppression of insulin levels may be useful in preventing pancreatic cancer by acting on multiple cell types. [ABSTRACT FROM AUTHOR]