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Coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB) causes a systemic inflammatory response that can worsen patient outcomes. Off-pump surgery has been associated with a reduced inflammatory response. The precise mechanisms and the role of extracellular vesicles (EVs) in this context are not fully understood. This study aimed to investigate the early immune response, including main T- and B-lymphocyte subsets, cytokine profiles, and plasma EVs, in patients undergoing off-pump (n = 18) and on-pump (n = 18) CABG. Thirty-six patients undergoing isolated CABG were enrolled in this randomized control study. Pre- and 24 h postoperative blood samples were analyzed for immune cell populations, cytokine levels, and plasma EV phenotyping. Off-pump CABG triggered a milder immune response than on-pump surgery. On-pump surgery led to greater changes in circulating EVs, particularly platelet- (CD62P+), endothelial- (CD31+), and B-cell-derived (CD19+), as well as platelet- and erythrocyte-derived aggregates (CD41+CD235a+). Levels of platelet-derived EVs, expressing both constitutional and activation markers (CD41+CD62P+) decreased in both groups of patients 24 h after surgery. On-pump cardiac procedures led to an increase in T-regulatory cell-derived EVs (CD73+CD39+), suggesting a potential mechanism for immune suppression compared to off-pump surgery. There were numerous correlations between EV levels and cytokine profiles following on-pump surgery, hinting at a close relationship. Leucocyte-derived EVs exhibited positive correlations with each other and with GRO but showed negative correlations with endothelial-derived EVs (CD90+ and CD31+). Additionally, CD73+ EVs demonstrated positive correlations with platelet counts and with erythrocyte-derived CD235a+ EVs. EV changes were significantly greater after on-pump surgery, highlighting a more pronounced response to this type of surgery and emphasizing the role of EVs as regulators of post-surgical inflammation.

Abstract In online single‐sided partial discharge (PD) location, the measured PD reflection patterns are affected by the characteristics of all the components of the associated power network. This paper analyses the performance of a PD location method based on electromagnetic time reversal (EMTR) theory, when interfering reflections contribute to the transient signals emitted by the PD event. The topology analysed is formed from a ring main unit (RMU) in a medium voltage grid with mixed cross‐linked polyethylene and paper‐insulated lead‐covered (PILC) cable sections. The PD reflection patterns, observed at the RMU, are disturbed by the reflections coming from the impedance discontinuities of the circuit and by the reflections coming from the cable ends of the PILC cables connected to the RMU. The simulated configuration is chosen such that classical location techniques tend to fail due to overlapping peaks and other signal distortion. This is because the classic techniques are based on identifying individual reflection peaks from which the PD source can be determined via differences in time of arrival. The numerical investigation shows that the accuracy of the EMTR‐based location method is robust against these effects, achieving a PD localisation with an error less than the 0.1%. The results also show that the EMTR‐based method can localise PDs using a PD monitoring point located somewhere along the network and not necessarily at the line termination.

Abstract Time reversal exploits the invariance of electromagnetic wave propagation in reciprocal and lossless media to localize radiating sources. Time‐reversed measurements are back‐propagated in a simulated domain and converge to the unknown source location. The focusing time (i.e. the simulation instant at which the fields converge to the source location) and the source location can be identified using field maxima, entropy, time kurtosis, and space kurtosis. This paper analyses the spatial energy‐density distribution of time‐reversed electromagnetic fields by introducing a convergence metric based on the spatial average and variance of the energy density. It is analytically proven that the proposed metric identifies the focusing time and the source location, with direct links to the source frequency content. The analytical results are verified in a free‐space numerical simulation and the proposed metric is then compared to existing ones in a simulated inhomogeneous medium. Next, this metric is applied and compared in an experimental case study to localize electromagnetic interference sources. The proposed metric outperforms existing ones to identify the focusing time and can also be used to locate the source. Finally, because of its tensorial nature, it can handle anisotropic media, opening the door to quantitative analyses of time‐reversal focusing in metamaterials.

Abstract Activities of ATP binding cassette (ABC) proteins are regulated by multiple mechanisms, including protein interactions, phosphorylation, proteolytic processing, and/or oligomerization of the ABC protein itself. Here we present the structure of yeast cadmium factor 1 (Ycf1p) in its mature form following cleavage by Pep4p protease. Ycf1p, a C subfamily ABC protein (ABCC), is homologue of human multidrug resistance protein 1. Remarkably, a portion of cleaved Ycf1p forms a well-ordered dimer, alongside monomeric particles also present in solution. While numerous other ABC proteins have been proposed to dimerize, no high-resolution structures have been reported. Both phosphorylation of the regulatory (R) region and ATPase activity are lower in the Ycf1p dimer compared to the monomer, indicating that dimerization affects Ycf1p function. The interface between Ycf1p protomers features protein-protein interactions and contains bound lipids, suggesting that lipids stabilize the dimer. The Ycf1p dimer structure may inform the dimerization interfaces of other ABCC dimers.

Abstract Background To describe the societal costs during one year of follow-up among older adults seeking chiropractic care due to a new episode of low back pain (LBP), and to determine what factors predict high societal costs in this population. Methods Prospective cohort study, within chiropractic private practices (n = 38) in the Netherlands. 223 people ≥ 55 years of age with a new episode of LBP seeking chiropractic care participated. The primary outcome was total societal costs. High societal costs were defined as patients with costs in the top 20th percentile. The final prediction models were obtained using forward selection. Results were presented for the total population and stratified for retirement status. The model’s prognostic accuracy (Hosmer–Lemeshow X2, Nagelkerke’s R2) and discriminative ability [area under the receiver operating curve (AUC)] were assessed, and the models were internally validated using bootstrapping. Results The mean total annual societal cost per patient was €5297 [95% confidence interval (CI): 4191–6403]. The biggest cost driver was presenteeism (65% of total costs), and costs were higher among non-retired participants (€7759; 95% CI 6047–9470) than retired participants (€1892; 95% CI 1088–2695). In the total population, younger age [odds ratio (OR): 0.87 for each additional year; 95% CI 0.80–0.95], being male instead of female (OR 2.96; 95% CI 1.19–7.44), less alcohol intake (OR 0.49; 95% CI 0.20–1.19), working instead of retirement (OR 9.37; 95% CI 1.83–48.04), and more disability at baseline (OR 1.08; 95% CI 1.00–1.16) were found to be predictive of high societal costs. Working was found to be the strongest predictor for high societal costs. After internal validation, the model’s fit was good, it’s explained variance was moderate (28%) and their AUCs could be interpreted as moderate (0.85). For non-pensioners, the same predictive factors were identified as for the entire population. The costs for the retired participants showed too little variation to be able to predict high costs. Conclusions This study estimated the mean total annual societal cost of older adults seeking chiropractic care due to a new episode of LBP at €5297 (95% CI 4191–6403).These costs were mainly due to high levels of presenteeism, and extensively differed based upon work status.

Abstract Background Breast cancer, one of the most common forms of cancer, is associated with the highest cancer-related mortality among women worldwide. In comparison to other types of breast cancer, patients diagnosed with the triple-negative breast cancer (TNBC) subtype have the worst outcome because current therapies do not produce long-lasting responses. Hence, innovative therapies that produce persisting responses are a critical need. We previously discovered that hyperactivating purinergic receptors (P2RXs) by increasing extracellular adenosine triphosphate (eATP) concentrations enhances TNBC cell lines’ response to chemotherapy. Heparan sulfate inhibits multiple extracellular ATPases, so it is a molecule of interest in this regard. In turn, heparanase degrades polysulfated polysaccharide heparan sulfate. Importantly, previous work suggests that breast cancer and other cancers express heparanase at high levels. Hence, as heparan sulfate can inhibit extracellular ATPases to facilitate eATP accumulation, it may intensify responses to chemotherapy. We postulated that heparanase inhibitors would exacerbate chemotherapy-induced decreases in TNBC cell viability by increasing heparan sulfate in the cellular microenvironment and hence, augmenting eATP. Methods We treated TNBC cell lines MDA-MB 231, Hs 578t, and MDA-MB 468 and non-tumorigenic immortal mammary epithelial MCF-10A cells with paclitaxel (cytotoxic chemotherapeutic) with or without the heparanase inhibitor OGT 2115 and/or supplemental heparan sulfate. We evaluated cell viability and the release of eATP. Also, we compared the expression of heparanase protein in cell lines and tissues by immunoblot and immunohistochemistry, respectively. In addition, we examined breast-cancer-initiating cell populations using tumorsphere formation efficiency assays on treated cells. Results We found that combining heparanase inhibitor OGT 2115 with chemotherapy decreased TNBC cell viability and tumorsphere formation through increases in eATP and activation of purinergic receptors as compared to TNBC cells treated with single-agent paclitaxel. Conclusion Our data shows that by preventing heparan sulfate breakdown, heparanase inhibitors make TNBC cells more susceptible to chemotherapy by enhancing eATP concentrations.

Abstract The acetylation of autophagy protein 9 A (ATG9A) in the lumen of the endoplasmic reticulum (ER) by ATase1 and ATase2 regulates the induction of reticulophagy. Analysis of the ER-specific ATG9A interactome identified calreticulin (CALR), an ER luminal Ca+2-binding chaperone, as key for ATG9A activity. Specifically, if acetylated, ATG9A is sequestered by CALR and prevented from engaging FAM134B and SEC62. Under this condition, ATG9A is unable to activate the autophagy core machinery. In contrast, when non-acetylated, ATG9A is released by CALR and able to engage FAM134B and SEC62. In this study, we report that Ca+2 dynamics across the ER membrane regulate the ATG9A-CALR interaction as well as the ability of ATG9A to trigger reticulophagy. We show that the Ca+2-binding sites situated on the C-domain of CALR are essential for the ATG9A-CALR interaction. Finally, we show that K359 and K363 on ATG9A can influence the ATG9A-CALR interaction. Collectively, our results disclose a previously unidentified aspect of the complex mechanisms that regulate ATG9A activity. They also offer a possible area of intersection between Ca+2 metabolism, acetyl-CoA metabolism, and ER proteostasis.

Abstract Background Cancer survivors (CS) comprise a particularly high-risk group for both de-novo and recurrent malignancies after solid organ transplantation. Case presentation We report a case of relapsed melanoma, presented as metastatic disease seven months after heart transplantation in a patient who had an early-stage melanoma resected 25 years prior. Treatment with a combination of dabrafenib, a BRAF inhibitor, and trametinib, a mitogen-activated protein kinase (MEK) inhibitor resulted in a near-complete metabolic response, without major adverse effects. Conclusion This case demonstrates the increased risk of recurrence in CS with melanoma, which can persist decades after cancer diagnosis. These patients may be amenable to treatment using modern treatment modalities in oncology.

Abstract Recent studies have established that cellular electrostatic interactions are more influential than assumed previously. Here, we use cryo-EM and perform steady-state kinetic studies to investigate electrostatic interactions between cytochrome (cyt.) c and the complex (C) III2-IV supercomplex from Saccharomyces cerevisiae at low salinity. The kinetic studies show a sharp transition with a Hill coefficient ≥2, which together with the cryo-EM data at 2.4 Å resolution indicate multiple cyt. c molecules bound along the supercomplex surface. Negatively charged loops of CIII2 subunits Qcr6 and Qcr9 become structured to interact with cyt. c. In addition, the higher resolution allows us to identify water molecules in proton pathways of CIV and, to the best of our knowledge, previously unresolved cardiolipin molecules. In conclusion, the lowered electrostatic screening renders engagement of multiple cyt. c molecules that are directed by electrostatically structured CIII2 loops to conduct electron transfer between CIII2 and CIV.

Abstract Background Exposure to phenols has been linked in animal models and human populations to cardiac function alterations and cardiovascular diseases, although their effects on cardiac electrical properties in humans remains to be established. This study aimed to identify changes in electrocardiographic (ECG) parameters associated with environmental phenol exposure in adults of a midwestern large cohort known as the Fernald Community Cohort (FCC). Methods During the day of the first comprehensive medical examination, urine samples were obtained, and electrocardiograms were recorded. Cross-sectional linear regression analyses were performed. Results Bisphenol A (BPA) and bisphenol F (BPF) were both associated with a longer PR interval, an indication of delayed atrial-to-ventricle conduction, in females (p

Abstract In chronic musculoskeletal conditions, the prognosis tends to be more informative than the diagnosis for the future course of the disease. Many studies have identified clusters of patients who seemingly share similar pain trajectories. In a dataset of low back pain (LBP) patients, pain trajectories have been identified, and distinct trajectory types have been defined, making it possible to create pattern recognition software that can classify patients into respective pain trajectories reflecting their condition. It has been suggested that the classification of pain trajectories may create clinically meaningful subgroups of patients in an otherwise heterogeneous population of patients with LBP. A software tool was created that combined the ability to recognise the pain trajectory of patients with a system that could create subgroups of patients based on their characteristics. This tool is primarily meant for researchers to analyse trends in large heterogeneous datasets without large losses of data. Prospective analysis of pain trajectories is not directly helpful for clinicians. However, the tool might aid in the identification of patient characteristics which have predictive capabilities of the most likely trajectory a patient might experience in the future. This will help clinicians to tailor their advice and treatment for a specific patient.

Abstract Background Despite recent advances in lung cancer therapeutics and improving overall survival, disparities persist among socially disadvantaged populations. This study aims to determine the effects of neighborhood deprivation indices (NDI) on lung cancer mortality. This is a multicenter retrospective cohort study assessing the relationship between NDI and overall survival adjusted for age, disease stage, and DNA methylation among biopsy-proven lung cancer patients. State-specific NDI for each year of sample collection were computed at the U.S. census tract level and dichotomized into low- and high-deprivation. Results A total of 173 non small lung cancer patients were included, with n = 85 (49%) and n = 88 (51%) in the low and high-deprivation groups, respectively. NDI was significantly higher among Black patients when compared with White patients (p = 0.003). There was a significant correlation between DNA methylation and stage for HOXA7, SOX17, ZFP42, HOXA9, CDO1 and TAC1. Only HOXA7 DNA methylation was positively correlated with NDI. The high-deprivation group had a statistically significant shorter survival than the low-deprivation group (p = 0.02). After adjusting for age, race, stage, and DNA methylation status, belonging to the high-deprivation group was associated with higher mortality with a hazard ratio of 1.81 (95%CI: 1.03–3.19). Conclusions Increased neighborhood-level deprivation may be associated with liquid biopsy DNA methylation, shorter survival, and increased mortality. Changes in health care policies that consider neighborhood-level indices of socioeconomic deprivation may enable a more equitable increase in lung cancer survival.

Abstract While criminal legal involvement is a structural determinant of health, both administrative and national longitudinal cohort data are collected and made available in a way that prevents a full understanding of this relationship. Administrative data are both collected and overseen by the same entity and are incomplete, delayed, and/or uninterpretable. Cohort data often only ask these questions to the most vulnerable, and do not include all types of criminal legal involvement, when this involvement occurs in someone’s life, or family and community involvement. To achieve a more optimized data landscape and to facilitate population-level research on criminal legal involvement and health, (1) individual administrative level data must be made available and able to be linked across carceral systems, (2) a national data archive must be made to maintain and make criminal legal data available to researchers, and (3) a nationally representative, longitudinal study focused on those with criminal legal involvement is necessary. By beginning to critically think about how future data could be collated and collected, we can begin to provide more robust evidence around how the criminal legal system impacts the health of our society and, in turn, create policy reform.