Mechanisms of CD40-dependent cDC1 licensing beyond costimulation.

CD40 signaling in classical type 1 dendritic cells (cDC1s) is required for CD8 T cell-mediated tumor rejection, but the underlying mechanisms are incompletely understood. Here, we identified CD40-induced genes in cDC1s, including Cd70, Tnfsf9, Ptgs2 and Bcl2l1, and examined their contributions to anti-tumor immunity. cDC1-specific inactivation of CD70 and COX-2, and global CD27 inactivation, only partially impaired tumor rejection or tumor-specific CD8 T cell expansion. Loss of 4-1BB, alone or in Cd27-/- mice, did not further impair anti-tumor immunity. However, cDC1-specific CD40 inactivation reduced cDC1 mitochondrial transmembrane potential and increased caspase activation in tumor-draining lymph nodes, reducing migratory cDC1 numbers in vivo. Similar impairments occurred during in vitro antigen presentation by Cd40-/- cDC1s to CD8+ T cells, which were reversed by re-expression of Bcl2l1. Thus, CD40 signaling in cDC1s not only induces costimulatory ligands for CD8+ T cells but also induces Bcl2l1 that sustains cDC1 survival during priming of anti-tumor responses.

Role of PFKFB3-driven glycolysis in vessel sprouting.

Vessel sprouting by migrating tip and proliferating stalk endothelial cells (ECs) is controlled by genetic signals (such as Notch), but it is unknown whether metabolism also regulates this process. Here, we show that ECs relied on glycolysis rather than on oxidative phosphorylation for ATP production and that loss of the glycolytic activator PFKFB3 in ECs impaired vessel formation. Mechanistically, PFKFB3 not only regulated EC proliferation but also controlled the formation of filopodia/lamellipodia and directional migration, in part by compartmentalizing with F-actin in motile protrusions. Mosaic in vitro and in vivo sprouting assays further revealed that PFKFB3 overexpression overruled the pro-stalk activity of Notch, whereas PFKFB3 deficiency impaired tip cell formation upon Notch blockade, implying that glycolysis regulates vessel branching.

Endothelial Cell Metabolism.

Endothelial cells (ECs) are more than inert blood vessel lining material. Instead, they are active players in the formation of new blood vessels (angiogenesis) both in health and (life-threatening) diseases. Recently, a new concept arose by which EC metabolism drives angiogenesis in parallel to well-established angiogenic growth factors (e.g., vascular endothelial growth factor). 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3-driven glycolysis generates energy to sustain competitive behavior of the ECs at the tip of a growing vessel sprout, whereas carnitine palmitoyltransferase 1a-controlled fatty acid oxidation regulates nucleotide synthesis and proliferation of ECs in the stalk of the sprout. To maintain vascular homeostasis, ECs rely on an intricate metabolic wiring characterized by intracellular compartmentalization, use metabolites for epigenetic regulation of EC subtype differentiation, crosstalk through metabolite release with other cell types, and exhibit EC subtype-specific metabolic traits. Importantly, maladaptation of EC metabolism contributes to vascular disorders, through EC dysfunction or excess angiogenesis, and presents new opportunities for anti-angiogenic strategies. Here we provide a comprehensive overview of established as well as newly uncovered aspects of EC metabolism.

Smoking exposure-induced bronchus-associated lymphoid tissue in donor lungs does not prevent tolerance induction after transplantation.

The presence of bronchus-associated lymphoid tissue (BALT) in donor lungs has been suggested to accelerate graft rejection after lung transplantation. Although chronic smoke exposure can induce BALT formation, the impact of donor cigarette use on alloimmune responses after lung transplantation is not well understood. Here, we show that smoking-induced BALT in mouse donor lungs contains Foxp3+ T cells and undergoes dynamic restructuring after transplantation, including recruitment of recipient-derived leukocytes to areas of pre-existing lymphoid follicles and replacement of graft-resident donor cells. Our findings from mouse and human lung transplant data support the notion that a donor's smoking history does not predispose to acute cellular rejection or prevent the establishment of allograft acceptance with comparable outcomes to nonsmoking donors. Thus, our work indicates that BALT in donor lungs is plastic in nature and may have important implications for modulating proinflammatory or tolerogenic immune responses following transplantation.

Nanoparticle targeting of neutrophil glycolysis prevents lung ischemia-reperfusion injury.

Neutrophils exacerbate pulmonary ischemia-reperfusion injury (IRI) resulting in poor short and long-term outcomes for lung transplant recipients. Glycolysis powers neutrophil activation, but it remains unclear if neutrophil-specific targeting of this pathway will inhibit IRI. Lipid nanoparticles containing the glycolysis flux inhibitor 2-deoxyglucose (2-DG) were conjugated to neutrophil-specific Ly6G antibodies (NP-Ly6G[2-DG]). Intravenously administered NP-Ly6G(2-DG) to mice exhibited high specificity for circulating neutrophils. NP-Ly6G(2-DG)-treated neutrophils were unable to adapt to hypoglycemic conditions of the lung airspace environment as evident by the loss of demand-induced glycolysis, reductions in glycogen and ATP content, and an increased vulnerability to apoptosis. NP-Ly6G(2-DG) treatment inhibited pulmonary IRI following hilar occlusion and orthotopic lung transplantation. IRI protection was associated with less airspace neutrophil extracellular trap generation, reduced intragraft neutrophilia, and enhanced alveolar macrophage efferocytotic clearance of neutrophils. Collectively, our data show that pharmacologically targeting glycolysis in neutrophils inhibits their activation and survival leading to reduced pulmonary IRI.

Facilitated Transport of EGFR Inhibitors Plays an Important Role in Their Cellular Uptake.

Epidermal growth factor receptor (EGFR) is a transmembrane protein commonly targeted by tyrosine kinase inhibitors (TKIs) as a front-line therapy for patients with many cancers including nonsmall cell lung cancer (NSCLC). Effective treatment requires efficient intracellular drug uptake and target binding. However, despite the recent success in the development of new TKI drugs, the mechanisms of uptake for many TKIs are still poorly understood due to the difficulty in imaging and measuring nonfluorescent drug molecules at a subcellular resolution. It has previously been shown that weakly basic TKI drugs are sequestered in lysosomes. Leveraging this property, we apply hyperspectral stimulated Raman scattering imaging to directly visualize and quantify two Food and Drug Administration-approved EGFR inhibitor drugs (lapatinib and afatinib) inside living cells and the changes in their cellular uptake upon the addition of organic cation transporter inhibitors. These single-cell quantitative measurements provide new insight into the role of membrane transporters in the uptake of TKI drugs in living cells.

Interventions for Concerning Patient-Reported Outcomes in Routine Cancer Care: A Systematic Review.

IMPORTANCE: Collecting patient-reported outcomes (PROs) in routine cancer care improves patient-clinician communication, decision making, and overall patient satisfaction. Recommendations exist regarding standardized ways to collect, store, and interpret PRO data. However, evidence on incorporating PROs into cancer process of care, especially the type of HIs that are warranted after observing a concerning PRO and the effectiveness of these HIs are lacking. OBJECTIVE: This study summarizes HIs triggered after PRO completion and their effectiveness in improving patient outcomes for adults being treated for cancer types that are resource intensive and associated with high symptom burden [i.e., gastrointestinal (GI), lung, and head and neck cancer (HNC)]. Secondary outcomes included factors associated with poor implementation of PROs. EVIDENCE REVIEW: A literature search of peer-reviewed publications on MEDLINE, CINAHL Plus, APA PsycInfo, Scopus, and Cochrane was conducted following PRISMA guidelines from 1 January 2012, to 31 July 2022. Trial and real-world studies describing HIs after PRO completion for adult patients being treated for GI, lung, and HNC were included. Sixteen studies involving 144,496 patients were included. The Joanna Briggs Institute critical appraisal checklist was used to assess risk of bias. FINDINGS: Of the 16 included studies, 5 included patients with HNC. Commonly used PRO measurement tools were the PRO-CTCAE and ESAS. Only three studies reported specific HIs delivered in response to concerning PROs and measured their effectiveness on patient outcomes. In all three studies, these HIs significantly improved cancer-related care. The most common HIs undertaken in response to concerning PROs were referrals to other specialists/allied healthcare professionals, medication changes, or self-management advice. Provider-related barriers to PRO measurement and delivery included the overwhelming number of alerts, the time required to address each PRO and the unclear role of healthcare providers in response to these alerts. Patient-related barriers included lower digital literacy and socioeconomic status, older age, rural living, and patients suffering from GI and HNC. CONCLUSIONS AND RELEVANCE: This review highlights that PRO-triggered HIs are heterogenous and can improve patient quality of life. Further studies are necessary to determine the types of interventions with the greatest impact on patient care and outcomes.

Clinical and molecular effects of oral CCR4 antagonist RPT193 in atopic dermatitis: A Phase 1 study.

BACKGROUND: RPT193 is an orally administered small molecule antagonist of the human C-C motif chemokine receptor 4 (CCR4) that inhibits the migration and downstream activation of T-helper Type 2 (Th2) cells. We investigated single- and multiple-ascending doses of RPT193 in healthy subjects, and multiple doses of RPT193 in subjects with moderate-to-severe atopic dermatitis (AD). METHODS: This was a first-in-human randomized, placebo-controlled Phase 1a/1b monotherapy study (NCT04271514) to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and CCR4 surface receptor occupancy in eligible healthy subjects and subjects with moderate-to-severe AD. Clinical efficacy and skin biomarker effects of RPT193 monotherapy were assessed as exploratory endpoints in AD subjects. RESULTS: In healthy (n = 72) and AD subjects (n = 31), once-daily RPT193 treatment was generally well tolerated, with no serious adverse events reported and all treatment-emergent adverse events reported as mild/moderate. In AD subjects, numerically greater improvements in clinical efficacy endpoints were observed with RPT193 monotherapy versus placebo up to the end of the treatment period (Day 29), with statistically significant improvement, compared to Day 29 and placebo, observed 2 weeks after the end of treatment (Day 43) on several endpoints (p < .05). Moreover, significant changes in the transcriptional profile were seen in skin biopsies of RPT193-treated versus placebo-treated subjects at Day 29, which were also significantly correlated with improvements in clinical efficacy measures. CONCLUSIONS: To our knowledge, this is the first clinical study with an oral CCR4 antagonist that showed clinical improvement coupled with modulation of the cutaneous transcriptomic profile in an inflammatory skin disease.

Second harmonic generation microscopy of electromechanical reshaping on corneal collagen.

Refractive errors remain a global health concern, as a large proportion of the world's population is myopic. Current ablative approaches are costly, not without risks, and not all patients are candidates for these procedures. Electromechanical reshaping (EMR) has been explored as a viable cost-effective modality to directly shape tissues, including cartilage. In this study, stromal collagen structure and fibril orientation was examined before and after EMR with second-harmonic generation microscopy (SHG), a nonlinear multiphoton imaging method that has previously been used to study native corneal collagen with high spatial resolution. EMR, using a milled metal contact lens and potentiostat, was performed on the corneas of five extracted rabbit globes. SHG was performed using a confocal microscopy system and all images underwent collagen fibril orientation analysis. The collagen SHG signal in controls is uniform and is similarly seen in samples treated with pulsed potential, while continuous EMR specimens have reduced, nonhomogeneous signal. Collagen fibril orientation in native tissue demonstrates a broad distribution with suggestion of another peak evolving, while with EMR treated eyes a bimodal characteristic becomes readily evident. Pulsed EMR may be a means to correct refractive errors, as when comparing its SHG signal to negative control, preservation of collagen structures with little to no damage is observed. From collagen fiber orientation analysis, it can be inferred that simple DC application alters the structure of collagen. Future studies will involve histological assessment of these layers and multi-modal imaging analysis of dosimetry.

A competency framework on simulation modelling-supported decision-making for Master of Public Health graduates.

BACKGROUND: Simulation models are increasingly important for supporting decision-making in public health. However, due to lack of training, many public health professionals remain unfamiliar with constructing simulation models and using their outputs for decision-making. This study contributes to filling this gap by developing a competency framework on simulation model-supported decision-making targeting Master of Public Health education. METHODS: The study combined a literature review, a two-stage online Delphi survey and an online consensus workshop. A draft competency framework was developed based on 28 peer-reviewed publications. A two-stage online Delphi survey involving 15 experts was conducted to refine the framework. Finally, an online consensus workshop, including six experts, evaluated the competency framework and discussed its implementation. RESULTS: The competency framework identified 20 competencies related to stakeholder engagement, problem definition, evidence identification, participatory system mapping, model creation and calibration and the interpretation and dissemination of model results. The expert evaluation recommended differentiating professional profiles and levels of expertise and synergizing with existing course contents to support its implementation. CONCLUSIONS: The competency framework developed in this study is instrumental to including simulation model-supported decision-making in public health training. Future research is required to differentiate expertise levels and develop implementation strategies.

In EPAs we trust, is quality and safety a must? A cross-specialty analysis of entrustable professional activity guides.

PURPOSE: The inclusion of quality improvement (QI) and patient safety (PS) into CanMEDS reflects an expectation that graduating physicians are competent in these areas upon training completion. To ensure that Canadian postgraduate specialty training achieves this, the translation of QI/PS competencies into training standards as part of the implementation of competency-based medical education requires special attention. METHODS: We conducted a cross-specialty, multi-method analysis to examine how QI/PS was incorporated into the EPA Guides across 11 postgraduate specialties in Canada. RESULTS: We identify cross-specialty variability in how QI/PS is incorporated, positioned, and emphasized in EPAs and milestones. QI/PS was primarily referenced alongside clinical activities rather than as a sole competency or discrete activity. Patterns were characterized in how QI/PS became incorporated into milestones through repetition and customization. QI/PS was also decoupled, conceptualized, and emphasized differently across specialties. CONCLUSIONS: Variability in the inclusion of QI/PS in EPAs and milestones has important implications considering the visibility and influence of EPA Guides in practice. As specialties revisit and revise EPA Guides, there is a need to balance the standardization of foundational QI/PS concepts to foster shared understanding while simultaneously ensuring context-sensitive applications across specialties. Beyond QI/PS, this study illuminates the challenges and opportunities that lie in bridging theoretical frameworks with practical implementation in medical education, prompting broader consideration of how intrinsic roles and emergent areas are effectively incorporated into competency-based medical education.

A Thirteen-Year Analysis of Facial Fractures among Professional Soccer Players.

This study aims to identify the epidemiology and effects of facial fractures on return to play (RTP) in Major League Soccer (MLS) and the English Premier League (EPL). A total of 39 MLS players and 40 EPL players who sustained facial fractures from 2007 to 2019 were identified. Data on player demographics, the injury, and the impact of their injury on RTP were collected. Elbow-to-head was the most common mechanism of injury (20.3%). The most common fracture involved the nasal bone (48.3%). Most players (90%) RTP the same season. Players who sustained nasal fractures missed significantly fewer games (p < 0.001) than those who suffered other craniofacial fractures. Players treated surgically missed significantly more games (3.21 vs. 0.71, p = 0.006) and days (30.1 vs. 8.70, p = 0.002) than those managed nonoperatively. Significantly more EPL players who sustained facial fractures wore headgear upon RTP compared to MLS players (82% vs. 56%, p <0 .01). Most professional soccer players who sustain a facial fracture RTP the same season, but their recovery time can vary depending on the type of fracture, injury management, or injury severity. Our findings can help inform future craniofacial injury management as well as guidelines on player safety and fracture prevention.

Effect of Ward-Based High-Flow Nasal Cannula (HFNC) Oxygen Therapy on Critical Care Utilization During the COVID-19 Pandemic: A Retrospective Cohort Analysis.

BACKGROUND: Hospitals expanded critical care capacity during the COVID-19 pandemic by treating COVID-19 patients with high-flow nasal cannula oxygen therapy (HFNC) in non-traditional settings, including general internal medicine (GIM) wards. The impact of this practice on intensive care unit (ICU) capacity is unknown. OBJECTIVE: To describe how our hospital operationalized the use of HFNC on GIM wards, assess its impact on ICU capacity, and examine the characteristics and outcomes of treated patients. DESIGN: Retrospective cohort study of all patients treated with HFNC on GIM wards at a Canadian tertiary care hospital. PARTICIPANTS: All patients admitted with COVID-19 and treated with HFNC on GIM wards from December 28, 2020, to June 13, 2021, were included. MAIN MEASURES: We combined administrative data on critical care occupancy daily with chart-abstracted data for included patients to establish the total number of patients receiving ICU-level care at our hospital per day. We also collected data on demographics, medical comorbidities, illness severity, COVID-19 treatments, HFNC care processes, and patient outcomes. KEY RESULTS: We treated 124 patients with HFNC on the GIM wards (median age 66 years; 48% female). Patients were treated with HFNC for a median of 5 days (IQR 3 to 8); collectively, they received HFNC for a total of 740 hospital days, 71% of which were on GIM wards. At peak ICU capacity strain (144%), delivering HFNC on GIM wards added 20% to overall ICU capacity by managing up to 14 patients per day. Patients required a median maximal fraction of inspired oxygen of 80% (IQR 60 to 95). There were 18 deaths (15%) and 85 patients (69%) required critical care admission; of those, 40 (47%) required mechanical ventilation. CONCLUSIONS: With appropriate training and resources, treatment of COVID-19 patients with HFNC on GIM wards appears to be a feasible strategy to increase critical care capacity.

Characterizing Silicone Oil-Induced Protein Aggregation with Stimulated Raman Scattering Imaging.

Particles in biopharmaceutical products present high risks due to their detrimental impacts on product quality and safety. Identification and quantification of particles in drug products are important to understand particle formation mechanisms, which can help develop control strategies for particle formation during the formulation development and manufacturing process. However, existing analytical techniques such as microflow imaging and light obscuration measurement lack the sensitivity and resolution to detect particles with sizes smaller than 2 µm. More importantly, these techniques are not able to provide chemical information to determine particle composition. In this work, we overcome these challenges by applying the stimulated Raman scattering (SRS) microscopy technique to monitor the C-H Raman stretching modes of the proteinaceous particles and silicone oil droplets formed in the prefilled syringe barrel. By comparing the relative signal intensity and spectral features of each component, most particles can be classified as protein-silicone oil aggregates. We further show that morphological features are poor indicators of particle composition. Our method has the capability to quantify aggregation in protein therapeutics with chemical and spatial information in a label-free manner, potentially allowing high throughput screening or investigation of aggregation mechanisms.

The role of fatty acid ß-oxidation in lymphangiogenesis.

Lymphatic vessels are lined by lymphatic endothelial cells (LECs), and are critical for health. However, the role of metabolism in lymphatic development has not yet been elucidated. Here we report that in transgenic mouse models, LEC-specific loss of CPT1A, a rate-controlling enzyme in fatty acid ß-oxidation, impairs lymphatic development. LECs use fatty acid ß-oxidation to proliferate and for epigenetic regulation of lymphatic marker expression during LEC differentiation. Mechanistically, the transcription factor PROX1 upregulates CPT1A expression, which increases acetyl coenzyme A production dependent on fatty acid ß-oxidation. Acetyl coenzyme A is used by the histone acetyltransferase p300 to acetylate histones at lymphangiogenic genes. PROX1-p300 interaction facilitates preferential histone acetylation at PROX1-target genes. Through this metabolism-dependent mechanism, PROX1 mediates epigenetic changes that promote lymphangiogenesis. Notably, blockade of CPT1 enzymes inhibits injury-induced lymphangiogenesis, and replenishing acetyl coenzyme A by supplementing acetate rescues this process in vivo.

Structural mechanism of laforin function in glycogen dephosphorylation and lafora disease.

Glycogen is the major mammalian glucose storage cache and is critical for energy homeostasis. Glycogen synthesis in neurons must be tightly controlled due to neuronal sensitivity to perturbations in glycogen metabolism. Lafora disease (LD) is a fatal, congenital, neurodegenerative epilepsy. Mutations in the gene encoding the glycogen phosphatase laforin result in hyperphosphorylated glycogen that forms water-insoluble inclusions called Lafora bodies (LBs). LBs induce neuronal apoptosis and are the causative agent of LD. The mechanism of glycogen dephosphorylation by laforin and dysfunction in LD is unknown. We report the crystal structure of laforin bound to phosphoglucan product, revealing its unique integrated tertiary and quaternary structure. Structure-guided mutagenesis combined with biophysical and biochemical analyses reveal the basis for normal function of laforin in glycogen metabolism. Analyses of LD patient mutations define the mechanism by which subsets of mutations disrupt laforin function. These data provide fundamental insights connecting glycogen metabolism to neurodegenerative disease.

In vivo electrochemical lipolysis of fat in a Yucatan pig model: A proof of concept study.

OBJECTIVES: Traditional fat contouring is now regularly performed using numerous office- based less invasive techniques. However, some limitations of these minimally invasive techniques include high cost or limited selectivity with performing localized contouring and reduction of fat. These shortcomings may potentially be addressed by electrochemical lipolysis (ECLL), a novel approach that involves the insertion of electrodes into tissue followed by application of a direct current (DC) electrical potential. This results in the hydrolysis of tissue water creating active species that lead to fat necrosis and apoptosis. ECLL can be accomplished using a simple voltage-driven system (V-ECLL) or a potential-driven feedback cell (P-ECLL) both leading to water electrolysis and the creation of acid and base in situ. The aim of this study is to determine the long-lasting effects of targeted ECLL in a Yucatan pig model. METHODS: A 5-year-old Yucatan pig was treated with both V-ECLL and P-ECLL in the subcutaneous fat layer using 80:20 platinum:iridium needle electrodes along an 8 cm length. Dosimetry parameters included 5 V V-ECLL for 5, 10, and 20 minutes, and -1.5 V P-ECLL, -2.5 V P-ECLL, -3.5 V P-ECLL for 5 minutes. The pig was assessed for changes in fat reduction over 3 months with digital photography and ultrasound. After euthanasia, tissue sections were harvested and gross pathology and histology were examined. RESULTS: V-ECLL and P-ECLL treatments led to visible fat reduction (12.1%-27.7% and 9.4%-40.8%, respectively) and contour changes across several parameters. An increased reduction of the superficial fat layer occurred with increased dosimetry parameters with an average charge transfer of 12.5, 24.3, and 47.5 C transferred for 5 V V-ECLL for 5, 10, and 20 minutes, respectively, and 2.0, 11.5, and 24.0 C for -1.5 V P-ECLL, -2.5 V P-ECLL, -3.5 V P-ECLL for 5 minutes, respectively. These dose-dependent changes were also evidenced by digital photography, gross pathology, ultrasound imaging, and histology. CONCLUSIONS: ECLL results in selective damage and long-lasting changes to the adipose layer in vivo. These changes are dose-dependent, thus allowing for more precise contouring of target areas. P-ECLL has greater efficiency and control of total charge transfer compared to V-ECLL, suggesting that a low-voltage potentiostat treatment can result in fat apoptosis equivalent to a high-voltage DC system.

The Effect of the COVID-19 Pandemic on Digital Health-Seeking Behavior: Big Data Interrupted Time-Series Analysis of Google Trends.

BACKGROUND: Due to the emergency responses early in the COVID-19 pandemic, the use of digital health in health care increased abruptly. However, it remains unclear whether this introduction was sustained in the long term, especially with patients being able to decide between digital and traditional health services once the latter regained their functionality throughout the COVID-19 pandemic. OBJECTIVE: We aim to understand how the public interest in digital health changed as proxy for digital health-seeking behavior and to what extent this change was sustainable over time. METHODS: We used an interrupted time-series analysis of Google Trends data with break points on March 11, 2020 (declaration of COVID-19 as a pandemic by the World Health Organization), and December 20, 2020 (the announcement of the first COVID-19 vaccines). Nationally representative time-series data from February 2019 to August 2021 were extracted from Google Trends for 6 countries with English as their dominant language: Canada, the United States, the United Kingdom, New Zealand, Australia, and Ireland. We measured the changes in relative search volumes of the keywords online doctor, telehealth, online health, telemedicine, and health app. In doing so, we capture the prepandemic trend, the immediate change due to the announcement of COVID-19 being a pandemic, and the gradual change after the announcement. RESULTS: Digital health search volumes immediately increased in all countries under study after the announcement of COVID-19 being a pandemic. There was some variation in what keywords were used per country. However, searches declined after this immediate spike, sometimes reverting to prepandemic levels. The announcement of COVID-19 vaccines did not consistently impact digital health search volumes in the countries under study. The exception is the search volume of health app, which was observed as either being stable or gradually increasing during the pandemic. CONCLUSIONS: Our findings suggest that the increased public interest in digital health associated with the pandemic did not sustain, alluding to remaining structural barriers. Further building of digital health capacity and developing robust digital health governance frameworks remain crucial to facilitating sustainable digital health transformation.

Association between carotid atherosclerosis and brain activation patterns during the Stroop task in older adults: An fNIRS investigation.

There is an increasing body of evidence suggesting that vascular disease could contribute to cognitive decline and overt dementia. Of particular interest is atherosclerosis, as it is not only associated with dementia, but could be a potential mechanism through which cardiovascular disease directly impacts brain health. In this work, we evaluated the differences in functional near infrared spectroscopy (fNIRS)-based measures of brain activation, task performance, and the change in central hemodynamics (mean arterial pressure (MAP) and heart rate (HR)) during a Stroop color-word task in individuals with atherosclerosis, defined as bilateral carotid plaques (n = 33) and healthy age-matched controls (n = 33). In the healthy control group, the left prefrontal cortex (LPFC) was the only region showing evidence of activation when comparing the incongruous with the nominal Stroop test. A smaller extent of brain activation was observed in the Plaque group compared with the healthy controls (1) globally, as measured by oxygenated hemoglobin (p = 0.036) and (2) in the LPFC (p = 0.02) and left sensorimotor cortices (LMC)(p = 0.008) as measured by deoxygenated hemoglobin. There were no significant differences in HR, MAP, or task performance (both in terms of the time required to complete the task and number of errors made) between Plaque and control groups. These results suggest that carotid atherosclerosis is associated with altered functional brain activation patterns despite no evidence of impaired performance of the Stroop task or central hemodynamic changes.

NRF2 assessment in discarded liver allografts: A role in allograft function and salvage.

Antioxidant defence mechanisms, such as the nuclear factor-erythroid 2-related-factor-2 (NRF2) axis, are integral to oxidative stress responses and ischemic injury. Hepatic antioxidant capacity is contingent on parenchymal quality, and there is a need to develop new insights into key molecular mechanisms in marginal liver allografts that might provide therapeutic targets. This study examines the clinical relevance of NRF2 in donor livers and its response to normothermic machine perfusion (NMP). Discarded donor livers (n = 40) were stratified into a high NRF2 and low NRF2 group by quantifying NRF2 expression. High NRF2 livers had significantly lower transaminase levels, hepatic vascular inflammation and peri-portal CD3+ T cell infiltration. Human liver allografts (n = 8) were then exposed to 6-h of NMP and high NRF2 livers had significantly reduced liver enzyme alterations and improved lactate clearance. To investigate these findings further, we used a rat fatty-liver model, treating livers with an NRF2 agonist during NMP. Treated livers had increased NRF2 expression and reduced transaminase derangements following NMP compared to vehicle control. These results support the association of elevated NRF2 expression with improved liver function. Targeting this axis could have a rationale in future studies and NRF2 agonists may represent a supplemental treatment strategy for rescuing marginal donor livers.