Search

In this review, we have amalgamated the literature, taking a multimodal neuroimaging approach to quantify the relationship between neuronal firing and haemodynamics during a task paradigm (i.e., neurovascular coupling response), while considering confounding physiological influences. Original research articles that used concurrent neuronal and haemodynamic quantification in humans (n ≥ 10) during a task paradigm were included from PubMed, Scopus, Web of Science, EMBASE and PsychINFO. Articles published before 31 July 2023 were considered for eligibility. Rapid screening was completed by the first author. Two authors completed the title/abstract and full-text screening. Article quality was assessed using a modified version of the National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. A total of 364 articles were included following title/abstract and full-text screening. The most common combination was EEG/functional MRI (68.7%), with cognitive (48.1%) and visual (27.5%) tasks being the most common. The majority of studies displayed an absence/minimal control of blood pressure, arterial gas concentrations and/or heart rate (92.9%), and only 1.3% monitored these factors. A minority of studies restricted or collected data pertaining to caffeine (7.4%), exercise (0.8%), food (0.5%), nicotine (2.7%), the menstrual cycle (0.3%) or cardiorespiratory fitness levels (0.5%). The cerebrovasculature is sensitive to numerous factors; thus, to understand the neurovascular coupling response fully, better control for confounding physiological influences of blood pressure and respiratory metrics is imperative during study-design formulation. Moreover, further work should continue to examine sex-based differences, the influence of sex steroid hormone concentrations and cardiorespiratory fitness., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Setting: Alcohol is a major cause of health and social costs and harms in Canada. While research and awareness of harms caused by alcohol are on the rise, few transdisciplinary platforms exist that are committed to facilitating bold alcohol policy change to reduce health inequities and improve lives., Intervention: In response to feedback heard during engagement for the Canadian Alcohol Policy Evaluation project, an alcohol policy-focused community of practice (CoP) was launched in January 2022. Webinars, roundtable discussions, working group meetings, networking events, and a digital platform allow practitioners from various sectors (e.g. public health, alcohol regulation and distribution, public safety, justice, non-governmental organizations), researchers, and people with lived/living experience (PWLLE) to connect, share experiences and resources, and build capacity., Outcomes: More than 500 members have joined the CoP from all Canadian provinces and territories, and international jurisdictions. CoP members engage in learning opportunities, contribute to letter-writing campaigns in support of alcohol policy initiatives, and lead a working group focused on alcohol warning labels. Through the CoP, members report gaining and applying new knowledge in their work, while also establishing valuable connections and collaborations that have supported positive change., Implications: This cross-jurisdictional, intersectoral alcohol policy CoP facilitates knowledge sharing, networking, and collaboration among practitioners, policymakers, advocates, and PWLLE, while contributing to public health efforts to prevent alcohol harms. Furthermore, as transdisciplinary approaches continue to be prioritized in research and practice, this CoP offers an example that could be applied to other public health initiatives., Competing Interests: Declarations. Ethics approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (University of Victoria Human Research Ethics Board #21–0550) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Consent to participate: Not applicable. Consent for publication: Not applicable. Conflict of interest: The authors declare no competing interests. Disclaimer: The views and opinions expressed in this manuscript are those of the authors and do not necessarily represent those of funders., (© 2024. The Author(s) under exclusive license to The Canadian Public Health Association.)

Aims: The efficacy of intensive blood pressure (BP) control remains controversial, and the variability of HbA1c was a risk factor for macrovascular events in patients with type 2 diabetes. We investigated whether the HbA1c variability modifies the efficacy of intensive BP control., Methods: Data from the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD-BP) trial was utilized. K-means clustering was used to cluster patients into three groups based on the HbA1c variability score and baseline HbA1c values. Cox proportional hazard models and generalized linear models were used to measure the subgroup differences in intensive BP control treatment effects. The primary outcome was a composite of nonfatal myocardial infarction (MI), stroke, or death from cardiovascular causes., Results: In patients with low HbA1c variability rather than medium or high HbA1c variability, intensive BP control reduced the risk of the primary outcome on a relative scale (HR 0.60, 95%CI 0.40-0.90, p interaction was 0.03), non-fatal MI (HR 0.61, 95% CI 0.37-1.00, p interaction was 0.04) and stroke (HR 0.19, 95%CI 0.05-0.64, p interaction was 0.02) or absolute scale. Regardless of the variability group, intensive BP control did not reduce the risk of cardiovascular or all-cause mortality (p interaction >0.05) both on relative and absolute risk scales., Conclusion: HbA1c variability had effect on the efficacy of intensive BP control and intensive BP control brought a significant macrovascular benefit in patients with type 2 diabetes and low HbA1c variability., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

There are differences within the literature regarding the upper frequency cut-off point of the dynamic cerebral autoregulation (CA) high-pass filter. The projection pursuit regression approach has demonstrated that the upper frequency limit is ∼0.07 Hz, whereas another approach [transfer function analysis (TFA) phase approaching zero] indicated a theoretical upper frequency limit for the high-pass filter of 0.24 Hz. We investigated how these limits accurately represent the CA upper frequency limit, in addition to extending earlier findings with respect to biological sexes and across the cardiac cycle. Sixteen participants (nine females and seven males) performed repeated squat-stand manoeuvres at frequencies of 0.05, 0.10, 0.15, 0.20 and 0.25 Hz, with insonation of the middle and posterior cerebral arteries. Linear regression modelling with adjustment for sex and order of squat completion was used to compared TFA gain and phase with 0.25 Hz (above the theoretical limit of CA). The upper frequency limit of CA with TFA gain was within the range of 0.05-0.10 Hz, whereas TFA phase was within the range of 0.20-0.25 Hz, and consistent between vessels, between sexes and across the cardiac cycle. Females displayed greater middle cerebral artery gain compared with males (all P < 0.047), and no phase differences were present (all P > 0.072). Although sex-specific differences were present for specific TFA metrics at a given frequency, the upper frequency limit of autoregulation was similar between cerebral conduit vessels, cardiac cycle phase and biological sex. Future work is warranted to determine whether an upper frequency limit exists with respect to hysteresis analyses., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: Platelet-rich microvascular thrombi are common in severe COVID-19. Endogenous nitric oxide (NO)-signaling limits thrombus formation and previously we identified platelet subpopulations with a differential ability to produce NO based on the presence or absence of endothelial nitric oxide synthase (eNOS). eNOS expression is counter-regulated by cytokines, and COVID-19-associated immune/inflammatory responses may affect the transcriptome profile of megakaryocytes and their platelet progeny., Objectives: We investigated whether the percentage of eNOS-negative to eNOS-positive platelets increases in COVID-19 patients and whether this change may be due to the actions of pro-inflammatory cytokines on megakaryocytes., Methods: Platelets were isolated from hospitalized COVID-19 patients and COVID-19-negative controls. Platelet eNOS was measured by flow cytometry and plasma inflammatory cytokines by ELISA. Megakaryocytes from eNOS-GFP transgenic mice and the Meg-01 cell line were characterized to identify an appropriate model to study eNOS-based platelet subpopulation formation in response to inflammatory cytokines., Results: COVID-19 patients demonstrated a significant increase in eNOS-negative and a concomitant decrease in eNOS-positive platelets compared to controls, and this change was associated with disease severity as assessed by ICU admission. A higher eNOS-negative to -positive platelet percentage was associated with enhanced platelet activation as measured by surface CD62P. Accordingly, COVID-19 patients demonstrated higher TNF-α, IL-6, and IL-1β plasma concentrations than controls. Inflammatory cytokines associated with COVID-19 promoted eNOS-negative Meg-01 formation and enhanced subsequent eNOS-negative platelet-like particle formation., Conclusions: COVID-19 patients have a higher percentage of eNOS-negative to -positive platelets, likely as a result of inflammatory response reducing megakaryocyte eNOS expression, which predisposes to thrombosis., Competing Interests: Declaration of competing interest The authors have no competing interest to disclose with respect to the content of this manuscript., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Little is known regarding long-term consequences (≥5 years) of sport-related concussion (SRC) sustained during adolescence. Adolescent SRC has been linked to athlete considerations of sport participation and subsequent retirement from sport during this critical developmental period. Prolonged SRC symptoms can reduce ability to perform physical activity, and research suggests inactivity can extend years post-injury. Therefore, SRC may affect long-term physical activity, which may result in decreased cardiorespiratory fitness and increased adiposity., Objectives: (1) To examine cardiorespiratory fitness, adiposity and associations with physical activity between three groups: adolescent SRC 5-15 years prior; adolescent musculoskeletal injury (MSK) 5-15 years prior; and individuals who played adolescent sport but were uninjured. (2) To explore whether biological sex-modified relationships assessed by the primary objective., Methods: Young adults (16-33 years old) who sustained SRC ( n  = 54) or MSK ( n  = 52) during adolescent sport and uninjured individuals ( n  = 50) were recruited ( n  = 156) from previous Sport Injury Prevention Research Centre studies and word-of-mouth. Participants completed a cycle-ergometer maximal exertion test, dual-energy X-ray absorptiometry scanning, and wore actigraphs for 1-week post-testing. Outcome measures of cardiorespiratory fitness [peak oxygen consumption (VO 2peak [ml/min])] and adiposity [fat mass index (FMI)] were examined in relation to cohort, sex, time since injury, lean mass index and moderate-to-vigorous physical activity [daily MVPA (min)] via multiple linear regression., Results: In relation to the uninjured cohort, MSK (mean difference = 297.14 ml/min; β = 2.88; 95%CI: 0.99-4.76, p  = 0.003) and SRC (mean difference = 268.01 ml/min; β = 2.61; 95%CI: 0.77-4.44, p  = 0.006) cohorts demonstrated higher VO 2peak and this did not differ based on biological sex. FMI did not differ for MSK (mean difference= -0.10 kg/m 2 ; β= -0.02; 95%CI: -0.22-0.18, p  = 0.847) or SRC (mean difference=-0.22 kg/m 2 ; β= -0.05; 95%CI: -0.24-0.15, p  = 0.642) cohorts relative to the uninjured cohort for both males and females., Conclusions: It is possible to maintain adequate long-term cardiorespiratory fitness and adiposity following adolescent SRC relative to those who only sustained sport related MSK injuries or did not sustain significant injuries as adolescents/adults.

Background: The objective of this research was the development and evaluation of 203 Pb-labelled panitumumab ( 203 Pb-PSC-panitumumab) as an immuno-SPECT radioligand for the detection of EGFR + head and neck squamous cell carcinoma (HNSCC) in a patient-derived xenograft (PDX) mouse model. The 51.9 h physical half-life and favourable γ-emission (279 keV; 81%) of 203 Pb offer an excellent opportunity for developing immuno-SPECT radioligands. Moreover, 203 Pb has a complementary therapeutic radionuclide ( 212 Pb), making 203 Pb and 212 Pb an ideal matched radiotheranostic pair., Results: Radiolabeling of panitumumab was performed at a pH of 5.0 and room temperature for 5-10 min with [ 203 Pb]Pb(OAc) 2 , and the incorporation efficiency was determined using radio-TLC. 203 Pb-PSC-panitumumab (~ 10 MBq, 140 μl of saline) was injected into the tail vein of NRG mice bearing subcutaneous (s.c.) HNSCC patient-derived xenografts (PDX). SPECT/CT images were acquired at 48 and 120 h post-injection. For biodistribution studies, mice were euthanized five days after 203 Pb-panitumumab injection. The tumour and normal tissues were collected and weighed, and uptake of 203 Pb was measured in a γ-counter. The uptake was calculated as the percent injected dose per gram of each tissue (ID%/g). Blocking experiments were performed by pretreating a group of mice (n = 5) with 1 mg of panitumumab 1 h before administering 203 Pb-PSC-panitumumab. 4-5 chelators of a new lead-specific chelator (PSC) were attached per antibody; radiolabeling efficiency was 99.2 ± 0.7%. The isolated radiochemical yield of 203 Pb-PSC-panitumumab was 41.4 ± 8% (n = 5), and the molar activity was 1.2 ± 0.35 GB/mg. SPECT imaging and biodistribution confirmed high accumulation and retention of 203 Pb-PSC-panitumumab in the tumour (26% ID/g) at 120 h post-injection (p.i.), which could be reduced to 6.2%ID/g at 120 h p.i. by predosing with panitumumab (1 mg) confirming EGFR specificity of 203 Pb-PSC-panitumumab uptake., Conclusions: Panitumumab was successfully and reproducibly labelled with 203 Pb in high radiochemical purity using the chelator PSC-NCS. 203 Pb-PSC-panitumumab was specifically accumulated and retained in EGFR + tumours in NRG mice with s.c. HNSCC PDX. 203 Pb-PSC-panitumumab is a suitable immuno-SPECT radioligand for imaging EGFR + tumours and has great potential for combining with 212 Pb-PSC-panitumumab in a radiotheranostic strategy for imaging and treating HNSCC., Competing Interests: Declarations. Ethics approval and consent to participate: All experimental protocols were approved by the Research Ethics Board at the University Health Network (Protocol No. 12–5639). All methods were performed per the ethical standards laid down in the Declaration of Helsinki and its later amendments or comparable ethical standards. Consent for publication: Not applicable. Competing interests: All authors declare no competing financial or non-financial interests., (© 2024. The Author(s).)

Background: This study explored a novel multimodal neuroimaging approach to assess neurovascular coupling (NVC) in humans using electroencephalography (EEG), functional near-infrared spectroscopy (fNIRS), and transcranial Doppler ultrasound (TCD)., Methods: Fifteen participants (nine females; age 19-32) completed concurrent EEG-fNIRS-TCD imaging during motor (finger tapping) and visual ("Where's Waldo?") tasks, with synchronized monitoring of blood pressure, capnography, and heart rate. fNIRS assessed microvascular oxygenation within the frontal, motor, parietal, and occipital cortices, while the middle and posterior cerebral arteries (MCA/PCA) were insonated using TCD. A 16-channel EEG set-up was placed according to the 10-20 system. Wilcoxon signed-rank tests were used to compare physiological responses between the active and resting phases of the tasks, while cross-correlations with zero legs compared cerebral and systemic hemodynamic responses across both tasks., Results: Time-frequency analysis demonstrated a reduction in alpha and low beta band power in electrodes C3/C4 during finger tapping (p<0.045) and all electrodes during the Waldo task (all p<0.001). During Waldo, cross-correlation analysis demonstrated the change in oxygenated hemoglobin and cerebral blood velocity had a moderate-to-strong negative correlation with systemic physiological influences, highlighting the measured change resulted from neuronal input. Deoxygenated hemoglobin displayed the greatest negative cross-correlation with the MCA/PCA within the motor cortices and visual during the motor and visual tasks, respectively (range:0.54, -0.82)., Conclusions: This investigation demonstrated the feasibility of the proposed EEG-fNIRS-TCD response to comprehensively assess the NVC response within human, specifically quantifying the real-time temporal synchrony between neuronal activation (EEG), microvascular oxygenation changes (fNIRS), and conduit artery velocity alterations (TCD)., Competing Interests: Declaration of competing interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024. Published by Elsevier Inc.)

Background: Persons (henceforth, women) who have hypertensive disorders of pregnancy (HDP) are at risk of premature cardiovascular disease (CVD). While largely preventable through lifestyle management, many women and clinicians are unaware of the risk. Based on prior research, we developed a question prompt tool (QPT) on preventing and managing CVD after HDP. The purpose of this study was to refine QPT design., Methods: We recruited Canadian women who had HDP and clinicians who might care for them using multiple strategies, conducted telephone interviews with consenting participants, and used qualitative description and inductive content analysis to derive themes., Results: We interviewed 21 women who varied in HDP type, CVD status, years since HDP pregnancy, age, geography and ethno-cultural group; and 21 clinicians who varied in specialty (midwife, nurse practitioner, family physician, internist, obstetrician, cardiologist), geography and years in practice. Participating women and clinicians agreed on needed improvements: more instructions, lay and gender-neutral language, links to additional information, more space for answers, graphic appeal, and both print and electronic format. Both groups identified similar barriers: clinicians lack time/willingness, and low language/health literacy and access to technology among women; enablers: translated, credible source/endorser, culturally relevant, organized by health trajectory stages; and likely benefits: raise awareness, empower women, encourage them to adopt healthy lifestyle. Women desired exposure to the QPT before or during pregnancy, while clinicians recommended waiting until postpartum to avoid overwhelming women. Similarly, most women said the QPT should be available through multiple avenues to empower them for health self-advocacy, while clinicians thought they should introduce the QPT to women, and decide when and which questions to address. To mitigate reluctance, clinicians recommended self-directed educational materials accompany the QPT., Conclusions: We will use this information to refine QPT design and plan for future evaluation. If found to be effective and widely disseminated, the QPT could improve awareness and communication about this issue, and may reduce CVD risk in many women who have hypertensive pregnancies. Ongoing research is needed to more fully understand how QPTs support patient-clinician communication, and how to alert and prime both patients and clinicians to use QPTs., (© 2024. The Author(s).)

Cerebral hemodynamics have been quantified during exercise via transcranial Doppler ultrasound, as it has high-sensitivity to movement artifacts and displays temporal superiority. Currently, limited research exists regarding how different exercise modalities and postural changes impact the cerebrovasculature across the cardiac cycle. Ten participants (4 females and 6 males) ages 20-29 completed three exercise tests (treadmill, supine, and upright cycling) to volitional fatigue. Physiological data collected included middle cerebral artery velocity (MCAv), blood pressure (BP), heart rate, and respiratory parameters. Normalized data were analyzed for variance and effect sizes were calculated to examine differences between physiological measures across the three exercise modalities. Systolic MCAv was greater during treadmill compared to supine and upright cycling ( p  < 0.001, (large) effect size), and greater during upright versus supine cycling ( p  < 0.017, (large)). Diastolic MCAv was lower during treadmill versus cycling exercise only at 60% maximal effort ( p  < 0.005, (moderate)) and no differences were observed between upright and supine cycling. No main effect was found for mean and diastolic BP ( p  > 0.05, (negligible)). Systolic BP was lower during treadmill versus supine cycling at 40% and 60% intensity ( p  < 0.05, (moderate-large)) and greater during supine versus upright at only 60% intensity ( p  < 0.003, (moderate)). The above differences were not explained by partial pressure of end-tidal carbon dioxide levels (main effect: p  = 0.432) . The current study demonstrates the cerebrovascular and cardiovascular systems respond heterogeneously to different exercise modalities and aspects of the cardiac cycle. As physiological data were largely similar between tests, differences associated with posture and modality are likely contributors., Competing Interests: The authors declare they have no conflicts of interest.

Intravascular imaging has become an integral part of the diagnostic and management strategies for intracoronary pathologies. In this White Paper we summarize current evidence and its implications on the use of intravascular imaging in interventional cardiology practice. The areas addressed are planning and optimization of percutaneous coronary intervention, management of stent failure, and evaluation of ambiguous coronary lesions and myocardial infarction with nonobstructive coronary disease. The findings presented followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system in an expert consensus process that involved a diverse writing group vetted by a review group. Expert consensus was achieved around 9 statements. Use of intravascular imaging in guiding percutaneous revascularization is supported by high-quality evidence, particularly for lesions with increased risk of recurrent events or stent failure. Specific considerations for intravascular imaging guidance of intervention in left main lesions, chronic occlusion lesions, and in patients at high risk of contrast nephropathy are explored. Use of intravascular imaging to identify pathologies associated with stent failure and guide repeat intervention, resolve ambiguities in lesion assessment, and establish diagnoses in patients who present with myocardial infarction with nonobstructive coronary disease is supported by moderate- to low-quality evidence. Each topic is accompanied by clinical pointers to aid the practicing interventional cardiologist in implementation of the White Paper findings. The findings presented in this White Paper will help to guide the use of intravascular imaging toward situations in which the balance of efficacy, safety, and cost are most optimal., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Despite the well-recognized association between pre-existing diabetes mellitus and stillbirth or perinatal mortality, there remain knowledge gaps about the strength of association across different populations. The primary objective of this systematic review and meta-analysis was to quantify the association between pre-existing diabetes and stillbirth or perinatal mortality, and secondarily, to identify risk factors predictive of stillbirth or perinatal mortality among those with pre-existing diabetes., Data Sources: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials from inception to April 2022., Methods of Study Selection: Cohort studies and randomized controlled trials in English or French that examined the association between pre-existing diabetes and stillbirth or perinatal mortality (as defined by the original authors) or identified risk factors for stillbirth and perinatal mortality in individuals with pre-existing diabetes were included. Data extraction was performed independently and in duplicate with the use of prespecified inclusion and exclusion criteria. Assessment for heterogeneity and risk of bias was performed. Meta-analyses were completed with a random-effects model., Tabulation, Integration, and Results: From 7,777 citations, 91 studies met the inclusion criteria. Pre-existing diabetes was associated with higher odds of stillbirth (37 studies; pooled odds ratio [OR] 3.74, 95% CI, 3.17-4.41, I2 =82.5%) and perinatal mortality (14 studies; pooled OR 3.22, 95% CI, 2.54-4.07, I2 =82.7%). Individuals with type 1 diabetes had lower odds of stillbirth (pooled OR 0.81, 95% CI, 0.68-0.95, I2 =0%) and perinatal mortality (pooled OR 0.73, 95% CI, 0.61-0.87, I2 =0%) compared with those with type 2 diabetes. Prenatal care and prepregnancy diabetes care were significantly associated with lower odds of stillbirth (OR 0.26, 95% CI, 0.11-0.62, I2 =87.0%) and perinatal mortality (OR 0.41, 95% CI, 0.29-0.59, I2 =0%)., Conclusion: Pre-existing diabetes confers a more than threefold increased odds of both stillbirth and perinatal mortality. Maternal type 2 diabetes was associated with a higher risk of stillbirth and perinatal mortality compared with maternal type 1 diabetes., Systematic Review Registration: PROSPERO, CRD42022303112., Competing Interests: Financial Disclosure Lois E. Donovan reports in-kind donations and reduced costs for study supplies for investigator-initiated trials from Medtronic, Dexcom, Tandem Diabetes Care, and Inter-analytics. Patricia Lemieux reports receiving honorary from Dexcom for their advisory board. Jennifer M. Yamamoto has received in-kind donations for study supplies from Abbott. The other authors did not report any potential conflicts of interest., (Copyright © 2024 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: DNA repair plays a major role in maintaining genomic stability, thus limiting the transformation of normal cells into cancer cells. However, in cancer patients treated with DNA-targeting drugs, DNA repair can decrease efficacy by removing the damage generated by such molecules that is needed to induce pharmacological activity. Inhibiting DNA repair thus represents an interesting approach to potentiating the activity of chemotherapy in this setting., Objectives: Here, we continue the characterization of an inhibitor of the interaction between Excision Repair Cross-Complementing Rrodent repair deficiency complementation group 1 (ERCC1) and Xeroderma Pigmentousum group F (XPF) (B9), two key proteins of nucleotide excision repair., Methods: We used various cell lines and co-incubation studies for the determination of cell survival and DNA repair capacities., Results: We show that it is synergistic with other platinum derivatives than previously described, and that synergy is lacking in cells not expressing ERCC1 or XPF. Finally, a series of experiments show that potentiation is observed only in cells expressing wild-type p53., Conclusion: Our results confirm the mechanism of action of our ERCC1-XPF inhibitor and give important additional data on this approach to enhance the activity of already existing cancer drugs., (© 2025 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

A substantial portion of patients infected with SARS-CoV-2 experience prolonged complications, known as Long COVID (LC). A subset of these patients exhibits the most debilitating symptoms, similar to those defined in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We performed bulk RNA sequencing (RNAseq) on the whole blood of LC with ME/CFS, at least 12 months post-onset of the acute disease, and compared them with controls. We found that LC patients had a distinct transcriptional profile compared to controls. Key findings include the upregulation of genes involved in immune dysregulation and neuronal development, such as Fezf2, BRINP2, HOXC12, MEIS2, ZFHX3, and RELN. These genes are linked to neuroinflammatory responses, cognitive impairments, and hematopoietic disturbances, suggesting ongoing neurological and immune disturbances in LC patients. RELN, encoding the Reelin protein, was notably elevated in LC patients, potentially serving as a biomarker for LC pathogenesis due to its role in inflammation and neuronal function. Immune cell analysis showed altered profiles in LC patients, with increased activated memory CD4 + T cells and neutrophils, and decreased regulatory T cells and NK cells, reflecting immune dysregulation. Changes in cytokine and chemokine expression further underscore the chronic inflammatory state in LC patients. Notably, a unique upregulation of olfactory receptors (ORs) suggest alternative roles for ORs in non-olfactory tissues. Pathway analysis revealed upregulation in ribosomal RNA processing, amino acid metabolism, protein synthesis, cell proliferation, DNA repair, and mitochondrial pathways, indicating heightened metabolic and immune demands. Conversely, downregulated pathways, such as VEGF signaling and TP53 activity, point to impaired tissue repair and cellular stress responses. Overall, our study underscores the complex interplay between immune and neuronal dysfunction in LC patients, providing insights into potential diagnostic biomarkers and therapeutic targets. Future research is needed to fully understand the roles and interactions of these genes in LC pathophysiology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation (AF) represents a global epidemic. Although international AF practice guidelines indicate weight loss for patients with AF and comorbid obesity (BMI ≥ 30 kg/m 2 ) to alleviate symptom burden and improve prognosis, few cardiac rehabilitation (CR) programs include targeted weight loss treatment., Aims: This RCT protocol will evaluate the efficacy of a "Small Changes" behavioral weight loss treatment (BWLT) to produce clinically relevant (≥ 10%) weight loss among patients with AF and obesity undergoing CR, relative to CR alone. Secondary aims are to establish efficacy of CR + BWLT for improving AF symptoms, AF risk factors, and health-related quality of life., Methods: Adults (18 +) with AF and obesity will be recruited and randomized to receive CR + BWLT (intervention) or CR-only (control). Controls will receive CR consisting of supervised exercise and risk factor self-management for 12 weeks. The intervention group will receive CR plus BWLT (12 weekly, group-based virtual sessions, followed by 12 weeks of follow-up support). Weight and AF-risk factors will be assessed at pre-randomization, 12 weeks, 24 weeks, and 52 weeks. AF burden will be assessed using 30-s ECGs recorded bidaily and with AF symptoms. The primary endpoint of weight loss will be calculated from baseline to 52 weeks as a percentage of starting weight. Intention-to-treat analyses will compare the proportion in each group achieving ≥ 10% weight loss. Assuming success rates of 5% and 30% among controls and intervention groups, respectively, and a 30% loss to follow-up, 120 patients (60 per group) will provide 80% power to detect a difference using a two-sided independent test of proportions (alpha = 5%)., Impact: This clinical trial will be the first to demonstrate that adding BWLT to CR promotes clinically meaningful weight loss among patients with AF and comorbid obesity. Findings will inform design and execution of a large efficacy trial of long-term (e.g., 5-year) clinical endpoints (e.g., AF severity, mortality). Implementing weight control interventions designed to target the AF substrate in CR could dramatically reduce morbidity and enhance quality of life among patients living with AF in Canada., Trial Registration: ClinicalTrials.gov registration number: NCT05600829. Registered October 31, 2022., (© 2024. The Author(s).)

This article provides an overview of preclinical theranostic radiopharmaceutical development, highlighting aspects of the preclinical development stages that can lead towards a clinical trial. The key stages of theranostic radiopharmaceutical development are outlined, including target selection, tracer development, radiopharmaceutical synthesis, automation and quality control, in vitro radiopharmaceutical analysis, selecting a suitable in vivo model, preclinical imaging and pharmacokinetic analysis, preclinical therapeutic analysis, dosimetry, toxicity, and preparing for clinical translation. Each stage is described and augmented with examples from the literature. Finally, an outlook on the prospects for the radiopharmaceutical theranostics field is provided., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

A directional sensitivity of the cerebral pressure-flow relationship has been described using repeated squat-stands. Oscillatory lower body negative pressure (OLBNP) is a reproducible method to characterize dynamic cerebral autoregulation (dCA). It could represent a safer method to examine the directional sensitivity of the cerebral pressure-flow relationship within clinical populations and/or during pharmaceutical administration. Therefore, examining the cerebral pressure-flow directional sensitivity during an OLBNP-induced cyclic physiological stress is crucial. We calculated changes in middle cerebral artery mean blood velocity (MCAv) per alterations to mean arterial pressure (MAP) to compute ratios adjusted for time intervals (ΔMCAv T /ΔMAP T ) with respect to the minimum-to-maximum MCAv and MAP, for each OLBNP transition (0 to -90 Torr), during 0.05 Hz and 0.10 Hz OLBNP. We then compared averaged ΔMCAv T /ΔMAP T during OLBNP-induced MAP increases (INC) (ΔMCAv T / Δ MAP T INC ) and decreases (DEC) (ΔMCAv T / Δ MAP T DEC ). Nineteen healthy participants [9 females; 30 ± 6 years] were included. There were no differences in ΔMCAv T /ΔMAP T between INC and DEC at 0.05 Hz. ΔMCAv T / Δ MAP T INC (1.06 ± 0.35 vs. 1.33 ± 0.60 cm⋅s -1 /mmHg; p = 0.0076) was lower than ΔMCAv T / Δ MAP T DEC at 0.10 Hz. These results support OLBNP as a model to evaluate the directional sensitivity of the cerebral pressure-flow relationship., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Although tumors of Li-Fraumeni syndrome (LFS) have a premalignant or dormant phase that could be exploited by early imaging detection, this has been underevaluated in the literature. We present a case series of patients with LFS followed by imaging over time to highlight patterns of growth of tumors and hotspots of missed tumors in this population. Clinical and imaging features were available for 29 tumors of 24 carriers of a germline TP53 pathogenic variant, developed between 1999 and 2023 were retrospectively reviewed in a single tertiary pediatric center. Imaging characteristics of tumors were evaluated with MRI, CT, and radiographs. Local invasion, time interval for developing primary cancer, and/or recurrent disease and metastasis, and factors that delayed the tumor diagnosis were assessed. In patients with multiple tumors the median time intervals for development of first, second, and third primary cancers were 45.9, 79.8, and 28.1 months, respectively. Hotspots of missed tumors included superficial soft tissues, areas close to bones, on the scalp, in tissues around the adrenal region and in small hypodense lesions on brain CT. In conclusion, the pattern of growth of tumors is variable and erratic in LFS patients with some tumors presenting with a dormant pattern., Competing Interests: A.S.D. is the Principal Investigator of the following grants unrelated to the current study: Novo Nordisk (Research Grant), Terry Fox Foundation (Research Grant), PSI Foundation (Research Grant), Society of Pediatric Radiology (Research Grant), Radiological Society of North America (Education Grant). The remaining authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Pharmacoepidemiology has emerged as a crucial field in evaluating the use and effects of medications in large populations to ensure their safe and effective use. This study aimed to assess the agreement of cardiac medication use between a provincial medication database, the Pharmaceutical Information Network (PIN), and reconciled medication data from confirmation through patient interviews for patients referred to cardiac rehabilitation., Methods: The study included data from patients referred to the TotalCardiology Rehabilitation CR program, and medication data was available in both TotalCardiology Rehabilitation charts and PIN. The accuracy of medication data obtained from patient interviews was compared to that obtained from PIN with proportions and kappa statistics to evaluate the reliability of PIN data in assessing medication use., Results: Patient-reported usage was higher for statins (41.6 %) vs. 38.4 %), ACE/ARB, beta-blockers (75.7 %) vs. 73.7 %), DOAC (3.5 %) vs. 2.6 %), and ADP-receptor antagonists (71.0 %) vs. 68.1 %) than if PIN was used. Patient-reported usage data was lower for Ezetimibe (4.7 vs. 4.8 %), Aldosterone antagonists (5.4 %) vs. 5.5 %), digoxin (0.9 %) vs. 1.0 %), calcium channel blockers (19.2 vs. 19.9 %) and warfarin (7.2 %) vs. 8.1 %). The results indicated that the differences between the two sources were very small, with an average agreement of 95.3 % and a kappa of 0.70., Conclusion: The study's results, which show a high level of agreement between PIN and patient self-reporting, affirm the reliability of PIN data as a source for obtaining an accurate assessment of medication use. This finding is crucial in the context of pharmacoepidemiology research, where the accuracy of data is paramount. Further research to explore the complementary use of both data sources will be valuable., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Background : The incorporation of radionuclides into peptides and larger biomolecules requires efficient and sometimes biorthogonal reaction conditions, to which click chemistry provides a convenient approach. Methods : Traditionally, click-based radiolabeling techniques have focused on classical click chemistry, such as copper(I)-catalyzed alkyne-azide [3+2] cycloaddition (CuAAC), strain-promoted azide-alkyne [3+2] cycloaddition (SPAAC), traceless Staudinger ligation, and inverse electron demand Diels-Alder (IEDDA). Results : However, newly emerging click-based radiolabeling techniques, including tyrosine-click, sulfo-click, sulfur(VI) fluoride exchange (SuFEx), thiol-ene click, azo coupling, hydrazone formations, oxime formations, and RIKEN click offer valuable alternatives to classical click chemistry. Conclusions : This review will discuss the applications of these techniques in peptide radiochemistry.

Introduction: Cerebrovascular reactivity (CVR) describes the vasculature's response to vasoactive stimuli, where prior investigations relied solely on mean data, rather than exploring cardiac cycle differences., Methods: Seventy-one participants (46 females and 25 males) from two locations underwent TCD measurements within the middle or posterior cerebral arteries (MCA, PCA). Females were tested in the early-follicular phase. The hypercapnia response was assessed using a rebreathing protocol (93% oxygen and 7% carbon dioxide) or dynamic end-tidal forcing as a cerebral blood velocity (CBv) change from 40 to 55-Torr. The hypocapnia response was quantified using a hyperventilation protocol as a CBv change from 40 to 25-Torr. Absolute and relative CVR slopes were compared across cardiac cycle phases, vessels, and biological sexes using analysis of covariance with Tukey post-hoc comparisons., Results: No differences were found between hypercapnia methods used (p > 0.050). Absolute hypercapnic slopes were highest in systole (p < 0.001), with no cardiac cycle differences for absolute hypocapnia (p > 0.050). Relative slopes were largest in diastole and smallest in systole for both hypercapnia and hypocapnia (p < 0.001). Females exhibited greater absolute CVR responses (p < 0.050), while only the relative systolic hypercapnic response was different between sexes (p = 0.001). Absolute differences were present between the MCA and PCA (p < 0.001), which vanished when normalizing data to baseline values (p > 0.050)., Conclusion: Cardiac cycle variations impact CVR responses, with females displaying greater absolute CVR in some cardiac phases during the follicular window. These findings are likely due to sex differences in endothelial receptors/signalling pathways. Future CVR studies should employ assessments across the cardiac cycle., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Artificial photosynthesis holds immense promise for sustainable clean energy harvesting, with recent strides in material engineering with the earth abundant elements enabling efficient utilization of the visible solar spectrum for photoelectrochemical catalytic water splitting. Here, we have investigated the impact of substitutional Cu doping at all three cation sites in Ba2YNbO6 (BYN) using density functional theory calculations at the Heyd-Scuseria-Ernzerhof-06 level. One of the key findings is that the defect formation energy follows the hierarchy Nb > Ba > Y. The presence of an oxygen vacancy (OV) enhances the co-solubility of Cu substitution of Nb, particularly when placed outside the CuO6 unit, while it has a contrary effect for Y substitution. Cu replacement reduces the bandgap as Nb > Y ≫ Ba vis-à-vis pure BYN, while extending it into the visible part of the solar spectrum for Nb and Y replacement cases, albeit with OV causing a slight blue shift to them, without reducing the oxidation state of Cu due to strong charge-delocalization. Cu doping at Y and Nb sites retains the direct band transition character of BYN, a feature removed by OV. While all the bare Cu doped systems exhibit formation of a weak electron polaron, the placement of OV tends to annihilate this except for the system comprising first nearest neighbor placement of an OV relative to the Cu substitution at an Nb site. Notably, Cu doping at the Nb site significantly enhances optical activity, particularly ∼2.0-2.5 eV, resulting in promising candidates for photoelectrochemical catalysts., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Minimally invasive mitral valve surgery (MiMVS) has been increasing in prevalence. This review focuses on the approaches, clinical outcomes, and patient selection for MiMVS. There are 4 minimally invasive approaches to the mitral valve: right mini-thoracotomy (including video-assisted and fully endoscopic), robotic mitral surgery, and transapical beating heart off-pump neochordal repair. Advantages over conventional surgery include less blood loss and transfusion, improved postoperative mobility, shorter length of stay, less postoperative atrial fibrillation, fewer surgical site infections, and improved cosmesis. This range of minimally invasive techniques will continue to evolve, providing options that are tailored for different patient populations., (Copyright © 2024 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Coronary artery disease (CAD) is a leading cause of mortality worldwide. Severe symptomatic CAD is treated with coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI). Alternative CABG (ACABG) approaches including thoracotomy, off-pump, total endoscopic, and robotic-assisted CABG are increasing in prevalence to address the increased early risk of CABG. This systematic review and meta-analysis aims to review the contemporary literature comparing outcomes after ACABG and PCI. Pubmed, Medline, and Embase were systematically searched by 2 authors for articles comparing the outcomes after ACABG and PCI. A total of 1154 articles were screened, and 11 were included in this review. The RevMan 5.4 software was used to perform a meta-analysis of the pooled data. Individual studies found rates of long-term survival, major adverse cardiovascular and cerebrovascular events (MACCE), myocardial infarction (MI), and repeat revascularization either favored ACABG or did not differ significantly. Pooled estimates of the compiled data identified rates of MACCE, MI, and repeat revascularization favored ACABG. The results of this review demonstrated the favorable rates of long-term mortality, MACCE, MI, and repeat revascularization for ACABG in addition to similar short-term mortality and stroke when compared with PCI. Advancement of both CABG and PCI continues to improve patient outcomes. With the increasing prevalence of ACABG, similar studies will need to be undertaken with further direct comparisons between ACABG and PCI. Finally, hybrid revascularization should continue to be explored for its combined benefits of long-term outcomes, short-term safety, and ability to achieve complete revascularization., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Due to the shortage of donor organs, an increasing number of transplant organs are harvested after circulatory arrest (donation after circulatory death [DCD]). Using a translational porcine model of DCD, this study developed and evaluated a protocol based on cardioprotection by multidrug postconditioning to optimize resuscitation of DCD hearts during ex situ heart perfusion (ESHP)., Methods: Hearts of female pigs (45.0 ± 4.5 kg) were procured following a clinically identical DCD protocol, consisting of the termination of ventilator support and confirmation of circulatory arrest, followed by a 15-min standoff period. DCD hearts were randomly allocated to ESHP (38.4°C) in the absence (untreated, N = 5) or presence (treated, N = 5) of a postconditioning treatment added to the perfusate, consisting of Intralipid (1%), sevoflurane (2% v/v), and remifentanil (3 nM). All hearts were perfused with blood and Krebs-Henseleit solution (1:1) for 60 min in Langendorff mode and for an additional 300 min in working mode for a total perfusion time of 6 h. Oxidative capacity and detailed left ventricular mechanical function under an increasing workload (left atrial pressure, 6 to 12 mmHg) were assessed hourly. Left ventricular tissue was snap-frozen at the end of ESHP and used for molecular analyses., Results: Left ventricular inotropy (LVdP/dtmax) did not decline over time in treated DCD hearts and was significantly higher at the end of the protocol as compared with untreated DCD hearts (ΔLVdP/dtmax = 440 mmHg/s; P = 0.009). Treated DCD hearts exhibited persistently higher left ventricular stroke work index during the 6-h period of ESHP, whereas untreated DCD hearts displayed a significant decline (change in left ventricular stroke work index = -3.10 ml · mmHg/g; P(time within untreated group) < 0.001). Treated DCD hearts displayed higher metabolic activity as measured by oxygen consumption (ΔO2 = 3.11 ml O2 · min-1 · 100 g-1; P = 0.004) and released lower amounts of cell-free mitochondrial DNA into the perfusate, a marker of potential graft dysfunction. Treated hearts also used fatty acids from Intralipid as an energy source, whereas untreated DCD hearts showed glyceroneogenesis with triglyceride accumulation and depletion of tricarboxylic acid cycle intermediates; reduced mitochondrial complex I, II, and III activities with accumulation of mitochondrial NADH, and signs of ultrastructural damage., Conclusions: A translationally relevant protective ESHP protocol consisting of treatment with Intralipid, sevoflurane, and remifentanil markedly accelerated functional recovery and improved viability of DCD hearts., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)