Blood-pool MRI assessment of myocardial microvascular reactivity

PurposeThe ability to non-invasively image myocardial microvascular dilation and constriction is essential to assessing intact function and dysfunction. Yet, conventional measurements based on blood oxygenation are not specific to changes in blood volume. The purpose of this study was to extend to the heart a blood-pool MRI approach for assessing vasomodulation in the presence of blood gas changes and investigate if sex-related differences exist.MethodsAnimals [five male and five female healthy Sprague Dawley rats (200–500 g)] were intubated, ventilated, and cycled through room air (normoxia) and hypercapnia (10% CO2) in 10-minute cycles after i.v. injection of blood-pool agent Ablavar (0.3 mmol/kg). Pre-contrast T1 maps and T1-weighted 3D CINE were acquired on a 3 Tesla preclinical MRI scanner, followed by repeated 3D CINE every 5 min until the end of the gas regime. Invasive laser Doppler flowmetry of myocardial perfusion was performed to corroborate MRI results.ResultsMyocardial microvascular dilation to hypercapnia and constriction to normoxia were readily visualized on T1 maps. Over 10 min of hypercapnia, female myocardial T1 reduced by 20% (vasodilation), while no significant change was observed in the male myocardium. After return to normoxia, myocardial T1 increased (vasoconstriction) in both sexes (18% in females and 16% in males). Laser Doppler perfusion measurements confirmed vasomodulatory responses observed on MRI.ConclusionBlood-pool MRI is sensitive and specific to vasomodulation in the myocardial microcirculation. Sex-related differences exist in the healthy myocardium in response to mild hypercapnic stimuli

The idea of discrimination and its impact on tort liability in Palestinian legislation

This study focuses on the question of tort liability for damages committed by an underage, especially when he or she is not under the control of a third party, and if the tort liability means that, in the event of harm, it must be compensated, does this mean that an underage is held liable to the extent that he or she causes harm to another person regardless of age or mental state? The exercise of the discretionary responsibility of the distinguished underage for all his or her harmful acts is recognized in jurisprudence and law. s responsibility has been discussed in depth in its jurisprudence and judiciary, this entailed differing status legislation on this issue, and some of the legislation discriminated a condition for the omission. Another aspect does not require discrimination, applying how Palestinian legislation establishes the discretionary liability of privileged underages. What is his position on the extent to which this responsibility is incumbent upon the unmarked underage? Accordingly, the study reviewed the underage's derogatory liability for wrongful acts in the Journal of Judicial Provisions, thus addressing the underage's tort liability for wrongful acts in the Civil Offences Act and the Palestinian Civil Code Bill. Therefore, after reviewing the items of the study that are the subject of the response to the study's problem, the study concluded that the Journal of Judicial Provisions does not establish the requirement of discrimination for the performance of default liability. There is no difference between a distinct underage or a non-distinctive underage, where it is required to establish tort liability or guarantee that the underage has to do directly or cause, in direct terms, it has made the immediate underage a guarantor, even if he did not intend and deliberately do so, it guarantees damage. As for the cause, the underage causing intentional harm is required to be a guarantor of the injury inflicted on others. We found that the Code of Judicial Provisions does not assess or know the responsibility of the supervisory officer. Nor did it specify a specific age of discrimination, and we concluded that an undisclosed underage would be liable for any wrongful act. Nor did the magazine explicitly provide for liability for the actions of another, Since the magazine based its warranty on a no-harm-no-damage rule, A underage is liable for the harm he or she causes either by his or her act or as a guardian of the object. On the other hand, the Civil Offences Act did not require discrimination against underage, He asserted that a civil offense is not brought against a person who committed it under the age of 2. Unlike the Palestinian Civil Code bill that made the notion of discrimination liable for default, Where the age of discrimination is set at seven years, who is considered to be distinctive and therefore responsible for his harmful act, whether personal or other or for doing something in his custody. Those who do not do it are considered non-distinctive and the origin is not responsible for it. However, the draft imposes exceptional and precautionary liability on the unmarked underage in the interest of the injured person, considering the litigants' statu

An Efficient T1 Contrast Agent for Labeling and Tracking Human Embryonic Stem Cells on MRI

Noninvasive cell tracking in vivo has the potential to advance stem cell-based therapies into the clinic. Magnetic resonance imaging (MRI) provides an excellent image-guidance platform; however, existing MR cell labeling agents are fraught with limited specificity. To address this unmet need, we developed a highly efficient manganese porphyrin contrast agent, MnEtP, using a two-step synthesis. In vitro MRI at 3 Tesla on human embryonic stem cells (hESCs) demonstrated high labeling efficiency at a very low dose of 10 µM MnEtP, resulting in a four-fold lower T1 relaxation time. This extraordinarily low dose is ideal for labeling large cell numbers required for large animals and humans. Cell viability and differentiation capacity were unaffected. Cellular manganese quantification corroborated MRI findings, and the agent localized primarily on the cell membrane. In vivo MRI of transplanted hESCs in a rat demonstrated excellent sensitivity and specificity of MnEtP for noninvasive stem cell tracking.Peer Reviewe

Positive-contrast cellular MRI of embryonic stem cells for tissue regeneration using a highly efficient T1 MRI contrast agent

Purpose: To investigate the feasibility of high-sensitivity cellular MRI of embryonic stem (ES) cells using a novel cell permeable and cell retentive T1 contrast agent. Materials and Methods: Mouse ES cells were labeled with a novel manganese porphyrin contrast agent, MnAMP, at 0.1 mM over 2 to 24 h and retained in contrast-free medium for up to 24 h postlabeling. MRI was performed on a 3 Tesla clinical scanner; T1 and T2 relaxation times were measured. Quantification of manganese content was performed using atomic absorption spectroscopy. Viability and proliferation assays were done for the longest labeling interval. Differentiation capacity was assessed using the hanging drop method to direct differentiation toward cardiomyocytes. Results: MnAMP-labeled ES cells exhibited over a fourfold decrease in T1 compared with unlabeled cells, and maintained up to a threefold decrease 24 h postlabeling. Viability and proliferation were not affected. Most importantly, labeled ES cells differentiated into functional cardiomyocytes that exhibited normal contractility patterns. Conclusion: MnAMP-based cellular MRI is a very high sensitivity T1 approach for cellular imaging. It has the potential for noninvasive in vivo monitoring of stem cell therapy in cardiac regeneration and other tissue engineering and regenerative medicine applications.Contract grant sponsor: Heart & Stroke Foundation; contract grant number: 000223; Contract grant sponsor: Natural Sciences and Engineering Research Council of Canada (NSERC); contract grant numbers: 355795 and 489075. Hai-Ling Cheng is supported by the Heart & Stroke Foundation, University of Toronto IBBME Director’s Kickstart Award, and Natural Sciences and Engineering Research Council of Canada (NSERC). Xiao-an Zhang is also supported by NSERC

A manganese porphyrin-based T1 contrast agent for cellular MR imaging of human embryonic stem cells

MRI for non-invasive cell tracking is recognized for enabling pre-clinical research on stem cell therapy. Yet, adoption of cellular imaging in stem cell research has been restricted to sites with experience in MR contrast agent synthesis and to small animal models that do not require scaled-up synthesis. In this study, we demonstrate the use of a gadolinium-free T1 contrast agent for tracking human embryonic stem cells. The agent, MnPNH2, is an easily synthesized manganese porphyrin that can be scaled for large cell numbers. MRI was performed on a 3 T clinical scanner. Cell pellets labeled at different MnPNH2 concentrations for 24 hours demonstrated a decrease in T1 relaxation time of nearly two-fold (P < 0.05), and cellular contrast was maintained for 24 hours (P < 0.05). Cell viability (Trypan blue) and differentiation (embryoid body formation) were unaffected. Cell uptake of Mn on inductively coupled plasma atomic emission spectroscopy corroborated MRI findings, and fluorescence microscopy revealed the agent localized mainly in cell-cell boundaries and cell nuclei. Labeled cells transplanted in rats demonstrated the superior sensitivity of MnPNH2 for in-vivo cell tracking.We thank Dr. Michael Laflamme and Ms. Tamilla Valdman Sadikov for guidance on maintaining human embryonic stem cells. A.V. is supported by an NSERC scholarship (CGS-M) and Ontario Graduate Scholarships (OGS). H.-L.M.C. is funded by the Natural Sciences and Engineering Research Council of Canada (#355795), the Heart and Stroke Foundation of Canada (#000223), funds from the Ted Rogers Centre for Heart Research, the Canada First Research Excellence Fund/Medicine by Design Cycle 1 Team Project Award, and the Canada Foundation for Innovation/Ontario Research Fund (#34038)

Clinical Perspectives on 3D Bioprinting Paradigms for Regenerative Medicine

Three-dimensional (3D) bioprinting is an emerging manufacturing technology that layers living cells and biocompatible natural or synthetic materials to build complex, functional living tissue with the requisite 3D geometries. This technology holds tremendous promise across a plethora of applications as diverse as regenerative medicine, pathophysiological studies, and drug testing. Despite some success demonstrated in early attempts to recreate complex tissue structures, however, the field of bioprinting is very much in its infancy. There are a variety of challenges to building viable, functional, and lasting 3D structures, not the least of which is translation from a research to a clinical setting. In this review, the current translational status of 3D bioprinting is assessed for several major tissue types in the body (skin, bone/cartilage, cardiovascular, central/peripheral nervous systems, skeletal muscle, kidney, and liver), recent breakthroughs and current challenges are highlighted, and future prospects for this exciting research field are discussed. We begin with an overview of the technology itself, followed by a detailed discussion of the current approaches relevant for bioprinting different tissues for regenerative medicine.This research was funded by the Natural Sciences and Engineering Research Council of Canada (NSERC), grant number 355795 (HLMC) and Ted Rogers Centre for Heart Research. SL is funded by the Heart & Stroke Richard Lewar Centre of Excellence for Cardiovascular Research. BRK is funded by an NSERC scholarship and the Wildcat Fellowship. ZW is funded by the Connaught International Scholarhship. DNP is funded by an NSERC scholarship

SARS-CoV-2 vaccination modelling for safe surgery to save lives: data from an international prospective cohort study

Background: Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. Methods: The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and mortality in an international cohort study (surgical patients), and community SARS-CoV-2 incidence and case fatality data (general population). NNV estimates were stratified by age (18-49, 50-69, 70 or more years) and type of surgery. Best- and worst-case scenarios were used to describe uncertainty. Results: NNVs were more favourable in surgical patients than the general population. The most favourable NNVs were in patients aged 70 years or more needing cancer surgery (351; best case 196, worst case 816) or non-cancer surgery (733; best case 407, worst case 1664). Both exceeded the NNV in the general population (1840; best case 1196, worst case 3066). NNVs for surgical patients remained favourable at a range of SARS-CoV-2 incidence rates in sensitivity analysis modelling. Globally, prioritizing preoperative vaccination of patients needing elective surgery ahead of the general population could prevent an additional 58 687 (best case 115 007, worst case 20 177) COVID-19-related deaths in 1 year. Conclusion: As global roll out of SARS-CoV-2 vaccination proceeds, patients needing elective surgery should be prioritized ahead of the general population

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23–0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research