Absorption and pharmacokinetics of bupivacaine after bilateral topical administration in tonsillar fossae for posttonsillectomy pain relief.

No previous studies have investigated the systemic absorption of bupivacaine when used topically for posttonsillectomy pain. The present study was undertaken to investigate the pharmacokinetics of bupivacaine after administration by a swab in the tonsillar fossae over 4 min after tonsillectomy. Eleven adult patients undergoing elective tonsillectomy were recruited. After removal of both tonsils, each of the two tonsillar fossae was covered with a swab moistened with 2 mL of bupivacaine 5 mg/mL, that is, a total of 20 mg bupivacaine. Blood samples were drawn after 0, 5, 10, 20, 30, 45, and 60 min. Bupivacaine was analyzed with an ultra-high-performance liquid chromatography-tandem mass spectrometry method. The highest single measured bupivacaine serum concentration was 23.2 ng/mL and took place 10 min after drug administration. Mean (±SD) Cmax was 11.4 ± 6.0 ng/mL and mean tmax was 11.3 ± 4.7 min. Mean t1/2 was 31.6 ± 9.3 min. As the toxic concentration threshold has been reported to be in the interval 1500-4500 ng/mL, the concentrations measured were well below 2% of the lowest cited toxic threshold. In conclusion, this study shows that applying 4 mL of bupivacaine 5 mg/mL by a swab in the tonsillar fossae posttonsillectomy yields very low plasma concentrations, suggesting its safe application without any risk of systemic toxic effects.

Pneumothorax during shoulder surgery. / Pneumothorax under skulderkirurgi.

Background: Pneumothorax following shoulder arthroscopy, although rare, is documented in over 30 PubMed case reports as occurring during or within 10 hours post-procedure. Case Presentation: A fit septuagenarian underwent a two-hour arthroscopic rotator cuff repair with IV anaesthesia and laryngeal mask airway, without a nerve block. With one hour remaining of the operation, the patient had desaturation and hypotension. Lung sliding was absent on ultrasound and x-ray confirmed left-sided tension pneumothorax. Successful thoracic drain insertion and lung re-expansion facilitated his recovery, allowing discharge after 24 hours and symptom-free status at 6 months. Interpretation: This case highlights pneumothorax as an uncommon yet possible post-arthroscopic event. The speculated aetiology is the surgical procedure, where pump-induced pressure fluctuations may displace air into surrounding tissue. Instances of pneumomediastinum and subcutaneous emphysema without pneumothorax suggest arthroscopic origin of air. Prompt perioperative ultrasound can aid in detecting such critical complications.

Enantiomer-Specific Cardiovascular Effects of the Ketone Body 3-Hydroxybutyrate.

BACKGROUND: The ketone body 3-hydroxybutyrate (3-OHB) increases cardiac output (CO) by 35% to 40% in healthy people and people with heart failure. The mechanisms underlying the effects of 3-OHB on myocardial contractility and loading conditions as well as the cardiovascular effects of its enantiomeric forms, D-3-OHB and L-3-OHB, remain undetermined. METHODS AND RESULTS: Three groups of 8 pigs each underwent a randomized, crossover study. The groups received 3-hour infusions of either D/L-3-OHB (racemic mixture), 100% L-3-OHB, 100% D-3-OHB, versus an isovolumic control. The animals were monitored with pulmonary artery catheter, left ventricle pressure-volume catheter, and arterial and coronary sinus blood samples. Myocardial biopsies were evaluated with high-resolution respirometry, coronary arteries with isometric myography, and myocardial kinetics with D-[11C]3-OHB and L-[11C]3-OHB positron emission tomography. All three 3-OHB infusions increased 3-OHB levels (P<0.001). D/L-3-OHB and L-3-OHB increased CO by 2.7 L/min (P<0.003). D-3-OHB increased CO nonsignificantly (P=0.2). Circulating 3-OHB levels correlated with CO for both enantiomers (P<0.001). The CO increase was mediated through arterial elastance (afterload) reduction, whereas contractility and preload were unchanged. Ex vivo, D- and L-3-OHB dilated coronary arteries equally. The mitochondrial respiratory capacity remained unaffected. The myocardial 3-OHB extraction increased only during the D- and D/L-3-OHB infusions. D-[11C]3-OHB showed rapid cardiac uptake and metabolism, whereas L-[11C]3-OHB demonstrated much slower pharmacokinetics. CONCLUSIONS: 3-OHB increased CO by reducing afterload. L-3-OHB exerted a stronger hemodynamic response than D-3-OHB due to higher circulating 3-OHB levels. There was a dissocitation between the myocardial metabolism and hemodynamic effects of the enantiomers, highlighting L-3-OHB as a potent cardiovascular agent with strong hemodynamic effects.

Femoral Nailing in a Porcine Model Causes Bone Marrow Emboli in the Lungs and Systemic Emboli in the Heart and Brain.

Background: Shaft fractures of the femur are commonly treated with intramedullary nailing, which can release bone marrow emboli into the bloodstream. Emboli can travel to the lungs, impairing gas exchange and causing inflammation. Occasionally, emboli traverse from the pulmonary to the systemic circulation, hindering perfusion and resulting in injuries such as heart and brain infarctions, known as fat embolism syndrome. We studied the extent of systemic bone marrow embolization in a pig model. Methods: Twelve anesthetized pigs underwent bilateral intramedullary nailing of the femur, while 3 animals served as sham controls. Monitoring included transesophageal echocardiography (TEE), pulse oximetry, electrocardiography, arterial blood pressure measurement, and blood gas and troponin-I analysis. After surgery, animals were monitored for 240 minutes before euthanasia. Post mortem, the heart, lungs, and brain were biopsied. Results: Bone marrow emboli were found in the heart and lungs of all 12 of the pigs that underwent intramedullary nailing and in the brains of 11 of them. No emboli were found in the sham group. The pigs subjected to intramedullary nailing exhibited significant hypoxia (PaO2/FiO2 ratio, 410 mm Hg [95% confidence interval (CI), 310 to 510) compared with the sham group (594 mm Hg [95% CI, 528 to 660]). The nailing group exhibited ST-segment alterations consistent with myocardial ischemia and a significant increase in the troponin-I level compared with the sham group (1,580 ng/L [95% CI, 0 to 3,456] versus 241 ng/L [95% CI, 0 to 625] at the 240-minute time point; p = 0.005). TEE detected emboli in the right ventricular outflow tract, but not systemically, in the nailing group. Conclusions: Bilateral intramedullary nailing caused bone marrow emboli in the lungs and systemic emboli in the heart and brain in this pig model. The observed clinical manifestations were consistent with coronary and pulmonary emboli. TEE detected pulmonary but not systemic embolization. Clinical Relevance: Femoral intramedullary nailing in humans is likely to result in embolization as described in our pig model. Focused monitoring is necessary for detection of fat embolism syndrome. Absence of visual emboli in the left ventricle on TEE does not exclude the occurrence of systemic bone marrow emboli.

Corrigendum: Iatrogenic air embolism: pathoanatomy, thromboinflammation, endotheliopathy, and therapies.

[This corrects the article DOI: 10.3389/fimmu.2023.1230049.].

Real-time feedback on chest compression efficacy by hands-free carotid Doppler in a porcine model.

Aim: Current guidelines for cardiopulmonary resuscitation (CPR) recommend a one-size-fits-all approach in relation to the positioning of chest compressions. We recently developed RescueDoppler, a hands-free Doppler ultrasound device for continuous monitoring of carotid blood flow velocity during CPR. The aim of the present study is to investigate whether RescueDoppler via real-time hemodynamic feedback, could identify both optimal and suboptimal compression positions. Methods: In this model of animal cardiac arrest, we induced ventricular fibrillation in five domestic pigs. Manual chest compressions were performed for ten seconds at three different positions on the sternum in random order and repeated six times. We analysed Time Average Velocity (TAV) with chest compression position as a fixed effect and animal, position, and sequential time within animals as random effects. Furthermore, we compared TAV to invasive blood pressure from the contralateral carotid artery. Results: We were able to detect changes in TAV when altering positions. The positions with the highest (range 19 to 48 cm/s) and lowest (6-25 cm/s) TAV were identified in all animals, with corresponding peak pressure 50-81 mmHg, and 46-64 mmHg, respectively. Blood flow velocity was, on average, highest at the middle position (TAV 33 cm/s), but with significant variability between animals (SD 2.8) and positions within the same animal (SD 9.3). Conclusion: RescueDoppler detected TAV changes during CPR with alternating chest compression positions, identifying the position yielding maximal TAV. Future clinical studies should investigate if RescueDoppler can be used as a real-time hemodynamical feedback device to guide compression position.

Aspiration Pneumonia.

Aspiration pneumonia is a lower respiratory tract infection that results from inhalation of foreign material, often gastric and oropharyngeal contents. It is important to distinguish this from a similar entity, aspiration with chemical pneumonitis, as treatment approaches may differ. An evolving understanding of the human microbiome has shed light on the pathogenesis of aspiration pneumonia, suggesting that dysbiosis, repetitive injury, and inflammatory responses play a role in its development. Risk factors for aspiration events involve a complex interplay of anatomical and physiological dysfunctions in the nervous, gastrointestinal, and pulmonary systems. Current treatment strategies have shifted away from anaerobic organisms as leading pathogens. Prevention of aspiration pneumonia primarily involves addressing oropharyngeal dysphagia, a significant risk factor for aspiration pneumonia, particularly among elderly individuals and those with cognitive and neurodegenerative disorders.

Iatrogenic air embolism: pathoanatomy, thromboinflammation, endotheliopathy, and therapies.

Iatrogenic vascular air embolism is a relatively infrequent event but is associated with significant morbidity and mortality. These emboli can arise in many clinical settings such as neurosurgery, cardiac surgery, and liver transplantation, but more recently, endoscopy, hemodialysis, thoracentesis, tissue biopsy, angiography, and central and peripheral venous access and removal have overtaken surgery and trauma as significant causes of vascular air embolism. The true incidence may be greater since many of these air emboli are asymptomatic and frequently go undiagnosed or unreported. Due to the rarity of vascular air embolism and because of the many manifestations, diagnoses can be difficult and require immediate therapeutic intervention. An iatrogenic air embolism can result in both venous and arterial emboli whose anatomic locations dictate the clinical course. Most clinically significant iatrogenic air emboli are caused by arterial obstruction of small vessels because the pulmonary gas exchange filters the more frequent, smaller volume bubbles that gain access to the venous circulation. However, there is a subset of patients with venous air emboli caused by larger volumes of air who present with more protean manifestations. There have been significant gains in the understanding of the interactions of fluid dynamics, hemostasis, and inflammation caused by air emboli due to in vitro and in vivo studies on flow dynamics of bubbles in small vessels. Intensive research regarding the thromboinflammatory changes at the level of the endothelium has been described recently. The obstruction of vessels by air emboli causes immediate pathoanatomic and immunologic and thromboinflammatory responses at the level of the endothelium. In this review, we describe those immunologic and thromboinflammatory responses at the level of the endothelium as well as evaluate traditional and novel forms of therapy for this rare and often unrecognized clinical condition.

HOW SHOULD TRANEXAMIC ACID BE ADMINISTERED IN HEMORRHAGIC SHOCK? CONTINUOUS SERUM CONCENTRATION MEASUREMENTS IN A SWINE MODEL.

ABSTRACT: Background : Tranexamic acid (TXA) reduces mortality in trauma patients. Intramuscular (IM) administration could be advantageous in low-resource and military settings. Achieving the same serum concentration as intravenous (IV) administration is important to achieve equal mortality reduction. Therefore, we aimed to investigate whether dividing an IM dose of TXA between two injection sites and whether an increase in dose would lead to serum concentrations comparable to those achieved by IV administration. Methods : Norwegian landrace pigs (n = 29) from a course in hemostatic emergency surgery were given TXA 1 h after start of surgery. Blood samples were drawn at 0, 5, 10, 15, 20, 25, 35, 45, 60, and 85 min. The samples were centrifuged and serum TXA concentrations quantified with liquid chromatography-tandem mass spectrometry. The use of two injection sites was compared with distributing the dose on one injection site, and a dose of 15 mg/kg was compared with a dose of 30 mg/kg. All IM groups were compared with IV administration. Results : The groups were in a similar degree of shock. Increasing the IM dose from the standard of 15 mg/kg to 30 mg/kg resulted in significantly higher serum concentrations of TXA, comparable to those achieved by IV administration. Distributing the IM dose on two injection sites did not affect drug uptake, as shown by equal serum concentrations. Conclusions : For IM administration of TXA, 30 mg/kg should be the standard dose. With a short delay, IM administration will provide equal serum concentrations as IV administration, above what is considered necessary to inhibit fibrinolysis.

Epigenetic memory of coronavirus infection in innate immune cells and their progenitors.

Inflammation can trigger lasting phenotypes in immune and non-immune cells. Whether and how human infections and associated inflammation can form innate immune memory in hematopoietic stem and progenitor cells (HSPC) has remained unclear. We found that circulating HSPC, enriched from peripheral blood, captured the diversity of bone marrow HSPC, enabling investigation of their epigenomic reprogramming following coronavirus disease 2019 (COVID-19). Alterations in innate immune phenotypes and epigenetic programs of HSPC persisted for months to 1 year following severe COVID-19 and were associated with distinct transcription factor (TF) activities, altered regulation of inflammatory programs, and durable increases in myelopoiesis. HSPC epigenomic alterations were conveyed, through differentiation, to progeny innate immune cells. Early activity of IL-6 contributed to these persistent phenotypes in human COVID-19 and a mouse coronavirus infection model. Epigenetic reprogramming of HSPC may underlie altered immune function following infection and be broadly relevant, especially for millions of COVID-19 survivors.

Increased thromboinflammatory load in hereditary angioedema.

C1 inhibitor (C1Inh) is a serine protease inhibitor involved in the kallikrein-kinin system, the complement system, the coagulation system, and the fibrinolytic system. In addition to the plasma leakage observed in hereditary angioedema (HAE), C1Inh deficiency may also affect these systems, which are important for thrombosis and inflammation. The aim of this study was to investigate the thromboinflammatory load in C1Inh deficiency. We measured 27 cytokines including interleukins, chemokines, interferons, growth factors, and regulators using multiplex technology. Complement activation (C4d, C3bc, and sC5b-C9/TCC), haemostatic markers (ß-thromboglobulin (ß-TG), thrombin-antithrombin complexes (TAT), prothrombin fragment 1 + 2 (F1 + 2), active plasminogen activator inhibitor-1 (PAI-1), and the neutrophil activation marker myeloperoxidase (MPO) were measured by enzyme immunoassays. Plasma and serum samples were collected from 20 patients with HAE type 1 or 2 in clinical remission and compared with 20 healthy age- and sex-matched controls. Compared to healthy controls, HAE patients had significantly higher levels of tumour necrosis factor (TNF), interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-7, IL-9, IL-12, and IL-17A, chemokine ligand (CXCL) 8, chemokine ligand (CCL) 3, CCL4, IL-1 receptor antagonist (IL-1RA), granulocyte-macrophage colony-stimulating factor (GM-CSF), fibroblast growth factor (FGF) 2 and platelet-derived growth factor (PDGF)-BB. HAE patients also had higher levels of TAT and F1 + 2. Although granulocyte colony-stimulating factor (G-CSF), ß-TG and PAI-1 were higher in HAE patients, the differences did not reach statistical significance after correction for multiple testing. In conclusion, C1Inh deficiency is associated with an increased baseline thromboinflammatory load. These findings may reflect that HAE patients are in a subclinical attack state outside of clinically apparent oedema attacks.

Hands-free continuous carotid Doppler ultrasound for detection of the pulse during cardiac arrest in a porcine model.

Background/Purpose: Pulse palpation is an unreliable method for diagnosing cardiac arrest. To address this limitation, continuous hemodynamic monitoring may be a viable solution. Therefore, we developed a novel, hands-free Doppler system, RescueDoppler, to detect the pulse continuously in the carotid artery. Methods: In twelve pigs, we evaluated RescueDopplers potential to measure blood flow velocity in three situations where pulse palpation of the carotid artery was insufficient: (1) systolic blood pressure below 60 mmHg, (2) ventricular fibrillation (VF) and (3) pulseless electrical activity (PEA). (1) Low blood pressure was induced using a Fogarty balloon catheter to occlude the inferior vena cava. (2) An implantable cardioverter-defibrillator induced VF. (3) Myocardial infarction after microembolization of the left coronary artery caused True-PEA. Invasive blood pressure was measured in the contralateral carotid artery. Time-averaged blood flow velocity (TAV) in the carotid artery was related to mean arterial pressure (MAP) in a linear mixed model. Results: RescueDoppler identified pulsatile blood flow in 41/41 events with systolic blood pressure below 60 mmHg, with lowest blood pressure of 19 mmHg. In addition the absence of spontaneous circulation was identified in 21/21 VF events and true PEA in 2/2 events. The intraclass correlation coefficient within animals for TAV and MAP was 0.94 (95% CI. 0.85-0.98). Conclusions: In a porcine model, RescueDoppler reliably identified pulsative blood flow with blood pressures below 60 mmHg. During VF and PEA, circulatory arrest was rapidly and accurately demonstrated. RescueDoppler could potentially replace unreliable pulse palpation during cardiac arrest and cardiopulmonary resuscitation.

Intravenous and oral whole body ketone dosimetry, biodistribution, metabolite correction and kinetics studied by (R)-[1-11C]ß-hydroxybutyrate ([11C]OHB) PET in healthy humans.

BACKGROUND: Ketones are increasingly recognized as an important and possibly oxygen sparing source of energy in vital organs such as the heart, the brain and the kidneys. Drug treatments, dietary regimens and oral ketone drinks designed to deliver ketones for organ and tissue energy production have therefore gained popularity. However, whether ingested ketones are taken up by various extra-cerebral tissues and to what extent is still largely unexplored. It was therefore the aim of this study to use positron emission tomography (PET) to explore the whole body dosimetry, biodistribution and kinetics of the ketone tracer (R)-[1-11C]ß-hydroxybutyrate ([11C]OHB). Six healthy subjects (3 women and 3 men) underwent dynamic PET studies after both intravenous (90 min) and oral (120 min) administration of [11C]OHB. Dosimetry estimates of [11C]OHB was calculated using OLINDA/EXM software, biodistribution was assessed visually and [11C]OHB tissue kinetics were obtained using an arterial input function and tissue time-activity curves. RESULTS: Radiation dosimetry yielded effective doses of 3.28 [Formula: see text]Sv/MBq (intravenous administration) and 12.51 [Formula: see text]Sv/MBq (oral administration). Intravenous administration of [11C]OHB resulted in avid radiotracer uptake in the heart, liver, and kidneys, whereas lesser uptake was observed in the salivary glands, pancreas, skeletal muscle and red marrow. Only minimal uptake was noted in the brain. Oral ingestion of the tracer resulted in rapid radiotracer appearance in the blood and radiotracer uptake in the heart, liver and kidneys. In general, [11C]OHB tissue kinetics after intravenous administration were best described by a reversible 2-tissue compartmental model. CONCLUSION: The PET radiotracer [11C]OHB shows promising potential in providing imaging data on ketone uptake in various physiologically relevant tissues. As a result, it may serve as a safe and non-invasive imaging tool for exploring ketone metabolism in organs and tissues of both patients and healthy individuals. Trial registration Clinical trials, NCT0523812, Registered February 10th 2022, https://clinicaltrials.gov/ct2/show/NCT05232812?cond=NCT05232812&draw=2&rank=1 .

Management of pneumonia in the critically ill.

Pneumonias continue to be major public health issues and are commonly encountered in the intensive care setting. The most common types of pneumonia leading to critical illness include severe community acquired pneumonia, hospital acquired pneumonia, and ventilator associated pneumonia. Early evaluation, diagnosis, and escalation to appropriate levels of care are imperative to improving survival. Treatment remains challenging with the need to balance antibiotic stewardship and minimizing patient harm. As evidenced in the most recent society guidelines, the identification of risk factors for severe disease and the causative pathogens are crucial in guiding the most appropriate therapy.

Scalable Randomized Benchmarking of Quantum Computers Using Mirror Circuits.

The performance of quantum gates is often assessed using some form of randomized benchmarking. However, the existing methods become infeasible for more than approximately five qubits. Here we show how to use a simple and customizable class of circuits-randomized mirror circuits-to perform scalable, robust, and flexible randomized benchmarking of Clifford gates. We show that this technique approximately estimates the infidelity of an average many-qubit logic layer, and we use simulations of up to 225 qubits with physically realistic error rates in the range 0.1%-1% to demonstrate its scalability. We then use up to 16 physical qubits of a cloud quantum computing platform to demonstrate that our technique can reveal and quantify crosstalk errors in many-qubit circuits.

Dental and Periodontal Health in Acute Intermittent Porphyria.

In the inherited metabolic disorder acute intermittent porphyria (AIP), high sugar intake prevents porphyric attacks due to the glucose effect and the following high insulin levels that may lower AIP disease activity. Insulin resistance is a known risk factor for periodontitis and sugar changes diabetogenic hormones and affects dental health. We hypothesized differences in homeostasis model assessment (HOMA) scores for insulin resistance in AIP cases vs. controls and in those with periodontitis. Our aim was to systematically study dental health in AIP as poor dental health was previously only described in case reports. Further, we aimed to examine if poor dental health and kidney failure might worsen AIP as chronic inflammation and kidney failure might increase disease activity. In 47 AIP cases and 47 matched controls, X-rays and physical examination of clinical attachment loss (CAL), probing pocket depth (PPD), and decayed missing filled teeth (DMFT) were performed. Dietary intake was evaluated through a diet logbook. Plasma cytokines and diabetogenic hormones were measured using multiplex technology and urine porphobilinogen and kidney and liver function by routine methods. An excel spreadsheet from the University of Oxford was used to estimate HOMA scores; beta cell function, HOMA%B (%B), insulin sensitivity, HOMA%S (%S), and insulin resistance HOMA-IR (IR), based on glucose and plasma (P) C-peptide. The Wilcoxon matched-pairs signed rank test, the Mann−Whitney U-test, and Spearman's non-parametric correlation were used. Insulin (p = 0.007) and C-peptide (p = 0.006) were higher in the AIP cases with periodontitis versus those without. In AIP patients, the liver fibrosis index 4 correlated with DMFT (p < 0.001) and CAL ≥4 mm (p = 0.006); the estimated glomerular filtration rate correlated with DMFT (p < 0.001) and CAL ≥4 mm (p = 0.02). CAL ≥4 mm was correlated with chemokine ligand 11 and interleukin (IL)-13 (p = 0.04 for both), and PPD >5 mm was correlated with plasminogen activator inhibitor-1 (p = 0.003) and complement component 3 (p = 0.02). In conclusion, dental health in AIP cases was correlated with insulin resistance, inflammatory markers, and biomarkers of kidney and liver function, demonstrating that organ damage in the kidney and liver are associated with poorer dental health.

Fungal Enzymes Involved in Plastics Biodegradation.

Plastic pollution is a growing environmental problem, in part due to the extremely stable and durable nature of this polymer. As recycling does not provide a complete solution, research has been focusing on alternative ways of degrading plastic. Fungi provide a wide array of enzymes specialized in the degradation of recalcitrant substances and are very promising candidates in the field of plastic degradation. This review examines the present literature for different fungal enzymes involved in plastic degradation, describing their characteristics, efficacy and biotechnological applications. Fungal laccases and peroxidases, generally used by fungi to degrade lignin, show good results in degrading polyethylene (PE) and polyvinyl chloride (PVC), while esterases such as cutinases and lipases were successfully used to degrade polyethylene terephthalate (PET) and polyurethane (PUR). Good results were also obtained on PUR by fungal proteases and ureases. All these enzymes were isolated from many different fungi, from both Basidiomycetes and Ascomycetes, and have shown remarkable efficiency in plastic biodegradation under laboratory conditions. Therefore, future research should focus on the interactions between the genes, proteins, metabolites and environmental conditions involved in the processes. Further steps such as the improvement in catalytic efficiency and genetic engineering could lead these enzymes to become biotechnological applications in the field of plastic degradation.

Spontaneous partial recovery of striatal dopaminergic uptake despite nigral cell loss in asymptomatic MPTP-lesioned female minipigs.

The Göttingen minipig is a large animal with a gyrencephalic brain that expresses -complex behavior, making it an attractive model for Parkinson's disease research. Here, we investigate the temporal evolution of presynaptic dopaminergic function for 14 months after injections of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the minipig using a multi-tracer longitudinal positron emission tomography (PET) design. We injected seven sedated minipigs with 1-2 mg/kg of MPTP, and two with saline, three times a week over four weeks. We monitored behavioral deficits using a validated motor scale and walking mat. Brains were imaged with (+)-⍺-[11C]-dihydrotetrabenazine ([11C]-DTBZ) and [18F]-dihydroxyphenylalanine ([18F]-FDOPA) PET at baseline and 1, 3, 10 and 14 months after MPTP injection, and immunohistochemistry was used to assess nigral cell loss. The minipigs showed mild bradykinesia and impaired coordination at early timepoints after MPTP. PET revealed decreases of striatal [11C]-DTBZ and [18F]-FDOPA uptake post-MPTP with partial spontaneous recovery of [18F]-FDOPA after 10 months. Postmortem analysis estimated an MPTP-induced nigral loss of 57% tyrosine hydroxylase+ and 43% Nissl-stained cells. Normal motor function despite substantial damage to the dopaminergic system is consistent with prodromal Parkinson's disease, and offers an opportunity for testing disease-modifying therapies. However, partial spontaneous recovery of dopamine terminal function must be taken into account in future studies.

A Novel Porcine Model of Ischemia-Reperfusion Injury After Cross-Clamping the Thoracic Aorta Revealed Substantial Cardiopulmonary, Thromboinflammatory and Biochemical Changes Without Effect of C1-Inhibitor Treatment.

Ischemic injury worsens upon return of blood and innate immunity including the complement system play a central role in ischemia-reperfusion injury (IRI) as in thoracic aortic surgery. Complement component1 inhibitor (C1-INH) has been shown to reduce IRI and is a broad-acting plasma cascade inhibitor. We established a new porcine model of IRI by cross-clamping the thoracic aorta and evaluated the global changes occurring in organ function, systemic inflammatory response and organ damage with or without treatment with C1-INH-concentrate. Twenty-four piglets (8.8-11.1 kg) underwent 45 minutes clamping of the thoracic aorta at the Th8 level. Upfront 12 piglets received human saline and 12 received C1-INH (250 IU/kg) intravenously. Three sham animals received thoracic opening without clamping. Reperfusion lasted 5 hours. We studied ten cardiorespiratory markers, three hematologic markers, eleven inflammatory markers, and twelve organ damage markers over the whole experimental period. Postmortem tissue homogenates from seven organs were examined for inflammatory markers and analysed by two-way repeated-measures ANOVA, area under the curve or unpaired t-tests. By excluding sham and combining treated and untreated animals, the markers reflected a uniform, broad and severe organ dysfunction. The mean and range fold change from before cross-clamp onset to maximum change for the different groups of markers were: cardiorespiratory 1.4 (0.2-3.7), hematologic 1.9 (1.2-2.7), plasma inflammatory 19.5 (1.4-176) and plasma organ damage 2.9 (1.1-8.6). Treatment with C1-INH had only a marginal effect on the IRI-induced changes, reaching statistical significance only for the plasma complement activation product TCC (p=0.0083) and IL-4 (p=0.022) and INF-α (p=0.016) in the colon tissue. In conclusion, the present novel model of porcine global IRI is forceful with regards to central markers and could generally be applicable for pathophysiological studies. C1-INH treatment had no significant effect, but the model allows for future testing of other drugs attenuating IRI globally.

Two-qubit silicon quantum processor with operation fidelity exceeding 99.

Silicon spin qubits satisfy the necessary criteria for quantum information processing. However, a demonstration of high-fidelity state preparation and readout combined with high-fidelity single- and two-qubit gates, all of which must be present for quantum error correction, has been lacking. We use a two-qubit Si/SiGe quantum processor to demonstrate state preparation and readout with fidelity greater than 97%, combined with both single- and two-qubit control fidelities exceeding 99%. The operation of the quantum processor is quantitatively characterized using gate set tomography and randomized benchmarking. Our results highlight the potential of silicon spin qubits to become a dominant technology in the development of intermediate-scale quantum processors.