ABSTRACT
SARS-CoV-2-specific memory T cells will likely prove critical for long-term immune protection against COVID-19. Here, we systematically mapped the functional and phenotypic landscape of SARS-CoV-2-specific T cell responses in unexposed individuals, exposed family members, and individuals with acute or convalescent COVID-19. Acute-phase SARS-CoV-2-specific T cells displayed a highly activated cytotoxic phenotype that correlated with various clinical markers of disease severity, whereas convalescent-phase SARS-CoV-2-specific T cells were polyfunctional and displayed a stem-like memory phenotype. Importantly, SARS-CoV-2-specific T cells were detectable in antibody-seronegative exposed family members and convalescent individuals with a history of asymptomatic and mild COVID-19. Our collective dataset shows that SARS-CoV-2 elicits broadly directed and functionally replete memory T cell responses, suggesting that natural exposure or infection may prevent recurrent episodes of severe COVID-19.
Subject(s)
Convalescence , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , T-Lymphocytes/immunology , Adult , Antibodies, Viral/immunology , Asymptomatic Infections , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/pathology , Female , Humans , Immunologic Memory , Male , Middle Aged , Pandemics , Pneumonia, Viral/pathology , SARS-CoV-2ABSTRACT
Mucosal-associated invariant T (MAIT) cells are an abundant population of unconventional T cells in humans and play important roles in immune defense against microbial infections. Severe COVID-19 is associated with strong activation of MAIT cells and loss of these cells from circulation. In the present study, we investigated the capacity of MAIT cells to recover after severe COVID-19. In longitudinal paired analysis, MAIT cells initially rebounded numerically and phenotypically in most patients at 4 mo postrelease from the hospital. However, the rebounding MAIT cells displayed signs of persistent activation with elevated expression of CD69, CD38, and HLA-DR. Although MAIT cell function was restored in many patients, a subgroup displayed a predominantly PD-1high functionally impaired MAIT cell pool. This profile was associated with poor expression of IFN-γ and granzyme B in response to IL-12 + L-18 and low levels of polyfunctionality. Unexpectedly, although the overall T cell counts recovered, normalization of the MAIT cell pool failed at 9-mo follow-up, with a clear decline in MAIT cell numbers and a further increase in PD-1 levels. Together, these results indicate an initial transient period of inconsistent recovery of MAIT cells that is not sustained and eventually fails. Persisting MAIT cell impairment in previously hospitalized patients with COVID-19 may have consequences for antimicrobial immunity and inflammation and could potentially contribute to post-COVID-19 health problems.
Subject(s)
COVID-19 , Mucosal-Associated Invariant T Cells , Humans , HLA-DR Antigens , InflammationABSTRACT
Lack of the established noninvasive diagnostic biomarkers causes delay in diagnosis of lung cancer (LC). The aim of this study was to explore the association between inflammatory and cancer-associated plasma proteins and LC and thereby discover potential biomarkers. Patients referred for suspected LC and later diagnosed with primary LC, other cancers, or no cancer (NC) were included in this study. Demographic information and plasma samples were collected, and diagnostic information was later retrieved from medical records. Relative quantification of 92 plasma proteins was carried out using the Olink Immuno-Onc-I panel. Association between expression levels of panel of proteins with different diagnoses was assessed using generalized linear model (GLM) with the binomial family and a logit-link function, considering confounder effects of age, gender, smoking, and pulmonary diseases. The analysis showed that the combination of five plasma proteins (CD83, GZMA, GZMB, CD8A, and MMP12) has higher diagnostic performance for primary LC in both early and advanced stages compared with NC. This panel demonstrated lower diagnostic performance for other cancer types. Moreover, inclusion of four proteins (GAL9, PDCD1, CD4, and HO1) to the aforementioned panel significantly increased the diagnostic performance for primary LC in advanced stage as well as for other cancers. Consequently, the collective expression profiles of select plasma proteins, especially when analyzed in conjunction, might have the potential to distinguish individuals with LC from NC. This suggests their utility as predictive biomarkers for identification of LC patients. The synergistic application of these proteins as biomarkers could pave the way for the development of diagnostic tools for early-stage LC detection.
ABSTRACT
OBJECTIVE: The authors sought to explore the role of iron supplementation in the management of neurodevelopmental disorders among children and youths. METHODS: A systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was undertaken. A subset of results was suitable for meta-analysis. The quality of the evidence and strength of the clinical recommendations were assessed by using the Grading of Recommendations, Assessment, Development, and Evaluation method, and critical appraisal was conducted with the Joanna Briggs Institute critical appraisal tools. RESULTS: Nine articles met inclusion criteria. These articles included studies of attention-deficit hyperactivity disorder (ADHD) (N=7), autism spectrum disorder (N=1), and Tourette's syndrome (N=1). Three randomized controlled trials evaluating iron supplementation for ADHD hyperactivity symptom severity (124 participants: placebo, N=56; supplement, N=68) met inclusion criteria for a meta-analysis. Effect sizes for the placebo and supplement groups were moderate (Cohen's d=0.76) and large (Cohen's d=1.70), respectively, although these differences were not significant. The impact of iron supplementation on inattentive ADHD symptom severity was examined in two trials (75 participants: placebo, N=31; supplement, N=44). Large, nonsignificant effect sizes were demonstrated for the placebo (Cohen's d=1.66) and supplementation (Cohen's d=3.19) groups. The quality of the evidence and strength of the clinical recommendations were considered very low. CONCLUSIONS: Further research is needed to examine the role of iron supplementation in the management of ADHD and neurodevelopmental disorders more generally. Additionally, iron supplementation comes with risks, including death in the case of overdose.
Subject(s)
Dietary Supplements , Neurodevelopmental Disorders , Humans , Iron/administration & dosage , Attention Deficit Disorder with Hyperactivity/drug therapy , Child , Autism Spectrum Disorder/drug therapy , AdolescentABSTRACT
BACKGROUND: With access to antiretroviral therapy (ART) HIV infection is a chronic manageable condition and non-sexually transmissible. Yet, many people living with HIV still testify about experiencing HIV-related stigma and discrimination. It is well-documented that HIV-related stigma and discrimination continue to be critical barriers to prevention, treatment, care and quality of life. From an individual stigma-reduction intervention perspective, it is essential to identify individual and interpersonal factors associated with HIV-related stigma manifestations. To address this issue and to expand the literature, the aim of this study was to assess the prevalence of HIV-related stigma manifestations and their associated factors among a diverse sample of people living with HIV in Sweden. METHOD: Data from 1 096 participants were derived from a nationally representative, anonymous cross-sectional survey "Living with HIV in Sweden". HIV-related stigma manifestations were assessed using the validated Swedish 12-item HIV Stigma Scale encompassing four HIV-related stigma manifestations: personalised stigma, concerns with public attitudes towards people living with HIV, concerns with sharing HIV status, and internalized stigma. Variables potentially associated with the HIV-related stigma manifestations were divided into four categories: demographic characteristics, clinical HIV factors, distress and ART adherence, and available emotional HIV-related support. Four multivariable hierarchical linear regression analyses were employed to explore the associations between multiple contributors and HIV-related stigma manifestations. RESULTS: The most dominating stigma feature was anticipation of HIV-related stigma. It was manifested in high scores on concerns with sharing HIV status reported by 78% of the participants and high scores on concerns about public attitudes towards people living with HIV reported by 54% of the participants. High scores on personalised stigma and internalized stigma were reported by around one third of the participants respectively. Between 23 and 31% of the variance of the four reported HIV-related stigma manifestations were explained mainly by the same pattern of associated factors including female gender, shorter time since HIV diagnosis, feelings of hopelessness, non-sharing HIV status, and lack of available emotional HIV-related support. CONCLUSION: The most dominating stigma feature was anticipation of stigma. Female gender, shorter time since HIV diagnosis, feelings of hopelessness, non-sharing HIV status, and lack of available emotional HIV-related support constituted potential vulnerability factors of the four HIV-related stigma manifestations. Our findings highlight the vital necessity to support people living with HIV to increase their resilience to stigma in its different forms. Exploring associated factors of HIV-related stigma manifestations may give an indication of what circumstances may increase the risk of stigma burden and factors amenable to targeted interventions. As individual stigma-reductions interventions cannot be performed isolated from HIV-related stigma and discrimination in society, a key challenge is to intensify anti-stigma interventions also on the societal level.
Subject(s)
HIV Infections , Social Stigma , Humans , HIV Infections/psychology , HIV Infections/epidemiology , Female , Male , Sweden/epidemiology , Adult , Middle Aged , Cross-Sectional Studies , Prevalence , Young Adult , AdolescentABSTRACT
Dendritic cells (DCs) and monocytes are crucial mediators of innate and adaptive immune responses during viral infection, but misdirected responses by these cells may contribute to immunopathology. Here, we performed high-dimensional flow cytometry-analysis focusing on mononuclear phagocyte (MNP) lineages in SARS-CoV-2-infected patients with moderate and severe COVID-19. We provide a deep and comprehensive map of the MNP landscape in COVID-19. A redistribution of monocyte subsets toward intermediate monocytes and a general decrease in circulating DCs was observed in response to infection. Severe disease coincided with the appearance of monocytic myeloid-derived suppressor cell-like cells and a higher frequency of pre-DC2. Furthermore, phenotypic alterations in MNPs, and their late precursors, were cell-lineage-specific and associated either with the general response against SARS-CoV-2 or COVID-19 severity. This included an interferon-imprint in DC1s observed in all patients and a decreased expression of the coinhibitory molecule CD200R in pre-DCs, DC2s, and DC3 subsets of severely sick patients. Finally, unsupervised analysis revealed that the MNP profile, alone, pointed to a cluster of COVID-19 nonsurvivors. This study provides a reference for the MNP response to SARS-CoV-2 infection and unravels mononuclear phagocyte dysregulations associated with severe COVID-19.
Subject(s)
COVID-19/immunology , Mononuclear Phagocyte System/immunology , SARS-CoV-2/immunology , Adult , COVID-19/epidemiology , COVID-19/metabolism , COVID-19/virology , Cytokines/immunology , Dendritic Cells/immunology , Female , Humans , Interferons/immunology , Male , Middle Aged , Monocytes/immunology , Mononuclear Phagocyte System/metabolism , Severity of Illness Index , SwedenABSTRACT
Since the outset of the COVID-19 pandemic, increasing evidence suggests that the innate immune responses play an important role in the disease development. A dysregulated inflammatory state has been proposed as a key driver of clinical complications in COVID-19, with a potential detrimental role of granulocytes. However, a comprehensive phenotypic description of circulating granulocytes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients is lacking. In this study, we used high-dimensional flow cytometry for granulocyte immunophenotyping in peripheral blood collected from COVID-19 patients during acute and convalescent phases. Severe COVID-19 was associated with increased levels of both mature and immature neutrophils, and decreased counts of eosinophils and basophils. Distinct immunotypes were evident in COVID-19 patients, with altered expression of several receptors involved in activation, adhesion, and migration of granulocytes (e.g., CD62L, CD11a/b, CD69, CD63, CXCR4). Paired sampling revealed recovery and phenotypic restoration of the granulocytic signature in the convalescent phase. The identified granulocyte immunotypes correlated with distinct sets of soluble inflammatory markers, supporting pathophysiologic relevance. Furthermore, clinical features, including multiorgan dysfunction and respiratory function, could be predicted using combined laboratory measurements and immunophenotyping. This study provides a comprehensive granulocyte characterization in COVID-19 and reveals specific immunotypes with potential predictive value for key clinical features associated with COVID-19.
Subject(s)
COVID-19/immunology , Granulocytes/immunology , COVID-19/blood , COVID-19/diagnosis , COVID-19/physiopathology , Granulocytes/cytology , Humans , Immunity, Innate , Immunophenotyping , Leukocyte Count , Lung/physiopathology , Models, Biological , Organ Dysfunction Scores , SARS-CoV-2 , Severity of Illness IndexABSTRACT
Importance: There is uncertainty about whether prolonged infusions of ß-lactam antibiotics improve clinically important outcomes in critically ill adults with sepsis or septic shock. Objective: To determine whether prolonged ß-lactam antibiotic infusions are associated with a reduced risk of death in critically ill adults with sepsis or septic shock compared with intermittent infusions. Data Sources: The primary search was conducted with MEDLINE (via PubMed), CINAHL, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov from inception to May 2, 2024. Study Selection: Randomized clinical trials comparing prolonged (continuous or extended) and intermittent infusions of ß-lactam antibiotics in critically ill adults with sepsis or septic shock. Data Extraction and Synthesis: Data extraction and risk of bias were assessed independently by 2 reviewers. Certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation approach. A bayesian framework was used as the primary analysis approach and a frequentist framework as the secondary approach. Main Outcomes and Measures: The primary outcome was all-cause 90-day mortality. Secondary outcomes included intensive care unit (ICU) mortality and clinical cure. Results: From 18 eligible randomized clinical trials that included 9108 critically ill adults with sepsis or septic shock (median age, 54 years; IQR, 48-57; 5961 men [65%]), 17 trials (9014 participants) contributed data to the primary outcome. The pooled estimated risk ratio for all-cause 90-day mortality for prolonged infusions of ß-lactam antibiotics compared with intermittent infusions was 0.86 (95% credible interval, 0.72-0.98; I2 = 21.5%; high certainty), with a 99.1% posterior probability that prolonged infusions were associated with lower 90-day mortality. Prolonged infusion of ß-lactam antibiotics was associated with a reduced risk of intensive care unit mortality (risk ratio, 0.84; 95% credible interval, 0.70-0.97; high certainty) and an increase in clinical cure (risk ratio, 1.16; 95% credible interval, 1.07-1.31; moderate certainty). Conclusions and Relevance: Among adults in the intensive care unit who had sepsis or septic shock, the use of prolonged ß-lactam antibiotic infusions was associated with a reduced risk of 90-day mortality compared with intermittent infusions. The current evidence presents a high degree of certainty for clinicians to consider prolonged infusions as a standard of care in the management of sepsis and septic shock. Trial Registration: PROSPERO Identifier: CRD42023399434.
ABSTRACT
We have developed a new three-component catalytic coupling reaction of alkynyl boronates, diazomethanes, and aliphatic/aromatic ketones in the presence of BINOL derivatives. The reaction proceeds with a remarkably high enantio- and diastereoselectivity (up to three contiguous stereocenters) affording tertiary CF3-allenols in a single operational step. The reaction proceeds under mild, neutral, metal-free conditions, which leads to a high level of functional group tolerance.
ABSTRACT
Corona disease 2019 (COVID-19) affects multiple organ systems. Recent studies have indicated perturbations in the circulating metabolome linked to COVID-19 severity. However, several questions pertain with respect to the metabolome in COVID-19. We performed an in-depth assessment of 1129 unique metabolites in 27 hospitalized COVID-19 patients and integrated results with large-scale proteomic and immunology data to capture multiorgan system perturbations. More than half of the detected metabolic alterations in COVID-19 were driven by patient-specific confounding factors ranging from comorbidities to xenobiotic substances. Systematically adjusting for this, a COVID-19-specific metabolic imprint was defined which, over time, underwent a switch in response to severe acute respiratory syndrome coronavirus-2 seroconversion. Integration of the COVID-19 metabolome with clinical, cellular, molecular, and immunological severity scales further revealed a network of metabolic trajectories aligned with multiple pathways for immune activation, and organ damage including neurological inflammation and damage. Altogether, this resource refines our understanding of the multiorgan system perturbations in severe COVID-19 patients.
Subject(s)
COVID-19/immunology , COVID-19/metabolism , Metabolome/immunology , SARS-CoV-2 , Adolescent , Adult , Aged , COVID-19/complications , Case-Control Studies , Central Nervous System Diseases/etiology , Central Nervous System Diseases/immunology , Central Nervous System Diseases/metabolism , Cohort Studies , Female , Humans , Male , Metabolomics , Middle Aged , Organ Specificity , Pandemics , Phenotype , Proteomics , Severity of Illness Index , Young AdultABSTRACT
BACKGROUND: COVID-19 remains a major public health challenge, requiring the development of tools to improve diagnosis and inform therapeutic decisions. As dysregulated inflammation and coagulation responses have been implicated in the pathophysiology of COVID-19 and sepsis, we studied their plasma proteome profiles to delineate similarities from specific features. METHODS: We measured 276 plasma proteins involved in Inflammation, organ damage, immune response and coagulation in healthy controls, COVID-19 patients during acute and convalescence phase, and sepsis patients; the latter included (i) community-acquired pneumonia (CAP) caused by Influenza, (ii) bacterial CAP, (iii) non-pneumonia sepsis, and (iv) septic shock patients. RESULTS: We identified a core response to infection consisting of 42 proteins altered in both COVID-19 and sepsis, although higher levels of cytokine storm-associated proteins were evident in sepsis. Furthermore, microbiologic etiology and clinical endotypes were linked to unique signatures. Finally, through machine learning, we identified biomarkers, such as TRIM21, PTN and CASP8, that accurately differentiated COVID-19 from CAP-sepsis with higher accuracy than standard clinical markers. CONCLUSIONS: This study extends the understanding of host responses underlying sepsis and COVID-19, indicating varying disease mechanisms with unique signatures. These diagnostic and severity signatures are candidates for the development of personalized management of COVID-19 and sepsis.
Subject(s)
COVID-19 , Community-Acquired Infections , Pneumonia , Sepsis , Humans , COVID-19/complications , Proteomics , Inflammation/complications , BiomarkersABSTRACT
BACKGROUND: Accurate kinetic modeling of 18F-fluorodeoxyglucose ([18F]-FDG) positron emission tomography (PET) data requires accurate knowledge of the available tracer concentration in the plasma during the scan time, known as the arterial input function (AIF). The gold standard method to derive the AIF requires collection of serial arterial blood samples, but the introduction of long axial field of view (LAFOV) PET systems enables the use of non-invasive image-derived input functions (IDIFs) from large blood pools such as the aorta without any need for bed movement. However, such protocols require a prolonged dynamic PET acquisition, which is impractical in a busy clinical setting. Population-based input functions (PBIFs) have previously shown potential in accurate Patlak analysis of [18F]-FDG datasets and can enable the use of shortened dynamic imaging protocols. Here, we exploit the high sensitivity and temporal resolution of a LAFOV PET system and explore the use of PBIF with abbreviated protocols in [18F]-FDG total body kinetic modeling. METHODS: Dynamic PET data were acquired in 24 oncological subjects for 65 min following the administration of [18F]-FDG. IDIFs were extracted from the descending thoracic aorta, and a PBIF was generated from 16 datasets. Five different scaled PBIFs (sPBIFs) were generated by scaling the PBIF with the AUC of IDIF curve tails using various portions of image data (35-65, 40-65, 45-65, 50-65, and 55-65 min post-injection). The sPBIFs were compared with the IDIFs using the AUCs and Patlak Ki estimates in tumor lesions and cerebral gray matter. Patlak plot start time (t*) was also varied to evaluate the performance of shorter acquisitions on the accuracy of Patlak Ki estimates. Patlak Ki estimates with IDIF and t* = 35 min were used as reference, and mean bias and precision (standard deviation of bias) were calculated to assess the relative performance of different sPBIFs. A comparison of parametric images generated using IDIF and sPBIFs was also performed. RESULTS: There was no statistically significant difference between AUCs of the IDIF and sPBIFs (Wilcoxon test: P > 0.05). Excellent agreement was shown between Patlak Ki estimates obtained using sPBIF and IDIF. Using the sPBIF55-65 with the Patlak model, 20 min of PET data (i.e., 45 to 65 min post-injection) achieved < 15% precision error in Ki estimates in tumor lesions compared to the estimates with the IDIF. Parametric images reconstructed using the IDIF and sPBIFs with and without an abbreviated protocol were visually comparable. Using Patlak Ki generated with an IDIF and 30 min of PET data as reference, Patlak Ki images generated using sPBIF55-65 with 20 min of PET data (t* = 45 min) provided excellent image quality with structural similarity index measure > 0.99 and peak signal-to-noise ratio > 55 dB. CONCLUSION: We demonstrate the feasibility of performing accurate [18F]-FDG Patlak analysis using sPBIFs with only 20 min of PET data from a LAFOV PET scanner.
Subject(s)
Fluorodeoxyglucose F18 , Neoplasms , Humans , Feasibility Studies , Positron-Emission Tomography/methods , Arteries , Neoplasms/diagnostic imagingABSTRACT
These practice guidelines provide evidence-based recommendations on the management of neuromuscular monitoring and antagonism of neuromuscular blocking agents during and after general anesthesia. The guidance focuses primarily on the type and site of monitoring and the process of antagonizing neuromuscular blockade to reduce residual neuromuscular blockade.
Subject(s)
Anesthetics , Delayed Emergence from Anesthesia , Neuromuscular Blockade , Neuromuscular Blocking Agents , Humans , Anesthesiologists , Neuromuscular MonitoringABSTRACT
Radium-226 carbonate was synthesized from radium-barium sulfate (226Ra0.76Ba0.24SO4) at room temperature and characterized by X-ray powder diffraction (XRPD) and extended X-ray absorption fine structure (EXAFS) techniques. XRPD revealed that fractional crystallization occurred and that two phases were formedâthe major Ra-rich phase, Ra(Ba)CO3, and a minor Ba-rich phase, Ba(Ra)CO3, crystallizing in the orthorhombic space group Pnma (no. 62) that is isostructural with witherite (BaCO3) but with slightly larger unit cell dimensions. Direct-space ab initio modeling shows that the carbonate oxygens in the major Ra(Ba)CO3 phase are highly disordered. The solubility of the synthesized major Ra(Ba)CO3 phase was studied from under- and oversaturation at 25.1 °C as a function of ionic strength using NaCl as the supporting electrolyte. It was found that the decimal logarithm of the solubility product of Ra(Ba)CO3 at zero ionic strength (log10 Ksp0) is -7.5(1) (2σ) (s = 0.05 g·L-1). This is significantly higher than the log10 Ksp0 of witherite of -8.56 (s = 0.01 g·L-1), supporting the disordered nature of the major Ra(Ba)CO3 phase. The limited co-precipitation of Ra2+ within witherite, the significantly higher solubility of pure RaCO3 compared to witherite, and thermodynamic modeling show that the results obtained in this work for the major Ra(Ba)CO3 phase are also applicable to pure RaCO3. The refinement of the EXAFS data reveals that radium is coordinated by nine oxygens in a broad bond distance distribution with a mean Ra-O bond distance of 2.885(3) Å (1σ). The Ra-O bond distance gives an ionic radius of Ra2+ in a 9-fold coordination of 1.545(6) Å (1σ).
ABSTRACT
The set of guidelines for good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents was developed following an international consensus conference in Copenhagen in 1996 (Viby-Mogensen et al., Acta Anaesthesiol Scand 1996, 40, 59-74); the guidelines were later revised and updated following the second consensus conference in Stockholm in 2005 (Fuchs-Buder et al., Acta Anaesthesiol Scand 2007, 51, 789-808). In view of new devices and further development of monitoring technologies that emerged since then, (e.g., electromyography, three-dimensional acceleromyography, kinemyography) as well as novel compounds (e.g., sugammadex) a review and update of these recommendations became necessary. The intent of these revised guidelines is to continue to help clinical researchers to conduct high-quality work and advance the field by enhancing the standards, consistency, and comparability of clinical studies. There is growing awareness of the importance of consensus-based reporting standards in clinical trials and observational studies. Such global initiatives are necessary in order to minimize heterogeneous and inadequate data reporting and to improve clarity and comparability between different studies and study cohorts. Variations in definitions of endpoints or outcome variables can introduce confusion and difficulties in interpretation of data, but more importantly, it may preclude building of an adequate body of evidence to achieve reliable conclusions and recommendations. Clinical research in neuromuscular pharmacology and physiology is no exception.
Subject(s)
Neuromuscular Blockade , Neuromuscular Blocking Agents , Humans , Neuromuscular Blocking Agents/pharmacology , Sugammadex , Neuromuscular Blockade/methodsABSTRACT
BACKGROUND: Apnoeic oxygenation with high-flow nasal oxygen prolongs the safe apnoeic period during induction of general anaesthesia. However, central haemodynamic effects and the characteristics of central gaseous exchange remain unexplored. OBJECTIVE: To describe mean pulmonary arterial pressure along with arterial and mixed venous blood gases and central haemodynamic parameters during apnoeic oxygenation with low-flow and high-flow nasal oxygen in pigs. DESIGN: Experimental crossover study. SETTING: Animal study of 10 healthy Swedish landrace pigs at Karolinska Institutet, Sweden, April-May 2021. INTERVENTION: The pigs were anaesthetised, their tracheas intubated and their pulmonary arteries catheterised. The animals were preoxygenated and paralysed before apnoea. Apnoeic periods between 45 and 60âmin were implemented with either 70 or 10âlâmin -1 100% O 2 delivered via nasal catheters. In addition, seven animals underwent an apnoea without fresh gas flow. Cardiopulmonary parameters and blood gases were measured repeatedly. MAIN OUTCOME MEASURES: Mean pulmonary arterial pressure during apnoeic oxygenation with high-flow and low-flow oxygen. RESULTS: Nine pigs completed two apnoeic periods of at least 45âmin with a Pa O 2 not lower than 13âkPa. The mean pulmonary arterial pressure increased during 45âmin of apnoea, from 18â±â1 to 33â±â2âmmHg and 18â±â1 to 35â±â2âmmHg, at 70 and 10âlâmin -1 O 2 , respectively ( P â<â0.001); there was no difference between the groups ( P â=â0.87). The Pa CO 2 increased by 0.48â±â0.07 and 0.52â±â0.04âkPaâmin -1 , at 70 and 10âlâmin -1 O 2 , respectively; there was no difference between the groups ( P â=â0.22). During apnoea without fresh gas flow, the SpO 2 declined to less than 85% after 155â±â11âs. CONCLUSION: During apnoeic oxygenation in pigs, the mean pulmonary arterial pressure increased two-fold and Pa CO 2 five-fold after 45âmin, while the arterial oxygen levels were maintained over 13âkPa, irrespective of high-flow or low-flow oxygen.
Subject(s)
Apnea , Oxygen , Swine , Animals , Apnea/therapy , Cross-Over Studies , Respiration, Artificial , HemodynamicsABSTRACT
OBJECTIVES: Death literacy is a recent conceptualization representing both individual and community competence, for example, a set of knowledge and skills for engaging in end-of-life-related situations. Little is yet known about which factors are associated with death literacy. A cross-sectional survey using the Swedish version of the Death Literacy Index, the DLI-S, was therefore conducted to explore associations between death literacy and sociodemographic, health, and experience variables. METHODS: A quota sample of 503 adults (mean age 49.95 ± 17.92), recruited from an online Swedish survey panel, completed a survey comprising the DLI-S and background questions. RESULTS: A hierarchical regression model with 3 blocks explained 40.5% of the variance in death literacy, F(22, 477) = 14.75. The sociodemographic factors age, gender, education, widowhood, and religious/spiritual belief accounted for 13.7% of the variance. Adding professional care factors contributed to an additional 15.8% of variance, with working in health care being significantly associated with death literacy. Including experiential factors explained another 11.0% of the variance, of which experiences of caring for and supporting dying and grieving people, both in a work, volunteer, or personal context, were positively associated with death literacy. SIGNIFICANCE OF RESULTS: This study contributes a tentative explanatory model of the influence of different factors on death literacy, outlining both direct and indirect associations. Our findings also support the hypothesized experiential basis for death literacy development in the Swedish context. The moderate degree of overall variance explained suggests there may be additional factors to consider to better understand the death literacy construct and how its development may be supported.
ABSTRACT
Homologation of trisubstituted fluoroalkenes followed by allylboration of aldehyde, ketone and imine substrates is suitable for synthesis of ß-fluorohydrin and amine products. In the presence of (R)-iodo-BINOL catalyst enantioselectivities up to 99 % can be achieved by formation of a single stereoisomer with adjacent stereocenters, of which one is a tertiary C-F center.
ABSTRACT
The Karolinska KI/K COVID-19 Immune Atlas project was conceptualized in March 2020 as a part of the academic research response to the developing SARS-CoV-2 pandemic. The aim was to rapidly provide a curated dataset covering the acute immune response towards SARS-CoV-2 infection in humans, as it occurred during the first wave. The Immune Atlas was built as an open resource for broad research and educational purposes. It contains a presentation of the response evoked by different immune and inflammatory cells in defined naïve patient-groups as they presented with moderate and severe COVID-19 disease. The present Resource Article describes how the Karolinska KI/K COVID-19 Immune Atlas allow scientists, students, and other interested parties to freely explore the nature of the immune response towards human SARS-CoV-2 infection in an online setting.
ABSTRACT
PURPOSE: To investigate the kinetics of 18F-fluorodeoxyglucose (18F-FDG) by positron emission tomography (PET) in multiple organs and test the feasibility of total-body parametric imaging using an image-derived input function (IDIF). METHODS: Twenty-four oncological patients underwent dynamic 18F-FDG scans lasting 65 min using a long axial FOV (LAFOV) PET/CT system. Time activity curves (TAC) were extracted from semi-automated segmentations of multiple organs, cerebral grey and white matter, and from vascular structures. The tissue and tumor lesion TACs were fitted using an irreversible two-tissue compartment (2TC) and a Patlak model. Parametric images were also generated using direct and indirect Patlak methods and their performances were evaluated. RESULTS: We report estimates of kinetic parameters and metabolic rate of glucose consumption (MRFDG) for different organs and tumor lesions. In some organs, there were significant differences between MRFDG values estimated using 2TC and Patlak models. No statistically significant difference was seen between MRFDG values estimated using 2TC and Patlak methods in tumor lesions (paired t-test, P = 0.65). Parametric imaging showed that net influx (Ki) images generated using direct and indirect Patlak methods had superior tumor-to-background ratio (TBR) to standard uptake value (SUV) images (3.1- and 3.0-fold mean increases in TBRmean, respectively). Influx images generated using the direct Patlak method had twofold higher contrast-to-noise ratio in tumor lesions compared to images generated using the indirect Patlak method. CONCLUSION: We performed pharmacokinetic modelling of multiple organs using linear and non-linear models using dynamic total-body 18F-FDG images. Although parametric images did not reveal more tumors than SUV images, the results confirmed that parametric imaging furnishes improved tumor contrast. We thus demonstrate the feasibility of total-body kinetic modelling and parametric imaging in basic research and oncological studies. LAFOV PET can enhance dynamic imaging capabilities by providing high sensitivity parametric images and allowing total-body pharmacokinetic analysis.