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Persistent symptoms following SARS-CoV-2 infection are increasingly reported, although the drivers of post-acute sequelae (PASC) of COVID-19 are unclear. Here we assessed 214 individuals infected with SARS-CoV-2, with varying disease severity, for one year from COVID-19 symptom onset to determine the early correlates of PASC. A multivariate signature detected beyond two weeks of disease, encompassing unresolving inflammation, anemia, low serum iron, altered iron-homeostasis gene expression and emerging stress erythropoiesis; differentiated those who reported PASC months later, irrespective of COVID-19 severity. A whole-blood heme-metabolism signature, enriched in hospitalized patients at month 1-3 post onset, coincided with pronounced iron-deficient reticulocytosis. Lymphopenia and low numbers of dendritic cells persisted in those with PASC, and single-cell analysis reported iron maldistribution, suggesting monocyte iron loading and increased iron demand in proliferating lymphocytes. Thus, defects in iron homeostasis, dysregulated erythropoiesis and immune dysfunction due to COVID-19 possibly contribute to inefficient oxygen transport, inflammatory disequilibrium and persisting symptomatology, and may be therapeutically tractable.
\n \n\n \n \nHerpesviruses modulate immune control to secure lifelong infection. The mechanisms Human Cytomegalovirus (HCMV) employs in this regard can reveal unanticipated aspects of cellular signaling involved in antiviral immunity. Here, we describe a novel relationship between the TGF-\u03b2 family cytokine BMP9 and HCMV infection. We identify a cross-talk between BMP9-induced and IFN receptor-mediated signaling, showing that BMP9 boosts the transcriptional response to and antiviral activity of IFN\u03b2, thereby enhancing viral restriction. We also show that BMP9 is secreted by human fibroblasts upon HCMV infection. However, HCMV infection impairs BMP9-induced enhancement of the IFN\u03b2 response, indicating that this signaling role of BMP9 is actively targeted by HCMV. Indeed, transmembrane proteins US18 and US20, which downregulate type I BMP receptors, are necessary and sufficient to cause inhibition of BMP9-mediated boosting of the antiviral response to IFN\u03b2. HCMV lacking US18 and US20 is more sensitive to IFN\u03b2. Thus, HCMV has a mutually antagonistic relationship with BMP9, which extends the growing body of evidence that BMP signaling is an underappreciated modulator of innate immunity in response to viral infection.
\n \n\n \n \nSummaryKabuki syndrome is a genetic disorder characterised by distinctive facial features, developmental delays, and multisystem congenital anomalies. Endocrine complications such as premature thelarche and short stature are common, whereas disorders of glycaemic control are less frequent. We describe a 23-year-old white female referred to the diabetes clinic for hyperglycaemia during haemodialysis. She was subsequently diagnosed with Kabuki syndrome based on characteristic clinical features, confirmed by detecting a heterozygous pathogenic variant in KMT2D. She was known to have had multiple congenital anomalies at birth, including complex congenital heart disease and a single dysplastic ectopic kidney, and received a cadaveric transplanted kidney at the age of 13. She had hyperglycaemia consistent with post-transplant diabetes mellitus (DM) and was started on insulin. Examination at the time revealed truncal obesity. She developed acute graft rejection and graft failure 14 months post-transplant and she was started on haemodialysis. Her blood glucose levels normalised post-graft explant, but she was hyperglycaemic again during haemodialysis at the age of 23. Given her clinical phenotype, negative diabetes antibodies and normal pancreas on ultrasound, she was assumed to have type 2 DM and achieved good glycaemic control with gliclazide.Learning pointsInvolve clinical genetics early in the investigative pathway of sick neonates born with multiple congenital anomalies to establish a diagnosis to direct medical care. Consider the possibility of Kabuki syndrome (KS) in the differential diagnoses in any neonate with normal karyotyping or microarray analysis and with multiple congenital anomalies (especially cardiac, renal, or skeletal), dysmorphic facial features, transient neonatal hypoglycaemia and failure to thrive. Consider the possibility of diabetes as an endocrine complication in KS patients who are obese or who have autoimmune disorders.
\n \n\n \n \nBACKGROUND: The optimal hemoglobin (Hb) threshold for red blood cell transfusions in adult patients with myelodysplastic syndromes (MDS) has not been defined. STUDY DESIGN AND METHODS: We conducted a pilot randomized multi-center study of two transfusion algorithms (liberal, to maintain Hb 110-120\u2009g/L, transfuse 2\u2009units if Hb\u2009
\n \n\n \n \nBackground: Vascular cell adhesion molecule-1 (VCAM-1+) endothelial cell-derived extracellular vesicles (EC-EVs) are augmented in cardiovascular disease, where they can signal the deployment of immune cells from the splenic reserve. Endothelial cells in culture activated with pro-inflammatory tumor necrosis factor-\u03b1 (TNF-a) also release VCAM-1+ EC-EVs. However, isolating VCAM-1+ EC-EVs from conditioned cell culture media for subsequent in-depth analysis remains challenging. Aim: We utilized the extracellular vesicles (EV) microfluidics herringbone chip (EVHB-Chip), coated with anti-VCAM-1 antibodies, for selective capture of VCAM-1+ cells and EC-EVs. Methods and Results: Engineered EA.hy926 endothelial cells overexpressing VCAM-1 (P < 0.001 versus control) showed increased binding to the VCAM-1-EV HB-Chip versus an IgG device. TNF-\u03b1-stimulated human umbilical cord vein endothelial cells (HUVECs) exhibited elevated VCAM-1 protein levels (P < 0.001) and preferential binding to the VCAM-1-EV HB-Chip versus the IgG device. HUVECs stimulated with TNF-\u03b1 showed differential gene expression of intercellular adhesion molecule-1 (ICAM-1) (P < 0.001) and VCAM-1 (P < 0.001) by digital droplet PCR versus control cells. HUVEC-derived EC-EVs were positive for CD9, CD63, HSP70, and ALIX and had a modal size of 83.5 nm. Control and TNF-\u03b1-stimulated HUVEC-derived EC-EV cultures were captured on the VCAM-1-EV HB-Chip, demonstrating selective capture. VCAM-1+ EC-EV were significantly enriched for ICAM-1 (P < 0.001) mRNA transcripts. Conclusion: This study presents a novel approach using theEV HB-Chip, coated with anti-VCAM-1 antibodies and digital droplet PCR for the study of VCAM-1+ EC-EVs. Isolation of VCAM-1+ EC-EV from heterogeneous sources such as conditioned cell culture media holds promise for subsequent detailed characterization, and may facilitate the study of VCAM-1+ EC-EVs in cardiovascular and metabolic diseases, for disease monitoring and therapeutic insights.
\n \n\n \n \nBackgroundWarfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor.MethodsIn this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran--110 mg or 150 mg twice daily--or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism.ResultsRates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051).ConclusionsIn patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600.)
\n \n\n \n \nIntroductionTo support decisions about thrombectomy provision, we have previously estimated the annual UK population eligible for treatment as \u223c10% of stroke admissions. Since then, eight further randomised trials that could alter the eligibility rate have reported in 2021-23. We updated our estimates of the eligible population from these trials and other recent studies.Patients and methodsAn updated decision tree describing the EVT eligible population for UK stroke admissions was produced. Decision criteria were derived from the highest level of evidence available. For nodes where no specific RCT data existed, evidence was obtained from the latest systematic review(s) or the highest quality observational data.ResultsWe estimate that 15,420 (approximately 15%) of admitted UK stroke patients are now eligible for thrombectomy, or 14,930 if advanced brain imaging using MRI/CT perfusion or collateral assessment were used in all patients. This is a 54% increase in our previous estimate in 2021. Over 50% of LAO strokes are now potentially eligible for thrombectomy. The increase in eligibility is principally due to a much larger cohort of later presenting and/or larger ischaemic core patients.ConclusionMost previously independent LAO stroke patients presenting within 24\u2009h, even in the presence of a large ischaemic core on initial non-contrast CT, should be considered for thrombectomy with use of advanced brain imaging in those presenting beyond 12\u2009h to identify salvageable penumbral brain tissue. Treatment in most patients remains critically time-dependent and our estimates should be interpreted with this in mind.
\n \n\n \n \nIntroduction: In a drip-and-ship model for endovascular thrombectomy (EVT), early identification of large vessel occlusion (LVO) and timely referral to a comprehensive center (CSC) are crucial when patients are admitted to an acute stroke center (ASC). Several artificial intelligence (AI) decision-aid tools are increasingly being used to facilitate the rapid identification of LVO. This retrospective cohort study aimed to evaluate the impact of deploying e-Stroke AI decision support software in the hyperacute stroke pathway on process metrics and patient outcomes at an ASC in the United Kingdom. Methods: Except for the deployment of e-Stroke on 01 March 2020, there were no significant changes made to the stroke pathway at the ASC. The data were obtained from a prospective stroke registry between 01 January 2019 and 31 March 2021. The outcomes were compared between the 14 months before and 12 months after the deployment of AI (pre-e-Stroke cohort vs. post-e-Stroke cohort) on 01 March 2020. Time window analyses were performed using Welch\u2019s t-test. Cochran\u2013Mantel\u2013Haenszel test was used to compare changes in disability at 3 months assessed by modified Rankin Score (mRS) ordinal shift analysis, and Fisher\u2019s exact test was used for dichotomised mRS analysis. Results: In the pre-e-Stroke cohort, 19 of 22 patients referred received EVT. In the post-e-Stroke cohort, 21 of the 25 patients referred were treated. The mean door-in-door-out (DIDO) and door-to-referral times in pre-e-Stroke vs. post-e-Stroke cohorts were 141 vs. 79 min (difference 62 min, 95% CI 96.9\u201326.8 min, p < 0.001) and 71 vs. 44 min (difference 27 min, 95% CI 47.4\u20135.4 min, p = 0.01), respectively. The adjusted odds ratio (age and NIHSS) for mRS ordinal shift analysis at 3 months was 3.14 (95% CI 0.99\u201310.51, p = 0.06) and the dichotomized mRS 0\u20132 at 3 months was 16% vs. 48% (p = 0.04) in the pre- vs. post-e-Stroke cohorts, respectively. Conclusion: In this single-center study in the United Kingdom, the DIDO time significantly decreased since the introduction of e-Stroke decision support software into an ASC hyperacute stroke pathway. The reduction in door-in to referral time indicates faster image interpretation and referral for EVT. There was an indication of an increased proportion of patients regaining independent function after EVT. However, this should be interpreted with caution given the small sample size. Larger, prospective studies and further systematic real-world evaluation are needed to demonstrate the widespread generalisability of these findings.
\n \n\n \n \nBACKGROUND: Protein glycosylation is an enzymatic process known to reflect an individual's physiologic state and changes thereof. The impact of metabolic interventions on plasma protein N-glycosylation has only been sparsely investigated. OBJECTIVE: To examine alterations in plasma protein N-glycosylation following changes in caloric intake and bariatric surgery. SETTING: University of Texas Southwestern Medical Center, US and Oxford University Hospitals, UK. METHODS: This study included 2 independent patient cohorts that recruited 10 and 37 individuals with obesity undergoing a period of caloric restriction followed by bariatric surgery. In both cohorts, clinical data were collated, and the composition of plasma protein N-glycome was analyzed chromatographically. Linear mixed models adjusting for age, sex, and multiple testing (false discovery rate
\n \n\n \n \nOBJECTIVE: Artificial intelligence (AI) is a developing field in the context of healthcare. As this technology continues to be implemented in patient care, there is a growing need to understand the thoughts and experiences of stakeholders in this area to ensure that future AI development and implementation is successful. The aim of this study was to conduct a literature search of qualitative studies exploring the opinions of stakeholders such as clinicians, patients, and technology experts in order to establish the most common themes and ideas that have been presented in this research. METHODS: A literature search was conducted of existing qualitative research on stakeholder beliefs about the use of AI use in healthcare. Twenty-one papers were selected and analysed resulting in the development of four key themes relating to patient care, patient-doctor relationships, lack of education and resources, and the need for regulations. RESULTS: Overall, patients and healthcare workers are open to the use of AI in care and appear positive about potential benefits. However, concerns were raised relating to the lack of empathy in interactions of AI tools, and potential risks that may arise from the data collection needed for AI use and development. Stakeholders in the healthcare, technology, and business sectors all stressed that there was a lack of appropriate education, funding, and guidelines surrounding AI, and these concerns needed to be addressed to ensure future implementation is safe and suitable for patient care. CONCLUSION: Ultimately, the results found in this study highlighted that there was a need for communication between stakeholder in order for these concerns to be addressed, mitigate potential risks, and maximise benefits for patients and clinicians alike. The results also identified a need for further qualitative research in this area to further understand stakeholder experiences as AI use continues to develop.
\n \n\n \n \nBACKGROUND: Limited information exists on postoperative hypocortisolism and hypothalamus-pituitary-adrenal axis recovery in patients with adrenal incidentaloma following unilateral adrenalectomy. We evaluated frequency of postoperative hypocortisolism and predictors for recovery in non-aldosterone-producing adrenocortical adenoma patients after unilateral adrenalectomy. METHODS: A retrospective analysis of 32 adrenal incidentaloma patients originally included in the ITACA trial (NCT04127552) with confirmed non-aldosterone-producing adrenocortical adenoma undergoing unilateral adrenalectomy from September 2019 to April 2023 was conducted. Preoperative assessments included adrenal MRI, anthropometrics, evaluation of comorbidities, adrenal function assessed via ACTH, urinary free cortisol, and 1\u00a0mg dexamethasone suppression test. ACTH and serum cortisol or Short Synacthen test were performed within 6\u00a0days, 6 weeks, 6 months, and a year after surgery. RESULTS: Six days postoperative, 18.8% of patients had normal adrenal function. Among those with postoperative hypocortisolism, 53.8% recovered by 6 weeks. Patients with earlier adrenal recovery (6 weeks) had lower preoperative 1\u00a0mg dexamethasone suppression test (median 1\u00a0mg dexamethasone suppression test 76.2 [61.8-111.0] nmol/L vs 260.0 [113.0-288.5] nmol/L, p\u2009
\n \n\n \n \nThe perception of adipose tissue as a metabolically quiescent tissue, primarily responsible for lipid storage and energy balance (with some endocrine, thermogenic, and insulation functions), has changed. It is now accepted that adipose tissue is a crucial regulator of metabolic health, maintaining bidirectional communication with other organs including the cardiovascular system. Additionally, adipose tissue depots are functionally and morphologically heterogeneous, acting not only as sources of bioactive molecules that regulate the physiological functioning of the vasculature and myocardium but also as biosensors of the paracrine and endocrine signals arising from these tissues. In this way, adipose tissue undergoes phenotypic switching in response to vascular and/or myocardial signals (proinflammatory, profibrotic, prolipolytic), a process that novel imaging technologies are able to visualize and quantify with implications for clinical prognosis. Furthermore, a range of therapeutic modalities have emerged targeting adipose tissue metabolism and altering its secretome, potentially benefiting those at risk of cardiovascular disease. Expected final online publication date for the Annual Review of Physiology, Volume 86 is February 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
\n \n\n \n \nArterial Spin Labelling (ASL) imaging derives a perfusion image by tracing the accumulation of magnetically labeled blood water in the brain. As the image generated has an intrinsically low signal to noise ratio (SNR), multiple measurements are routinely acquired and averaged, at a penalty of increased scan duration and opportunity for motion artefact. However, this strategy alone might be ineffective in clinical settings where the time available for acquisition is limited and patient motion are increased. This study investigates the use of an Independent Component Analysis (ICA) approach for denoising ASL data, and its potential for automation. 72 ASL datasets (pseudo-continuous ASL; 5 different post-labeling delays: 400, 800, 1200, 1600, 2000\u202fm\u202fs; total volumes\u202f=\u202f60) were collected from thirty consecutive acute stroke patients. The effects of ICA-based denoising (manual and automated) where compared to two different denoising approaches, aCompCor, a Principal Component-based method, and Enhancement of Automated Blood Flow Estimates (ENABLE), an algorithm based on the removal of corrupted volumes. Multiple metrics were used to assess the changes in the quality of the data following denoising, including changes in cerebral blood flow (CBF) and arterial transit time (ATT), SNR, and repeatability. Additionally, the relationship between SNR and number of repetitions acquired was estimated before and after denoising the data. The use of an ICA-based denoising approach resulted in significantly higher mean CBF and ATT values (p\u202f
\n \n\n \n \nPURPOSE: There is a need to develop methods that reliably quantify characteristics associated with vulnerable carotid plaque. Greyscale median (GSM) and shear wave elastography (SWE) are two techniques that may improve individual plaque risk stratification. SWE, which quantifies Young's Modulus (YM) to estimate tissue stiffness, has been researched in the liver, breast, thyroid and prostate, but its use in carotid plaques is novel. MATERIALS AND METHODS: The aim of this study was to quantify YM and GSM of plaques and compare to histology. 25 patients (64% male) with a mean age of 76 underwent both clinical and SWE imaging. The mean GSM was quantified over a cardiac cycle. The mean YM was quantified in multiple regions within the plaque over 5 frames. Histological features were assessed following carotid endarterectomy. RESULTS: The mean YM of unstable plaques was significantly lower than that of stable plaques (50.0 kPa vs. 79.1 kPa; p = 0.027). The presence of intra-plaque hemorrhage, thrombus and increasing numbers of foam cells was also associated with a significantly lower YM. Plaque YM did not correlate well with plaque GSM (r =\u200a .12). The mean plaque GSM was the same in both unstable and stable plaques. Fibrous plaques had a significantly higher GSM (p = 0.036). CONCLUSION: In conclusion, SWE provides additional information on plaque stiffness which may be of clinical benefit to help identify vulnerable plaque, and warrants further study.
\n \n\n \n \nPreviously reported only a few times before, we present a case of extracranial vertebral dissection and spontaneous frontoparietal subarachnoid hemorrhage (SAH) in the puerperium, discussing possible mechanisms and difficulties in management. A 35-year-old woman presented 10 days postcaesarean section with neck pain and vertigo with normal initial investigations. Following recurrent vertigo, headache, and ataxia, imaging revealed a frontoparietal SAH and vertebral artery dissection. The patient was consequently treated with aspirin, and then following a return of symptoms 3 weeks later, warfarin therapy was continued for 6 months. The possible underlying mechanisms for this case are discussed, including reversible cervical vasoconstriction syndrome and posterior reversible encephalopathy syndrome, although neither was identified. The small SAH alongside recurrent posterior circulation symptoms resulted in the initiation of antithrombotic therapy. This report supports studies demonstrating higher incidence of cervicocephalic arterial dissection in the puerperium. Moreover, the heterogeneous presentation and manifestations of such cases require individualized treatment, and warrant studies into underlying mechanisms behind extracranial dissection and nonaneurysmal SAH.
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