A reply to "TCR+/BCR+ dual-expressing cells and their associated public BCR clonotype are not enriched in type 1 diabetes".

We have recently identified a novel lymphocyte that is a dual expresser (DE) of TCRαß and BCR. DEs in T1D patients are predominated by a public BCR clonotype (clone-x) that encodes a potent autoantigen that cross-activates insulin-reactive T cells. Betts and colleagues were able to detect DEs but alleged to not detect high DE frequency, clone-x, or similar clones in T1D patients. Unfortunately, the authors did not follow our methods and when they did, their flow cytometric data at two sites were conflicting. Moreover, contrary to their claim, we identified clones similar to clone-x in their data along with clones bearing the core motif (DTAMVYYFDYW). Additionally, their report of no increased usage of clone-x VH/DH genes by bulk B cells confirms rather than challenges our results. Finally, the authors failed to provide data verifying purity of their sorted DEs, making it difficult to draw reliable conclusion of their repertoire analysis. This Matters Arising Response paper addresses the Japp et al. (2021) Matters Arising paper, published concurrently in Cell.

A Public BCR Present in a Unique Dual-Receptor-Expressing Lymphocyte from Type 1 Diabetes Patients Encodes a Potent T Cell Autoantigen.

T and B cells are the two known lineages of adaptive immune cells. Here, we describe a previously unknown lymphocyte that is a dual expresser (DE) of TCR and BCR and key lineage markers of both B and T cells. In type 1 diabetes (T1D), DEs are predominated by one clonotype that encodes a potent CD4 T cell autoantigen in its antigen binding site. Molecular dynamics simulations revealed that this peptide has an optimal binding register for diabetogenic HLA-DQ8. In concordance, a synthetic version of the peptide forms stable DQ8 complexes and potently stimulates autoreactive CD4 T cells from T1D patients, but not healthy controls. Moreover, mAbs bearing this clonotype are autoreactive against CD4 T cells and inhibit insulin tetramer binding to CD4 T cells. Thus, compartmentalization of adaptive immune cells into T and B cells is not absolute, and violators of this paradigm are likely key drivers of autoimmune diseases.

A mutagenesis study of autoantigen optimization for potential T1D vaccine design.

A previously reported autoreactive antigen, termed the X-idiotype, isolated from a unique cell population in Type 1 diabetes (T1D) patients, was found to stimulate their CD4+ T cells. This antigen was previously determined to bind more favorably than insulin and its mimic (insulin superagonist) to HLA-DQ8, supporting its strong role in CD4+ T cell activation. In this work, we probed HLA-X-idiotype-TCR binding and designed enhanced-reactive pHLA-TCR antigens using an in silico mutagenesis approach which we functionally validated by cell proliferation assays and flow cytometry. From a combination of single, double, and swap mutations, we identified antigen-binding sites p4 and p6 as potential mutation sites for HLA binding affinity enhancement. Site p6 is revealed to favor smaller but more hydrophobic residues than the native tyrosine, such as valine (Y6V) and isoleucine (Y6I), indicating a steric mechanism in binding affinity improvement. Meanwhile, site p4 methionine mutation to hydrophobic residues isoleucine (M4I) or leucine (M4L) modestly increases HLA binding affinity. Select p6 mutations to cysteine (Y6C) or isoleucine (Y6I) exhibit favorable TCR binding affinities, while a swap p5-p6 tyrosine-valine double mutant (V5Y_Y6V) and a p6-p7 glutamine-glutamine double mutant (Y6Q_Y7Q) exhibit enhanced HLA binding affinity but weakened TCR affinity. This work holds relevance to potential T1D antigen-based vaccine design and optimization.

Synchronous primary malignancies of papillary thyroid carcinoma and Hodgkin lymphoma: Interventions and outcome.

Thyroid carcinoma is uncommon. Papillary thyroid carcinoma (PTC) represents the majority of differentiated thyroid carcinoma and is a recognised complication of prior exposure to ionizing radiation. Even more uncommon is the synchronous occurrence of PTC with Hodgkin lymphoma (HL) as multiple primary malignancies. We report a 33-year-old mother of three who developed asymptomatic thyroid nodule for four years, and neck swelling for the recent ten months. She denied constitutional symptoms or B symptoms, and thyroid profiles were normal. Initially, metastatic thyroid cancer was suspected based on ultrasound scan findings of enlarged left thyroid gland and enlarged supraclavicular lymph nodes (LN). However, fine needle aspiration examinations of the thyroid nodule were inconclusive, and the supraclavicular LN was suspicious of HL. Computerised tomography scan detected a large mass at the thyroid glands and lymphadenopathies in the mediastinal, hilar, subcarinal and axilla with dimensions up to 6 cm. Left hemi-thyroidectomy with left supraclavicular LN biopsy revealed PTC in the left thyroid lobe measuring 38 x 25 x 18 mm, and the left supraclavicular LN was not definitive of HL. Completion thyroidectomy on the right side, bilateral central neck dissection and excision biopsy of the right supraclavicular LN revealed the presence of HL in the right supraclavicular LN, and both HL and metastatic PTC in right central LN. After multidisciplinary discussions, the patient received chemotherapy at four weeks postoperatively and achieved complete remission. This report highlights the importance of patient-centered approach and multidisciplinary consensus within lack of established guidelines, given rarity of the case.

Expression of unique gene signature distinguishes TCRαß+ /BCR+ dual expressers from CD3+ CD14+ doublets.

Increasing evidence shows pathophysiological significance of rare immune cells, necessitating the need for reliable and proper methods for their detection and analysis. We have recently identified a new lymphocyte that coexpresses lineage markers of T- and B-cells including T cell receptor and B cell receptor (called dual expressers, DEs). Because of the peculiar phenotype of DEs, we used multiple techniques to authenticate their identity (fluorescence-activated cell sorting [FACS], scRNAseq, EBV cell lines, and imaging flow cytometry). In an recent article published in this journal, Burel and colleagues successfully detected DEs using FACS and imaging microscopy. Yet they claimed, based on the profile of what they called naturally occurring CD3+ CD14+ T cell/monocyte complexes that the scRNAseq signature of DEs resembles that of cell-cell complexes. Serious flaws in their analysis, however, invalidate their conclusions. Unlike the CD3+ CD14+ complexes, DEs have a distinct identity due to expression of a unique set of signature genes. Without a clear explanation, Burel and colleagues excluded these genes from their analysis, thereby effectively stripped DEs from their identity. Inclusion of these genes as described in this communication restores the identity of DEs. Moreover, contrary to the claim of Burel and colleagues, B- and T-cell specific genes are similarly expressed in DE cells.

The importance of worldwide governance indicators for transitions toward sustainable bioenergy industry.

This study examined the impact of worldwide governance indicators on the sustainability of the bioenergy industry in selected European countries for the period 1996-2018. Applying the Fixed Effect (FE) Model, the results reveal that the bioenergy industry can significantly grow by improving the quality of worldwide governance indicators in European countries, especially in Western European Countries (WEC). Government effectiveness, rule of law, regulatory quality, and voice and accountability are found to be increasing the growth of the bioenergy industry. Precisely, the results further show that the magnitude of the effect of government effectiveness, voice and accountability, and Gross Domestic Product (GDP) on bioenergy output is higher in Western European Countries (WEC) as compared to the Central and Eastern European Countries (CEEC). Also, the findings further elaborate that the significant positive impact of regulatory quality and rule of law on bioenergy output is higher in CEEC countries compared to the WEC countries. The finding implies that the growth of the bioenergy industry in European countries can be effectively increased by improving the practice and quality of worldwide governance indicators. The study recommends for European countries to increase the efficiency of worldwide governance in their bioenergy industry to increase the sustainability of bioenergy production and reduce Dioxide Carbon (CO2) emissions. Policymakers in these countries should also invest more in worldwide governance to increase its effectiveness and transparency in the bioenergy industry. The authorities should equally emphasize the effectiveness and transparency of worldwide governance indicators to attain bioenergy security and lessen the dependence on fossil fuels.

Discontinuation of Transmission Precautions for COVID-19 Patients: Polymerase Chain Reaction Diagnostics, Patient Delays, and Cycle Threshold Values.

BACKGROUND: The decision of when it is safe to discontinue transmission-based precautions for SARS-CoV-2 coronavirus disease 2019 (COVID-19) hospitalized patients has been controversial. The Centers for Disease Control and Prevention offered reverse transcriptase polymerase chain reaction (PCR) diagnostic test- or symptom-based guidelines. METHODS: A retrospective chart review of Vidant Health system, Eastern North Carolina, was conducted. Length of stay, days in isolation unit, and date appropriate for discharge or isolation discontinuation based on the symptom-based strategy were recorded. RESULTS: Of 196 COVID hospitalized patients, 34 had repeated COVID PCR tests 3 or more days from their first positive test result. Half of these patients experienced delays in release from transmission-based precautions because of repeated positive PCR test results and use of the test-based approach. This resulted in an additional 166 days of hospitalization, costing an estimated $415,000. Furthermore, 2 subjects had a combined 16-day delay in necessary medical procedures. Most of the COVID PCR platforms yield quantitative results in the form of cycle threshold (Ct) values, the number of cycles needed to detect the genome. These values have also been used to assess whether patients are likely to remain contagious. None of our patients who met the criteria for symptom-based strategy for transmission-based precaution discontinuation had positive PCR test results with Ct values lower than 25, but 4 had Ct values lower than 30. CONCLUSIONS: Concerns surround immunocompromised patients and those treated with steroids who might be delayed or incapable of stopping viral replication and thus remain contagious. Our results suggest that clinicians use all available data including Ct values to evaluate the safety of discontinuation of transmission precautions.

TCR+CD4-CD8- (double negative) T cells protect from cisplatin-induced renal epithelial cell apoptosis and acute kidney injury.

Acute kidney injury (AKI) due to cisplatin is a significant problem that limits its use as an effective chemotherapeutic agent. T cell receptor+CD4-CD8- double negative (DN) T cells constitute the major T cell population in the human and mouse kidney, express programmed cell death protein (PD)-1, and protect from ischemic AKI. However, the pathophysiological roles of DN T cells in cisplatin-induced AKI is unknown. In this study, wild-type mice were treated with cisplatin (30 mg/kg) or vehicle, and the effects on kidney DN T cell numbers and function were measured. In vitro experiments evaluated effects of kidney DN T cells on cisplatin-induced apoptosis and PD ligand 1 (PD-L1) in renal epithelial cells. Adoptive transfer experiments assessed the therapeutic potential of DN T cells during cisplatin-induced AKI. Our results show that kidney DN T cell population increased at 24 h and declined by 72 h after cisplatin treatment. Cisplatin treatment increased kidney DN T cell proliferation, apoptosis, CD69, and IL-10 expression, whereas CD62L, CD44, IL-17A, interferon-γ, and TNF-α were downregulated. Cisplatin treatment decreased both PD-1 and natural killer 1.1 subsets of kidney DN T cells with a pronounced effect on the PD-1 subset. In vitro kidney DN T cell coculture decreased cisplatin-induced apoptosis in kidney proximal tubular epithelial cells, increased Bcl-2, and decreased cleaved caspase 3 expression. Cisplatin-induced expression of PD ligand 1 was reduced in proximal tubular epithelial cells cocultured with DN T cells. Adoptive transfer of DN T cells attenuated kidney dysfunction and structural damage from cisplatin-induced AKI. These results demonstrate that kidney DN T cells respond rapidly and play a protective role during cisplatin-induced AKI.

Syndecan-1 Regulates Psoriasiform Dermatitis by Controlling Homeostasis of IL-17-Producing γδ T Cells.

IL-17 is a potent proinflammatory cytokine that drives pathogenesis of multiple autoimmune diseases, including psoriasis. A major source of pathogenic IL-17 is a subset of γδ T cells (Tγδ17) that acquires the ability to produce IL-17 while developing in the thymus. The mechanisms that regulate homeostasis of Tγδ17 cells and their roles in psoriasis, however, are not fully understood. In this paper, we show that the heparan sulfate proteoglycan syndecan-1 (sdc1) plays a critical role in regulating homeostasis of Tγδ17 cells and modulating psoriasis-like skin inflammation in mice. sdc1 was predominantly expressed by Tγδ17 cells (but not IL-17- Tγδ cells) in the thymus, lymph nodes, and dermis. sdc1 deficiency significantly and selectively increased the frequency and absolute numbers of Tγδ17 cells by mechanisms that included increased proliferation and decreased apoptosis. Adoptive transfer experiments ruled out a significant role of sdc1 expressed on nonhematopoietic cells in halting expansion and proliferation of sdc1-deficient Tγδ17 cells. When subjected to imiquimod-induced psoriasiform dermatitis, Tγδ17 cells in sdc1KO mice displayed heightened responses accompanied by significantly increased skin inflammation than their wild-type counterparts. Furthermore, transferred sdc1-deficient γδ T cells caused more severe psoriasiform dermatitis than their sdc1-sufficient counterparts in TCR-ßδ KO hosts. The results uncover a novel role for sdc1 in controlling homeostasis of Tγδ17 cells and moderating host responses to psoriasis-like inflammation.

Activation and Proliferation of PD-1+ Kidney Double-Negative T Cells Is Dependent on Nonclassical MHC Proteins and IL-2.

BACKGROUND: CD4- CD8- double-negative (DN) αß T cells with innate-like properties represent a significant component of T cells in human and mouse kidneys. They spontaneously proliferate in the steady state and protect against ischemic AKI. However, the mechanisms regulating DN T cell homeostasis and responses to external danger signals from "sterile" inflammation remain poorly understood. METHODS: We used knockout mice, functional assays, and an established ischemic AKI model to investigate the role of various MHC class I and II molecules in regulating kidney DN T cells. We also studied human nephrectomy samples. RESULTS: Deficiency of ß2m-dependent MHC class I (but not MHC class II) molecules led to significant reduction in frequency or absolute numbers of kidney DN T cells due to impaired activation, proliferation, increased apoptosis, and loss of an NK1.1+ subset of DN T cells. The remaining DN T cells in ß2m knockout mice mainly comprised a programmed cell death protein-1 receptor (PD-1+) subset that depends on IL-2 provided by conventional T cells for optimal homeostasis. However, this PD-1+ subset remained highly responsive to changes in milieu, demonstrated by responses to infused lymphocytes. It was also the major responder to ischemic AKI; the NK1.1+ subset and CD8+ T cells had minimal responses. We found both DN T cell subsets in normal and cancerous human kidneys, indicating possible clinical relevance. CONCLUSIONS: DN T cells, a unique population of kidney T cells, depend on nonclassical ß2m molecules for homeostasis and use MHC-independent mechanisms to respond to external stimuli. These results have important implications for understanding the role these cells play during AKI and other immune cell-mediated kidney diseases.

IL-17 and limits of success.

Interleukin-17 (IL-17) is a potent proinflammatory cytokine that protects a host against fungal and extracellular bacterial infections. On the other hand, excessive or dysregulated production of IL-17 underlines susceptibility to autoimmune disease. Consequently, blocking IL-17 has become an effective strategy for modulating several autoimmune diseases, including multiple sclerosis (MS), psoriasis, and rheumatoid arthritis (RA). Notably, however, IL-17 blockade remains ineffective or even pathogenic against important autoimmune diseases such as inflammatory bowel disease (IBD). Furthermore, the efficacy of IL-17 blockade against other autoimmune diseases, including type 1 diabetes (T1D) is currently unknown and waiting results of ongoing clinical trials. Coming years will determine whether the efficacy of IL-17 blockade is limited to certain autoimmune diseases or can be expanded to other autoimmune diseases. These efforts include new clinical trials aimed at testing second-generation agents with the goal of increasing the efficiency, spectrum, and ameliorating side effects of IL-17 blockade. Here we briefly review the roles of IL-17 in the pathogenesis of selected autoimmune diseases and provide updates on ongoing and recently completed trials of IL-17 based immunotherapies.

Effect of Tris-egg Yolk, Soya Milk, and Liposome-based Extenders on Sahiwal (Bos indicus) Sperm Quality during Pre- and Post-Cryopreservation Stages.

BACKGROUND: Even though there are plenty of semen cryopreservation extenders available, their adoption is limited. Although normal tris-based egg yolk (EYC) extender is widely used, it leads to compromised post-thaw sperm quality. OBJECTIVE: To find a standard semen extender, six different semen extenders were validated. METHODS: In a split study, six aliquots of zebu cattle fresh semen ejaculate were cryopreserved in extenders containing egg yolk obtained from hen which was reared either in 1) normal, 2) omega-3 enriched, and 3) herbal enriched diet supplementation, and egg yolk free extenders such as 4) soya lecithin, 5) Bioxcell and 6) Optixcell. RESULT: Significantly poor sperm quality and kinematics were observed in extender containing herbal egg yolk. However, omega-3 enriched egg yolk extender was on par with EYC. Among all extenders, soya lecithin and bioxcell have shown better sperm quality. Sperm motility was significantly higher in semen extended in liposome-based extender Optixcell. CONCULSION: Optixcell can be considered as a standard extender for cattle semen cryopreservation to maintain adequate sperm quality required for artificial insemination.

A perforation procedure for pulmonary atresia with intact ventricular septum : Egyptian experience and adaptations.

BACKGROUND: Pulmonary atresia with intact ventricular septum (PA-IVS) is an uncommon disorder with significant morphological heterogeneity. The use of percutaneous radiofrequency (RF)-assisted perforation of the atretic valve and subsequent balloon dilation provides a relatively easy but expensive procedure that is expected to establish ante-grade flow through the pulmonary valve in most patients. OBJECTIVES: The aim of the study was to attempt a cost reduction by using catheters and wires readily available in our catheter laboratory. METHODS: A total of 50 patients presenting with PA-IVS to Cairo University Children's Hospital (CUCH) were taken to the catheterization laboratory for radiofrequency perforation using the Baylis RFP-100 generator (Baylis Medical, Montréal, Canada) or the stiff end of a coronary wire. A hybrid approach was used in selected cases. RESULTS: The overall success rate for valve perforation was 92% (46 cases), 80% of which had successful primary perforation (40 cases). Success correlated with both tricuspid valve (TV) annulus and pulmonary valve (PV) annulus Z-scores, with P values of 0.2 and 0.5, respectively. CONCLUSION: The management of PA-IVS is complex. This is a disease that necessitates a dedicated team and working collaboration between the cardiologists and cardiac surgeons. Cost limitation is essential in developing countries and innovative ideas to reduce costs are essential, especially if comparable success can be expected.

Catching an ectopic caesarean scar pregnancy - Radiological perspective.

Caesarean scar implantation is one of the rarest form of ectopic pregnancies and most unwanted complication of caesarean scar. However, with the increasing numbers of caesarean section performed, caesarean scar pregnancy (CSP) may be on the rise. The diagnosis is often difficult, but establishing an accurate diagnosis of CSP in the early first trimester is utmost important to prevent its detrimental consequences of uterine rupture and fatal haemorrhage. Hence, we present a case to highlight the role of imaging in diagnosing and managing this condition to prevent its associated high morbidity and mortality.

Double-Negative αß T Cells Are Early Responders to AKI and Are Found in Human Kidney.

Ischemia-reperfusion injury (IRI) is a major cause of AKI, and previous studies established important roles for conventional CD4(+) T cells, natural killer T cells, and CD4(+)CD25(+)FoxP3(+) Tregs in AKI pathogenesis. We recently identified CD4(-)CD8(-) (double-negative; DN) T cells as an important subset of αß T cell receptor-positive cells residing in mouse kidney. However, little is known about the pathophysiologic functions of kidney DN T cells. In this study, we phenotypically and functionally characterized murine kidney DN T cells in the steady state and in response to IRI. Unlike CD4(+) and CD8(+) T cells, DN T cells in the steady state expressed high levels of CD69, CD28, and CD40L; differentially expressed IL-27 and IL-10 anti-inflammatory cytokines; spontaneously proliferated at a very high rate; and suppressed in vitro proliferation of activated CD4(+) T cells. Within the first 3-24 hours after IRI, kidney DN T cells expanded significantly and upregulated expression of IL-10. In adoptive transfer experiments, DN T cells significantly protected recipients from AKI by an IL-10-dependent mechanism. DN T cells also made up a large fraction of the T cell compartment in human kidneys. Our results indicate that DN T cells are an important subset of the resident αß(+) T cell population in the mammalian kidney and are early responders to AKI that have anti-inflammatory properties.

Syndecan-1 identifies and controls the frequency of IL-17-producing naïve natural killer T (NKT17) cells in mice.

Invariant natural killer T (iNKT) cells recognize glycolipids as antigens and diversify into NKT1 (IFN-γ), NKT2 (IL-4), and NKT17 (IL-17) functional subsets while developing in the thymus. Mechanisms that govern the balance between these functional subsets are poorly understood due, partly, to the lack of distinguishing surface markers. Here we identify the heparan sulfate proteoglycan syndecan-1 (sdc1) as a specific marker of naïve thymic NKT17 cells in mice and show that sdc1 deficiency significantly increases thymic NKT17 cells at the expense of NKT1 cells, leading to impaired iNKT cell-derived IFN-γ, both in vitro and in vivo. Using surface expression of sdc1 to identify NKT17 cells, we confirm differential tissue localization and interstrain variability of NKT17 cells, and reveal that NKT17 cells express high levels of TCR-ß, preferentially use Vß8, and are more highly sensitive to ɑ-GalCer than to CD3/CD28 stimulation. These findings provide a novel, noninvasive, simple method for identification, and viable sorting of naïve NKT17 cells from unmanipulated mice, and suggest that sdc1 expression negatively regulates homeostasis in iNKT cells. In addition, these findings lay the groundwork for investigating the mechanisms by which sdc1 regulates NKT17 cells.

Ventriculo-peritoneal shunt independence following successful treatment of Gram negative (E. coli) ventriculitis: Case report and review of the literature.

We report a case of tumour-related hydrocephalus in a child treated with a ventriculo-peritoneal shunt which subsequently became infected with gram negative bacteria (Escherichia coli). After successful treatment of the infection the patient became shunt independent and has remained so for over 2 years. Gram negative ventriculitis is associated with diminished cerebro-spinal fluid production and we discuss the literature to date regarding this phenomenon.

Double negative (DN) αß T cells: misperception and overdue recognition.

CD4(-)CD8(-)double negative (DN) αß T cells are legitimate components of the normal immune system. However, they are poorly understood and largely ignored by immunologists because of their historical association with the lymphoproliferation that occurs in mice (lpr and gld) and humans (autoimmune lymphoproliferative syndromes patients) with impaired Fas-mediated apoptosis where they are considered abnormal T cells. We believe that the traditional view that DN T cells that cause lymphoproliferation (hereafter referred to as lpr DN T cells) are CD4 and CD8 T cells that lost their coreceptor, conceived more than two decades ago, is flawed and that conflating lpr DN T cells with DN T cells found in normal immune system (hereafter referred to as nDN T cells) is unnecessarily dampening interest of this potentially important cell type. To begin rectifying these misperceptions, we will revisit the traditional view of lpr DN T cells and show that it does not hold true in light of recent immunological advances. In lieu of it, we offer a new model proposing that Fas-mediated apoptosis actively removes normally existing DN T cells from the periphery and that impaired Fas-mediated apoptosis leads to accumulation of these cells rather than de novo generation of DN T cells from activated CD4 or CD8 T cells. By doing so, we hope to provoke a new discussion that may lead to a consensus about the origin of lpr DN T cells and regulation of their homeostasis by the Fas pathway and reignite wider interest in nDN T cells.

Interleukin-10 paradox: A potent immunoregulatory cytokine that has been difficult to harness for immunotherapy.

Interleukin-10 (IL-10) is arguably the most potent anti-inflammatory cytokine. It is produced by almost all the innate and adaptive immune cells. These cells also serve as its targets, indicating that IL-10 secretion and action is highly regulated and perhaps compartmentalized. Consistent with this notion, various efforts directed at systemic administration of IL-10 to modulate autoimmune diseases (type 1 diabetes, multiple sclerosis, rheumatoid arthritis, psoriasis) have produced conflicting and largely inconsequential effects. On the other hand, IL-10 can promote humoral immune responses, enhancing class II expression on B cells and inducing immunoglobulin (Ig) production. Consequently, the high IL-10 level in systemic lupus erythematosus (SLE) patients is considered pathogenic and its blockade ameliorates the disease. In this perspective, we review preclinical findings and results of recent clinical studies using exogenous IL-10 to treat the aforementioned autoimmune diseases. In addition, given the limited success of IL-10 supplementation, we suggest that future studies should be expanded beyond modulating the delivery modes to include developing new strategies to protect and replenish the endogenous sources of IL-10. As an example, we provide evidence that aberrant Fas-mediated deletion of IL-10-producing B cells subverts the immunoregulatory role of IL-10 in autoimmune diabetes and that modulation of the Fas pathway preserves the IL-10-producing B cells and completely protects NOD mice from developing the disease.

Associations of chronic heart failure with outcome in acute ischaemic stroke patients who received systemic thrombolysis: analysis from VISTA.

BACKGROUND AND PURPOSE: There are concerns that systemic thrombolysis might not achieve clinically important outcome amongst chronic heart failure (CHF) patients with acute ischaemic stroke. Our aim was to investigate the relevance of CHF on the outcome of acute stroke patients who received thrombolysis. METHODS: A non-randomized cohort analysis was conducted using data obtained from the Virtual International Stroke Trials Archive. The association of outcome amongst CHF patients with thrombolysis treatment was described using the modified Rankin scale (mRS) distribution at day 90, stratified by the presence of atrial fibrillation. Dichotomized outcomes were considered as a secondary end-point. RESULTS: 5677 patients were identified, of whom 2366 (41.7%) received thombolysis. Five hundred and three (8.9%) patients had CHF, of whom 209 (41.6%) received thrombolysis. The presence of CHF was associated with a negative impact on overall stroke outcome [odds ratio (OR) 0.73 (95% confidence interval (CI) 0.62-0.87), P < 0.001]. However, thrombolysis treatment was associated with favourable functional outcome using ordinal mRS, irrespective of CHF status, after adjustment for age and baseline National Institutes of Health Stroke Scale [OR 1.44 (95% CI 1.04-2.01, P = 0.029) for CHF patients versus OR 1.50 (95% CI 1.36-1.66, P < 0.001) for non-CHF patients]. CHF patients had higher mortality at day 90 than non-CHF patients. There was no significant difference for recurrent stroke or symptomatic intracerebral haemorrhage within 7 days of the initial stroke between CHF and thrombolysis groups. CONCLUSIONS: Chronic heart failure was associated with a worse outcome with or without thrombolysis. However, acute stroke patients who received thrombolysis had more favourable outcome regardless of CHF status, compared with their untreated peers. Our findings should reassure clinicians considering systemic thrombolysis treatment in hyperacute ischaemic stroke patients with CHF.