Pulmonary complications of hematopoietic stem cell transplantation include infections and graft-versus-host diseases, such as idiopathic pneumonia syndrome (IPS). Conflicting data exist regarding the ...role of the interferon (IFN)-gamma-producing Th1 CD4(+) T-cell subset and IL-17A in IPS.
To determine the role of IFN-gamma and IL-17A in the establishment of pulmonary graft-versus-host disease.
A semiallogeneic murine model based on C57BL/6 x BALB/c as recipients with transplantation of BALB/c RAG2(-/-) bone marrow and transfer of different genetic knockout T cells (T-bet(-/-), IFN-gamma(-/-), IFN-gammaR(-/-)) on a BALB/c background. Lung tissue was examined for parenchymal changes and infiltrating cells by histology and fluorescence-activated cell sorter analysis.
After transfer of semiallogeneic bone marrow together with donor CD4(+) T cells lacking IFN-gamma or T-bet-a T-box transcription factor controlling Th1 commitment-we found severe inflammation in the lungs, but no enhancement in other organs. In contrast, wild-type donor CD4(+) T cells mediated minimal inflammation only, and donor CD8(+) T cells were not required for IPS development. Mechanistically, the absence of IFN-gamma or IFN-gamma signaling in pulmonary parenchymal cells promoted expansion of IL-17A-producing CD4(+) T cells and local IL-17A release. In vivo depletion of IL-17A reduced disease severity.
One mechanism of IFN-gamma protection against IPS is negative regulation of the expansion of pathogenic IL-17A-producing CD4(+) T cells through interaction with the IFN-gamma receptor on the pulmonary parenchymal cell population.
Left ventricular remodeling following acute myocardial infarction results in progressive myocardial dysfunction and adversely affects prognosis.
To investigate the efficacy of paroxetine-mediated ...G-protein-coupled receptor kinase 2 inhibition to mitigate adverse left ventricular remodeling in patients presenting with acute myocardial infarction.
This double-blind, placebo-controlled randomized clinical trial was conducted at Bern University Hospital, Bern, Switzerland. Patients with acute anterior ST-segment elevation myocardial infarction with left ventricular ejection fraction (LVEF) of 45% or less were randomly allocated to 2 study arms between October 26, 2017, and September 21, 2020.
Patients in the experimental arm received 20 mg of paroxetine daily; patients in the control group received a placebo daily. Both treatments were provided for 12 weeks.
The primary end point was the difference in patient-level improvement of LVEF between baseline and 12 weeks as assessed by cardiac magnetic resonance tomography. Secondary end points were changes in left ventricular dimensions and late gadolinium enhancement between baseline and follow-up.
Fifty patients (mean SD age, 62 13 years; 41 men 82%) with acute anterior myocardial infarction were randomly allocated to paroxetine or placebo, of whom 38 patients underwent cardiac magnetic resonance imaging both at baseline and 12 weeks. There was no difference in recovery of LVEF between the experimental group (mean SD change, 4.0% 7.0%) and the control group (mean SD change, 6.3% 6.3%; mean difference, -2.4% 95% CI, -6.8% to 2.1%; P = .29) or changes in left ventricular end-diastolic volume (mean difference, 13.4 95% CI, -12.3 to 39.0 mL; P = .30) and end-systolic volume (mean difference, 11.4 95% CI, -3.6 to 26.4 mL; P = .13). Late gadolinium enhancement as a percentage of the total left ventricular mass decreased to a larger extent in the experimental group (mean SD, -13.6% 12.9%) compared with the control group (mean SD, -4.5% 9.5%; mean difference, -9.1% 95% CI, -16.6% to -1.6%; P = .02).
In this trial, treatment with paroxetine did not improve LVEF after myocardial infarction compared with placebo.
ClinicalTrials.gov Identifier: NCT03274752.
Objectives
We sought to systematically evaluate the external validity of a contemporary randomized controlled stent trial (BIOSCIENCE).
Methods
Baseline characteristics and clinical outcomes of ...patients enrolled into the BIOSCIENCE trial at Bern University Hospital (
n
= 1216) were compared to those of patients included in the CARDIOBASE Bern PCI Registry at the same institution (
n
= 1045). The primary study endpoint was the rate of target lesion failure (TLF), defined as a composite of cardiac death, target vessel-myocardial infarction (MI) or target lesion revascularization (TLR), at 1 year.
Results
Women were underrepresented in the RCT compared to the registry (25 vs. 29.4 %,
p
= 0.020). Non-participants were older compared to study participants (69.2 ± 12.4 vs. 67.0 ± 11.6,
p
< 0.001), and had a higher prevalence of previous cerebrovascular events (10.8 vs. 5.2 %,
p
< 0.001), and chronic renal failure (35.5 vs. 15.6 %,
p
< 0.001). ST-segment elevation myocardial infarction (STEMI) and Killip class IV at presentation were more common among non-participants than participants (30.7 vs. 21.1 %,
p
< 0.001 and 7.8 vs. 0.4 %,
p
< 0.001, respectively). At 1 year, non-participants experienced a significantly higher rate of TLF, (15.0 vs. 6.5 %,
p
< 0.001), and patient-oriented composite endpoint (POCE), including death, MI or any repeat revascularization (21.6 vs. 11.2 %,
p
< 0.001). There was a significant interaction between POCE and presence or absence of an acute coronary syndrome in participants versus non-participants, respectively (
p
= 0.009).
Conclusions
Non-participants of this all-comers trial had a higher risk profile and adverse prognosis compared to study participants. Further efforts are needed to improve the external validity of contemporary RCTs.
Summary
We present genome‐wide gene expression patterns as a time series through the infection cycle of the fungal pine needle blight pathogen,
D
othistroma septosporum
, as it invades its gymnosperm ...host,
P
inus radiata
. We determined the molecular changes at three stages of the disease cycle: epiphytic/biotrophic (early), initial necrosis (mid) and mature sporulating lesion (late). Over 1.7 billion combined plant and fungal reads were sequenced to obtain 3.2 million fungal‐specific reads, which comprised as little as 0.1% of the sample reads early in infection. This enriched dataset shows that the initial biotrophic stage is characterized by the up‐regulation of genes encoding fungal cell wall‐modifying enzymes and signalling proteins. Later necrotrophic stages show the up‐regulation of genes for secondary metabolism, putative effectors, oxidoreductases, transporters and starch degradation. This in‐depth through‐time transcriptomic study provides our first snapshot of the gene expression dynamics that characterize infection by this fungal pathogen in its gymnosperm host.
The association of postprocedural high-sensitivity troponin T (hs-TnT) with prognosis of non-ST-segment elevation myocardial infarction (NSTEMI) patients is incompletely investigated.
To assess the ...prognostic value of hs-TnT in NSTEMI patients undergoing early percutaneous coronary intervention (PCI).
This study included 3783 patients with NSTEMI undergoing early PCI. Preprocedural and peak postprocedural hs-TnT was measured. Patients were divided into 3 groups: a group with postprocedural hs-TnT in the 1st tertile (hs-TnT <105ng/L; n=1264), a group with postprocedural hs-TnT in the 2nd tertile (hs-TnT ≥105ng/L to 470ng/L; n=1258) and a group with postprocedural hs-TnT in the 3rd tertile (hs-TnT >470ng/L; n=1261). The primary outcome was 1-year all-cause mortality.
Overall, there were 299 deaths: 59 (5.5%), 98 (8.2%) and 142 deaths (12.6%) among patients of the 1st, 2nd and 3rd postprocedural hs-TnT tertiles (unadjusted hazard ratio HR=1.65, 95% confidence interval CI 1.20 to 2.67; P=0.002 for tertile 2 vs tertile 1 and unadjusted HR=2.41 1.79–3.25; P<0.001 for tertile 3 vs tertile 1). After adjustment postprocedural hs-TnT was independently associated with the risk of all-cause mortality (adjusted HR=1.22 1.13–1.33, P<0.001 for 1 unit higher log hs-TnT). Postprocedural hs-TnT improved the risk prediction of the model of all-cause mortality (the C statistic of the model without with baseline variables only and with incorporation of postprocedural hs-TnT was 0.759 0.732–0.782 and 0.772 0.746–0.794, respectively; P<0.001).
In patients with NSTEMI undergoing early PCI, postprocedural hs-TnT is independently associated with increased risk of mortality up to 1year after PCI.
•Post-procedural high-sensitivity cardiac troponin T (hs-TnT) was associated with 1-year mortality in patients with NSTEMI after PCI.•An increase in the post-procedural hs-TnT of >70xthe 99th percentile URL correlated with the increased risk of mortality.•hs-TnT improved the discriminatory power of the multivariable models regarding prediction of mortality.
T helper cells can support the functions of CD8(+) T cells against persistently infecting viruses such as murine lymphocytic choriomeningitis virus (LCMV), cytomegalovirus, hepatitis C virus and HIV. ...These viruses often resist complete elimination and remain detectable at sanctuary sites, such as the kidneys and other extralymphatic organs. The mechanisms underlying this persistence are not well understood. Here we show that mice with potent virus-specific T-cell responses have reduced levels and delayed formation of neutralizing antibodies, and these mice fail to clear LCMV from extralymphatic epithelia. Transfer of virus-specific B cells but not virus-specific T cells augmented virus clearance from persistent sites. Virus elimination from the kidneys was associated with the formation of IgG deposits in the interstitial space, presumably from kidney-infiltrating B cells. CD8(+) T cells in the kidneys of mice that did not clear virus from this site were activated but showed evidence of exhaustion. Thus, we conclude that in this model of infection, site-specific virus persistence develops as a consequence of potent immune activation coupled with reductions in virus-specific neutralizing antibodies. Our results suggest that sanctuary-site formation depends both on organ anatomy and on the induction of different adaptive immune effector mechanisms. Boosting T-cell responses alone may not reduce virus persistence.
Our aim was to compare, in a large unprotected left main coronary artery (ULMCA) all-comer registry, the long-term clinical outcome after percutaneous coronary intervention (PCI) with ...first-generation drug-eluting stents (DES) versus coronary artery bypass grafting (CABG) in patients with acute coronary syndrome (ACS).
Of a total of 2,775 patients enrolled in the Drug Eluting Stents for Left Main Coronary Artery Disease (DELTA) multicentre registry, 379 (13.7%) patients with ACS treated with PCI (n=272) or CABG (n=107) were analysed. Baseline demographics were considerably different in the two groups before propensity matching. No significant differences emerged for the composite endpoint of all-cause death, myocardial infarction (MI), and cerebrovascular accident (HR 1.11, 95% CI: 0.63-1.94; p=0.727), all-cause death (HR 1.26, 95% CI: 0.68-2.32; p=0.462), the composite endpoint of all-cause death and MI (HR 1.02, 95% CI: 0.56-1.84; p=0.956), and major adverse cardiac and cerebrovascular events (HR 0.82, 95% CI: 0.50-1.36; p=0.821). However, a higher incidence of target vessel revascularisation (HR 4.67, 95% CI: 1.33-16.47; p=0.008) was observed in the PCI compared with the CABG group, which was confirmed in the propensity score-matched analysis.
In the DELTA all-comer, multinational registry, PCI for ACS in ULMCA is associated with comparable clinical outcomes to those observed with CABG at long-term follow-up, despite the use of first-generation DES.
Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide. The majority of patients treated with interferon alpha do not have a sustained ...response with clearance of the virus. The molecular mechanisms underlying interferon resistance are poorly understood. Interferon-induced activation of the Jak-STAT (signal transducer and activator of transcription) signal transduction pathway is essential for the induction of an antiviral state. Interference of viral proteins with the Jak-STAT pathway could be responsible for interferon resistance in patients with chronic HCV.
We have analyzed interferon-induced signal transduction through the Jak-STAT pathway in transgenic mice that express HCV proteins in their liver cells. STAT activation was investigated with Western blots, immunofluorescence, and electrophoretic mobility shift assays. Virus challenge experiments with lymphocytic choriomeningitis virus were used to demonstrate the functional importance of Jak-STAT inhibition.
STAT signaling was found to be strongly inhibited in liver cells of HCV transgenic mice. The inhibition occurred in the nucleus and blocked binding of STAT transcription factors to the promoters of interferon-stimulated genes. Tyrosine phosphorylation of STAT proteins by Janus kinases at the interferon receptor was not inhibited. This lack in interferon response resulted in an enhanced susceptibility of the transgenic mice to infection with a hepatotropic strain of lymphocytic choriomeningitis virus.
Interferon-induced intracellular signaling is impaired in HCV transgenic mice. Interference of HCV proteins with interferon-induced intracellular signaling could be an important mechanism of viral persistence and treatment resistance.
Patients who are vulnerable to hemodynamic or electrical disorders (VP) are often excluded from clinical trials and data on the optimal access-site or antithrombotic treatment are limited. We ...assessed outcomes of transradial vs transfemoral access and bivalirudin vs unfractionated heparin (UFH) in VP with acute coronary syndrome undergoing invasive management.
The MATRIX trial randomized 8404 patients to radial or femoral access and 7213 patients to bivalirudin or UFH. Among them, 934 (11.1%) were deemed VP due to advanced Killip class (n = 808), cardiac arrest (n = 168), or both (n = 42). The 30-day coprimary outcomes were major adverse cardiovascular and cerebrovascular events (MACE: death, myocardial infarction, or stroke) and net adverse clinical events (NACE: MACE or major bleeding).
MACE and NACE were similarly reduced with radial vs femoral access in VP and non-VP. Transradial access was also associated with consistent relative benefits in all-cause and cardiovascular mortality or Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding with greater absolute benefits in VP. The effects of bivalirudin vs UFH on MACE and NACE were consistent in VP and non-VP. Bivalirudin was associated with lower all-cause and cardiovascular mortality in VP but not in non-VP, with borderline interaction testing. Bivalirudin reduced bleeding in both VP and non-VP with a larger absolute benefit in VP.
In acute coronary syndrome patients undergoing invasive management, the effects of randomized treatments were consistent in VP and non-VP, but absolute risk reduction with radial access and bivalirudin were greater in VP, with a 5- to 10-fold lower number needed to treat for benefits.
Trial registry number: NCT01433627.
A menudo se excluye de los ensayos clínicos a los pacientes hemodinámica o eléctricamente vulnerables, por lo que escasea la información sobre el acceso vascular y el tratamiento antitrombótico óptimos. En este trabajo se estudia la evolución de los pacientes vulnerables con síndrome coronario agudo tratados invasivamente según el acceso fuera radial o femoral y el tratamiento fuera con bivalirudina o con heparina no fraccionada (HNF).
El estudio MATRIX aleatorizó a 8.404 pacientes a acceso radial o femoral y a 7.213 pacientes a bivalirudina o a HNF. Se consideró vulnerables a 934 pacientes (11,1%) debido a clase Killip avanzada (808), parada cardiaca (168) o ambas a la vez (42). El objetivo primario compuesto a 30 días fueron los eventos cardiovasculares y cerebrovasculares mayores (MACE: muerte, infarto de miocardio e ictus) y los eventos clínicos adversos netos (NACE: MACE o hemorragia grave).
El acceso radial, comparado con el femoral, redujo los MACE y NACE de modo similar en pacientes vulnerables y no vulnerables. El acceso radial se asoció con un claro beneficio relativo en la mortalidad total y cardiovascular y las hemorragias BARC 3 o 5, con mayor beneficio absoluto en los pacientes vulnerables. Los efectos de la bivalirudina comparada con la HNF en MACE y NACE concuerdan entre pacientes vulnerables y no vulnerables. La bivalirudina se asoció con menores mortalidad cardiovascular y por todas las causas en pacientes vulnerables, pero no en los no vulnerables, con test de interacción en el límite. La bivalirudina redujo las hemorragias en ambos grupos de pacientes, con un beneficio absoluto mayor en el caso de los pacientes vulnerables.
En pacientes con síndrome coronario agudo sometidos a tratamiento invasivo, los efectos de los tratamientos aleatorizados fueron concordantes entre los pacientes vulnerables y los no vulnerables, pero la reducción del riesgo absoluto del acceso radial y bivalirudina fue mayor en los vulnerables, con una reducción de 5 a 10 veces en el número de pacientes que es necesario tratar.
Número de registro: NCT01433627.
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