Multi-Drug Resistance in Bacterial Genomes-A Comprehensive Bioinformatic Analysis.

Antimicrobial resistance is presently one of the greatest threats to public health. The excessive and indiscriminate use of antibiotics imposes a continuous selective pressure that triggers the emergence of multi-drug resistance. We performed a large-scale analysis of closed bacterial genomes to identify multi-drug resistance considering the ResFinder antimicrobial classes. We found that more than 95% of the genomes harbor genes associated with resistance to disinfectants, glycopeptides, macrolides, and tetracyclines. On average, each genome encodes resistance to more than nine different classes of antimicrobial drugs. We found higher-than-expected co-occurrences of resistance genes in both plasmids and chromosomes for several classes of antibiotic resistance, including classes categorized as critical according to the World Health Organization (WHO). As a result of antibiotic-resistant priority pathogens, higher-than-expected co-occurrences appear in plasmids, increasing the potential for resistance dissemination. For the first time, co-occurrences of antibiotic resistance have been investigated for priority pathogens as defined by the WHO. For critically important pathogens, co-occurrences appear in plasmids, not in chromosomes, suggesting that the resistances may be epidemic and probably recent. These results hint at the need for new approaches to treating infections caused by critically important bacteria.

Plasmids Increase the Competitive Ability of Plasmid-Bearing Cells Even When Transconjugants Are Poor Donors, as Shown by Computer Simulations.

Bacterial cells often suffer a fitness cost after conjugative plasmids' entry because these cells replicate slower than plasmid-free cells. Compensatory mutations may appear after tens of or a few hundred generations, reducing or eliminating this cost. A previous work based on a mathematical model and computer simulations has shown that plasmid-bearing cells already adapted to the plasmid may gain a fitness advantage when plasmids transfer into neighboring plasmid-free cells because these cells are still unadapted to the plasmid. These slow-growing transconjugants use fewer resources, which can benefit donor cells. However, opportunities for compensatory mutations in transconjugants increase if these cells become numerous (through replication or conjugation). Moreover, transconjugants also gain an advantage when transferring the plasmid, but the original donors may be too distant from conjugation events to gain an advantage. To understand which consequence prevails, we performed further computer simulations allowing versus banning transfer from transconjugants. The advantage to donors is higher if transconjugants do not transfer plasmids, mainly when donors are rare and when the plasmid transfer rate (from donors) is high. These results show that conjugative plasmids are efficient biological weapons even if the transconjugant cells are poor plasmid donors. After some time, conjugative plasmids gain other host-benefit genes, such as virulence and drug-resistance.

Plasmid Costs Explain Plasmid Maintenance, Irrespective of the Nature of Compensatory Mutations.

Conjugative plasmids often carry virulence and antibiotic-resistant genes. Therefore, understanding the behavior of these extra-chromosomal DNA elements gives insights into their spread. Bacteria frequently replicate slower after plasmids' entry, an observation inconsistent with the plasmids' ubiquity in nature. Several hypotheses explain the maintenance of plasmids among bacterial communities. However, the numerous combinations of bacterial species and strains, plasmids, and environments claim a robust elucidatory mechanism of plasmid maintenance. Previous works have shown that donor cells already adapted to the plasmid may use the plasmid as a 'weapon' to compete with non-adapted plasmid-free cells. Computer simulations corroborated this hypothesis with a wide range of parameters. Here we show that donor cells benefit from harboring conjugative plasmids even if compensatory mutations in transconjugant cells occur in the plasmid, not on chromosomes. The advantage's leading causes are as follows: mutations take time to appear, many plasmids remain costly, and re-transfer of mutated plasmids usually occurs in sites distant to the original donors, implying little competition between these cells. Research in previous decades cautioned against uncritical acceptance of the hypothesis that resistance cost helps to preserve antibiotics' effectiveness. This work gives a new twist to this conclusion by showing that costs help antibiotic-resistant bacteria to compete with plasmid-free cells even if compensatory mutations appear in plasmids.

The Impact of Non-Pathogenic Bacteria on the Spread of Virulence and Resistance Genes.

This review discusses the fate of antimicrobial resistance and virulence genes frequently present among microbiomes. A central concept in epidemiology is the mean number of hosts colonized by one infected host in a population of susceptible hosts: R0. It characterizes the disease's epidemic potential because the pathogen continues its propagation through susceptible hosts if it is above one. R0 is proportional to the average duration of infections, but non-pathogenic microorganisms do not cause host death, and hosts do not need to be rid of them. Therefore, commensal bacteria may colonize hosts for prolonged periods, including those harboring drug resistance or even a few virulence genes. Thus, their R0 is likely to be (much) greater than one, with peculiar consequences for the spread of virulence and resistance genes. For example, computer models that simulate the spread of these genes have shown that their diversities should correlate positively throughout microbiomes. Bioinformatics analysis with real data corroborates this expectation. Those simulations also anticipate that, contrary to the common wisdom, human's microbiomes with a higher diversity of both gene types are the ones that took antibiotics longer ago rather than recently. Here, we discuss the mechanisms and robustness behind these predictions and other public health consequences.

Estuarine Aquacultures at the Crossroads of Animal Production and Antibacterial Resistance: A Metagenomic Approach to the Resistome.

It is recognized that the spread of antibiotic resistance (AR) genes among aquatic environments, including aquaculture and the human environment, can have detrimental effects on human and animal health and the ecosystem. Thus, when transmitted to the human microbiome or pathogens, resistance genes risk human health by compromising the eventual treatment of infections with antibiotic therapy. This study aimed to define the resistance profile of aquaculture farms and their potential risk for spreading. Twenty-four sediments from oyster and gilthead sea bream aquaculture farms located in three Portuguese river estuaries (17 sediments from Sado, 4 from Aveiro, and 3 from Lima) were studied by comparative metagenomic analysis. The computation of the diversity of genes conferring resistance per antibiotic class revealed a significant increase in aminoglycosides, beta-lactams, disinfectants, quinolones, and tetracyclines counts. In all geographic locations under study, the most diverse AR genes confer resistance to the macrolides, tetracyclines and oxazolidinones classes, all of which are medically important for human and animal therapies, as well as resistance to disinfectants. The diversity of mobile genetic elements correlated with the number of AR genes such as tetracyclines, suggesting that AR could be easily mobilized among bacterial genomes and microbiomes.

Are Virulence and Antibiotic Resistance Genes Linked? A Comprehensive Analysis of Bacterial Chromosomes and Plasmids.

Although pathogenic bacteria are the targets of antibiotics, these drugs also affect hundreds of commensal or mutualistic species. Moreover, the use of antibiotics is not only restricted to the treatment of infections but is also largely applied in agriculture and in prophylaxis. During this work, we tested the hypothesis that there is a correlation between the number and the genomic location of antibiotic resistance (AR) genes and virulence factor (VF) genes. We performed a comprehensive study of 16,632 reference bacterial genomes in which we identified and counted all orthologues of AR and VF genes in each of the locations: chromosomes, plasmids, or in both locations of the same genome. We found that, on a global scale, no correlation emerges. However, some categories of AR and VF genes co-occur preferentially, and in the mobilome, which supports the hypothesis that some bacterial pathogens are under selective pressure to be resistant to specific antibiotics, a fact that can jeopardize antimicrobial therapy for some human-threatening diseases.

Harmful behaviour through plasmid transfer: a successful evolutionary strategy of bacteria harbouring conjugative plasmids.

Conjugative plasmids are extrachromosomal mobile genetic elements pervasive among bacteria. Plasmids' acquisition often lowers cells' growth rate, so their ubiquity has been a matter of debate. Chromosomes occasionally mutate, rendering plasmids cost-free. However, these compensatory mutations typically take hundreds of generations to appear after plasmid arrival. By then, it could be too late to compete with fast-growing plasmid-free cells successfully. Moreover, arriving plasmids would have to wait hundreds of generations for compensatory mutations to appear in the chromosome of their new host. We hypothesize that plasmid-donor cells may use the plasmid as a 'weapon' to compete with plasmid-free cells, particularly in structured environments. Cells already adapted to plasmids may increase their inclusive fitness through plasmid transfer to impose a cost to nearby plasmid-free cells and increase the replication opportunities of nearby relatives. A mathematical model suggests conditions under which the proposed hypothesis works, and computer simulations tested the long-term plasmid maintenance. Our hypothesis explains the maintenance of conjugative plasmids not coding for beneficial genes. This article is part of the theme issue 'The secret lives of microbial mobile genetic elements'.

Valor Prognóstico de Níveis Elevados de Troponina I Isolados em Pacientes sem Síndrome Coronariana Aguda Admitidos no Serviço de Emergência / Prognostic Value of Isolated Elevated Troponin I Levels in Patients without Acute Coronary Syndrome Admitted to the Emergency Department

Resumo Fundamento: Embora a elevação não isquêmica da troponina seja frequentemente observada em pacientes admitidos no pronto-socorro (PS), não há consenso quanto ao seu manejo. Objetivos: Este estudo teve como objetivo caracterizar os pacientes admitidos no PS com elevação da troponina não-isquêmica e identificar potenciais preditores de mortalidade nessa população. Métodos: Este estudo observacional retrospectivo incluiu pacientes do PS com resultado positivo no teste da troponina entre junho e julho de 2015. Pacientes com diagnóstico clínico de síndrome coronariana aguda (SCA) foram excluídos. Os dados demográficos dos pacientes e as variáveis clínicas e laboratoriais foram extraídos dos prontuários médicos. Os dados do seguimento foram obtidos por 16 meses ou até a ocorrência de morte. O nível de significância estatística foi de 5%. Resultados: A elevação da troponina sem SCA foi encontrada em 153 pacientes no PS. A mediana (IIQ) de idade dos pacientes foi de 78 (19) anos, 80 (52,3%) eram do sexo feminino e 59 (38,6%) morreram durante o seguimento. A mediana do período de seguimento (IIQ) foi de 477 (316) dias. Os sobreviventes eram significativamente mais jovens 76 (24) vs. 84 (13) anos; p=0,004) e apresentaram uma maior proporção de elevação da troponina isolada (sem elevação da creatina quinase ou mioglobina) em duas avaliações consecutivas: 48 (53,9%) vs. 8 (17,4%), p<0,001. Os sobreviventes também apresentaram menor taxa de tratamento antiplaquetário e internação no mesmo dia. Na regressão logística multivariada com ajuste para variáveis significativas na análise univariada, a elevação isolada da troponina em duas avaliações consecutivas mostrou hazard ratio = 0,43 (IC95% 0,17-0,96, p=0,039); hospitalização, tratamento antiplaquetário anterior e idade permaneceram independentemente associados à mortalidade. Conclusões: A elevação isolada da troponina em duas medidas consecutivas foi um forte preditor de sobrevida em pacientes no PS com elevação da troponina, mas sem SCA.

Abstract Background: Although non-ischemic troponin elevation is frequently seen in patients admitted to the emergency department (ED), consensus regarding its management is lacking. Objectives: This study aimed to characterize patients admitted to the ED with non-ischemic troponin elevation and to identify potential mortality predictors in this population. Methods: This retrospective observational study included ED patients with a positive troponin test result between June and July of 2015. Patients with a clinical diagnosis of acute coronary syndrome (ACS) were excluded. Data on patient demographics and clinical and laboratory variables were extracted from medical records. Follow-up data were obtained for 16 months or until death occurred. The statistical significance level was 5%. Results: Troponin elevation without ACS was found in 153 ED patients. The median (IQR) patient age was 78 (19) years, 80 (52.3%) were female and 59(38.6%) died during follow-up. The median (IQR) follow-up period was 477(316) days. Survivors were significantly younger 76 (24) vs. 84 (13) years; p=0.004) and featured a higher proportion of isolated troponin elevation (without creatine kinase or myoglobin elevation) in two consecutive evaluations: 48 (53.9%) vs. 8 (17.4%), p<0.001. Survivors also presented a lower rate of antiplatelet treatment and same-day hospitalization. In the multivariate logistic regression with adjustment for significant variables in the univariate analysis, isolated troponin elevation in two consecutive evaluations showed a hazard ratio= 0.43 (95%CI 0.17-0.96, p=0.039); hospitalization, previous antiplatelet treatment and age remained independently associated with mortality. Conclusions: Isolated troponin elevation in two consecutive measurements was a strong predictor of survival in ED patients with troponin elevation but without ACS.

Bacterial persistence is essential for susceptible cell survival in indirect resistance, mainly for lower cell densities.

Antibiotic-susceptible bacteria may survive bactericidal antibiotics if other co-inhabiting bacteria detoxify the medium through antibiotic degradation or modification, a phenomenon denominated as indirect resistance. However, it is unclear how susceptible cells survive while the medium is still toxic. One explanation relies on the speed of detoxification, and another, non-exclusive explanation, relies on persistence, a state of bacterial dormancy where cells with low metabolic activity and growth rates are phenotypically tolerant to antibiotics and other cytotoxic substances. Here we simulated the fate of susceptible cells in laboratory experiments in the context of indirect resistance to understand whether persistence is necessary to explain the survival of susceptible cells. Depending on the strain and experimental conditions, the decay of persister populations may follow an exponential or a power-law distribution. Therefore, we studied the impact of both distributions in the simulations. Moreover, we studied the impact of considering that persister cells have a mechanism to sense the presence of a toxic substance-a mechanism that would enable cells to leave the dormant state when the medium becomes nontoxic. The simulations show that surviving susceptible cells under indirect resistance may originate both from persister and non-persister populations if the density of detoxifying cells is high. However, persistence was necessary when the initial density of detoxifying cells was low, although persister cells remained in that dormancy state for just a few hours. Finally, the results of our simulations are consistent both with exponential and power-law decay of the persistence population. Whether indirect resistance involves persistence should impact antibiotic treatments.

COVID-19 Lockdowns May Reduce Resistance Genes Diversity in the Human Microbiome and the Need for Antibiotics.

Recently, much attention has been paid to the COVID-19 pandemic. Yet bacterial resistance to antibiotics remains a serious and unresolved public health problem that kills hundreds of thousands of people annually, being an insidious and silent pandemic. To contain the spreading of the SARS-CoV-2 virus, populations confined and tightened hygiene measures. We performed this study with computer simulations and by using mobility data of mobile phones from Google in the region of Lisbon, Portugal, comprising 3.7 million people during two different lockdown periods, scenarios of 40 and 60% mobility reduction. In the simulations, we assumed that the network of physical contact between people is that of a small world and computed the antibiotic resistance in human microbiomes after 180 days in the simulation. Our simulations show that reducing human contacts drives a reduction in the diversity of antibiotic resistance genes in human microbiomes. Kruskal-Wallis and Dunn's pairwise tests show very strong evidence (p < 0.000, adjusted using the Bonferroni correction) of a difference between the four confinement regimes. The proportion of variability in the ranked dependent variable accounted for by the confinement variable was η2 = 0.148, indicating a large effect of confinement on the diversity of antibiotic resistance. We have shown that confinement and hygienic measures, in addition to reducing the spread of pathogenic bacteria in a human network, also reduce resistance and the need to use antibiotics.

The Perfect Condition for the Rising of Superbugs: Person-to-Person Contact and Antibiotic Use Are the Key Factors Responsible for the Positive Correlation between Antibiotic Resistance Gene Diversity and Virulence Gene Diversity in Human Metagenomes.

Human metagenomes with a high diversity of virulence genes tend to have a high diversity of antibiotic-resistance genes and vice-versa. To understand this positive correlation, we simulated the transfer of these genes and bacterial pathogens in a community of interacting people that take antibiotics when infected by pathogens. Simulations show that people with higher diversity of virulence and resistance genes took antibiotics long ago, not recently. On the other extreme, we find people with low diversity of both gene types because they took antibiotics recently-while antibiotics select specific resistance genes, they also decrease gene diversity by eliminating bacteria. In general, the diversity of virulence and resistance genes becomes positively correlated whenever the transmission probability between people is higher than the probability of losing resistance genes. The positive correlation holds even under changes of several variables, such as the relative or total diversity of virulence and resistance genes, the contamination probability between individuals, the loss rate of resistance genes, or the social network type. Because the loss rate of resistance genes may be shallow, we conclude that the transmission between people and antibiotic usage are the leading causes for the positive correlation between virulence and antibiotic-resistance genes.

Prognostic Value of Isolated Elevated Troponin I Levels in Patients without Acute Coronary Syndrome Admitted to the Emergency Department. / Valor Prognóstico de Níveis Elevados de Troponina I Isolados em Pacientes sem Síndrome Coronariana Aguda Admitidos no Serviço de Emergência.

BACKGROUND: Although non-ischemic troponin elevation is frequently seen in patients admitted to the emergency department (ED), consensus regarding its management is lacking. OBJECTIVES: This study aimed to characterize patients admitted to the ED with non-ischemic troponin elevation and to identify potential mortality predictors in this population. METHODS: This retrospective observational study included ED patients with a positive troponin test result between June and July of 2015. Patients with a clinical diagnosis of acute coronary syndrome (ACS) were excluded. Data on patient demographics and clinical and laboratory variables were extracted from medical records. Follow-up data were obtained for 16 months or until death occurred. The statistical significance level was 5%. RESULTS: Troponin elevation without ACS was found in 153 ED patients. The median (IQR) patient age was 78 (19) years, 80 (52.3%) were female and 59(38.6%) died during follow-up. The median (IQR) follow-up period was 477(316) days. Survivors were significantly younger 76 (24) vs. 84 (13) years; p=0.004) and featured a higher proportion of isolated troponin elevation (without creatine kinase or myoglobin elevation) in two consecutive evaluations: 48 (53.9%) vs. 8 (17.4%), p<0.001. Survivors also presented a lower rate of antiplatelet treatment and same-day hospitalization. In the multivariate logistic regression with adjustment for significant variables in the univariate analysis, isolated troponin elevation in two consecutive evaluations showed a hazard ratio= 0.43 (95%CI 0.17-0.96, p=0.039); hospitalization, previous antiplatelet treatment and age remained independently associated with mortality. CONCLUSIONS: Isolated troponin elevation in two consecutive measurements was a strong predictor of survival in ED patients with troponin elevation but without ACS.

FUNDAMENTO: Embora a elevação não isquêmica da troponina seja frequentemente observada em pacientes admitidos no pronto-socorro (PS), não há consenso quanto ao seu manejo. OBJETIVOS: Este estudo teve como objetivo caracterizar os pacientes admitidos no PS com elevação da troponina não-isquêmica e identificar potenciais preditores de mortalidade nessa população. MÉTODOS: Este estudo observacional retrospectivo incluiu pacientes do PS com resultado positivo no teste da troponina entre junho e julho de 2015. Pacientes com diagnóstico clínico de síndrome coronariana aguda (SCA) foram excluídos. Os dados demográficos dos pacientes e as variáveis clínicas e laboratoriais foram extraídos dos prontuários médicos. Os dados do seguimento foram obtidos por 16 meses ou até a ocorrência de morte. O nível de significância estatística foi de 5%. RESULTADOS: A elevação da troponina sem SCA foi encontrada em 153 pacientes no PS. A mediana (IIQ) de idade dos pacientes foi de 78 (19) anos, 80 (52,3%) eram do sexo feminino e 59 (38,6%) morreram durante o seguimento. A mediana do período de seguimento (IIQ) foi de 477 (316) dias. Os sobreviventes eram significativamente mais jovens 76 (24) vs. 84 (13) anos; p=0,004) e apresentaram uma maior proporção de elevação da troponina isolada (sem elevação da creatina quinase ou mioglobina) em duas avaliações consecutivas: 48 (53,9%) vs. 8 (17,4%), p<0,001. Os sobreviventes também apresentaram menor taxa de tratamento antiplaquetário e internação no mesmo dia. Na regressão logística multivariada com ajuste para variáveis significativas na análise univariada, a elevação isolada da troponina em duas avaliações consecutivas mostrou hazard ratio = 0,43 (IC95% 0,17­0,96, p=0,039); hospitalização, tratamento antiplaquetário anterior e idade permaneceram independentemente associados à mortalidade. CONCLUSÕES: A elevação isolada da troponina em duas medidas consecutivas foi um forte preditor de sobrevida em pacientes no PS com elevação da troponina, mas sem SCA.

The Social Distancing Imposed To Contain COVID-19 Can Affect Our Microbiome: a Double-Edged Sword in Human Health.

Hygienic measures imposed to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and contain COVID-19 have proven effective in controlling the pandemic. In this article, we argue that these measures could impact the human microbiome in two different and disparate ways, acting as a double-edged sword in human health. New lines of research have shown that the diversity of human intestinal and oropharyngeal microbiomes can shape pulmonary viral infection progression. Here, we suggest that the disruption in microbial sharing, as it is associated with dysbiosis (loss of bacterial diversity associated with an imbalance of the microbiota with deleterious consequences for the host), may worsen the prognosis of COVID-19 disease. In addition, social detachment can also decrease the rate of transmission of antibiotic-resistant bacteria. Therefore, it seems crucial to perform new studies combining the pandemic control of COVID-19 with the diversity of the human microbiome.

Aortic valve microcalcification and cardiovascular risk: an exploratory study using sodium fluoride in high cardiovascular risk patients.

18F-sodium fluoride (18F-NaF) has been used to access aortic stenosis in clinical research setting. It is known that its uptake is related with microcalcification. The purpose of this study was to assess the relationship between 18F-NaF uptake by the aortic valve and cardiovascular risk. Twenty-five patients with risk factors for cardiovascular disease, without known cardiovascular disease or aortic stenosis underwent PET-CT with 18F-NaF. Cardiovascular risk was assessed through the ASCVD (Atherosclerotic Cardiovascular Disease) risk calculator. Aortic valve 18F-NaF (AoVCUL) uptake was evaluated through the corrected uptake per lesion (CUL = max SUV - mean blood-pool SUV). Calcium score was obtained through cardiac CT. The patients present a mean age of 63.90 ± 8.60 years and 56% males. The mean ASCVD was of 28.76 ± 18.96 (M 25, IQR 38.50). The mean aortic valve calcium score (AoVCaSc) was of 53.24 ± 164.38 (M 6; IQR 29.75) and the AoVCUL was of 0.50 ± 0.10 (M 0.52, IQR 0.15). The patients were classified according to the ASCVD: patients with a risk greater or equal than the 50th percentile of the ASCVD risk and patients with a risk lower than the 50th percentile. The AoVCUL was evaluated in both groups: AoVCUL = 0.56 ± 0.10 vs 0.42 ± 0.15, p = 0.02; AoVCaSc was of 0 in 11 patients (44%) and those with an ASCVD greater or equal than the 50th percentile had a mean AoVCaSc of 8.00 ± 13.80, and those with an ASCVD risk lower than the 50th percentile had a mean AoVCaSc of 95.00 ± 223.45; p = 0.09. In this study microcalcification, evaluated through 18F-NaF on PET-CT, was related with cardiovascular risk. Although the score of calcium seems to be higher in higher cardiovascular risk patients, no significant difference was found between groups.

A Rare Complication of Implantable Cardiac Defibrillator Placement.

Implantable cardiac defibrillators (ICDs) are a popular and effective option in heart failure with left ventricular systolic dysfunction patients. Although frequently underdiagnosed, inadvertent malposition can lead to endocardial damage and thrombotic events. As ICD implants tend to increase in the following years, the recognition of their complications is critical. The authors present a case of a 64-year-old female with advanced heart failure and ICD malposition. This accidental discovery was denounced by the presence of a right bundle branch block (RBBB) pattern and later confirmed by echocardiography which showed the lead tip in contact with the midsegment of the left ventricular anterolateral wall. As the patient's hospitalization was complicated with refractory ascites and cardiogenic shock, she underwent cardiac transplantation, with no recurrence of heart failure symptoms. An electrocardiogram showing a RBBB pattern during VVI pacing should arise the suspicion of inadvertent incorrect placement of a pacing/ICD lead. The many facets of echocardiography should be used for the diagnosis of this complication, as they were paramount in this case, as highlighted.

Left atrial mechanics in moderate mitral valve disease: earlier markers of damage.

While the impairment of left atrial (LA) mechanics in mitral valve disease is well known, the exact onset of reservoir, conduit, and contractile dysfunction in mitral stenosis (MS) and mitral regurgitation (MR) remains unclear. We aimed to clarify the LA deformation mechanics in patients with moderate mitral valve disease. We conducted a prospective observational study of 80 patients with moderate isolated MR, 80 patients with moderate isolated MS, and 64 age-matched controls without mitral valve disease. Strain (ɛ) and strain rate (SR) on speckle tracking echocardiography were assessed as indicators of LA and right atrium (RA) reservoir (ɛsys, SRs), conduit (ɛe, SRe), and contractile (ɛa, SRa) functions. Conventional echocardiographic parameters of the left ventricle (LV) were also assessed. Comparisons were conducted according to mitral valve pathology (MR patients, MS patients, controls). The mean LV ejection fraction, end-diastolic diameter, and global longitudinal strain did not differ across the groups. The pulmonary artery systolic pressure, LA volume indexed to body surface area, and LA mechanics were significantly impaired in mitral valve disease (patients vs controls). While LA ɛ did not vary between MR and MS, MR patients had better LA SRs and SRe but worse SRa (p < 0.01). SRe > - 0.65% had higher specificity for MS, with an area under the curve of 0.85 (p < 0.01). RA mechanics were significantly impaired in mitral valve disease (patients vs controls) but did not vary significantly with disease pathology (MS vs MR). Patients with moderate mitral valve disease exhibit early and pathology-specific changes in the LA deformation mechanics, manifesting mainly as impaired contractile-phase SR in MR and impaired conduit-phase SR in MS. Our findings highlight SR as a potentially useful early marker of LA dysfunction in relation to mitral valve disease.

Closure of bronchopleural fistula by a septal occluder device: a case for close collaboration between heart and lung specialists.

We present the case of a 66-year-old woman who underwent right inferior lobectomy for pulmonary carcinoma and developed persistent bronchopleural fistula (BPF) that was not amenable to surgical intervention (two surgical failures). The patient presented with a persistent cough and dyspnoea, which was treated with a hybrid procedure using fluoroscopy and bronchoscopy. A 7 mm Amplatzer septal occluder device (ASOD) was successfully inserted into the BPF. Two weeks after the procedure, a small fistula developed, which was treated by endoscopically guided biologic glue embolisation. At 2-month, 6-month and 12-month follow-up visits, clinical examinations and endoscopic imaging confirmed the complete occlusion of the BPF. Obvious migration of the ASOD was not apparent, and the patient has remained asymptomatic. The success of an endoscopic BPF closure with the use of hybrid techniques was achieved because of a collaborative effort by a multidisciplinary team.

Mind Bomb Regulates Cell Death during TNF Signaling by Suppressing RIPK1's Cytotoxic Potential.

Tumor necrosis factor (TNF) is an inflammatory cytokine that can signal cell survival or cell death. The mechanisms that switch between these distinct outcomes remain poorly defined. Here, we show that the E3 ubiquitin ligase Mind Bomb-2 (MIB2) regulates TNF-induced cell death by inactivating RIPK1 via inhibitory ubiquitylation. Although depletion of MIB2 has little effect on NF-κB activation, it sensitizes cells to RIPK1- and caspase-8-dependent cell death. We find that MIB2 represses the cytotoxic potential of RIPK1 by ubiquitylating lysine residues in the C-terminal portion of RIPK1. Our data suggest that ubiquitin conjugation of RIPK1 interferes with RIPK1 oligomerization and RIPK1-FADD association. Disruption of MIB2-mediated ubiquitylation, either by mutation of MIB2's E3 activity or RIPK1's ubiquitin-acceptor lysines, sensitizes cells to RIPK1-mediated cell death. Together, our findings demonstrate that Mind Bomb E3 ubiquitin ligases can function as additional checkpoint of cytokine-induced cell death, selectively protecting cells from the cytotoxic effects of TNF.

Signal Integration by the IκB Protein Pickle Shapes Drosophila Innate Host Defense.

Pattern recognition receptors are activated following infection and trigger transcriptional programs important for host defense. Tight regulation of NF-κB activation is critical to avoid detrimental and misbalanced responses. We describe Pickle, a Drosophila nuclear IκB that integrates signaling inputs from both the Imd and Toll pathways by skewing the transcriptional output of the NF-κB dimer repertoire. Pickle interacts with the NF-κB protein Relish and the histone deacetylase dHDAC1, selectively repressing Relish homodimers while leaving other NF-κB dimer combinations unscathed. Pickle's ability to selectively inhibit Relish homodimer activity contributes to proper host immunity and organismal health. Although loss of pickle results in hyper-induction of Relish target genes and improved host resistance to pathogenic bacteria in the short term, chronic inactivation of pickle causes loss of immune tolerance and shortened lifespan. Pickle therefore allows balanced immune responses that protect from pathogenic microbes while permitting the establishment of beneficial commensal host-microbe relationships.