Early Wave Research Articles

Initial presenting symptoms andseverity of SARS-CoV-2 Wild type, theDelta variant and the Omicron variant infected cases in early fourth wave ofepidemics in Myanmar

Initial presenting symptoms andseverity of SARS-CoV-2 Wild type, theDelta variant and the Omicron variant infected cases in early fourth wave ofepidemics in Myanmar

Neonatal Hyperoxia Activates Activating Transcription Factor 4 to Stimulate Folate Metabolism and Alveolar Epithelial Type 2 Cell Proliferation.

Oxygen supplementation in preterm infants disrupts alveolar epithelial type 2 (AT2) cell proliferation through poorly understood mechanisms. Here, newborn mice are used to understand how hyperoxia stimulates an early aberrant wave of AT2 cell proliferation that occurs between Postnatal Days (PNDs) 0 and 4. RNA-sequencing analysis of AT2 cells isolated from PND4 mice revealed hyperoxia stimulates expression of mitochondrial-specific methylenetetrahydrofolate dehydrogenase 2 and other genes involved in mitochondrial one-carbon coupled folate metabolism and serine synthesis. The same genes are induced when AT2 cells normally proliferate on PND7 and when they proliferate in response to the mitogen fibroblast growth factor 7. However, hyperoxia selectively stimulated their expression via the stress-responsive activating transcription factor 4 (ATF4). Administration of the mitochondrial superoxide scavenger mitoTEMPO during hyperoxia suppressed ATF4 and thus early AT2 cell proliferation, but it had no effect on normative AT2 cell proliferation seen on PND7. Because ATF4 and methylenetetrahydrofolate dehydrogenase are detected in hyperplastic AT2 cells of preterm infant humans and baboons with bronchopulmonary dysplasia, dampening mitochondrial oxidative stress and ATF4 activation may provide new opportunities for controlling excess AT2 cell proliferation in neonatal lung disease.

Single-Cell Monitoring of Activated Innate Immune Signaling by a d2eGFP-Based Reporter Mimicking Time-Restricted Activation of IFNB1 Expression.

The innate immune system represents a balanced first line of defense against infection. Type I interferons (IFNs) are key regulators of the response to viral infections with an essential early wave of IFN-β expression, which is conditional, time-restricted, and stochastic in its nature. The possibility to precisely monitor individual cells with active IFNB1 transcription during innate signaling requires a robust reporter system that mimics the endogenous IFN-β signal. Here, we present a reporter system based on expression of a destabilized version of eGFP (d2eGFP) from a stably integrated reporter cassette containing the IFNB1 promoter and 3’-untranslated region, enabling both spatial and temporal detection of regulated IFNB1 expression. Specifically, this reporter permits detection, quantification, and isolation of cells actively producing d2eGFP in a manner that fully mimics IFN-β production allowing tracking of IFNB1 gene activation and repression in monocytic cells and keratinocytes. Using induced d2eGFP expression as a readout for activated immune signaling at the single-cell level, we demonstrate the application of the reporter for FACS-based selection of cells with genotypes supporting cGAS-STING signaling. Our studies provide a novel approach for monitoring on/off-switching of innate immune signaling and form the basis for investigating genotypes affecting immune regulation at the single-cell level.

Factors associated with SARS-CoV-2 test positivity in long-term care homes: A population-based cohort analysis using machine learning

BackgroundSARS-Cov-2 infection rates are high among residents of long-term care (LTC) homes. We used machine learning to identify resident and community characteristics predictive of SARS-Cov-2 infection.MethodsWe linked 26 population-based health and administrative databases to identify the population of all LTC residents tested for SARS-Cov-2 infection in Ontario, Canada. Using ensemble-based algorithms, we examined 484 factors, including individual-level demographics, healthcare use, comorbidities, functional status, and laboratory results; and community-level characteristics to identify factors predictive of infection. Analyses were performed separately for January to April (early wave 1) and May to August (late wave 1).FindingsAmong 80,784 LTC residents, 64,757 (80.2%) were tested for SARS-Cov-2 (median age 86 (78–91) years, 30.6% male), of whom 10.2% of 33,519 and 5.2% of 31,238 tested positive in early and late wave 1, respectively. In the late phase (when restriction of visitors, closure of communal spaces, and universal masking in LTC were routine), regional-level characteristics comprised 33 of the top 50 factors associated with testing positive, while laboratory values and comorbidities were also predictive. The c-index of the final model was 0.934, and sensitivity was 0.887. In the highest versus lowest risk quartiles, the odds ratio for infection was 114.3 (95% CI 38.6–557.3). LTC-related geographic variations existed in the distribution of observed infection rates and the proportion of residents at highest risk.InterpretationMachine learning informed evaluation of predicted and observed risks of SARS-CoV-2 infection at the resident and LTC levels, and may inform initiatives to improve care quality in this setting.FundingFunded by a Canadian Institutes of Health Research, COVID-19 Rapid Research Funding Opportunity grant (# VR4 172736) and a Peter Munk Cardiac Centre Innovation Grant. Dr. D. Lee is the Ted Rogers Chair in Heart Function Outcomes, University Health Network, University of Toronto. Dr. Austin is supported by a Mid-Career investigator award from the Heart and Stroke Foundation. Dr. McAlister is supported by an Alberta Health Services Chair in Cardiovascular Outcomes Research. Dr. Kaul is the CIHR Sex and Gender Science Chair and the Heart & Stroke Chair in Cardiovascular Research. Dr. Rochon holds the RTO/ERO Chair in Geriatric Medicine from the University of Toronto. Dr. B. Wang holds a CIFAR AI chair at the Vector Institute.

An Early Wave of Macrophage Infiltration Intertwined with Antigen-Specific Proinflammatory T Cells and Browning of Adipose Tissue Characterizes the Onset of Orbital Inflammation in a Mouse Model of Graves' Orbitopathy.

Background: Graves' orbitopathy (GO) is an autoimmune-driven manifestation of Graves' disease (GD) where pathogenic autoantibodies to the thyrotropin receptor (TSHR) activate orbital fibroblasts/preadipocytes in the orbital tissue to induce inflammation and extracellular matrix deposition. Since there are significant limitations to study immunological and proinflammatory mediator expression in early and during disease progression in GO patients, we used our experimental mouse model to elucidate early pathogenic processes. Methods: We have developed a robust mouse model of GD/GO induced by electroporation immunization of plasmid encoding human TSHR A-subunit, comprising multiple injections over a course of 15 weeks to fully recapitulate the orbital pathology. In this study, we investigated kinetics of GO development in the model by serial analyses of immunological and cellular parameters during course of orbital inflammation. Results: Pathogenic anti-TSHR antibodies with thyroid-stimulating properties developed early after the second immunization step with concomitant induction of hyperthyroidism. Examination of orbital tissue showed an early wave of macrophage infiltration followed subsequently by CD3+ T cells into the orbital tissue. Examination of antigen-specific T cell activity using recombinant human A-subunit protein showed high CD8+ T cell proliferation during this early phase of disease onset, whereas effector CD4+ T cells and CD25+FOXP3+ regulatory T cells (Tregs) were downregulated. The early phase of disease was also characterized by abundant presence of proinflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Moreover, as the disease progressed, there was significant increase in browning of orbital fat tissue, which may be dependent on the proinflammatory milieu and/or the increased thyroid hormone levels during the established hyperthyroid status. Conclusions: This work revealed early infiltration of macrophages in the orbital region and induction of pathogenic anti-TSHR antibodies during disease onset in the model. This was followed subsequently by influx of CD8+ T cells specific for TSHR coupled with reduction in Tregs and substantial increase in brown adipose tissue. These new insights into the development of orbital inflammation in the model have implications for testing new therapeutic regimens by targeting macrophage function during early phases of orbital inflammation in the model.

Programmed gene expression change in mouse skin after ultraviolet radiation damage.

Ultraviolet (UV) radiation is a major cause of skin damage and carcinogenesis. Here, we systematically analyse the acute gene expression change in skin in vivo after UV exposure, aiming to establish the common C57BL/6 mouse strain as a convenient model for future pathological research and drug discovery. The back fur of C57BL/6 mice was depilated, and a mixed UV light source was used to irradiate the skin. Full-thickness skin samples were collected at 0, 0.5, 2, 6, 12 and 24h. Total RNAs were extracted and subjected to RNA sequencing analysis. We found that the gene expression change in mouse skin is highly similar to previous reports in human skin. These include down-regulation of differentiation-related genes and extracellular matrix genes, and up-regulation of cytokine/chemokine genes. An early wave of activator protein 1 (AP-1) expression is induced, whereas activation of the p53 pathway is not significant. The impact of the AP-1 transcription factors and the antioxidant tea polyphenols is discussed. The analysis of acute gene expression change in skin after UV irradiation provides a starting point to investigate how the skin responds to genotoxic stress.

Comparative study of clinical features and vaccination status in Omicron and non-Omicron infected patients during the third wave in Mumbai, India.

The Omicron variant-mediated COVID-19 wave is responsible for a global tsunami of cases. There is scarce data about the clinical and epidemiological characteristic analyses of the third wave. We present the data of COVID-19 patients from Mumbai region during the early third wave by taking S-gene target failure (SGTF) as a proxy for probable Omicron cases. We collected retrospective data of RT-PCR-confirmed (COVID-19) patients, and measured the proportion of possible Omicron cases by SGTF. We segregated and analyzed the clinical and lab data of patients with outcomes such as differing symptoms, vaccination coverage, previous infection, and travel history. We also performed a trend analysis of Mumbai's COVID-19 data before and during the third wave. All patients had mild clinical symptoms while few were asymptomatic. Myalgia was more significantly present in SGTF/Omicron cases compared to non-SGTF/Delta patients. Out of the total 101 COVID-positive individuals, 94 individuals (93%) had taken two doses of COVID vaccine. Among these 94 individuals, 9 (8.9%) had been previously infected with COVID 19 in the first or second waves. 77.7% of the previously infected were now infected with Omicron variant and only 22.3% by a non-Omicron variant. Rapid rise and fall during the third wave in Mumbai was due to Omicron cases gradually replacing Delta. The overall milder clinical spectrum in both Omicron and Delta cases imply that vaccines might not be effective against re-infection but can attenuate disease severity and mortality, as evident by high coverage of vaccination in the country.

Impact of COVID-19 first wave on the in-hospital length of stay of operated proximal femur fracture patients in an industrial hospital in Eastern India.

Objective:The objective of this article is to study the impact of coronavirus disease 2019 (COVID-19) pandemic first wave on the in-hospital length of stay of operated proximal femur fractures.Materials and Methods:A retrospective analysis of data collected through the electronic record system of the hospital, after applying inclusion and exclusion criteria, was done. The data were collected from the pre-pandemic, early part first wave and later part first wave of COVID-19 pandemic to calculate the average preoperative stay (POS) and total length of stay (LOS) of operated proximal femur fracture patients. Also, a sub-analysis of POS and LOS was done as per age (male/female), sex (<60/≥60 years) and fracture subtype (intertrochanteric, neck of femur and subtrochanteric fracture) of the patients to study if any of these had a significant direct impact on the POS and LOS.Results:The LOS and POS were found to be significantly increased during early part of first wave of COVID-19 pandemic in comparison to the pre-pandemic era (13.6 ± 7.7 days vs. 11.1 ± 5.7 days). The later part of the first wave of the pandemic however saw the LOS and POS to return to near pre-pandemic values, although still remaining higher.Conclusion:The study highlights that unpreparedness during the early part of the unprecedented pandemic event leads to a significant increase in LOS of operated patients with its associated implications; however, prompt action by the government, hospital administration and hospital staff the LOS could be reduced to near pre-pandemic values in the later part of the first wave of the pandemic. Analysis of the causes that lead to a significant increase in LOS can help for better future management of similar events in future.

Transcriptomic Insights on the Preventive Action of Apple (cv Granny Smith) Skin Wounding on Superficial Scald Development.

Superficial scald is a post-harvest chilling storage injury leading to browning of the surface of the susceptible cv Granny Smith apples. Wounding of skins has been reported to play a preventive role on scald development however its underlying molecular factors are unknown. We have artificially wounded the epidermal and sub-epidermal layers of apple skins consistently obtaining the prevention of superficial scald in the surroundings of the wounds during two independent vintages. Time course RNA-Seq analyses of the transcriptional changes in wounded versus unwounded skins revealed that two transcriptional waves occurred. An early wave included genes up-regulated by wounding already after 6 h, highlighting a specific transcriptional rearrangement of genes connected to the biosynthesis and signalling of JA, ethylene and ABA. A later transcriptional wave, occurring after three months of cold storage, included genes up-regulated exclusively in unwounded skins and was prevented from its occurrence in wounded skins. A significant portion of these genes was related to decay of tissues and to the senescence hormones ABA, JA and ethylene. Such changes suggest a wound-inducible reversed hormonal balance during post-harvest storage which may explain the local inhibition of scald in wounded tissues, an aspect that will need further studies for its mechanistic explanation.

Facilitation of Motor Evoked Potentials in Response to a Modified 30 Hz Intermittent Theta-Burst Stimulation Protocol in Healthy Adults.

Theta-burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation (rTMS) developed to induce neuroplasticity. TBS usually consists of 50 Hz bursts at 5 Hz intervals. It can facilitate motor evoked potentials (MEPs) when applied intermittently, although this effect can vary between individuals. Here, we sought to determine whether a modified version of intermittent TBS (iTBS) consisting of 30 Hz bursts repeated at 6 Hz intervals would lead to lasting MEP facilitation. We also investigated whether recruitment of early and late indirect waves (I-waves) would predict individual responses to 30 Hz iTBS. Participants (n = 19) underwent single-pulse TMS to assess MEP amplitude at baseline and variations in MEP latency in response to anterior-posterior, posterior-anterior, and latero-medial stimulation. Then, 30 Hz iTBS was administered, and MEP amplitude was reassessed at 5-, 20- and 45-min. Post iTBS, most participants (13/19) exhibited MEP facilitation, with significant effects detected at 20- and 45-min. Contrary to previous evidence, recruitment of early I-waves predicted facilitation to 30 Hz iTBS. These observations suggest that 30 Hz/6 Hz iTBS is effective in inducing lasting facilitation in corticospinal excitability and may offer an alternative to the standard 50 Hz/5 Hz protocol.

613 Fontan associated nephropathy: does diastolic function play a role?

Abstract Aims In Fontan patients, the pathophysiology of diastolic function and its relationship with systemic complications are still not well understood. Methods and results This is a prospective study including patients who underwent Fontan completion in our centre between 1993 and 2016. We excluded patients with major congenital renal anomalies, those who underwent cardiac transplantation and redo-Fontan patients. All the subjects underwent clinical evaluation, laboratory exams with complete renal and hepatic function, transient hepatic elastography, and complete cardiac evaluation. We used Schwartz equation for estimating glomerular filtration rate in patients younger than 18 years, and CDK-EPI equation for adult patients. We enrolled 35 patients, 46% female (N = 16), and 54% male (N = 19). Medium age was 17 years old (range: 10–31 years old). Medium time from Fontan completion was 160 months (range: 57–340 months). Ten patients had a functional single left ventricle (FSLV, 28.5%) and 21 a functional single right ventricle (FSRV, 60%); four patients had an undetermined single ventricle (11.5%). Data from renal function assessment showed a prevalence of stage 2 chronic kidney disease (eGFR: 60–89 ml/min 1.73 mq). Of those, 11% with creatinine-based equation and 26% (N = 9) when using cystatin C-based equation, with one patients showing a moderate reduced loss of kidney function (eGFR: 40–59 ml/min/1.73 mq). Most of the patients with reduced eGFR measured with cystatin C were FSRV (89%). None had laboratory markers of acute tubular damage, but four patients had signs of chronic tubular dysfunction with elevation of beta 2 microglobulin (13%). Echocardiographic evaluation of diastolic function showed two patients with baseline E/A &amp;lt; 1 (6%, tot N = 33) and 11/33 (33%) pts with abnormal E/E′ (&amp;gt;12). All of them were FSRV patients (100%). Interestingly, statistical correlation between diastolic parameters and renal function showed a significant association between tubular damage parameters, such as alfa1microglobulin and beta2microglobulin, and E/E′ (Pearson’s R 0.4 and 0.48, respectively, P &amp;lt; 0.05), both for FSLV and FSRV patients. Diastolic function appeared to be associated also with glomerular filtration: we found a statistically significant direct correlation between diastolic pulmonary wave deceleration time (dt D wave) and creatinine value (Pearson’s R 0.49, P &amp;lt; 0.05). Supporting the role of diastolic function in Fontan systemic complications is the linear correlation we found with hepatic tests: higher values of aspartate aminotransferase and of gamma-glutamyltransferase were associated with worse diastolic ventricular filling (longer dt D wave and E wave deceleration time, lower TDI early diastolic wave; Pearson’s R 0.45, 0.5, and −0.41, respectively, P &amp;lt; 0.05). Conclusions Fontan-related nephropathy is associated with worsening diastolic function, which was more represented in FSRV patients. Diastolic function is also associated with liver disease in Fontan patients. Those data suggest renal and liver function should be closely monitored in patients with impaired diastolic function.

The influence of the 2020 COVID-19 pandemic on the implantation rates of cardiac implantable electronic devices in Germany: changes between 2020 Q1–Q3 and 2019 Q1–Q3

ABSTRACTAimDuring the early phase of the COVID-19 pandemic, hospital admissions for several medical and surgical conditions have declined. Few data are available with respect to elective cardiac implantable electronic devices (CIEDs) implantation. The aim of the present study was to determine the impact of the COVID-19 pandemic on the monthly CIED implantation rates in Germany.Methods and ResultsThe monthly rates of CIED implantation for the 2019 pre- and 2020 pandemic periods were retrieved from the “Institute für das Entgeltsystem im Krankenhaus” (InEK) using OPS codes to identify pacemakers (PMs), implantable cardioverter/defibrillators (ICDs) and cardiac resynchronisation therapy (CRT) systems. Compared with 2019, the COVID-19 pandemic was associated with an overall decline of CIED implantation rates of -2.6%, reaching -22,9% in April 2020. Stratified by device type, the patterns of implantation were similar between PMs and ICDs, with maximal declines of -24.3% and -23.2% in April, respectively. Thereafter, the implantation rates gradually increased before stabilizing to rates similar to those observed in 2019. CRT implantation rates also declined in the early pandemic wave, but the overall 2020 rates increased by +4.3% likely driven by an increase of +16.5% (June to September). All observed percentage differences of monthly device type related implantation rates demonstrated a statistical significance.ConclusionsThe COVID-19 pandemic had a significant impact on the implantation of CIEDs in Germany. A differential pattern of resource utilization was observed with a catch-up effect for PMs and ICDs. The implantation rates of CRT also declined, but they increased rapidly and remained higher than those of 2019.

Clinical, laboratory, and radiological characteristics of COVID-19-infected children admitted to pediatric intensive care unit: a single-center experience

BackgroundDuring the second wave of COVID-19, there is an increasing incidence of reported cases in children compared to the early wave. Data on the clinical and laboratory characteristics of COVID-19 in children are evolving, and reports on the characteristics and outcomes of severe COVID-19 in children are still under evaluation. We aimed to describe the clinical, laboratory, and radiological characteristics and outcomes of children with COVID-19 infection admitted to the pediatric intensive care unit (PICU).ResultsThe study included 27 children with COVID-19 infection. Fever, respiratory, and gastrointestinal (GIT) symptoms were predominant presenting symptoms in our patients. The median age of our patients was 9 months (2 m–12 years). Comorbidity was reported in 59.3%. The typical laboratory findings were leukocytosis, lymphopenia, elevated C-reactive proteins levels, and elevated d-dimer levels. The most frequent radiological findings were ground-glass opacities in 100% of patients and bilateral findings in 96%, while cardiomegaly was found in 44% of patients. The multisystem inflammatory syndrome was reported in 33% of patients with GIT symptoms were the most frequent presenting symptoms. Myocarditis was reported in 22% of patients. The mortality rate in this cohort was 14.8%. On multivariate analysis, the only predictor of mortality was the development of MIS-C.ConclusionsCOVID-19 is more severe in children with comorbid conditions. Fever, respiratory and gastrointestinal (GIT) symptoms were predominant presenting symptoms. MIS-C is of increasing concern in children with high mortality rates.

COVID-19 critical illness in pregnancy.

Although the pregnant population was affected by early waves of the COVID-19 pandemic, increasing transmission and severity due to new viral variants has resulted in an increased incidence of severe illness during pregnancy in many regions. Critical illness and respiratory failure are relatively uncommon occurrences during pregnancy, and there are limited high-quality data to direct management. This paper reviews the current literature on COVID-19 management as it relates to pregnancy, and provides an overview of critical care support in these patients. COVID-19 drug therapy is similar to that used in the non-pregnant patient, including anti-inflammatory therapy with steroids and IL-6 inhibitors, although safety data are limited for antiviral drugs such as remdesivir and monoclonal antibodies. As both pregnancy and COVID-19 are thrombogenic, thromboprophylaxis is essential. Endotracheal intubation is a higher risk during pregnancy, but mechanical ventilation should follow usual principles. ICU management should be directed at optimizing maternal well-being, which in turn will benefit the fetus.

Temporal dynamics of persistent germinal centers and memory B cell differentiation following respiratory virus infection.

SummaryFollowing infection or immunization, memory B cells (MBCs) and long-lived plasma cells provide humoral immunity that can last for decades. Most principles of MBC biology have been determined with hapten-protein carrier models or fluorescent protein immunizations. Here, we examine the temporal dynamics of the germinal center (GC) B cell and MBC response following mouse influenza A virus infection. We find that antiviral B cell responses within the lung-draining mediastinal lymph node (mLN) and the spleen are distinct in regard to duration, enrichment for antigen-binding cells, and class switching dynamics. While splenic GCs dissolve after 6 weeks post-infection, mLN hemagglutinin-specific (HA+) GCs can persist for 22 weeks. Persistent GCs continuously differentiate MBCs, with “peak” and “late” GCs contributing equal numbers of HA+ MBCs to the long-lived compartment. Our findings highlight critical aspects of persistent GC responses and MBC differentiation following respiratory virus infection with direct implications for developing effective vaccination strategies.

Changes in the epidemiology of ventilator-associated events over the course of the coronavirus disease 2019 (COVID-19) pandemic.

Management of critically ill coronavirus disease 2019 (COVID-19) patients has evolved considerably during the pandemic. We investigated rates and causes of ventilator-associated events (VAEs) in COVID-19 patients in the late versus early waves in 4 Massachusetts hospitals. VAE rates per episode decreased, rates per ventilator day were stable, and most cases were caused by acute respiratory distress syndrome (ARDS).

Constraints on Crustal P Wave Structure With Leaking Mode Dispersion Curves

AbstractClassic surface wave imaging relies mainly on the dispersion of Rayleigh waves or Love waves. In addition to these types of waves, waveforms that arrive prior to the S wave also exhibit dispersion. These early dispersed waves are controlled mainly by the leaking modes and are rarely used for imaging. We applied the frequency‐Bessel transform method to waveforms that arrive before the S wave and successfully extracted multiple leaking mode dispersion curves. The extracted “0th” mode shows continuous sensitivity to S wave velocity (Vs) and mass density structure whereas the “higher” modes behave more like surface waves that are sensitive to P wave velocity (Vp) structure in the crust. Thus, the “higher” modes can be used to invert the Vp structure, which can compensate for the fact that conventional surface wave imaging methods are mainly sensitive to Vs structure.

The association of tissue doppler E/e' ratio with poor survival is modified by gender and is attenuated with advanced age

Abstract Introduction Contemporary guidelines recommend a universal cutoff of 14 for the ratio between early mitral flow wave and early diastolic mitral annulus velocity measured by tissue doppler (E/e' ratio). While age-dependent normal E/e' values have been suggested, outcome data is lacking. Purpose We sought to evaluate the modification effect of age and gender on the prognostic value of the E/e' ratio. Methods Consecutive patients who underwent echocardiographic evaluation between 2009 and 2021 (N=104,315) in a single tertiary cardiovascular center. Patients with left or right ventricular dysfunction, any significant valvular disease, structural heart disease or evidence of pulmonary hypertension were excluded. Cancer and mortality data were available for all subjects from national registries. Patients with a metastatic malignancy at baseline or during follow up were excluded. Cox regression models were applied. Results Overall, 44,541 patients were included in the final analysis. Mean age was 55±17, 59% were male and 63% of the exams were performed in an outpatient setting. An elevated E/e' ratio above 14 was documented in 2,598 (7%) patients. During a median follow-up of 5.7 (IQR 2.8–9.1) years, 5,015 (11.3%) patients died. Kaplan Meier survival analysis demonstrated that the cumulative probability of death at 6 years was 23.4% (21.6–25.3) among patients with elevated E/e' ratio compared with 9.7% (9.3–10.0) among patients with E/e'&amp;lt;14 (p Log rank &amp;lt;0.001). This difference was less significant as age progressed (figure 1). Multivariate cox-regression model yielded consistent results such that an elevated E/e' ratio was associated with 2.66-fold increased risk of death during follow up (95% CI 2.44–2.89, p&amp;lt;0.001), and there was a decline in the increased risk and significant as age advanced in both genders (figure 2). Interaction analysis was significant for both gender and age such the association of elevated E/e' ratio with poor survival was more significant among men compared with women and among young vs. older subjects. Among women, elevated E/e' was associated with 2.4-fold increased risk of death versus 2.7-fold increased risk among men. Similarly, the hazard ratio for death associated with elevated E/e' was 2.29 (95% CI 1.74–3.02), 1.8 (95% CI 1.5–2.1), 1.13 (95% CI 0.97–1.31) and 1.07 (95% CI 0.92–1.25) for the age groups of &amp;lt;60, 60–70, 70–80 and &amp;gt;80, respectively. In a sensitivity analysis, similar findings were seen in when excluding patients with mild hypertrophy (maximal wall thickness &amp;gt;12mm) and without any mitral annulus calcification. Conclusion In apparently normal hearts, an elevated E/e' ratio is independently associated with increased mortality. This association is more pronounced among men and is attenuated with increased age. This study supports the need for gender-specific and age-specified outcome data with respect to measures of diastolic dysfunction. Funding Acknowledgement Type of funding sources: None. Survival by age and gender groupsE/e' &amp;gt;14 and mortality by age and gender

Self-renewal of peripheral nerve resident macrophage: does it represent a unique activation status?

Self-renewal of peripheral nerve resident macrophage: does it represent a unique activation status?

The stem rust fungus Puccinia graminis f. sp. tritici induces centromeric small RNAs during late infection that are associated with genome-wide DNA methylation

BackgroundSilencing of transposable elements (TEs) is essential for maintaining genome stability. Plants use small RNAs (sRNAs) to direct DNA methylation to TEs (RNA-directed DNA methylation; RdDM). Similar mechanisms of epigenetic silencing in the fungal kingdom have remained elusive.ResultsWe use sRNA sequencing and methylation data to gain insight into epigenetics in the dikaryotic fungus Puccinia graminis f. sp. tritici (Pgt), which causes the devastating stem rust disease on wheat. We use Hi-C data to define the Pgt centromeres and show that they are repeat-rich regions (~250 kb) that are highly diverse in sequence between haplotypes and, like in plants, are enriched for young TEs. DNA cytosine methylation is particularly active at centromeres but also associated with genome-wide control of young TE insertions. Strikingly, over 90% of Pgt sRNAs and several RNAi genes are differentially expressed during infection. Pgt induces waves of functionally diversified sRNAs during infection. The early wave sRNAs are predominantly 21 nts with a 5′ uracil derived from genes. In contrast, the late wave sRNAs are mainly 22-nt sRNAs with a 5′ adenine and are strongly induced from centromeric regions. TEs that overlap with late wave sRNAs are more likely to be methylated, both inside and outside the centromeres, and methylated TEs exhibit a silencing effect on nearby genes.ConclusionsWe conclude that rust fungi use an epigenetic silencing pathway that might have similarity with RdDM in plants. The Pgt RNAi machinery and sRNAs are under tight temporal control throughout infection and might ensure genome stability during sporulation.