Strong cardiovascular prognostic implication of quantitative left atrial contractile function assessed by cardiac magnetic resonance imaging in patients with chronic hypertension

<p>Abstract</p> <p>Background</p> <p>Progressive left ventricular (LV) diastolic dysfunction due to hypertension (HTN) alters left atrial (LA) contractile function in a predictable manner. While increased LA size is a marker of LV diastolic dysfunction and has been shown to be predictive of adverse cardiovascular outcomes, the prognostic significance of altered LA contractile function is unknown.</p> <p>Methods</p> <p>A consecutive group of patients with chronic hypertension but without significant valvular disease or prior MI underwent clinically-indicated CMR for assessment of left ventricular (LV) function, myocardial ischemia, or viability. Calculation of LA volumes used in determining LA emptying functions was performed using the biplane area-length method.</p> <p>Results</p> <p>Two-hundred and ten patients were included in this study. During a median follow-up of 19 months, 48 patients experienced major adverse cardiac events (MACE), including 24 deaths. Decreased LA contractile function (LAEF_Contractile) demonstrated strong unadjusted associations with patient mortality, non-fatal events, and all MACE. For every 10% reduction of LAEF_Contractile, unadjusted hazards to MACE, all-cause mortality, and non-fatal events increased by 1.8, 1.5, and 1.4-folds, respectively. In addition, preservation of the proportional contribution from LA contraction to total diastolic filling (Contractile/Total ratio) was strongly associated with lower MACE and patient mortality. By multivariable analyses, LAEF_Contractilewas the strongest predictor in each of the best overall models of MACE, all-cause mortality, and non-fatal events. Even after adjustment for age, gender, left atrial volume, and LVEF, LAEF_Contractilemaintained strong independent associations with MACE (p < 0.0004), all-cause mortality (p < 0.0004), and non-fatal events (p < 0.0004).</p> <p>Conclusions</p> <p>In hypertensive patients at risk for left ventricular diastolic dysfunction, a decreased contribution of LA contractile function to ventricular filling during diastole is strongly predictive of adverse cardiac events and death.</p

Interventions to Promote the Development of Motor Performance Skills in Primary School Aged Children with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis of Controlled Trials

Background: The development of proficiency in motor performance skills (MPS) builds the foundation for the complex movement skills required to participate in a range of sports and physical activities throughout the lifespan. Objective: To assess the efficacy of different intervention approaches on developing MPS proficiency in children with autism spectrum disorder (ASD) and examine the intervention factors that influence change. Method: Searches were completed in three databases (PubMed/MEDLINE, Scopus, Web of Science) up to March 2022. Only randomised controlled trials (RCTs) or controlled trials (CTs), that evaluated the effectiveness of interventions on overall MPS proficiency or specific MPS such as balance, running speed and agility, bilateral coordination, jumping, ball skills and push-ups in children (4–13 years old) were included. The DerSimonian and Laird random-effects model was used to compute the meta-analyses. The effect sizes were reported as Hedges’ g. Using a random-effects model, potential sources of heterogeneity were identified, including subgroup analyses (type of intervention), and single training factor analysis (total number of weeks, session frequency, total intervention time, total number of training sessions). In addition, a multivariate meta-regression calculation was performed for balance. The GRADE framework was applied to assess certainty of evidence. Results: Seventeen interventions (13 RCTs and 4 CTs) revealed significant differences among groups favouring the intervention group with moderate to very large effects. Significant (p 0.05) small-to-large effects of interventions were evident on overall motor performance skills (ES = 2.43), ball skills (ES = 2.95), jumping (ES = 1.89), bilateral coordination (ES = 2.21), push-ups (ES = 1.92), balance (ES = 1.56), running speed and agility (ES = 1.31). Multivariate meta-regression for balance revealed that total sessions, total intervention time and session frequency predicted (p = 0.009, p0.001, p = 0.036, respectively) the effects of interventions on change in balance performance. Conclusion: Structured interventions that explicitly teach traditional FMS or promote the development and learning of movement skills specifically associated with a type of physical activity or sport, effectively improve MPS in children with ASD. Education settings should implement ‘planned’ movement experiences or interventions as a strategy to promote MPS proficiency in children with ASD

Molecular Phenotypes Distinguish Patients with Relatively Stable from Progressive Idiopathic Pulmonary Fibrosis (IPF)

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic interstitial lung disease that is unresponsive to current therapy and often leads to death. However, the rate of disease progression differs among patients. We hypothesized that comparing the gene expression profiles between patients with stable disease and those in which the disease progressed rapidly will lead to biomarker discovery and contribute to the understanding of disease pathogenesis. METHODOLOGY AND PRINCIPAL FINDINGS: To begin to address this hypothesis, we applied Serial Analysis of Gene Expression (SAGE) to generate lung expression profiles from diagnostic surgical lung biopsies in 6 individuals with relatively stable (or slowly progressive) IPF and 6 individuals with progressive IPF (based on changes in DLCO and FVC over 12 months). Our results indicate that this comprehensive lung IPF SAGE transcriptome is distinct from normal lung tissue and other chronic lung diseases. To identify candidate markers of disease progression, we compared the IPF SAGE profiles in stable and progressive disease, and identified a set of 102 transcripts that were at least 5-fold up regulated and a set of 89 transcripts that were at least 5-fold down regulated in the progressive group (P-value</=0.05). The over expressed genes included surfactant protein A1, two members of the MAPK-EGR-1-HSP70 pathway that regulate cigarette-smoke induced inflammation, and Plunc (palate, lung and nasal epithelium associated), a gene not previously implicated in IPF. Interestingly, 26 of the up regulated genes are also increased in lung adenocarcinomas and have low or no expression in normal lung tissue. More importantly, we defined a SAGE molecular expression signature of 134 transcripts that sufficiently distinguished relatively stable from progressive IPF. CONCLUSIONS: These findings indicate that molecular signatures from lung parenchyma at the time of diagnosis could prove helpful in predicting the likelihood of disease progression or possibly understanding the biological activity of IPF

Brillouin light storage for 100 pulse widths

Signal processing based on stimulated Brillouin scattering (SBS) is limited by the narrow linewidth of the optoacoustic response, which confines many Brillouin applications to continuous wave signals or optical pulses longer than several nanoseconds. In this work, we experimentally demonstrate Brillouin interactions at the 150 ps time scale and a delay for a record 15 ns which corresponds to a delay of 100 pulse widths. This breakthrough experimental result was enabled by the high local gain of the chalcogenide waveguides as the optoacoustic interaction length reduces with pulse width. We successfully transfer 150ps-long pulses to traveling acoustic waves within a Brillouin-based memory setup. The information encoded in the optical pulses is stored for 15 ns in the acoustic field. We show the retrieval of eight amplitude levels, multiple consecutive pulses and low distortion in pulse shape. The extension of Brillouin-based storage to the ultra-short pulse regime is an important step for the realisation of practical Brillouin-based delay lines and other optical processing applications.Comment: 6 pages, 6 figure

Benzothiazole and Pyrrolone Flavivirus Inhibitors Targeting the Viral Helicase

The flavivirus nonstructural protein 3 (NS3) is a protease and helicase, and on the basis of its similarity to its homologue encoded by the hepatitis C virus (HCV), the flavivirus NS3 might be a promising drug target. Few flavivirus helicase inhibitors have been reported, in part, because few specific inhibitors have been identified when nucleic acid unwinding assays have been used to screen for helicase inhibitors. To explore the possibility that compounds inhibiting NS3-catalyzed ATP hydrolysis might function as antivirals even if they do not inhibit RNA unwinding in vitro, we designed a robust dengue virus (DENV) NS3 ATPase assay suitable for high-throughput screening. Members of two classes of inhibitory compounds were further tested in DENV helicase-catalyzed RNA unwinding assays, assays monitoring HCV helicase action, subgenomic DENV replicon assays, and cell viability assays and for their ability to inhibit West Nile virus (Kunjin subtype) replication in cells. The first class contained analogues of NIH molecular probe ML283, a benzothiazole oligomer derived from the dye primuline, and they also inhibited HCV helicase and DENV NS3-catalyzed RNA unwinding. The most intriguing ML283 analogue inhibited DENV NS3 with an IC50 value of 500 nM and was active against the DENV replicon. The second class contained specific DENV ATPase inhibitors that did not inhibit DENV RNA unwinding or reactions catalyzed by HCV helicase. Members of this class contained a 4-hydroxy-3-(5-methylfuran-2-carbonyl)-2H-pyrrol-5-one scaffold, and about 20 μM of the most potent pyrrolone inhibited both DENV replicons and West Nile virus replication in cells by 50%

Hero or anti-hero?: Narratives of newswork and journalistic identity construction in complex digital megastories

Exploring constructions of journalistic identity in a digital age has been a lively area of scholarship as the field of digital journalism studies has grown (Franklin 2013, 2014; Steensen and Ahva 2015). Yet despite many approaches to understanding digital change, key avenues for understanding changing constructions of identity remain underexplored. This paper addresses a conceptual void in research literature by employing semiotic and semantic approaches to analyse performances of journalistic identity in narratives of newswork facilitated by and focused on digital megaleaks. It seeks to aid understanding of the way narratives describe changing practices of newsgathering, and how journalists position themselves within these hybrid traditional/digital stories. Findings show news narratives reinforce the primacy of journalists within traditional boundaries of a journalistic field, and articulate a preferred imagination of journalistic identity. Methodologically, this paper shows how semantic and semiotic approaches lend themselves to studying narratives of newswork within journalistic metadiscourses to understand journalistic identity at the nexus of traditional and digital dynamics. The resultant portrait of journalistic identity channels a sociohistoric, romantic notion of the journalist as “the shadowy figure always to be found on the edges of the century’s great events” (Inglis 2002, xi), updated to accommodate modern, digital dynamics

Mutation L319Q in the PB1 Polymerase Subunit Improves Attenuation of a Candidate Live-Attenuated Influenza A Virus Vaccine

15 Pág. Centro de Investigación en Sanidad Animal (CISA)Influenza A viruses (IAV) remain emerging threats to human public health. Live-attenuated influenza vaccines (LAIV) are one of the most effective prophylactic options to prevent disease caused by influenza infections. However, licensed LAIV remain restricted for use in 2- to 49-year-old healthy and nonpregnant people. Therefore, development of LAIV with increased safety, immunogenicity, and protective efficacy is highly desired. The U.S.-licensed LAIV is based on the master donor virus (MDV) A/Ann Arbor/6/60 H2N2 backbone, which was generated by adaptation of the virus to growth at low temperatures. Introducing the genetic signature of the U.S. MDV into the backbone of other IAV strains resulted in varying levels of attenuation. While the U.S. MDV mutations conferred an attenuated phenotype to other IAV strains, the same amino acid changes did not significantly attenuate the pandemic A/California/04/09 H1N1 (pH1N1) strain. To attenuate pH1N1, we replaced the conserved leucine at position 319 with glutamine (L319Q) in PB1 and analyzed the in vitro and in vivo properties of pH1N1 viruses containing either PB1 L319Q alone or in combination with the U.S. MDV mutations using two animal models of influenza infection and transmission, ferrets and guinea pigs. Our results demonstrated that L319Q substitution in the pH1N1 PB1 alone or in combination with the mutations of the U.S. MDV resulted in reduced pathogenicity (ferrets) and transmission (guinea pigs), and an enhanced temperature sensitive phenotype. These results demonstrate the feasibility of generating an attenuated MDV based on the backbone of a contemporary pH1N1 IAV strain. IMPORTANCE Vaccination represents the most effective strategy to reduce the impact of seasonal IAV infections. Although LAIV are superior in inducing protection and sterilizing immunity, they are not recommended for many individuals who are at high risk for severe disease. Thus, development of safer and more effective LAIV are needed. A concern with the current MDV used to generate the U.S.-licensed LAIV is that it is based on a virus isolated in 1960. Moreover, mutations that confer the temperature-sensitive, cold-adapted, and attenuated phenotype of the U.S. MDV resulted in low level of attenuation in the contemporary pandemic A/California/04/09 H1N1 (pH1N1). Here, we show that introduction of PB1 L319Q substitution, alone or in combination with the U.S. MDV mutations, resulted in pH1N1 attenuation. These findings support the development of a novel LAIV MDV based on a contemporary pH1N1 strain as a medical countermeasure against currently circulating H1N1 IAV.This research was partially funded by the New York Influenza Center of Excellence (NYICE) (HHSN 272201400005C), and Emory-UGA (HHSN 272201400004C), members of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Department of Health and Human Services, Centers of Excellence for Influenza Research and Surveillance (CEIRS) network. The work was also supported by grants W81XWH-18-1-0460-PRMRP-DA (to L.M.-S.) and W81XWH-17-1-0168 (to S.D.) from the Department of Defense (DoD) Peer Reviewed Medical Research Program (PRMRP), as well as NIH R01 AI145332-01 (to L.M.-S.). This research was also partly funded by NIAID grant P01AI097092, by CEIRR (Center for Research on Influenza Pathogenesis and Transmission), a NIAID funded Center of Excellence for Influenza Research and Response (CEIRR, contract # 75N93021C00014) and by the Collaborative Influenza Vaccine Innovation Centers NIAID contract 75N93019C00051 to AG-S. A.N. received a “Ramon y Cajal” Incorporation grant (RYC-2017) from the Spanish Ministry of Science, Innovation. Finally, A.C. received support from NIH grants T32GM068411 and T32GM007356. Use of the Zeiss AxioImager.Z2 microscope and image analysis was performed at the Microscopy CoRE at the Icahn School of Medicine at Mount Sinai.Peer reviewe

Alteration of the unfolded protein response modifies neurodegeneration in a mouse model of Marinesco–Sjögren syndrome

Endoplasmic reticulum (ER) stress has been linked to the onset and progression of many diseases. SIL1 is an adenine nucleotide exchange factor of the essential ER lumen chaperone HSPA5/BiP that senses ER stress and is involved in protein folding. Mutations in the Sil1 gene have been associated with Marinesco–Sjögren syndrome, hallmarks of which include ataxia and cerebellar atrophy. We have previously shown that loss of SIL1 function in mouse results in ER stress, ubiquitylated protein inclusions, and degeneration of specific Purkinje cells in the cerebellum. Here, we report that overexpression of HYOU1/ORP150, an exchange factor that works in parallel to SIL1, prevents ER stress and rescues neurodegeneration in Sil1−/− mice, whereas decreasing expression of HYOU1 exacerbates these phenotypes. In addition, loss of DNAJC3/p58IPK, a co-chaperone that promotes ATP hydrolysis by BiP, ameliorates ER stress and neurodegeneration in Sil1−/− mice. These findings suggest that alterations in the nucleotide exchange cycle of BiP cause ER stress and neurodegeneration in Sil1-deficient mice. Our results present the first evidence of important genetic modifiers of Marinesco–Sjögren syndrome, and provide additional pathways for therapeutic intervention for this, and other ER stress-induced, diseases