The Suv39H1 methyltransferase inhibitor chaetocin causes induction of integrated HIV-1 without producing a T cell response

AbstractLatent HIV-1 (human immunodeficiency virus-1) provirus is unaffected by current AIDS (acquired immunodeficiency syndrome) therapies. We show here that chaetocin, an SUV39H1 histone methyltransferase inhibitor, causes 25-fold induction of latent HIV-1 expression, while producing minimal toxicity and without causing T cell activation. Induction is associated with loss of histone H3 lysine 9 (H3K9) trimethylation at the long terminal repeat (LTR) promoter, and a corresponding increase in H3K9 acetylation. The effect of chaetocin is amplified synergistically in combination with histone deacetylase (HDAC) inhibitors. These results indicate that chaetocin may provide a therapy to purge cells of latent HIV-1, possibly in combination with other chromatin remodeling drugs

Comparing knowledge, accessibility, and use of evidence-based chronic disease prevention processes across four countries

<p>Background: Evidence-based chronic disease prevention (EBCDP) effectively reduces incidence rates of many chronic diseases, but contextual factors influence the implementation of EBCDP worldwide. This study aims to examine the following contextual factors across four countries: knowledge, access, and use of chronic disease prevention processes.</p><p>Methods: In this cross-sectional study, public health practitioners (N = 400) from Australia (n = 121), Brazil (n = 76), China (n = 102), and the United States (n = 101) completed a 26-question survey on EBCDP. One-way ANOVA and Pearson's Chi-Square tests were used to assess differences in contextual factors of interest by country.</p><p>Results: Practitioners in China reported less knowledge of EBCDP processes (p < 0.001) and less use of repositories of evidence-based interventions, than those from other countries (p < 0.001). Academic journals were the most frequently used method for accessing information about evidence-based interventions across countries. When selecting interventions, Brazilian and Chinese practitioners were more likely to consider implementation ease while the Australian and United States practitioners were more likely to consider effectiveness (p < 0.001).</p><p>Conclusions: These findings can help inform and improve within and across country strategies for implementing EBCDP interventions.</p

Spitzer view on the evolution of star-forming galaxies from z=0 to z~3

We use a 24 micron selected sample containing more than 8,000 sources to study the evolution of star-forming galaxies in the redshift range from z=0 to z~3. We obtain photometric redshifts for most of the sources in our survey using a method based on empirically-built templates spanning from ultraviolet to mid-infrared wavelengths. The accuracy of these redshifts is better than 10% for 80% of the sample. The derived redshift distribution of the sources detected by our survey peaks at around z=0.6-1.0 (the location of the peak being affected by cosmic variance), and decays monotonically from z~1 to z~3. We have fitted infrared luminosity functions in several redshift bins in the range 0<z<~3. Our results constrain the density and/or luminosity evolution of infrared-bright star-forming galaxies. The typical infrared luminosity (L*) decreases by an order of magnitude from z~2 to the present. The cosmic star formation rate (SFR) density goes as (1+z)^{4.0\pm0.2} from z=0 to z=0.8. From z=0.8 to z~1.2, the SFR density continues rising with a smaller slope. At 1.2<z<3, the cosmic SFR density remains roughly constant. The SFR density is dominated at low redshift (z<0.5) by galaxies which are not very luminous in the infrared (L_TIR<1.e11 L_sun, where L_TIR is the total infrared luminosity, integrated from 8 to 1000 micron). The contribution from luminous and ultraluminous infrared galaxies (L_TIR>1.e11 L_sun) to the total SFR density increases steadily from z~0 up to z~2.5, forming at least half of the newly-born stars by z~1.5. Ultraluminous infrared galaxies (L_TIR>1.e12 L_sun) play a rapidly increasing role for z>~1.3.Comment: 28 pages, 17 figures, accepted for publication in Ap

IMI – Clinical Management Guidelines Report

Best practice clinical guidelines for myopia control involve an understanding of the epidemiology of myopia, risk factors, visual environment interventions, and optical and pharmacologic treatments, as well as skills to translate the risks and benefits of a given myopia control treatment into lay language for both the patient and their parent or caregiver. This report details evidence-based best practice management of the pre-, stable, and the progressing myope, including risk factor identification, examination, selection of treatment strategies, and guidelines for ongoing management. Practitioner considerations such as informed consent, prescribing off-label treatment, and guides for patient and parent communication are detailed. The future research directions of myopia interventions and treatments are discussed, along with the provision of clinical references, resources, and recommendations for continuing professional education in this growing area of clinical practice

A positron emission tomography imaging study to confirm target engagement in the lungs of patients with idiopathic pulmonary fibrosis following a single dose of a novel inhaled αvβ6 integrin inhibitor

© 2020 The Author(s). Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvβ6) integrin inhibitor, in participants with IPF. Methods: This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: Baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvβ6-specific ligand, [18F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (VT), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in VT > 0%) of ≥80%. Results: Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected VT at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI:-9 to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination. Conclusions: This study demonstrated engagement of the αvβ6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug. Trial registration: Clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017

In Vitro vs In Silico Detected SNPs for the Development of a Genotyping Array: What Can We Learn from a Non-Model Species?

Background: There is considerable interest in the high-throughput discovery and genotyping of single nucleotide polymorphisms (SNPs) to accelerate genetic mapping and enable association studies. This study provides an assessment of EST-derived and resequencing-derived SNP quality in maritime pine (Pinus pinaster Ait.), a conifer characterized by a huge genome size (~23.8 Gb/C). [br/] Methodology/Principal Findings: A 384-SNPs GoldenGate genotyping array was built from i/ 184 SNPs originally detected in a set of 40 re-sequenced candidate genes (in vitro SNPs), chosen on the basis of functionality scores, presence of neighboring polymorphisms, minor allele frequencies and linkage disequilibrium and ii/ 200 SNPs screened from ESTs (in silico SNPs) selected based on the number of ESTs used for SNP detection, the SNP minor allele frequency and the quality of SNP flanking sequences. The global success rate of the assay was 66.9%, and a conversion rate (considering only polymorphic SNPs) of 51% was achieved. In vitro SNPs showed significantly higher genotyping-success and conversion rates than in silico SNPs (+11.5% and +18.5%, respectively). The reproducibility was 100%, and the genotyping error rate very low (0.54%, dropping down to 0.06% when removing four SNPs showing elevated error rates). [br/] Conclusions/Significance: This study demonstrates that ESTs provide a resource for SNP identification in non-model species, which do not require any additional bench work and little bio-informatics analysis. However, the time and cost benefits of in silico SNPs are counterbalanced by a lower conversion rate than in vitro SNPs. This drawback is acceptable for population-based experiments, but could be dramatic in experiments involving samples from narrow genetic backgrounds. In addition, we showed that both the visual inspection of genotyping clusters and the estimation of a per SNP error rate should help identify markers that are not suitable to the GoldenGate technology in species characterized by a large and complex genome

Guidelines for studying diverse types of compound weather and climate events

Compound weather and climate events are combinations of climate drivers and/or hazards that contribute to societal or environmental risk. Studying compound events often requires a multidisciplinary approach combining domain knowledge of the underlying processes with, for example, statistical methods and climate model outputs. Recently, to aid the development of research on compound events, four compound event types were introduced, namely (1) preconditioned, (2) multivariate, (3) temporally compounding, and (4) spatially compounding events. However, guidelines on how to study these types of events are still lacking. Here, we consider four case studies, each associated with a specific event type and a research question, to illustrate how the key elements of compound events (e.g., analytical tools and relevant physical effects) can be identified. These case studies show that (1) impacts on crops from hot and dry summers can be exacerbated by preconditioning effects of dry and bright springs. (2) Assessing compound coastal flooding in Perth (Australia) requires considering the dynamics of a non-stationary multivariate process. For instance, future mean sea-level rise will lead to the emergence of concurrent coastal and fluvial extremes, enhancing compound flooding risk. (3) In Portugal, deep-landslides are often caused by temporal clusters of moderate precipitation events. Finally, (4) crop yield failures in France and Germany are strongly correlated, threatening European food security through spatially compounding effects. These analyses allow for identifying general recommendations for studying compound events. Overall, our insights can serve as a blueprint for compound event analysis across disciplines and sectors

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570