Safety of continuing mineralocorticoid receptor antagonist treatment in patients with heart failure with reduced ejection fraction and severe kidney disease: Data from Swedish Heart Failure Registry

AIMS Mineralocorticoid receptor antagonists (MRAs) improve outcomes in heart failure with reduced ejection fraction (HFrEF) but remain underused and are often discontinued especially in patients with chronic kidney disease (CKD) due to concerns on renal safety. Therefore, in a real-world HFrEF population we investigated the safety of MRA use, in terms of risk of renal events, any mortality and any hospitalization, across the estimated glomerular filtration rate (eGFR) spectrum including severe CKD. METHODS AND RESULTS We analysed patients with HFrEF (ejection fraction <40%), not on dialysis, from the Swedish Heart Failure Registry. We performed multivariable logistic regression models to investigate patient characteristics independently associated with MRA use, and univariable and multivariable Cox regression models to assess the associations between MRA use and outcomes. Of 33 942 patients, 17 489 (51%) received MRA, 32%, 45%, 54%, 54% with eGFR <30, 30-44, 45-59 or ≥60 ml/min/1.73 m$^{2}$ , respectively. An eGFR ≥60 ml/min/1.73 m$^{2}$ and patient characteristics linked with more severe HF were independently associated with more likely MRA use. In multivariable analyses, MRA use was consistently not associated with a higher risk of renal events (i.e. composite of dialysis/renal death/hospitalization for renal failure or hyperkalaemia) (hazard ratio [HR] 1.04, 95% confidence interval [CI] 0.98-1.10), all-cause death (HR 1.02, 95% CI 0.97-1.08) as well as of all-cause hospitalization (HR 0.99, 95% CI 0.95-1.02) across the eGFR spectrum including also severe CKD. CONCLUSIONS The use of MRAs in patients with HFrEF decreased with worse renal function; however their safety profile was demonstrated to be consistent across the entire eGFR spectrum

Clinical and Cost-Effectiveness of PSYCHOnlineTHERAPY: Study Protocol of a Multicenter Blended Outpatient Psychotherapy Cluster Randomized Controlled Trial for Patients With Depressive and Anxiety Disorders

Introduction: Internet- and mobile-based interventions (IMIs) and their integration into routine psychotherapy (i.e., blended therapy) can offer a means of complementing psychotherapy in a flexible and resource optimized way. Objective: The present study will evaluate the non-inferiority, cost-effectiveness, and safety of two versions of integrated blended psychotherapy for depression and anxiety compared to standard cognitive behavioral therapy (CBT). Methods: A three-armed multicenter cluster-randomized controlled non-inferiority trial will be conducted comparing two implementations of blended psychotherapy (PSYCHOnlineTHERAPYfix/flex) compared to CBT. Seventy-five outpatient psychotherapists with a CBT-license will be randomized in a 1:1:1 ratio. Each of them is asked to include 12 patients on average with depressive or anxiety disorders resulting in a total sample size of N = 900. All patients receive up to a maximum of 16 psychotherapy sessions, either as routine CBT or alternating with Online self-help sessions (fix: 8/8; flex: 0–16). Assessments will be conducted at patient study inclusion (pre-treatment) and 6, 12, 18, and 24 weeks and 12 months post-inclusion. The primary outcome is depression and anxiety severity at 18 weeks post-inclusion (post-treatment) using the Patient Health Questionnaire Anxiety and Depression Scale. Secondary outcomes are depression and anxiety remission, treatment response, health-related quality of life, patient satisfaction, working alliance, psychotherapy adherence, and patient safety. Additionally, several potential moderators and mediators including patient characteristics and attitudes toward the interventions will be examined, complemented by ecological day-to-day digital behavior variables via passive smartphone sensing as part of an integrated smart-sensing sub-study. Data-analysis will be performed on an intention-to-treat basis with additional per-protocol analyses. In addition, cost-effectiveness and cost-utility analyses will be conducted from a societal and a public health care perspective. Additionally, qualitative interviews on acceptance, feasibility, and optimization potential will be conducted and analyzed. Discussion: PSYCHOnlineTHERAPY will provide evidence on blended psychotherapy in one of the largest ever conducted psychotherapy trials. If shown to be non-inferior and cost-effective, PSYCHOnlineTHERAPY has the potential to innovate psychotherapy in the near future by extending the ways of conducting psychotherapy. The rigorous health care services approach will facilitate a timely implementation of blended psychotherapy into standard care

Management of emerging multidrug-resistant tuberculosis in a low-prevalence setting

AbstractMultidrug-resistant (MDR) tuberculosis (TB) is an emerging concern in communities with a low TB prevalence and a high standard of public health. Twenty-three consecutive adult MDR TB patients who were treated at our institution between 2007 and 2013 were reviewed for demographic characteristics and anti-TB treatment management, which included surgical procedures and long-term patient follow-up. This report of our experience emphasizes the need for an individualized approach as MDR TB brings mycobacterial disease management to a higher level of expertise, and for a balance to be found between international current guidelines and patient-tailored treatment strategies

Identification of the gC1qR sites for the HIV-1 viral envelope protein gp41 and the HCV core protein: Implications in viral-specific pathogenesis and therapy

A substantial body of evidence accumulated over the past 20 years supports the concept that gC1qR is a major pathogen-associated pattern recognition receptor (PRR). This conclusion is based on the fact that, a wide range of bacterial and viral ligands are able to exploit gC1qR to either suppress the host’s immune response and thus enhance their survival, or to gain access into cells to initiate disease. Of the extensive array of viral ligands that have affinity for gC1qR, the HIV-1 envelope glycoprotein gp41, and the core protein of hepatitis C virus (HCV) are of major interest as they are known to contribute to the high morbidity and mortality caused by these pathogens. While the HCV core protein binds gC1qR and suppresses T cell proliferation resulting in a significantly diminished immune response, the gp41 employs gC1qR to induce the surface expression of the NK cell ligand, NKp44L, on uninfected CD4+ T cells, thereby rendering them susceptible to autologous destruction by NKp44 receptor expressing NK cells. Because of the potential for the design of peptide-based or antibody-based therapeutic options, the present studies were undertaken to define the gC1qR interaction sites for these pathogen-associated molecular ligands. Employing a solid phase microplate-binding assay, we examined the binding of each viral ligand to wild type gC1qR and 11 gC1qR deletion mutants. The results obtained from these studies have identified two major HCV core protein sites on a domain of gC1qR comprising of residues 144-148 and 196-202. Domain 196-202 in turn, is located in the last half of the larger gC1qR segment encoded by exons IV-VI (residues 159-282), which was proposed previously to contain the site for HCV core protein. The major gC1qR site for gp41 on the other hand, was found to be in a highly conserved region encoded by exon IV and comprises of residues 174-180. Interestingly, gC1qR residues 174-180 also constitute the cell surface-binding site for soluble gC1qR (sgC1qR), which can bind to the cell surface in an autocrine/paracrine manner via surface expressed fibrinogen or other membrane molecules. The identification of the sites for these viral ligands should therefore provide additional targets for the design of peptide-based or antigen-based therapeutic strategies

Basal Immunoglobulin Signaling Actively Maintains Developmental Stage in Immature B Cells

In developing B lymphocytes, a successful V(D)J heavy chain (HC) immunoglobulin (Ig) rearrangement establishes HC allelic exclusion and signals pro-B cells to advance in development to the pre-B stage. A subsequent functional light chain (LC) rearrangement then results in the surface expression of IgM at the immature B cell stage. Here we show that interruption of basal IgM signaling in immature B cells, either by the inducible deletion of surface Ig via Cre-mediated excision or by incubating cells with the tyrosine kinase inhibitor herbimycin A or the phosphatidylinositol 3-kinase inhibitor wortmannin, led to a striking “back-differentiation” of cells to an earlier stage in B cell development, characterized by the expression of pro-B cell genes. Cells undergoing this reversal in development also showed evidence of new LC gene rearrangements, suggesting an important role for basal Ig signaling in the maintenance of LC allelic exclusion. These studies identify a previously unappreciated level of plasticity in the B cell developmental program, and have important implications for our understanding of central tolerance mechanisms

Brain Region–Specific Decrease in the Activity and Expression of Protein Kinase A in the Frontal Cortex of Regressive Autism

Autism is a severe neurodevelopmental disorder that is characterized by impaired language, communication, and social skills. In regressive autism, affected children first show signs of normal social and language development but eventually lose these skills and develop autistic behavior. Protein kinases are essential in G-protein-coupled, receptor-mediated signal transduction and are involved in neuronal functions, gene expression, memory, and cell differentiation. We studied the activity and expression of protein kinase A (PKA), a cyclic AMP–dependent protein kinase, in postmortem brain tissue samples from the frontal, temporal, parietal, and occipital cortices, and the cerebellum of individuals with regressive autism; autistic subjects without a clinical history of regression; and age-matched developmentally normal control subjects. The activity of PKA and the expression of PKA (C-α), a catalytic subunit of PKA, were significantly decreased in the frontal cortex of individuals with regressive autism compared to control subjects and individuals with non-regressive autism. Such changes were not observed in the cerebellum, or the cortices from the temporal, parietal, and occipital regions of the brain in subjects with regressive autism. In addition, there was no significant difference in PKA activity or expression of PKA (C-α) between non-regressive autism and control groups. These results suggest that regression in autism may be associated, in part, with decreased PKA-mediated phosphorylation of proteins and abnormalities in cellular signaling

Genomic footprints of activated telomere maintenance mechanisms in cancer.

Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXXtrunc) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXXtrunc tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer

Global collision-risk hotspots of marine traffic and the world’s largest fish, the whale shark

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Womersley, F. C., Humphries, N. E., Queiroz, N., Vedor, M., da Costa, I., Furtado, M., Tyminski, J. P., Abrantes, K., Araujo, G., Bach, S. S., Barnett, A., Berumen, M. L., Bessudo Lion, S., Braun, C. D., Clingham, E., Cochran, J. E. M., de la Parra, R., Diamant, S., Dove, A. D. M., Dudgeon, C. L., Erdmann, M. V., Espinoza, E., Fitzpatrick, R., González Cano, J., Green, J. R., Guzman, H. M., Hardenstine, R., Hasan, A., Hazin, F. H. V., Hearn, A. R., Hueter, R. E., Jaidah, M. Y., Labaja, J., Ladinol, F., Macena, B. C. L., Morris Jr., J. J., Norman, B. M., Peñaherrera-Palmav, C., Pierce, S. J., Quintero, L. M., Ramırez-Macías, D., Reynolds, S. D., Richardson, A. J., Robinson, D. P., Rohner, C. A., Rowat, D. R. L., Sheaves, M., Shivji, M. S., Sianipar, A. B., Skomal, G. B., Soler, G., Syakurachman, I., Thorrold, S. R., Webb, D. H., Wetherbee, B. M., White, T. D., Clavelle, T., Kroodsma, D. A., Thums, M., Ferreira, L. C., Meekan, M. G., Arrowsmith, L. M., Lester, E. K., Meyers, M. M., Peel, L. R., Sequeira, A. M. M., Eguıluz, V. M., Duarte, C. M., & Sims, D. W. Global collision-risk hotspots of marine traffic and the world’s largest fish, the whale shark. Proceedings of the National Academy of Sciences of the United States of America, 119(20), (2022): e2117440119, https://doi.org/10.1073/pnas.2117440119.Marine traffic is increasing globally yet collisions with endangered megafauna such as whales, sea turtles, and planktivorous sharks go largely undetected or unreported. Collisions leading to mortality can have population-level consequences for endangered species. Hence, identifying simultaneous space use of megafauna and shipping throughout ranges may reveal as-yet-unknown spatial targets requiring conservation. However, global studies tracking megafauna and shipping occurrences are lacking. Here we combine satellite-tracked movements of the whale shark, Rhincodon typus, and vessel activity to show that 92% of sharks’ horizontal space use and nearly 50% of vertical space use overlap with persistent large vessel (>300 gross tons) traffic. Collision-risk estimates correlated with reported whale shark mortality from ship strikes, indicating higher mortality in areas with greatest overlap. Hotspots of potential collision risk were evident in all major oceans, predominantly from overlap with cargo and tanker vessels, and were concentrated in gulf regions, where dense traffic co-occurred with seasonal shark movements. Nearly a third of whale shark hotspots overlapped with the highest collision-risk areas, with the last known locations of tracked sharks coinciding with busier shipping routes more often than expected. Depth-recording tags provided evidence for sinking, likely dead, whale sharks, suggesting substantial “cryptic” lethal ship strikes are possible, which could explain why whale shark population declines continue despite international protection and low fishing-induced mortality. Mitigation measures to reduce ship-strike risk should be considered to conserve this species and other ocean giants that are likely experiencing similar impacts from growing global vessel traffic.Funding for data analysis was provided by the UK Natural Environment Research Council (NERC) through a University of Southampton INSPIRE DTP PhD Studentship to F.C.W. Additional funding for data analysis was provided by NERC Discovery Science (NE/R00997/X/1) and the European Research Council (ERC-AdG-2019 883583 OCEAN DEOXYFISH) to D.W.S., Fundação para a Ciência e a Tecnologia (FCT) under PTDC/BIA/28855/2017 and COMPETE POCI-01–0145-FEDER-028855, and MARINFO–NORTE-01–0145-FEDER-000031 (funded by Norte Portugal Regional Operational Program [NORTE2020] under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund–ERDF) to N.Q. FCT also supported N.Q. (CEECIND/02857/2018) and M.V. (PTDC/BIA-COM/28855/2017). D.W.S. was supported by a Marine Biological Association Senior Research Fellowship. All tagging procedures were approved by institutional ethical review bodies and complied with all relevant ethical regulations in the jurisdictions in which they were performed. Details for individual research teams are given in SI Appendix, section 8. Full acknowledgments for tagging and field research are given in SI Appendix, section 7. This research is part of the Global Shark Movement Project (https://www.globalsharkmovement.org)

VLPs and particle strategies for cancer vaccines

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Global Spatial Risk Assessment of Sharks Under the Footprint of Fisheries

Effective ocean management and conservation of highly migratory species depends on resolving overlap between animal movements and distributions and fishing effort. Yet, this information is lacking at a global scale. Here we show, using a big-data approach combining satellite-tracked movements of pelagic sharks and global fishing fleets, that 24% of the mean monthly space used by sharks falls under the footprint of pelagic longline fisheries. Space use hotspots of commercially valuable sharks and of internationally protected species had the highest overlap with longlines (up to 76% and 64%, respectively) and were also associated with significant increases in fishing effort. We conclude that pelagic sharks have limited spatial refuge from current levels of high-seas fishing effort. Results demonstrate an urgent need for conservation and management measures at high-seas shark hotspots and highlight the potential of simultaneous satellite surveillance of megafauna and fishers as a tool for near-real time, dynamic management