tbuckley/cabot-search huggingface dataset:
Efficacy and safety of selexipag in patients with inoperable or persistent/recurrent CTEPH (SELECT randomised trial)
Authors: Nick H Kim, Richard Channick, Marion Delcroix, Michael Madani, Joanna Pepke-Zaba, Julian I Borissoff, Valerie Easton, Sophie Gesang, Dominik Richard, Hossein-Ardeschir Ghofrani
Journal: European Respiratory Journal (2024)

Background SELECT was the first global randomised controlled trial of selexipag with standard of care in patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension. Methods SELECT was a multicentre, randomised, double-blind, placebo-controlled, parallel-group, group-sequential, phase 3 study ( NCT03689244 ). Adults aged ≤85 years in WHO functional class I–IV, with a 6-minute walk distance (6 MWD) of 100–450 m, were randomised (1:1) to receive selexipag (200–1600 µg b.i.d. titration until individual maximum tolerated dose)+standard of care or placebo+standard of care. Patients were recruited into the haemodynamic set (first 91 randomised patients to undergo right heart catheterisation [RHC]; Week 20) or non-haemodynamic cohort (remaining patients, no RHC required). Primary endpoint was percent of baseline pulmonary vascular resistance (PVR; Week 20). Safety was also assessed. Results Of 321 patients screened, 128 were randomised (haemodynamic set: n=91 [selexipag: n=47; placebo: n=44]). In the haemodynamic set, 29 (31.9%) patients had previous pulmonary endarterectomy (PEA), 20 (22.0%) balloon pulmonary angioplasty (BPA), and 14 (15.4%) both PEA and BPA; 28 (30.8%) were inoperable. The Independent Data Monitoring Committee recommended to stop the study for futility as no statistically significant difference was observed for the primary endpoint (between-treatment geometric least squares mean ratio of PVR: 0.95 [95% CI 0.84, 1.07; p=0.412]). Adverse events were reported in 63 (98.4%) and 53 (82.8%) patients for selexipag and placebo, respectively. Conclusion SELECT was discontinued for futility, as no treatment effect on the primary endpoint (PVR) was observed. Safety data were consistent with the established safety profile of selexipag, with no new safety signals identified.
Integrated nasopharyngeal airway metagenome and asthma genetic risk endotyping of severe bronchiolitis in infancy and risk of childhood asthma
Authors: Zhaozhong Zhu, Ryohei Shibata, Kristi L Hoffman, Juwan Cormier, Jonathan M Mansbach, Liming Liang, Carlos A Camargo, Kohei Hasegawa
Journal: European Respiratory Journal (2024)

The severe bronchiolitis endotype characterized by a high abundance of H. influenzae, high proportion of RV-A and RV-C infections, and high asthma genetic risk had a significantly higher risk for developing asthma. Background Infants with bronchiolitis are at increased risk for developing asthma. Growing evidence suggests bronchiolitis is a heterogeneous condition. However, little is known about its biologically distinct subgroups based on the integrated metagenome and asthma genetic risk signature and their longitudinal relationships with asthma development. Methods In a multi-center prospective cohort study of infants with severe bronchiolitis ( i.e. , bronchiolitis requiring hospitalization), we profiled nasopharyngeal airway metagenome and virus at hospitalization, and calculated the polygenic risk score of asthma. Using similarity network fusion clustering approach, we identified integrated metagenome-asthma genetic risk endotypes. We also examined their longitudinal association with the risk of developing asthma by age six years. Results Of 450 infants with bronchiolitis (median age, 3 months), we identified five distinct endotypes—characterized by their nasopharyngeal metagenome, virus, and asthma genetic risk profiles. Compared with endotype A infants (who clinically resembled “classic” bronchiolitis), endotype E infants (characterized by a high abundance of H. influenzae , high proportion of RV-A and RV-C infections, and high asthma genetic risk) had a significantly higher risk for developing asthma (35.9% versus 16.7%; OR adj , 2.24; 95%CI, 1.02–4.97; p=0.046). The pathway analysis showed that endotype E had enriched microbial pathways ( e.g. , glycolysis, L-lysine, arginine metabolism) and host pathways ( e.g. , IFNs, IL-6/JAK/STAT3, fatty acids, MHC, and immunoglobin-related) (FDR&lt;0.05). Additionally, endotype E had a significantly higher proportion of neutrophils (FDR&lt;0.05). Conclusion In this multi-center prospective cohort study of infant bronchiolitis, the clustering analysis of integrated-omics data identified biologically distinct endotypes with differential risks for developing asthma.
Clinical response and on-treatment clinical remission with tezepelumab in a broad population of patients with severe, uncontrolled asthma: results over 2 years from the NAVIGATOR and DESTINATION studies
Authors: Michael E Wechsler, Guy Brusselle, J Christian Virchow, Arnaud Bourdin, Konstantinos Kostikas, Jean-Pierre Llanos, Stephanie L Roseti, Christopher S Ambrose, Gillian Hunter, David J Jackson, Mario Castro, Njira Lugogo, Ian D Pavord, Neil Martin, Christopher E Brightling
Journal: European Respiratory Journal (2024)

Background In asthma, clinical response is characterized by disease improvement with treatment, whereas clinical remission is characterized by long-term disease stabilization with or without ongoing treatment. The proportion of patients receiving tezepelumab who responded to treatment and those who achieved on-treatment clinical remission was assessed in the NAVIGATOR ( NCT03347279 ) and DESTINATION ( NCT03706079 ) studies of severe, uncontrolled asthma. Methods NAVIGATOR and DESTINATION were phase 3, randomized, double-blind, placebo-controlled studies; DESTINATION was an extension of NAVIGATOR. Complete clinical response was defined as achieving all of the following: ≥50% reduction in exacerbations versus the previous year, improvements in pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV 1 ) of ≥100 mL or ≥5%, improvements in Asthma Control Questionnaire (ACQ)-6 score of ≥0.5 and physicians’ assessment of asthma improvement. On-treatment clinical remission was defined as an ACQ-6 total score ≤1.5, stable lung function (pre-BD FEV 1 &gt;95% of baseline) and no exacerbations or use of oral corticosteroids during the time periods assessed. Results Higher proportions of tezepelumab than placebo recipients achieved complete clinical response over weeks 0–52 (46% versus 24%; OR: 2.83 [95% CI: 2.10–3.82]), and on-treatment clinical remission over weeks 0–52 (28.5% versus 21.9%; OR: 1.44 [95% CI: 0.95–2.19]) and weeks &gt;52–104 (33.5% versus 26.7%; OR: 1.44 [95% CI: 0.97–2.14]). Tezepelumab recipients who achieved on-treatment clinical remission versus complete clinical response at week 52 had better preserved lung function and lower inflammatory biomarkers at baseline, and fewer exacerbations in the 12 months before the study. Conclusions Among patients with severe, uncontrolled asthma, tezepelumab treatment was associated with an increased likelihood of achieving complete clinical response and on-treatment clinical remission compared with placebo. Both are clinically important outcomes but may be driven by different patient characteristics.
Decline in Vaccination Coverage by Age 24 Months and Vaccination Inequities Among Children Born in 2020 and 2021 — National Immunization Survey-Child, United States, 2021–2023
Authors: Holly A. Hill, David Yankey, Laurie D. Elam-Evans, Yi Mu, Michael Chen, Georgina Peacock, James A. Singleton
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Data from the National Immunization Survey-Child (NIS-Child) were analyzed to estimate coverage with childhood vaccines recommended by the Advisory Committee on Immunization Practices among U.S. children by age 24 months. Coverage with nearly all vaccines was lower among children born in 2020 and 2021 than it was among those born in 2018 and 2019, with declines ranging from 1.3 to 7.8 percentage points. Analyses of NIS-Child data for earlier birth cohorts have not revealed such widespread declines in routine childhood vaccination coverage. Coverage among children born during 2020-2021 varied by race and ethnicity, health insurance status, poverty status, urbanicity, and jurisdiction. Compared with non-Hispanic White children, coverage with four of the 17 vaccine measures was lower among non-Hispanic Black or African American children as well as Hispanic or Latino (Hispanic) and non-Hispanic American Indian or Alaska Native children. Coverage was also generally lower among those covered by Medicaid or other nonprivate insurance, uninsured children, children living below the federal poverty level, and children living in rural areas. Coverage varied widely by jurisdiction, especially coverage with ≥2 doses of influenza vaccine. Children born during 2020-2021 were born during or after the period of major disruption of primary care from the COVID-19 pandemic. Providers should review children's histories and recommend needed vaccinations during every clinical encounter. Addressing financial barriers, access issues, vaccine hesitancy, and vaccine-related misinformation can also help to increase coverage, reduce disparities, and protect all children from vaccine-preventable diseases. Strategies that have been found effective include implementation of standing orders and reminder and recall systems, strong physician recommendations to vaccinate, and use of immunization information systems to identify areas of lower coverage that could benefit from targeted interventions to increase immunization rates.
Vaccination Coverage by Age 24 Months Among Children Born During 2017–2021 — U.S.-Affiliated Pacific Islands
Authors: Ashley Tippins, E.M. Boyd, Kelsey C. Coy, Glodi Mutamba, Jennifer L. Kriss
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Childhood vaccination is one of the most successful public health interventions to improve life expectancy, decrease health care costs, and reduce the spread of preventable diseases. Using data from jurisdictional immunization information systems, vaccination coverage by age 24 months among children born during 2017-2021 in the U.S.-affiliated Pacific Islands was estimated for all vaccines included in jurisdictional programs. Progress toward the U.S. Healthy People 2030 and World Health Organization Immunization Agenda 2030 vaccination goals of ≥90% coverage by age 24 months with recommended vaccines was inconsistently met across jurisdictions. For example, coverage by age 24 months with ≥1 dose of measles, mumps, and rubella vaccine ranged from 68.2% to 91.6% by birth cohort in Federated States of Micronesia and from 87.4% to 96.6% in Palau; coverage with ≥4 doses of diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) ranged from 39.6% to 60.6% in Federated States of Micronesia and from 73.4% to 85.4% in Palau. Coverage as of June 1, 2024, increased for all vaccines across all jurisdictions and birth cohorts, indicating catch-up vaccination after age 24 months. For example, coverage with ≥4 doses of DTaP by June 1, 2024, ranged from 74.0% to 84.4% in American Samoa by birth cohort and from 91.6% to 94.8% in Palau. This report is the first comprehensive analysis of trends in childhood vaccination coverage in the U.S.-affiliated Pacific Islands; data in this report can be used to determine where additional efforts are needed to assess reasons for delayed vaccination of children and strategies to mitigate vaccination delays, specific to each jurisdiction.
Maternal Respiratory Syncytial Virus Vaccination and Receipt of Respiratory Syncytial Virus Antibody (Nirsevimab) by Infants Aged &lt;8 Months — United States, April 2024
Authors: Hilda Razzaghi, Emma Garacci, Katherine E. Kahn, Megan C. Lindley, Jefferson M. Jones, Shannon Stokley, Kayla Calhoun, Carla L. Black
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Respiratory syncytial virus (RSV) is the most common cause of hospitalization among U.S. infants. CDC recommends RSV vaccination for pregnant persons or administration of RSV antibody (nirsevimab) to infants aged <8 months to prevent RSV lower respiratory tract disease among infants. To determine maternal and infant RSV immunization coverage for the 2023-24 RSV season, CDC conducted an Internet panel survey during March 26-April 11, 2024. Among 678 women at 32-36 weeks' gestation during September 2023-January 2024, 32.6% reported receipt of an RSV vaccine any time during pregnancy. Among 866 women with an infant born during August 2023-March 2024, 44.6% reported receipt of nirsevimab by the infant. Overall, 55.8% of infants were protected by maternal RSV vaccine, nirsevimab, or both. Provider recommendation for maternal vaccination or infant nirsevimab was associated with higher immunization coverage, whereas lack of a provider recommendation was the main reason for not getting RSV immunization. The main reason for definitely or probably not getting nirsevimab for infants was concern about the long-term safety for the infant. Activities supporting providers to make RSV prevention recommendations and have informative conversations with patients might increase the proportion of infants protected against severe RSV disease. CDC and the American College of Obstetricians and Gynecologists have resources to assist providers in effectively communicating the importance of immunization.
COVID-19–Associated Hospitalizations and Maternal Vaccination Among Infants Aged &lt;6 Months — COVID-NET, 12 States, October 2022–April 2024
Authors: Fiona P. Havers, Michael Whitaker, Bhoomija Chatwani, Monica E. Patton, Christopher A. Taylor, Shua J. Chai, Breanna Kawasaki, Kimberly Yousey-Hindes, Kyle P. Openo, Patricia A. Ryan, Lauren Leegwater, Ruth Lynfield, Daniel M. Sosin, Bridget J. Anderson, Brenda Tesini, Melissa Sutton, H. Keipp Talbot, Andrea George, Jennifer Milucky, Darpun Sachdev, Nisha Alden, Emily Zmek, Lucy Witt, Maya L. Monroe, Elizabeth McCormick, Paige D'Heilly, Susan L. Ropp, Kerianne Engesser, Erin Licherdell, Sam Hawkins, William Schaffner, Holly Staten
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Infants aged <6 months are at increased risk for severe COVID-19 disease but are not yet eligible for COVID-19 vaccination; these children depend upon transplacental transfer of maternal antibody, either from vaccination or infection, for protection. COVID-19-Associated Hospitalization Surveillance Network (COVID-NET) data were analyzed to estimate COVID-19-associated hospitalization rates and identify demographic and clinical characteristics and maternal vaccination status of infants aged <6 months hospitalized with laboratory-confirmed COVID-19. During October 2022-April 2024, COVID-NET identified 1,470 COVID-19-associated hospitalizations among infants aged <6 months. COVID-19-associated hospitalization rates among young infants were higher than rates among any other age group, except adults aged ≥75 years, and are comparable to rates among adults aged 65-74 years. The percentage of hospitalized infants whose mothers had been vaccinated during pregnancy was 18% during October 2022-September 2023 and decreased to <5% during October 2023-April 2024. Severe outcomes among infants hospitalized with COVID-19 occurred frequently: excluding newborns hospitalized at birth, approximately one in five young infants hospitalized with COVID-19 required admission to an intensive care unit, nearly one in 20 required mechanical ventilation, and nine infants died during their COVID-19-associated hospitalization. To help protect pregnant persons and infants too young to be vaccinated, prevention for these groups should focus on ensuring that pregnant persons receive recommended COVID-19 vaccines.
Periodontal regeneration using platelet‐rich fibrin. Furcation defects: A systematic review with meta‐analysis
Authors: Richard J. Miron, Vittorio Moraschini, Nathan E. Estrin, Jamil Awad Shibli, Raluca Cosgarea, Karin Jepsen, Pia‐Merete Jervøe‐Storm, Anton Sculean, Søren Jepsen
Journal: Periodontology 2000 (2024)

Abstract The objective of the study was to compare the treatment outcomes of periodontal furcation defects by using platelet‐rich fibrin (PRF) with other commonly utilized modalities. The eligibility criteria comprised randomized controlled trials (RCTs) comparing the clinical outcomes of PRF with those of other modalities for the treatment of furcation defects. Studies were classified into 11 categories in 3 different groups as follows: Group I (addition of PRF): (1) open flap debridement (OFD) alone versus OFD/PRF, (2) OFD/bone graft (OFD/BG) versus OFD/BG/PRF; Group II (comparative studies to PRF): (3) OFD/BG versus OFD/PRF, (4) OFD/collagen membrane versus OFD/PRF, (5) OFD/PRP versus OFD/PRF, (6) OFD/rhBMP2 versus OFD/PRF; and Group III (addition of biomaterial/biomolecule to PRF): OFD/PRF versus … (7) OFD/PRF/BG, (8) OFD/PRF/amniotic membrane (AM), (9) OFD/PRF/metformin, (10) OFD/PRF/bisphosphonates, (11) OFD/PRF/statins. Weighted means and forest plots were calculated for the reduction of probing pocket depth (PPD), gain of vertical and horizontal clinical attachment levels (VCAL and HCAL), gain in vertical and horizontal bone levels (VBL, HBL), and radiographic bone fill (RBF). From 45 articles identified, 21 RCTs reporting on class II furcations were included. The use of OFD/PRF and OFD/BG/PRF statistically significantly reduced PPD and improved VCAL and HCAL when compared to OFD or OFD/BG, respectively. The comparison between OFD/PRF alone versus OFD/BG, OFD/CM, OFD/PRP, or OFD/rhBMP2 led to similar outcomes for all investigated parameters, including a reduction in PPD, VCAL/HCAL gain, and RBF. The additional incorporation of a BG to OFD/PRF only mildly improved outcomes, whereas the addition of AM improved clinical outcomes. The addition of small biomolecules such as metformin, bisphosphonates, or statins all led to significant improvements in PPD, VCAL, and HCAL when compared to OFD/PRF alone. Noteworthy, a very high heterogeneity was found in the investigated studies. The use of PRF significantly improved clinical outcomes in class II furcation defects when compared to OFD alone, with similar levels being observed between OFD/PRF and/or OFD/BG, OFD/CM, OFD/PRP, or OFD/rhBMP2. Future research geared toward better understanding potential ways to enhance the regenerative properties of PRF with various small biomolecules may prove valuable for future clinical applications. Future histological research investigating PRF in human furcation defects is largely needed. The use of PRF in conjunction with OFD statistically significantly improved PPD, VCAL, and HCAL values, yielding comparable outcomes to commonly used biomaterials. The combination of PRF to bone grafts or the addition of small biomolecules may offer additional clinical benefits, thus warranting future investigation.
Tackling exosome and nuclear receptor interaction: an emerging paradigm in the treatment of chronic diseases
Authors: Babu Santha Aswani, Mangala Hegde, Ravichandran Vishwa, Mohammed S Alqahtani, Mohamed Abbas, Hassan Ali Almubarak, Gautam Sethi, Ajaikumar B Kunnumakkara
Journal: Military Medical Research (2024)

Abstract Nuclear receptors (NRs) function as crucial transcription factors in orchestrating essential functions within the realms of development, host defense, and homeostasis of body. NRs have garnered increased attention due to their potential as therapeutic targets, with drugs directed at NRs demonstrating significant efficacy in impeding chronic disease progression. Consequently, these pharmacological agents hold promise for the treatment and management of various diseases. Accumulating evidence emphasizes the regulatory role of exosome-derived microRNAs (miRNAs) in chronic inflammation, disease progression, and therapy resistance, primarily by modulating transcription factors, particularly NRs. By exploiting inflammatory pathways such as protein kinase B (Akt)/mammalian target of rapamycin (mTOR), nuclear factor kappa-B (NF-κB), signal transducer and activator of transcription 3 (STAT3), and Wnt/β-catenin signaling, exosomes and NRs play a pivotal role in the panorama of development, physiology, and pathology. The internalization of exosomes modulates NRs and initiates diverse autocrine or paracrine signaling cascades, influencing various processes in recipient cells such as survival, proliferation, differentiation, metabolism, and cellular defense mechanisms. This comprehensive review meticulously examines the involvement of exosome-mediated NR regulation in the pathogenesis of chronic ailments, including atherosclerosis, cancer, diabetes, liver diseases, and respiratory conditions. Additionally, it elucidates the molecular intricacies of exosome-mediated communication between host and recipient cells via NRs, leading to immunomodulation. Furthermore, it outlines the implications of exosome-modulated NR pathways in the prophylaxis of chronic inflammation, delineates current limitations, and provides insights into future perspectives. This review also presents existing evidence on the role of exosomes and their components in the emergence of therapeutic resistance.
Widespread adaptive introgression of MHC genes across vertebrate hybrid zones
Authors: T Gaczorek, K Dudek, U Fritz, L Bahri-Sfar, S J E Baird, F Bonhomme, C Dufresnes, V Gvoždík, D Irwin, P Kotlík, S Marková, P McGinnity, M Migalska, J Moravec, L Natola, M Pabijan, K P Phillips, Y Schöneberg, A Souissi, J Radwan, W Babik
Journal: Molecular Biology and Evolution (2024)

Abstract Interspecific introgression is a potentially important source of novel variation of adaptive significance. Although multiple cases of adaptive introgression are well documented, broader generalizations about its targets and mechanisms are lacking. Multiallelic balancing selection, particularly when acting through rare allele advantage, is an evolutionary mechanism expected to favor adaptive introgression. This is because introgressed alleles are likely to confer an immediate selective advantage, facilitating their establishment in the recipient species even in the face of strong genomic barriers to introgression. Vertebrate major histocompatibility complex genes are well-established targets of long-term multiallelic balancing selection, so widespread adaptive major histocompatibility complex introgression is expected. Here, we evaluate this hypothesis using data from 29 hybrid zones formed by fish, amphibians, squamates, turtles, birds, and mammals at advanced stages of speciation. The key prediction of more extensive major histocompatibility complex introgression compared to genome-wide introgression was tested with three complementary statistical approaches. We found evidence for widespread adaptive introgression of major histocompatibility complex genes, providing a link between the process of adaptive introgression and an underlying mechanism. Our work identifies major histocompatibility complex introgression as a general mechanism by which species can acquire novel, and possibly regain previously lost, variation that may enhance defense against pathogens and increase adaptive potential.