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The omicron BA.1 bivalent booster is used globally. Previous open-label studies of the omicron BA.1 (Moderna mRNA-1273.214) booster showed superior neutralising antibody responses against omicron BA.1 and other variants compared with the original mRNA-1273 booster. We aimed to compare the safety and immunogenicity of omicron BA.1 monovalent and bivalent boosters with the original mRNA-1273 vaccine in a large, randomised controlled trial. In this large, randomised, observer-blind, active-controlled, phase 3 trial in the UK (28 hospital and vaccination clinic sites), individuals aged 16 years or older who had previously received two injections of any authorised or approved COVID-19 vaccine, with or without an mRNA vaccine booster (third dose), were randomly allocated (1:1) using interactive response technology to receive 50 μg omicron BA.1 monovalent or bivalent vaccines or 50 μg mRNA-1273 administered as boosters via deltoid intramuscular injection. The primary outcomes were safety and immunogenicity at day 29, including prespecified non-inferiority and superiority of booster immune responses, based on the neutralising antibody geometric mean concentration (GMC) ratios of the monovalent and bivalent boosters compared with mRNA-1273. Safety was assessed in all participants who received first or second boosters, and primary immunogenicity outcomes were assessed in all participants who received the planned booster dose, had pre-booster and day 29 antibody data, had no major protocol deviations, and who were SARS-CoV-2-negative. The study is registered with EudraCT (2022-000063-51) and ClinicalTrials.gov (NCT05249829) and is ongoing. Between Feb 16 and March 24, 2022, 724 participants were randomly allocated to receive omicron BA.1 monovalent (n=366) or mRNA-1273 (n=357), and between April 2 and June 17, 2022, 2824 participants were randomly allocated to receive omicron BA.1 bivalent (n=1418) or mRNA-1273 (n=1395) vaccines as second boosters. Median durations (months) between the most recent COVID-19 vaccine and study boosters were similar for omicron BA.1 monovalent (4·0 months [IQR 3·6–4·7]) and mRNA-1273 (4·1 [3·5–4·7]), and for the omicron BA.1 bivalent (5·5 [4·8–6·2]) and mRNA-1273 (5·4 [4·8–6·2]) boosters. The omicron BA.1 monovalent and bivalent boosters elicited superior neutralising GMCs against the omicron BA.1 variant compared with mRNA-1273, with GMC ratios of 1·68 (99% CI 1·45−1·95) and 1·53 (1·41−1·67) at day 29 post-booster doses in participants without previous SARS-CoV-2 infection. Both boosters induced non-inferior ancestral SARS-CoV-2 (Asp614Gly) immune responses with GMCs that were similar for the bivalent (2987·2 [95% CI 2814·9–3169·9]) versus mRNA-1273 (2911·3 [2750·9–3081·0]) and lower for the monovalent (2699·7 [2431·3–2997·7] vs 3020·6 [2776·5–3286·2]) boosters, with respective GMC ratios of 1·05 (99% CI 0·96–1·15) and 0·82 (95% CI 0·74–0·91). Results were comparable regardless of previous SARS-CoV-2 infection status. Incidences of solicited adverse reactions with the omicron BA.1 monovalent (335 [91·3%] of 367 participants) and omicron BA.1 bivalent (1285 [90·4%] of 1421 participants) boosters were similar to those observed previously for mRNA-1273, with no new safety concerns identified and no occurrences of fatal adverse events. Omicron-containing booster vaccines generated superior immunogenicity against omicron BA.1 and comparable immunogenicity against the original strain with no new safety concerns. It remains important to continuously monitor the immune responses and real-world vaccine effectiveness as divergent SARS-CoV-2 variants emerge. Moderna. [ABSTRACT FROM AUTHOR]

Observational studies have identified the potential prognostic value for severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) viral load and anti‐SARS‐CoV‐2 antibodies in coronavirus disease 2019 (COVID‐19). However, viral load in nasopharyngeal (NP) swabs produced inconsistent results in prognostic analyses, and the prognostic value of viral load or antibodies has not been confirmed in large clinical trials. COVACTA and REMDACTA were double‐blind, randomized, controlled trials with a combined enrollment of 1078 patients hospitalized with COVID‐19 treated with tocilizumab or placebo in COVACTA or tocilizumab plus remdesivir or placebo plus remdesivir in REMDACTA. We assessed the potential prognostic value of NP and serum SARS‐CoV‐2 viral load and serum anti‐SARS‐CoV‐2 antibodies at baseline as biomarkers for clinical outcomes in patients enrolled in these trials. In adjusted Cox proportional hazard models, serum viral load was a more reliable predictor of clinical outcomes than NP viral load; high serum viral load was associated with higher risk for death and mechanical ventilation/death and lower likelihood of hospital discharge (high vs. negative viral load hazard ratios [95% confidence interval {CI}] were 2.87 [1.57–5.25], 3.86 [2.23–6.68], and 0.23 [0.14–0.36], respectively, in COVACTA and 8.11 [2.95–22.26], 10.29 [4.5–23.55], and 0.21 [0.15–0.29], respectively, in REMDACTA) and high serum viral load correlated with levels of inflammatory cytokines and lung damage biomarkers. High anti‐SARS‐CoV‐2 spike protein antibody (ACOV2S) levels were associated with higher likelihood of hospital discharge (high vs. below the limit of quantification hazard ratios [95% CI] were 2.55 [1.59–4.08] for COVACTA and 1.54 [1.13–2.09] for REMDACTA). These results support the role of baseline SARS‐CoV‐2 serum viral load and ACOV2S antibody titers in predicting clinical outcomes for patients hospitalized with COVID‐19. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis: To determine the effect of povidone‐iodine (PVP‐I) nasal sprays on nasopharyngeal (NP) viral load as assessed by cycle threshold (Ct) on quantitative polymerase chain reaction (qPCR) of SARS‐CoV‐2 in outpatients. Study Design: Three arm, triple blinded, randomized, placebo‐controlled clinical trial. Methods: Participants were randomized within 5 days of testing positive for COVID‐19 to receive nasal sprays containing placebo (0.9% saline), 0.5% PVP‐I, or 2.0% PVP‐I. NP swabs for qPCR analysis were taken at baseline, 1‐hour post‐PVP‐I spray (two sprays/nostril), and 3 days post‐PVP‐I spray (20 sprays/nostril). Symptom and adverse event questionnaires were completed at baseline, day 3, and day 5. University of Pennsylvania Smell Identification Tests (UPSIT) were completed at baseline and day 30. Results: Mean Ct values increased over time in all groups, indicating declining viral loads, with no statistically significant difference noted in the rate of change between placebo and PVP‐I groups. The 2.0% PVP‐I group showed statistically significant improvement in all symptom categories; however, it also reported a high rate of nasal burning. Olfaction via UPSIT showed improvement by at least one category in all groups. There were no hospitalizations or mortalities within 30 days of study enrollment. Conclusions: Saline and low concentration PVP‐I nasal sprays are well tolerated. Similar reductions in SARS‐CoV‐2 NP viral load were seen over time in all groups. All treatment groups showed improvement in olfaction over 30 days. These data suggest that dilute versions of PVP‐I nasal spray are safe for topical use in the nasal cavity, but that PVP‐I does not demonstrate virucidal activity in COVID‐19 positive outpatients. Level of Evidence: 2 Laryngoscope, 132:2089–2095, 2022 [ABSTRACT FROM AUTHOR]

Background/Aim: Functional endoscopic sinus surgery (FESS) is frequently conducted for restoring sinus ventilation and function. Postoperative care is critical for success. However, loss to follow-up is disturbing. The specific aim of this study was to identify critical factors contributing to loss of patients to follow-up and how to improve it. Patients and Methods: A total of 221 patients with chronic rhinosinusitis undergoing FESS were enrolled. Patients were divided into three groups according to their follow-up after surgery: Less than 1 month (short-term), 1-3 months (medium-term) and more than 3 months (long-term). The gender, age, smoking status, comorbidities, laterality, Lund-Mackay score, 22-question Sinonasal Outcome Test, nasal obstruction Visual Analogue Scale and mucociliary clearance were evaluated for their contribution to better compliance in follow-up. Results: The results revealed that older patients had better compliance in followup compared with younger ones (p=0.0093). Other factors were not contributory (p>0.05). Conclusion: In contrast to the US, older patients in Taiwan have better compliance in postoperative follow-up, while younger ones require more education on the importance of follow-up. [ABSTRACT FROM AUTHOR]

Summary Circadian behavior in mammals is orchestrated by neurons within the suprachiasmatic nucleus (SCN), yet the neuronal population necessary for the generation of timekeeping remains unknown. We show that a subset of SCN neurons expressing the neuropeptide neuromedin S (NMS) plays an essential role in the generation of daily rhythms in behavior. We demonstrate that lengthening period within Nms neurons is sufficient to lengthen period of the SCN and behavioral circadian rhythms. Conversely, mice without a functional molecular clock within Nms neurons lack synchronous molecular oscillations and coherent behavioral daily rhythms. Interestingly, we found that mice lacking Nms and its closely related paralog, Nmu , do not lose in vivo circadian rhythms. However, blocking vesicular transmission from Nms neurons with intact cell-autonomous clocks disrupts the timing mechanisms of the SCN, revealing that Nms neurons define a subpopulation of pacemakers that control SCN network synchrony and in vivo circadian rhythms through intercellular synaptic transmission. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests that chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly heterogeneous disease with disparate inflammatory characteristics between different racial groups and geographies. Currently, little is known about possible underlying distinguishing factors between these inflammatory differences. Our aim was to interrogate differences in CRSwNP disease between White/non-Asian patients and Japanese patients by using whole transcriptome and single-cell RNA gene expression profiling of nasal polyps (NPs). We performed whole transcriptome RNA sequencing with endotype stratification of NPs from 8 White patients (residing in the United States) and 9 Japanese patients (residing in Japan). Reproducibility was confirmed by quantitative PCR in an independent validation set of 46 White and 31 Japanese patients. Single-cell RNA sequencing (scRNAseq) was used to stratify key cell types for contributory transcriptional signatures. Unsupervised clustering analysis identified 2 major endotypes that were present within both cohorts of patients with NPs and had previously been reported at the cytokine level: (1) type 2 endotype and (2) non–type 2 endotype. Importantly, there was a statistically significant difference in the proportion of these endotypes between these geographically distinct subgroups with NPs (P =.03). Droplet-based single-cell RNA sequencing further identified prominent type 2 inflammatory transcript expression: C-C motif chemokine ligand 13 (CCL13) and CCL18 in M2 macrophages, as well as cystatin SN (CST1) and CCL26 in basal, suprabasal, and secretory epithelial cells. NPs from both racial groups harbor the same 2 major endotypes, which we have determined to be present in differing ratios between each cohort with CRSwNP disease. Distinct inflammatory and epithelial cells contribute to the type 2 inflammatory profiles observed. [ABSTRACT FROM AUTHOR]

Abstract: The ability of the sigma1 receptor to interact with a huge range of drug structural classes coupled with its wide distribution in the body has contributed to it being implicated as a possible therapeutic target for a broad array of disorders ranging from substance abuse to depression to Alzheimer''s disease. Surprisingly, the reported affinity values for some sigma1 receptor ligands vary more than 50-fold. The potential of the sigma1 receptor as a pharmacotherapeutic target prompted us to develop an unambiguous assay system for measuring the affinity of ligands to the cloned human sigma1 receptor. In the course of characterizing this system and determining the true affinity values for almost three dozen compounds, it was discovered that some dopamine D4 receptor selective compounds bind sigma1 receptors with high affinity. A systematic analysis of haloperidol-like compounds revealed a clear structure–affinity relationship amongst clinically relevant butyrophenones. The antidepressant fluvoxamine, the drug of abuse methamphetamine, and the neurosteroid progesterone were amongst the many ligands whose interactions with the sigma1 receptor were confirmed with our screening assay. [Copyright &y& Elsevier]

Understanding the mechanisms of HIV tissue persistence necessitates the ability to visualize tissue microenvironments where infected cells reside; however, technological barriers limit our ability to dissect the cellular components of these HIV reservoirs. Here, we developed protein and nucleic acid in situ imaging (PANINI) to simultaneously quantify DNA, RNA, and protein levels within these tissue compartments. By coupling PANINI with multiplexed ion beam imaging (MIBI), we measured over 30 parameters simultaneously across archival lymphoid tissues from healthy or simian immunodeficiency virus (SIV)-infected nonhuman primates. PANINI enabled the spatial dissection of cellular phenotypes, functional markers, and viral events resulting from infection. SIV infection induced IL-10 expression in lymphoid B cells, which correlated with local macrophage M2 polarization. This highlights a potential viral mechanism for conditioning an immunosuppressive tissue environment for virion production. The spatial multimodal framework here can be extended to decipher tissue responses in other infectious diseases and tumor biology. [Display omitted] • Development of a method (PANINI) for multiplexed nucleic acid and protein imaging • Identification of orchestrated immune events in response to SIV infection • IL-10 levels in B cells and macrophages correlate with immunosuppression • Tissue microenvironmental cues can influence SIV viral transcription state Our understanding of persistent HIV tissue reservoirs is constrained by our limited ability to visualize the cellular components of these viral reservoirs. Jiang et al. develop a robust method that combines nucleic acid and protein imaging, termed PANINI, and use it to uncover the orchestrated immune events of retroviral lymphoid tissue reservoirs. [ABSTRACT FROM AUTHOR]

Background: Seasonal influenza remains a global public health concern. A messenger RNA (mRNA)-based quadrivalent seasonal influenza vaccine, mRNA-1010, was investigated in a 3-part, first-in-human, phase 1/2 clinical trial., Methods: In Parts 1-3 of this stratified, observer-blind study, adults aged ≥18 years old were randomly assigned to receive a single dose (6.25 µg to 200 µg) of mRNA-1010 or placebo (Part 1) or an active comparator (Afluria; Parts 2-3). Primary study objectives were assessment of safety, reactogenicity, and humoral immunogenicity of mRNA-1010, placebo (Part 1), or active comparator (Parts 2-3). Exploratory endpoints included assessment of cellular immunogenicity (Part 1) and antigenic breadth against vaccine heterologous (A/H3N2) strains (Parts 1-2)., Results: In all study parts, solicited adverse reactions were reported more frequently for mRNA-1010 than placebo or Afluria and most were grade 1 or 2 in severity. No vaccine-related serious adverse events or deaths were reported. In Parts 1-2, a single dose of mRNA-1010 (25 µg to 200 µg) elicited robust Day 29 hemagglutination inhibition (HAI) titers that persisted through 6 months. In Part 3, lower doses of mRNA-1010 (6.25 µg to 25 µg) elicited Day 29 HAI titers that were higher or comparable to Afluria for influenza A strains. Compared with Afluria, mRNA-1010 (50 µg) elicited broader A/H3N2 antibody responses (Part 2). mRNA-1010 induced greater T-cell responses than placebo at Day 8 that were sustained or stronger at Day 29 (Part 1)., Conclusions: Data support the continued development of mRNA-1010 as a seasonal influenza vaccine., Clinicaltrials.gov Identifier: NCT04956575 (https://clinicaltrials.gov/study/NCT04956575)., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Observational studies have identified the potential prognostic value for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral load and anti-SARS-CoV-2 antibodies in coronavirus disease 2019 (COVID-19). However, viral load in nasopharyngeal (NP) swabs produced inconsistent results in prognostic analyses, and the prognostic value of viral load or antibodies has not been confirmed in large clinical trials. COVACTA and REMDACTA were double-blind, randomized, controlled trials with a combined enrollment of 1078 patients hospitalized with COVID-19 treated with tocilizumab or placebo in COVACTA or tocilizumab plus remdesivir or placebo plus remdesivir in REMDACTA. We assessed the potential prognostic value of NP and serum SARS-CoV-2 viral load and serum anti-SARS-CoV-2 antibodies at baseline as biomarkers for clinical outcomes in patients enrolled in these trials. In adjusted Cox proportional hazard models, serum viral load was a more reliable predictor of clinical outcomes than NP viral load; high serum viral load was associated with higher risk for death and mechanical ventilation/death and lower likelihood of hospital discharge (high vs. negative viral load hazard ratios [95% confidence interval {CI}] were 2.87 [1.57-5.25], 3.86 [2.23-6.68], and 0.23 [0.14-0.36], respectively, in COVACTA and 8.11 [2.95-22.26], 10.29 [4.5-23.55], and 0.21 [0.15-0.29], respectively, in REMDACTA) and high serum viral load correlated with levels of inflammatory cytokines and lung damage biomarkers. High anti-SARS-CoV-2 spike protein antibody (ACOV2S) levels were associated with higher likelihood of hospital discharge (high vs. below the limit of quantification hazard ratios [95% CI] were 2.55 [1.59-4.08] for COVACTA and 1.54 [1.13-2.09] for REMDACTA). These results support the role of baseline SARS-CoV-2 serum viral load and ACOV2S antibody titers in predicting clinical outcomes for patients hospitalized with COVID-19., (© 2023 F. Hoffmann-La Roche Ltd and The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background/aim: Functional endoscopic sinus surgery (FESS) is frequently conducted for restoring sinus ventilation and function. Postoperative care is critical for success. However, loss to follow-up is disturbing. The specific aim of this study was to identify critical factors contributing to loss of patients to follow-up and how to improve it., Patients and Methods: A total of 221 patients with chronic rhinosinusitis undergoing FESS were enrolled. Patients were divided into three groups according to their follow-up after surgery: Less than 1 month (short-term), 1-3 months (medium-term) and more than 3 months (long-term). The gender, age, smoking status, comorbidities, laterality, Lund-Mackay score, 22-question Sinonasal Outcome Test, nasal obstruction Visual Analogue Scale and mucociliary clearance were evaluated for their contribution to better compliance in follow-up., Results: The results revealed that older patients had better compliance in follow-up compared with younger ones (p=0.0093). Other factors were not contributory (p>0.05)., Conclusion: In contrast to the US, older patients in Taiwan have better compliance in postoperative follow-up, while younger ones require more education on the importance of follow-up., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)