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RS Kumar,1 Manish Kumar Jain,2 Jitendra Singh Kushwaha,3 Santosh Patil,4 Vasanti Patil,5 Soumya Ghatak,6 Jayesh Sanmukhani,7 Ravindra Mittal7 1Department of Pulmonary Medicine, Government Medical College & Government General Hospital, Srikakulam, India; 2Department of Pulmonary Medicine, Maharaja Agrasen Superspeciality Hospital, Jaipur, India; 3Department of Medicine, Prakhar Hospital Pvt. Ltd, Kanpur, India; 4Department of ENT, Jeevan Rekha Hospital, Belgavi, India; 5Department of ENT, Rajarshi Chhatrapati Shahu Maharaj Government Medical College and CPR Hospital, Kolhapur, India; 6Department of ENT, College of Medicine and Sagore Dutta Hospital, Kolkata, India; 7Department of Clinical Research and Regulatory Affairs, Cadila Healthcare Limited, Ahmedabad, IndiaCorrespondence: Jayesh Sanmukhani, Department of Clinical Research and Regulatory Affairs, Cadila Healthcare Ltd, Ahmedabad, India, Tel +91 76000 12192, Email Jayesh_sanmukhani@yahoo.co.in; jayeshsanmukhani@zyduscadila.comObjective: To compare the efficacy and safety of a fixed dose combination of Fluticasone Furoate and Oxymetazoline Hydrochloride Nasal Spray 27.5/50 mcg (FDC) with Fluticasone Furoate Nasal Spray 27.5 mcg (Fluticasone) in the management of allergic rhinitis.Patients and Methods: A prospective, randomized, double-blind, two-arm, active-controlled, parallel, multicenter, comparative clinical study was conducted in patients with allergic rhinitis aged 18 years and above having moderate-to-severe nasal congestion.Results: A total of 250 patients were randomized (1:1) to receive either the FDC or Fluticasone alone in a dose of two sprays in each nostril once daily at night. There was a significantly (P< 0.001) greater reduction in night-time Total Nasal Symptom Score with the FDC as compared to Fluticasone at all the time points starting from as early as day 3 and sustained till the end of treatment (Day 28) (Day 3: − 3.1 vs − 2.2; Day 7: − 4.0 vs − 3.4; Day 14: − 5.7 vs − 5.0; Day 28: − 7.0 vs − 6.4). A significantly greater number of patients (P< 0.05) had complete relief in Nasal Congestion with the FDC (44.7%) as compared to Fluticasone (26.8%). Both the study medications were well tolerated by all the patients. The proportion of patients showing worsening of symptoms (rebound congestion/rhinitis medicamentosa) after stoppage of medication was similar in both groups (P> 0.05).Conclusion: The FDC was superior to Fluticasone alone in relieving the nasal congestion and reduction of Total Nasal Symptom Score in allergic rhinitis patients with moderate-to-severe nasal congestion when administered once daily in the evening. Oxymetazoline when used along with the nasal steroid in a once daily dose does not cause rebound congestion and rhinitis medicamentosa even after long-term continuous use of 28 days.Keywords: Fluticasone Furoate, oxymetazoline, nasal spray, allergic rhinitis, nasal congestion

Background:Hepatitis B coinfection is common in HIV-positive individuals and as antiretroviral therapy has made death due to AIDS less common, hepatitis has become increasingly important. Several drugs are available to treat hepatitis B. The most potent an

Treatment for hepatitis B (HBV), a global disease affecting over 400 million persons, has changed over the past 15 years. Many of the current treatments are oral therapies which suppress HBV viral load and improve liver-related outcomes. However, differences exist in the currently available therapies both in terms of potency and resistance. The newest HBV nucleotide to be approved for the treatment of hepatitis B is tenofovir disoproxil fumarate that when phosphorylated to its active form leads to DNA chain termination. Tenofovir is active against human immunodeficiency virus (HIV) and was approved for its treatment in 2001. It is also active against HBV and was approved for its treatment in 2008. Tenofovir has emerged as an effective and potent therapy against lamivudine resistant strains as well as wild type HBV. Tenofovir resistance to HBV is rare. Long-term use of tenofovir has been associated with renal and bone marrow toxicity in some HIV-infected patients. To date, this is the only oral therapy which is both potent and does not lead to viral resistance in both treatment naïve and experienced patients. Further studies in HBV mono-infected persons are needed to evaluate long-term impact of tenofovir use. [ABSTRACT FROM AUTHOR]

Discerning drug hepatotoxicity from viral hepatitis flares remains an ongoing problem unique to patients coinfected with HIV and hepatitis B (HBV). We present three such coinfected patients who have been on two anti-HBV agents, lamivudine and tenofovir disoproxil fumarate simultaneously, as part of highly active antiretroviral therapy (HAART). All three developed significant aminotransferase elevations 6-12 weeks after initiation of HAART despite being on two active HBV drugs. Two of the three patients were initially thought to have drug-related hepatotoxicity from HIV medications. It seems more likely that all three patients demonstrated hepatitis B reactivation of differing severity as the result of varying degrees of immune recovery. Distinguishing clearly between drug-related hepatotoxicity and hepatitis reactivation may be difficult but is important as their clinical management differs. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To compare the effectiveness of active to passive dissemination of the Canadian clinical practice guidelines (CPGs) for nutrition support for the mechanically ventilated critically ill adult patient. DESIGN: A cluster-randomized trial with a cross-sectional outcome assessment at baseline and 12 months later. SETTING: Intensive care units in Canada. PATIENTS: Consecutive samples of mechanically ventilated patients at each time period. INTERVENTIONS: In the active group, we provided multifaceted educational interventions including Web-based tools to dietitians. In the passive group, we mailed the CPGs to dietitians. MEASUREMENTS AND MAIN RESULTS: The primary end point of this study was nutritional adequacy of enteral nutrition; secondary end points measured were compliance with the CPGs, glycemic control, duration of stay in intensive care unit and hospital, and 28-day mortality. Fifty-eight sites were randomized. At baseline and follow-up, 623 and 612 patients were evaluated. Both groups were well matched in site and patient characteristics. Changes in enteral nutrition adequacy between the active and passive arms were similar (8.0% vs. 6.2%, p = .54). Median time spent in the target glucose range increased 10.1% in the active compared with 1.8% in the passive group (p = .001). In the subgroup of medical patients, enteral nutrition adequacy improved more in the active arm compared with the passive group (by 8.1%, p = .04), whereas no such differences were observed in surgical patients. When groups were combined, during the year of dissemination activities, there was an increase in enteral nutrition adequacy (from 43% to 50%, p < .001), an increase in the use of feeding protocols (from 64% to 76%, p = .03), and a decrease in patients on parenteral nutrition (from 26% to 21%, p = .04). There were no differences in clinical outcomes between groups or across time periods. CONCLUSIONS: Although active dissemination of the CPGs did improve glycemic control, it did not change other nutrition practices or patient outcomes except in a subgroup of medical patients. Overall, dissemination of the CPGs improved other important nutrition support practices but was not associated with improvements in clinical outcomes. [ABSTRACT FROM AUTHOR]

Objectives: This study was designed to determine adherence to outpatient beta-blocker therapy following acute myocardial infarction (AMI).Background: The importance of beta-blocker therapy after AMI is widely recognized. Outpatient adherence with this recommendation, however, is not well described.Methods: Data on 846 patients surviving AMI were studied. Factors associated with filling a beta-blocker prescription within 30 days postdischarge and the proportion of patients who were or were not discharged on beta-blockers who filled prescriptions for them by 30, 180, and 365 days post-AMI discharge were assessed.Results: Patients with a discharge order for beta-blocker therapy were more likely to fill a prescription in the first 30 days postdischarge (hazard ratio [HR] 15.82, 95% confidence interval [CI], 10.75 to 23.26). Patients older than age 75 years were less likely than those age <65 years to fill a prescription (HR 0.63, 95% CI 0.42 to 0.93). Gender, race, and being an ideal candidate did not affect beta-blocker use. Among patients who were discharged on beta-blockers, 85% of survivors had filled a prescription by 30 days postdischarge, and 63% and 61% were current users at 180 and 365 days, respectively. In contrast, only 8% of those patients with no discharge order for beta-blockers had filled such a prescription by 30 days, and 13% and 12% of patients were current users at 180 and 365 days, respectively.Conclusions: Patients not discharged on beta-blockers are unlikely to be started on them as outpatients. For patients who are discharged on beta-blockers after AMI, there is a significant decline in use after discharge. Quality improvement efforts need to be focused on improving discharge planning and to continue these efforts after discharge. [ABSTRACT FROM AUTHOR]

Circadian time of intake gates the cardioprotective effects of glucocorticoid administration in both healthy and infarcted hearts. The cardiomyocyte-specific glucocorticoid receptor (GR) and its cofactor, Krüppel-like factor 15 (KLF15), play critical roles in maintaining normal heart function in the long term and serve as pleiotropic regulators of cardiac metabolism. Despite this understanding, the cardiomyocyte-autonomous metabolic targets influenced by the concerted epigenetic action of the GR/KLF15 axis remain undefined. Here, we demonstrated the critical roles of the cardiomyocyte-specific GR and KLF15 in orchestrating a circadian-dependent glucose oxidation program within the heart. Combining integrated transcriptomics and epigenomics with cardiomyocyte-specific inducible ablation of GR or KLF15, we identified their synergistic role in the activation of adiponectin receptor expression (Adipor1) and the mitochondrial pyruvate complex (Mpc1/2), thereby enhancing insulin-stimulated glucose uptake and pyruvate oxidation. Furthermore, in obese diabetic (db/db) mice exhibiting insulin resistance and impaired glucose oxidation, light-phase prednisone administration, as opposed to dark-phase prednisone dosing, restored cardiomyocyte glucose oxidation and improved diastolic function. These effects were blocked by combined in vivo knockdown of GR and KLF15 levels in db/db hearts. In summary, this study leveraged the circadian-dependent cardioprotective effects of glucocorticoids to identify cardiomyocyte-autonomous targets for the GR/KLF15 axis in glucose metabolism.

Background & Aims: Despite a high prevalence of risk factors associated with hepatitis delta virus (HDV) infection among safety-net populations, data evaluating HDV testing and prevalence are limited. We aim to evaluate HDV testing practices and HDV prevalence among an ethnically diverse, multi-center cohort of safety-net patients with chronic hepatitis B (CHB)., Methods: We retrospectively evaluated 13,218 patients with CHB (54.2% male, 57.9% non-White minorities, 12.5% human immunodeficiency virus, and 23.0% hepatitis C virus) across 3 United States safety-net health systems from 2010 to 2022 to evaluate proportion tested for HDV and proportion positive among those tested. Adjusted multivariate logistic regression models evaluated for predictors of HDV testing and predictors of anti-HDV positive., Results: Anti-HDV testing was performed in 6.1% overall and in 4.9% that met American Association for the Study of Liver Diseases criteria for HDV testing. Greater odds of testing were observed in men vs women (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.27-1.75), Asian individuals vs White individuals (OR, 2.18; 95% CI, 1.74-2.72), Black/African American individuals vs White individuals (OR, 1.29; 95% CI, 1.07-1.56), and patients with Medicare or Medicaid. Among patients with CHB tested for HDV, 15.7% were positive (22.9% among those meeting American Association for the Study of Liver Diseases HDV testing criteria). Only 2 patients (1.6%) had follow-up HDV RNA testing. Greater proportion of anti-HDV positive was observed in patients with baseline cirrhosis (47.4% vs 13.3%; P < .001), and patients with Medicare or Medicaid vs those with commercial insurance., Conclusions: Among an ethnically diverse, multi-center safety-net cohort of patients with CHB, low rates of HDV testing were observed, even among those with high-risk HDV risk factors. Among those tested, 15.7% were positive, only 2 had follow up RNA testing. This highlights the need for greater awareness, education, and advocacy to improve HDV testing rates., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether a chemokine receptor type 2 antagonist, DMX-200 (repagermanium), in combination with an angiotensin receptor blocker, candesartan, improves clinical outcomes in people with COVID-19., Design: Prospective, multicentre, double-blind, placebo-controlled trial., Setting: Ten acute care hospitals in India., Participants: Adults <65 years old intended for hospital admission with moderate/severe COVID-19 disease (respiratory rate ≥24 breaths per minute or oxygen saturation ≤93% on room air)., Intervention: DMX-200 120 mg two times per day, or placebo, on background of titratable candesartan commencing at 4 mg two times per day, for 28 days., Main Outcome Measures: The primary endpoint was COVID-19 disease severity on a modified WHO Clinical Progression Scale (WHO scale) on day 14. Secondary outcomes included the WHO scale at days 28, 60, 90 and 180; intensive care unit (ICU) admission, respiratory failure or death within 28 days; length of hospitalisation; and requirement for ventilatory support or dialysis., Results: Between December 2021 and August 2022, 518 people were screened, with 49 randomised to DMX-200 or placebo on a background of candesartan. The study was terminated early due to recruitment barriers, including an external requirement to restrict enrolment to adults <65 years old, contributing to a 91% screen failure rate. The median WHO Clinical Progression Scale (WHO scale) score at day 14 for both groups was 1 (IQR 1-1), indicating most participants were discharged with no limitations on activities by this time. Formal comparison was not performed due to the small sample size. One participant receiving DMX-200 died of COVID-19 disease progression. No participants required ICU admission, ventilation or dialysis. Median length of hospitalisation in both groups was 6 days (IQR 6-7 days). WHO scale scores were similar at 28, 60, 90 and 180 days., Conclusion: Due to recruitment barriers, the study was unable to determine whether DMX-200 improves clinical outcomes in people with COVID-19., Trial Registration Number: ClinicalTrials.gov NCT05122182., Competing Interests: Competing interests: This work was an investigator-initiated study that received financial support from Dimerix Bioscience Pty Ltd who manufacture DMX-200., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The COVID-19 pandemic amplified known challenges associated with the conduct of inpatient clinical trials, while also introducing new ones that needed to be addressed., Methods: Stakeholders based in the United States who participated in the conduct of inpatient therapeutic trials for the treatment of COVID-19 as part of the Accelerating COVID-19 Therapeutic Interventions and Vaccines program identified challenges experienced in the conduct of these trials through a series of meeting to discuss and identify common themes. In addition, innovations developed to address these challenges and other potential solutions that may be utilized in future pandemics were highlighted., Results: Six thematic challenges including infection control considerations, the interplay between provision of clinical care and research, competing clinical trials, arduous consenting procedures, onerous procedural requirements, and participant recruitment including achieving representation of diverse populations were identified and are discussed here., Conclusions: Consideration of the lessons learned and recommendation outlined here may allow for more efficient conduct of inpatient clinical trials in future pandemics., Competing Interests: Dr. Beitler reports prior consulting fees from Sedana Medical, Global Blood Therapeutics, Biomarck, and Arrowhead for work on advisory committees unrelated to this manuscript, funds from Sedana Medical paid to Columbia University for work as principal investigator of a clinical trial unrelated to this manuscript, and fees from Hamilton Medical for work as medical monitor of a clinical trial unrelated to this manuscript., (© The Author(s) 2024.)

Background: Timely treatment of chronic hepatitis B (CHB) reduces risks of cirrhosis and hepatocellular carcinoma. Gaps in timely treatment persist, especially among underserved safety-net populations. We aim to evaluate gaps and disparities in CHB treatment in the United States., Methods: Adults with treatment-naive CHB without human immunodeficiency virus were identified from 2010 to 2018 across 3 safety-net health systems. CHB treatment eligibility was assessed using American Association for the Study of Liver Diseases (AASLD) criteria and alternative criteria, including the Simplified Approach for Hepatitis B Algorithm. Differences in CHB treatment between groups were evaluated using χ 2 methods, adjusted Kaplan-Meier methods, and adjusted Cox proportional hazards models., Results: Among 3749 patients with treatment-naive CHB (51.5% women, 38.7% White, 33.7% African American, 19.6% Asian, 24.6% cirrhosis), 30.0% were AASLD treatment eligible, among whom 31.0% were treated. Men were more likely than women to be treated (33.5% vs 26.6%, P < .01). On multivariable regression, there remained a trend toward greater treatment in men versus women (adjusted hazard ratio [aHR], 1.21 [95% confidence interval {CI}, .96-1.54]). Disparities by race/ethnicity and insurance status were observed. When exploring outcomes using SABA criteria, similar trends were observed. Among treatment-eligible patients, greater likelihood of treatment was observed in men versus women (aHR, 1.40 [95% CI, 1.14-1.70]) and in Asians versus Whites (aHR, 1.50 [95% CI, 1.16-1.94])., Conclusions: Among an ethnically diverse multicenter safety-net cohort of CHB patients, less than one-third of treatment-eligible patients received antiviral treatment. Significant disparities in CHB treatment were observed by sociodemographic characteristics., Competing Interests: Potential conflicts of interest. R. J. W. has received research grants (to his institution) from Gilead Sciences, Exact Sciences, Theratechnologies, and Durect Corporation, and has served in consulting roles without compensation for Gilead Sciences. M. K. J. has received investigator-initiated grant funding from Gilead Sciences paid to her institution. G. T. has received funding from Gilead Sciences (to his institution) not related to this study. M. T. has received investigator-initiated grant funding from Gilead Sciences paid to her institution. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: Once-daily inhalers have been shown to improve adherence leading to lesser discontinuation compared to twice- or thrice-daily inhalers in management of asthma. Combination of Vilanterol and Fluticasone Furoate (VI/FF) is approved for management of asthma and COPD and is available as a dry powder inhaler. Pressurized-Metered Dose Inhalers (pMDIs) offer ease-of-use and therapy alternatives for patients with low inspiratory flow. This study assessed the efficacy and safety of a new once-daily pMDI containing VI/FF in individuals diagnosed with persistent asthma., Methods: This phase 3, double-blind, randomized controlled study assessed the non-inferiority of VI/FF (12.5 mcg/50 mcg & 12.5 mcg/100 mcg; 2 puffs once-daily) over Formoterol Fumarate and Fluticasone Propionate (FOR/FP, 6 mcg/125 mcg & 6 mcg/250 mcg; 2 puffs twice-daily) in patients with persistent asthma. Primary outcome was change from baseline in trough FEV1 at the end of study (12 weeks). Adverse events and number of exacerbations were used to evaluate safety., Results: A total of 330 patients were randomized into VI/FF (165) and FOR/FP (165). Trough FEV1 significantly improved in both the groups at week 12, with a mean difference (VI/FF minus FOR/FP) being 54.75 mL (95% CI, 8.42-101.08 mL, p  = 0.02). The low dose VI/FF had similar efficacy to that of low dose FOR/FP and high dose VI/FF had similar efficacy to high dose FOR/FP. No serious adverse events were reported during the study., Conclusion: Once daily VI/FF pMDI was non-inferior to twice daily FOR/FP pMDI in patients with persistent asthma.

Background: Biomarker guided therapy could improve management of COVID-19 inpatients. Although some results indicate that antibody tests are prognostic, little is known about patient management using point-of-care (POC) antibody tests., Methods: COVID-19 inpatients were recruited to evaluate 2 POC tests: LumiraDX and RightSign. Ease of use data was collected. Blood was also collected for centralized testing using established antibody assays (GenScript cPass). A nested case-control study assessed if POC tests conducted on stored specimens were predictive of time to sustained recovery, mortality, and a composite safety outcome., Results: While both POC tests exhibited moderate agreement with the GenScript assay (both agreeing with 89% of antibody determinations), they were significantly different from the GenScript assay. Treating the GenScript assay as the gold standard, the LumiraDX assay had 99.5% sensitivity and 58.1% specificity while the RightSign assay had 89.5% sensitivity and 84.0% specificity. The LumiraDX assay frequently gave indeterminant results. Both tests were significantly associated with clinical outcomes., Conclusions: Although both POC tests deviated moderately from the GenScript assay, they predicted outcomes of interest. The RightSign test was easier to use and was more likely to detect those lacking antibody compared to the LumiraDX test treating GenScript as the gold standard., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Circadian time-of-intake gates the cardioprotective effects of glucocorticoid administration in both healthy and infarcted hearts. The cardiomyocyte-specific glucocorticoid receptor (GR) and its co-factor, Krüppel-like factor (Klf15), play critical roles in maintaining normal heart function in the long-term and serve as pleiotropic regulators of cardiac metabolism. Despite this understanding, the cardiomyocyte-autonomous metabolic targets influenced by the concerted epigenetic action of GR-Klf15 axis remain undefined. Here, we demonstrate the critical roles of the cardiomyocyte-specific GR and Klf15 in orchestrating a circadian-dependent glucose oxidation program within the heart. Combining integrated transcriptomics and epigenomics with cardiomyocyte-specific inducible ablation of GR or Klf15, we identified their synergistic role in the activation of adiponectin receptor expression ( Adipor1 ) and the mitochondrial pyruvate complex ( Mpc1/2 ), thereby enhancing insulin-stimulated glucose uptake and pyruvate oxidation. Furthermore, in obese diabetic ( db/db ) mice exhibiting insulin resistance and impaired glucose oxidation, light-phase prednisone administration, as opposed to dark-phase prednisone dosing, effectively restored cardiomyocyte glucose oxidation and improved diastolic function towards control-like levels in a sex-independent manner. Collectively, our findings uncover novel cardiomyocyte-autonomous metabolic targets of the GR-Klf15 axis. This study highlights the circadian-dependent cardioprotective effects of glucocorticoids on cardiomyocyte glucose metabolism, providing critical insights into chrono-pharmacological strategies for glucocorticoid therapy in cardiovascular disease., Competing Interests: Conflicts of interest – MQ is listed as co-inventor on a patent application related to intermittent glucocorticoid use filed by Northwestern University (PCT/US2019/068,618). All other authors declare they have no competing interests.

Numerous hydrological applications, such as soil erosion estimation, water resource management, and rain driven damage assessment, demand accurate and reliable rainfall erosivity data. However, the scarcity of gauge rainfall records and the inherent uncertainty in satellite and reanalysis-based rainfall datasets limit rainfall erosivity assessment globally. Here, we present a new global rainfall erosivity dataset (0.1° × 0.1° spatial resolution) integrating satellite (CMORPH and IMERG) and reanalysis (ERA5-Land) derived rainfall erosivity estimates with gauge rainfall erosivity observations collected from approximately 6,200 locations across the globe. We used a machine learning-based Gaussian Process Regression (GPR) model to assimilate multi-source rainfall erosivity estimates alongside geoclimatic covariates to prepare a unified high-resolution mean annual rainfall erosivity product. It has been shown that the proposed rainfall erosivity product performs well during cross-validation with gauge records and inter-comparison with the existing global rainfall erosivity datasets. Furthermore, this dataset offers a new global rainfall erosivity perspective, addressing the limitations of existing datasets and facilitating large-scale hydrological modelling and soil erosion assessments., (© 2024. The Author(s).)

The mechanical environment generated through the adhesive interaction of endothelial cells (ECs) with the matrix controls nuclear tension, preventing aberrant gene synthesis and the transition from restrictive to leaky endothelium, a hallmark of acute lung injury (ALI). However, the mechanisms controlling tension transmission to the nucleus and EC-restrictive fate remain elusive. Here, we demonstrate that, in a kinase-independent manner, focal adhesion kinase (FAK) safeguards tension transmission to the nucleus to maintain EC-restrictive fate. In FAK-depleted ECs, robust activation of the RhoA-Rho-kinase pathway increased EC tension and phosphorylation of the nuclear envelope protein, emerin, activating DNMT3a. Activated DNMT3a methylates the KLF2 promoter, impairing the synthesis of KLF2 and its target S1PR1 to induce the leaky EC transcriptome. Repleting FAK (wild type or kinase dead) or inhibiting RhoA-emerin-DNMT3a activities in damaged lung ECs restored KLF2 transcription of the restrictive EC transcriptome. Thus, FAK sensing and control of tension transmission to the nucleus govern restrictive endothelium to maintain lung homeostasis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

AlphaFold2 (AF2) models have had wide impact but mixed success in retrospective ligand recognition. We prospectively docked large libraries against unrefined AF2 models of the σ 2 and serotonin 2A (5-HT2A) receptors, testing hundreds of new molecules and comparing results with those obtained from docking against the experimental structures. Hit rates were high and similar for the experimental and AF2 structures, as were affinities. Success in docking against the AF2 models was achieved despite differences between orthosteric residue conformations in the AF2 models and the experimental structures. Determination of the cryo-electron microscopy structure for one of the more potent 5-HT2A ligands from the AF2 docking revealed residue accommodations that resembled the AF2 prediction. AF2 models may sample conformations that differ from experimental structures but remain low energy and relevant for ligand discovery, extending the domain of structure-based drug design.

Background: Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials., Methods: A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models., Results: Viral Ag ≥4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time., Conclusions: Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease., Competing Interests: Potential conflicts of interest. N. R. A. reports support for attending meetings and/or travel to their institution from the National Institutes of Health (NIH). D. L. B. reports consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, and participation on a Data Safety Monitoring Board (DSMB) or Advisory Board with Pfizer, Gilead, MSD, and ViiV; and support for attending meetings and/or travel from ViiV and Gilead. M. K. J. reports a grant to their institution from Gilead Sciences and a contract for a clinical trial to their institution from Regeneron; and a role on the HIV MA Board of Directors. J. P. H. reports consulting fees to the author from Pfizer, MSD, Menarini, Angelini, Zambon, and Tillots; payment or honoraria payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events to their institution and the author from Pfizer and to the author from MSD and Angelini; support for attending meetings and/or travel from MSD and Pfizer; and paid participation as a DSMB member for a TFT Pharmaceuticals clinical trial. K. K. reports grants or contracts to their institution from the NIH, COVID Vaccine Prevention Network, (NIH), Regeneron, Abbott, Pfizer, Romark, and Raisonance; royalties or licenses to book author for Elsevier; consulting fees to the author from Regeneron; payment for expert testimony to the author from the State of Florida; support for travel from Sanford Guide, Burroughs Wellcome Fund, ParaFrap, and the Infectious Diseases Society of America (IDSA) Board of Directors; patents planned, issued, or pending to University of South Florida (USF) F and USF faculty from 3D swabs; leadership or a fiduciary role on the Sanford Guide, Burroughs Wellcome Fund, IDSA board, and ParaFrap; and personal stocks from Gilead. S. L. P. reports grants paid to the University College London, which are completely separate from this work, with Medical Research Council, United Kingdom Research and Innovation, The European and Developing Countries Clinical Trial Partnership, Janssen-Cilag, Gilead Sciences, and ViiV Healthcare; participation as member of the DSMB for the TIPAL trial (The effectiveness and risks of Treating people with Idiopathic Pulmonary fibrosis with the Addition of Lansoprazole: a randomized placebo-controlled multicenter clinical trial). This is an academic trial funded in the United Kingdom by the National Institute for Health and Care Research (NIHR), UK. C. R. reports grants or contracts from NIH and participation on a DSMB or Advisory Board from Mayo Clinic and NIH. U. S. reports research grants or contracts from ViiV Healthcare and AstraZeneca; consulting fees from Shionogi, Paratek, ViiV, and Pfizer; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Shionogi, Pfizer, and Paratek. B. W. T. reports grants or contracts from Veterans Affairs (VA) Health Services and Development Service Center for Innovations in Quality, Effectiveness, and Safety (13-413), Agency for Healthcare Research and Quality (AHRQ), VA Rehabilitation Research and Development, and Peptilogics; consulting fees from Phiogen; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from the George Washington ID Board Review Course, the Warren Alpert Medical School of Brown University. A. A. G. reports grants to their institution from Centers for Disease Control, Department of Defense, Faron Pharmaceuticals, and AbbVie; participation on a DSMB or Advisory Board from NIH; and a role on the Scientific Advisory Board from Biomeme. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Serial measurement of virological and immunological biomarkers in patients admitted to hospital with COVID-19 can give valuable insight into the pathogenic roles of viral replication and immune dysregulation. We aimed to characterise biomarker trajectories and their associations with clinical outcomes., Methods: In this international, prospective cohort study, patients admitted to hospital with COVID-19 and enrolled in the Therapeutics for Inpatients with COVID-19 platform trial within the Accelerating COVID-19 Therapeutic Interventions and Vaccines programme between Aug 5, 2020 and Sept 30, 2021 were included. Participants were included from 108 sites in Denmark, Greece, Poland, Singapore, Spain, Switzerland, Uganda, the UK, and the USA, and randomised to placebo or one of four neutralising monoclonal antibodies: bamlanivimab (Aug 5 to Oct 13, 2020), sotrovimab (Dec 16, 2020, to March 1, 2021), amubarvimab-romlusevimab (Dec 16, 2020, to March 1, 2021), and tixagevimab-cilgavimab (Feb 10 to Sept 30, 2021). This trial included an analysis of 2149 participants with plasma nucleocapsid antigen, anti-nucleocapsid antibody, C-reactive protein (CRP), IL-6, and D-dimer measured at baseline and day 1, day 3, and day 5 of enrolment. Day-90 follow-up status was available for 1790 participants. Biomarker trajectories were evaluated for associations with baseline characteristics, a 7-day pulmonary ordinal outcome, 90-day mortality, and 90-day rate of sustained recovery., Findings: The study included 2149 participants. Participant median age was 57 years (IQR 46-68), 1246 (58·0%) of 2149 participants were male and 903 (42·0%) were female; 1792 (83·4%) had at least one comorbidity, and 1764 (82·1%) were unvaccinated. Mortality to day 90 was 172 (8·0%) of 2149 and 189 (8·8%) participants had sustained recovery. A pattern of less favourable trajectories of low anti-nucleocapsid antibody, high plasma nucleocapsid antigen, and high inflammatory markers over the first 5 days was observed for high-risk baseline clinical characteristics or factors related to SARS-CoV-2 infection. For example, participants with chronic kidney disease demonstrated plasma nucleocapsid antigen 424% higher (95% CI 319-559), CRP 174% higher (150-202), IL-6 173% higher (144-208), D-dimer 149% higher (134-165), and anti-nucleocapsid antibody 39% lower (60-18) to day 5 than those without chronic kidney disease. Participants in the highest quartile for plasma nucleocapsid antigen, CRP, and IL-6 at baseline and day 5 had worse clinical outcomes, including 90-day all-cause mortality (plasma nucleocapsid antigen hazard ratio (HR) 4·50 (95% CI 3·29-6·15), CRP HR 3·37 (2·30-4·94), and IL-6 HR 5·67 (4·12-7·80). This risk persisted for plasma nucleocapsid antigen and CRP after adjustment for baseline biomarker values and other baseline factors., Interpretation: Patients admitted to hospital with less favourable 5-day biomarker trajectories had worse prognosis, suggesting that persistent viral burden might drive inflammation in the pathogenesis of COVID-19, identifying patients that might benefit from escalation of antiviral or anti-inflammatory treatment., Funding: US National Institutes of Health., Competing Interests: Declaration of interests ALG reports receiving institutional funding from Novavax, institutional partnership with AstraZeneca, and being personally named as inventor on a patent used by AstraZeneca. DDM reports receiving grants from the Danish National Research Foundation. DL reports participation in a study funded by Gilead with no salary support. EM reports payments to his institution received from SciClone Pharmaceuticals, Regeneron Pharmaceuticals, Pfizer, Chemic Labs and KODA Therapeutics, and Cidara, and payment for participating in an advisory board for Basilea. KW reports honorarium for Acute Respiratory Distress Syndrome (ARDS) International Conference in 2023, and travel support from University of California San Francisco. MAM reports institutional funding by the US Department of Defence, Roche-Genetech, and Quantum Health, and personal consulting fees from Gilead, Novartis, and Johnson & Johnson. MKJ reports grants received from Regeneron, Laurent, and Gilead, honoraria from Gilead, and a leadership role with the HIV Medicine Association Board of Directors. PC reports consulting fees from Eli Lilly and Regeneron. All other authors declare no competing interests. All authors were not precluded from accessing data in the study., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Dementia with Lewy bodies (DLB) is a neurodegenerative condition often co-occurring with Alzheimer's disease (AD) pathology. Characterizing white matter tissue microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) may help elucidate the biological underpinnings of white matter injury in individuals with DLB. In this study, diffusion tensor imaging (DTI) and NODDI metrics were compared in 45 patients within the dementia with Lewy bodies spectrum (mild cognitive impairment with Lewy bodies (n = 13) and probable dementia with Lewy bodies (n = 32)) against 45 matched controls using conditional logistic models. We evaluated the associations of tau and amyloid-β with DTI and NODDI parameters and examined the correlations of AD-related white matter injury with Clinical Dementia Rating (CDR). Structural equation models (SEM) explored relationships among age, APOE ε4, amyloid-β, tau, and white matter injury. The DLB spectrum group exhibited widespread white matter abnormalities, including reduced fractional anisotropy, increased mean diffusivity, and decreased neurite density index. Tau was significantly associated with limbic and temporal white matter injury, which was, in turn, associated with worse CDR. SEM revealed that amyloid-β exerted indirect effects on white matter injury through tau. We observed widespread disruptions in white matter tracts in DLB that were not attributed to AD pathologies, likely due to α-synuclein-related injury. However, a fraction of the white matter injury could be attributed to AD pathology. Our findings underscore the impact of AD pathology on white matter integrity in DLB and highlight the utility of NODDI in elucidating the biological basis of white matter injury in DLB., (© 2024. The Author(s).)

Bitter taste sensing is mediated by type 2 taste receptors (TAS2Rs (also known as T2Rs)), which represent a distinct class of G-protein-coupled receptors 1 . Among the 26 members of the TAS2Rs, TAS2R14 is highly expressed in extraoral tissues and mediates the responses to more than 100 structurally diverse tastants 2-6 , although the molecular mechanisms for recognizing diverse chemicals and initiating cellular signalling are still poorly understood. Here we report two cryo-electron microscopy structures for TAS2R14 complexed with G gust (also known as gustducin) and G i1 . Both structures have an orthosteric binding pocket occupied by endogenous cholesterol as well as an intracellular allosteric site bound by the bitter tastant cmpd28.1, including a direct interaction with the α5 helix of G gust and G i1 . Computational and biochemical studies validate both ligand interactions. Our functional analysis identified cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator with direct agonist activity at TAS2R14. Moreover, the orthosteric pocket is connected to the allosteric site via an elongated cavity, which has a hydrophobic core rich in aromatic residues. Our findings provide insights into the ligand recognition of bitter taste receptors and suggest activities of TAS2R14 beyond bitter taste perception via intracellular allosteric tastants., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: Patients with dementia with Lewy bodies (DLB) may have Alzheimers disease (AD) pathology that can be detected by plasma biomarkers. Our objective was to evaluate plasma biomarkers of AD and their association with positron emission tomography (PET) biomarkers of amyloid and tau deposition in the continuum of DLB, starting from prodromal stages of the disease., Methods: The cohort included patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD), mild cognitive impairment with Lewy bodies (MCI-LB), or DLB, with a concurrent blood draw and PET scans., Results: Abnormal levels of plasma glial fibrillary acidic protein (GFAP) were found at the prodromal stage of MCI-LB in association with increased amyloid PET. Abnormal levels of plasma phosphorylated tau (p-tau)-181 and neurofilament light (NfL) were found at the DLB stage. Plasma p-tau-181 showed the highest accuracy in detecting abnormal amyloid and tau PET in patients with DLB., Discussion: The range of AD co-pathology can be detected with plasma biomarkers in the DLB continuum, particularly with plasma p-tau-181 and GFAP., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood., Methods: Participants enrolled in the Therapeutics for Inpatients with COVID-19 trials were randomized to nmAb versus placebo. Longitudinal differences between treatment and placebo groups in levels of plasma nucleocapsid antigen (N-Ag), anti-nucleocapsid antibody, C-reactive protein, interleukin-6, and D-dimer at enrollment, day 1, 3, and 5 were estimated using linear mixed models. A 7-point pulmonary ordinal scale assessed at day 5 was compared using proportional odds models., Results: Analysis included 2149 participants enrolled between August 2020 and September 2021. Treatment resulted in 20% lower levels of plasma N-Ag compared with placebo (95% confidence interval, 12%-27%; P < .001), and a steeper rate of decline through the first 5 days (P < .001). The treatment difference did not vary between subgroups, and no difference was observed in trajectories of other biomarkers or the day 5 pulmonary ordinal scale., Conclusions: Our study suggests that nmAb has an antiviral effect assessed by plasma N-Ag among hospitalized patients with COVID-19, with no blunting of the endogenous anti-nucleocapsid antibody response. No effect on systemic inflammation or day 5 clinical status was observed., Clinical Trials Registration: NCT04501978., Competing Interests: Potential conflicts of interest. A. L. G. reports receiving institutional funding from Novavax, insititutaional partnership with Astra Zeneca, and reports being personally named as inventor on a patent used by Astra Zeneca. D. D. M. reports receiving grant from the Danish National research Foundation. E. M. reports payments to his institution received from SciClone Pharmaceuticals, Regeneron Pharmaceuticals, Pfizer, Chemic Labs/KODA Therapeutics, Cidara, and Leidos Biomedical Research Inc; E. M. also reports being on an advisory board for Basilea. K. W. reports receiving a honorarium for international ARDS conference and travel support from UCSF. M. A. reports a grant from NINDS. M. A. M. reports institutional grants from NHLBI/NIAID, the department of defence, California Institute of Regeneration, Roche-Genentech, and Quantum Health. M. A. M. has also received personal consulting fees from Novartis, Pliant Therapeutics, Johnson and Johnson, Gilead, and Citius Pharmaceuticals. M. K. J. reports institutional grants from Gilead, Laurent, and Regeneron; personal consulting fees from Gilead; and personal honoraria from Cooper Clinic. S. T. is funded by grants from the Australian Medical Foundation and New South Wales Health. The remaining authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The human immunodeficiency virus (HIV) workforce continues to face a crisis, particularly in the southern United States. Adding to known issues of administrative burden and less competitive compensation, recent anti- lesbian, gay, bisexual, transgender and queer (LGBTQ+) legislation threatens the already strained HIV workforce. HIV care providers advocate for all aspects of their patient's lives, including those needing gender-affirming care. The recent legislative targets against transgender patients, which involves many people with HIV, will clearly add to the burden on individual HIV care providers and therefore the HIV workforce. Recruitment and retention efforts in states impacted by these laws will become increasingly difficult without advocacy for the patients we serve. The HIV workforce must work together with LGBTQ+ populations to address these recent laws and promote the well-being of all our patients and colleagues., Competing Interests: Potential conflicts of interest . M. K. J. reports a role on the Board of Directors for HIVMA. A. K. P. reports that she is listed as a co-investigator in 2 grants but is not a principal investigator (PI) of any grants (ie, there are no grants awarded directly to her); is an HIVMA board member and receives occasional support for travel to IDSA or HIVMA related meetings; roles as HIVMA Board Member and Vice-Chair Elect. C. F. K. reports grants to institution from Moderna, Novavax, Gilead Sciences, ViiV, Humanigen; a role as Vice chair of HIVMA. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The transcription factor Kruppel-like factor 4 (KLF4) regulates the expression of immunosuppressive and anti-thrombotic proteins. Despite its importance in maintaining homeostasis, the signals that control its expression and the mechanism of its transactivation remain unclarified. CD55 [aka decay accelerating factor (DAF)], now known to be a regulator of T and B cell responses, biases between pro- and anti-inflammatory processes by controlling autocrine C3a and C5a receptor (C3ar1/C5ar1) signaling in cells. The similarity in CD55's and KLF4's regulatory effects prompted analyses of their functional relationship. In vascular endothelial cells (ECs), CD55 upregulation accompanied KLF4 expression via a p-CREB and CREB Binding Protein (CBP) mechanism. In both ECs and macrophages, CD55 expression was essential for KLF4's downregulation of pro-inflammatory/pro-coagulant proteins and upregulation of homeostatic proteins. Mechanistic studies showed that upregulation of KLF4 upregulated CD55. The upregulated CD55 in turn enabled the recruitment of p-CREB and CBP to KLF4 needed for its transcription. Activation of adenylyl cyclase resulting from repression of autocrine C3ar1/C5ar1 signaling by upregulated CD55 concurrently led to p-CREB and CBP recruitment to KLF4-regulated genes, thereby conferring KLF4's transactivation. Accordingly, silencing CD55 in statin-treated HUVEC disabled CBP transfer from the E-selectin to the eNOS promoter. Importantly, silencing CD55 downregulated KLF4's expression. It did the same in untreated HUVEC transitioning from KLF4 low growth to KLF4 hi contact inhibition. KLF4's and CD55's function in ECs and macrophages thus are linked via a novel mechanism of gene transactivation. Because the two proteins are co-expressed in many cell types, CD55's activity may be broadly tied to KLF4's immunosuppressive and antithrombotic activities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 An, Zhou, Harland, Hussain, Strainic, Jain and Medof.)

Background: Delayed cord clamping (DCC) is a proven beneficial intervention, but the suggested timings of DCC vary from 30 to 300 seconds after birth or until cord pulsation stops. This study aimed to find the optimum timing of DCC to maximize the benefits such as an increase in hemoglobin, and hematocrit without increasing the risks of polycythemia and hyperbilirubinemia., Methods: We conducted a single-center prospective observational cohort study. All singleton neonates with gestational age ≥ 28 weeks born at the center in the 17 months of the study period from November 2020 to March 2022 were enrolled. Participants were divided into four groups based on DCC time: group A: <60 sec, group B: 60-119 sec, group C: 120-180 sec, and group D: >180 sec. The primary outcome was the levels of hemoglobin, hematocrit, and bilirubin at 48 hours of life., Results: Four hundred and eight neonates were enrolled. They were divided into four groups based on the timing of DCC (group A: n = 52, group B: n = 137, group C: n = 155, group D: n = 64). With an increase in the duration of DCC, there was an increase in the level of hemoglobin and hematocrit without an increase in the risk of polycythemia or neonatal hyperbilirubinemia. The benefits were best in group C (120-180 sec) and group D (>180 sec)., Conclusions: DCC of ≥ 120 seconds appears to be optimal where hemoglobin and hematocrit are highest without an increase in the risk of neonatal hyperbilirubinemia. The risk of adverse effects like polycythemia or neonatal hyperbilirubinemia requiring phototherapy did not increase even after extending the time of cord clamping to >180 seconds., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Malik et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)