EFFICACY AND SAFETY OF DAZODALIBEP (VIB4920/HZN4920) IN SUBJECTS WITH SJÖGREN'S SYNDROME: A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PROOF OF CONCEPT STUDY

BackgroundSjögren's syndrome (SS) is a chronic, systemic autoimmune disease affecting exocrine glands, primarily the salivary and tear glands, with potentially severe manifestations in multiple organs. No approved disease-modifying therapies exist. Dazodalibep (DAZ) is a biologic antagonist of CD40L.ObjectivesThe objective of this study was to evaluate the efficacy and safety of DAZ therapy in adult SS subjects with moderate-to-high systemic disease activity (NCT04129164).MethodsWe conducted a randomized, double-blind, placebo-controlled, crossover study to evaluate DAZ therapy in adult SS subjects with moderate-to-high systemic disease activity, as defined by a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score ≥ 5. Eligible subjects were randomized 1:1 to receive intravenous DAZ 1500 mg or placebo (PBO) Q2W x 3 doses, then Q4W x 4 additional doses. Starting on Day 169, subjects initially randomized to DAZ received PBO Q4W x 5 doses and subjects randomized to PBO received DAZ Q4W x 5 doses and were then followed for 12 weeks. The primary endpoint was the change from Baseline in ESSDAI at Day 169. Safety assessments included the incidence of adverse (AEs), serious AEs (SAEs), and AEs of special interest (AESIs).ResultsThe 74 randomized subjects all received ≥1 dose of study medication (DAZ, N=36;PBO, N=38). The baseline demographics and disease characteristics were balanced between the two groups. The change from Baseline to Day 169 in ESSDAI score (LS mean ± SE), was -6.3 ± 0.6 in DAZ-treated subjects compared to -4.1 ± 0.6 in the PBO group, a difference of -2.2 (p = 0.0167). Compared to the PBO group, the DAZ group showed positive trends in the EULAR Sjögren's Syndrome Patient Reported Index score, and Functional Assessment of Chronic Illness Therapy-Fatigue score at Day 169. A post-hoc responder analysis of subjects achieving high levels (5 and 6 points) of improvement on ESSDAI favored DAZ (61.1% and 60.0%) over PBO (35.1% and 34.3%).The reported AEs were generally mild through Day 169 and similar in frequency between treatment groups. The most frequently reported AEs occurring in ≥5% of DAZ-treated subjects and >PBO were COVID-19, diarrhea, dizziness, ligament sprain, upper respiratory tract infection, contusion, device allergy, fatigue, hypertension, and oropharyngeal pain. Two SAEs were reported in a single DAZ-treated subject: this subject was a 59-year-old female who experienced a grade 3 SAE of COVID-19 infection and later died of unknown cause 46 days after last administration of DAZ (12 days after COVID-19 diagnosis). There was a single AESI of herpes zoster in a DAZ-treated subject.ConclusionDAZ is a potential new therapy for the treatment of systemic disease activity in patients with SS. SS subjects with moderate-to-high systemic disease receiving DAZ experienced a statistically significant reduction in disease activity relative to PBO as measured by the improvement in ESSDAI score. Except for a case of severe COVID-19 infection, DAZ therapy in SS subjects appeared to be well tolerated. Larger controlled trials of DAZ therapy for SS are warranted to further explore its safety profile and confirm its clinical efficacy.Table 1.Efficacy and Safety DataPBO N=38DAZ 1500 mg N=36EfficacyΔESSDAI, LS mean (SE) †-4.1 (0.6)-6.3 (0.6)*ΔESSPRI, LS mean (SE) †-1.12 (0.29)-1.80 (0.31)ΔFACIT-Fatigue, LS mean (SE) †5.8 (1.6)8.1 (1.6)AE Summary, n (%)≥1 AE23 (60.5)28 (77.8)≥1 related AE8 (21)10 (27.8)≥1 SAE01 (2.8)≥1 related SAE00≥1 AE leading to discontinuation00≥1 AESI01 (2.8)≥1 Death01 (2.8)Efficacy endpoints as of Day 169;† Analyzed using MMRM;Comparisons vs PBO;*p<0.05;AE summaries based on AEs that occurred through Day 169;AE, adverse event;AESI, adverse event of special interest;ESSDAI, EULAR Sjögren's Syndrome Disease Activity Index;ESSPRI, EULAR Sjögren's Syndrome Patient Reported Index;FACIT-Fatigue, Functional Assessment of Chronic Illness Therapy-Fatigue;PBO, placebo;SAE, serious adverse eventFigure 1.AcknowledgementsFunded by Horizon herapeutics. Medical writing support provided by B Lujan, PhD, an employee of Horizon Therapeutics.Disclosure of InterestsE. William St. Clair Consultant of: Horizon Therapeutics, Bristol Myers Squibb, CSL Behring, Resolve Therapeutics, Sonoma Biotherapeutics. Royalties: UpToDate, Liangwei Wang Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Ilias Alevizos Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, William Rees Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Alan Baer Consultant of: Bristol Myers Squibb, Wan Fai Ng Consultant of: Novartis, GlaxoSmithKline, Abbvie, BMS, Sanofi, MedImmune, Janssen and UCB, Ghaith Noaiseh Consultant of: Novartis, Chiara Baldini Consultant of: GSK, and Sanofi.

E-LEARNING AND PRACTICAL PERFORMANCE IN MUSCULOSKELETAL ULTRASOUND - A MULTICENTER RANDOMIZED STUDY

BackgroundThe COVID-19 pandemic has forced a change in the teaching approach when educating physicians. Several training programs have been digitally transformed, including complex procedures such as ultrasound [1]. Recent studies have suggested the possibilities for practicing theoretical and practical ultrasound skills using online platforms, e.g., e-learning [2]. Even though the effect of e-learning on theoretical knowledge is unquestionable, the impact on practical skills is unknown. Thus, it is essential to examine the effect of e-learning on the development of practical skills.ObjectivesTo examine the effect of pre-course e-learning on residents' practical performance in musculoskeletal ultrasound (MSUS). Moreover, to examine the effect of pre-course e-learning on residents' satisfaction with the following face-to-face MSUS course.MethodsWe designed a multi-center randomized controlled study following the CONSORT statement. Residents with no or little MSUS experience were randomized to either an e-learning group or a traditional group. One week before a 2-day face-to-face MSUS course, the e-learning group received access to an interactive platform consisting of online lectures, assignments, and practical instruction videos aligned with the content of the following course. The traditional group only received standard pre-course information (program, venue, and time). All participants performed a pre- and post-course practical MSUS examination and were assessed by two individual raters, blinded to the group allocation, using the validated Objective Structured Assessment of Ultrasound skills (OSAUS) tool. Finally, the participants filled out a subjective satisfaction questionnaire, the Intrinsic Motivation Inventory (IMI).ResultsTwenty-eight participants completed the study. There were no statistically significant differences in the pre- or post-course practical MSUS performance between the e-learning group and the traditional group;the mean pre-course OSAUS score (±SD) in the e-learning group was 5.4±3.7 compared to 5.2±2.4 in the traditional group, p=0.8, whereas the post-course OSAUS score in the e-learning group was 11.1±2.8 compared to 10.9±2.4 in the traditional group, p=0.8 (Figure 1). There was a significant difference between the mean pre- and post-course scores (p<0.001) for both groups. The OSAUS assessment tool demonstrated excellent inter-rater reliability (ICC=0.84). There were no significant differences between the groups regarding their subjective satisfaction with the course measured by the IMI score.ConclusionWe found no significant impact of pre-course e-learning on novices' acquisition of practical MSUS skills or on trainees' satisfaction with the course. Hands-on training is of utmost importance and improves MSUS performance significantly. The OSAUS assessment tool is an applicable tool for the assessment of trainees' MSUS competences and demonstrated excellent interrater reliability.References[1]Strobel D et al. Ultraschall Med 2022;43:428-434.[2]Kan TL et al. Adv Med Educ Pract 2015;6:171-175AcknowledgementsWe would like to express our appreciation to the residents, healthy volunteers, and raters who donated their time to participate in this study. Moreover, the authors thank Søren Grimstrup for statistical assistance. We would like to thank the TOYOTA foundation for financial support for the purchase of an ultrasound machine.Disclosure of InterestsNone Declared.

ENHANCED SURVEILLANCE FOR THE DETECTION OF PSORIATIC ARTHRITIS IN A UK PRIMARY CARE PSORIASIS POPULATION VERSUS USUAL CARE: RESULTS AT 24 MONTHS FROM THE THE TOTAL BURDEN OF PSORIASIS (TUDOR) RANDOMISED CONTROL TRIAL

BackgroundDelay in the diagnosis of psoriatic arthritis may be associated with poorer outcome. However, the effectiveness of strategies to enable early detection of psoriatic arthritis in a primary care population with psoriasis have not been investigated in a prospective randomised control trial.ObjectivesThe primary objective was to determine whether early detection of undiagnosed PsA in people with psoriasis by an enhanced surveillance (ES) intervention compared to standard care (SC) improves outcome in physical function at 24 months post-registration. Secondary objectives were to compare disease activity and impact of disease between groups in those participants diagnosed with PsA.MethodsA multi-centre, prospective, parallel group cluster randomised controlled trial in patients with psoriasis with no prior diagnosis of PsA was conducted. GP practices were randomised in a 1:1 allocation ratio with stratification for GP practice list size and Central Commissioning Group (CCG). A total of 133 GP practices and 2226 participants were required to achieve a target sample size for the primary analysis population of 148 participants (74 per group) with a positive diagnosis of PsA;the latter corresponding to 80% power for detecting the MCID in the primary outcome measure of 0.35 units. Participants recruited were managed according to either SC, or ES by annual rheumatological assessment. Participants with suspected inflammatory arthritis were referred, via their GP, to the local rheumatology outpatient clinic at participating hospitals for an assessment of PsA by the ‘treating rheumatologist' (ES arm: at baseline, 12 and 24 months;SC arm: at 24 months). Participants diagnosed with PsA then entered the PsA-care pathway element of the trial. The primary outcome measure was the HAQ_DI at 24 months post registration in participants diagnosed with PsA. Secondary outcome measures, PASDAS and PsAID-12, were assessed over time in participants with a positive diagnosis of PsA.ResultsA total of 2225 participants across 135 GP practices were registered, corresponding to 1123 allocated to ES and 1102 to SC;primary analysis population consisted of 87 participants with a positive diagnosis of PsA: 64 in ES, 23 in SC (Figure one). Baseline characteristics were similar across both treatment groups. The adjusted odds ratio (OR) for achieving a HAQ-DI score of 0 at 24 months post registration in ES compared to SC was 0.64 (95% CI (0.17, 2.38)), indicating no evidence of a difference between treatment groups (p=0.5075). Moreover, the adjusted OR of achieving a higher (non-zero) HAQ-DI score at 24 months post registration in ES relative to SC arm was 1.12 (95% CI: 0.67, 1.86), again indicating no evidence of a difference between the two treatment groups (p=0.6612). There was high variability on the impact of the disease between participants over time, although the impact is generally low in this group of participants with an ‘early' diagnosis of PsA. Moreover, the overall PASDAS score and component scores over time post PsA diagnosis show high variability in PsA disease activity. No adverse events were reported.ConclusionThere was insufficient evidence that early diagnosis by ES and subsequent treatment improves physical function compared to SC in patients with psoriasis. Limitations included the trial being underpowered for demonstrating the pre-specified treatment effect;only 6.2% of participants recruited had a positive diagnosis of PsA, much lower than assumed (18%). The imbalance observed between treatment groups (~ 3:1 ratio (ES:SC)), is largely explained by the lower proportion of participants especially in the SC arm attending the screening visit at 24 months, and delays between referral and attending appointment with the treating clinician, all further exacerbated by the Covid-19 pandemic. Furthermore, a longer duration of follow-up may be necessary to detect differences in outcome and is planned.ReferencesNil.Figure 1.AcknowledgementsThis project was funded by the National Institute for Health Research (NIHR)Programme rants for Applied Research programme.Disclosure of InterestsNone Declared.

BIMEKIZUMAB MAINTAINED IMPROVEMENTS IN EFFICACY ENDPOINTS AND HAD A CONSISTENT SAFETY PROFILE THROUGH 52 WEEKS IN PATIENTS WITH NON-RADIOGRAPHIC AND RADIOGRAPHIC AXIAL SPONDYLOARTHRITIS: RESULTS FROM TWO PARALLEL PHASE 3 STUDIES

BackgroundBimekizumab (BKZ), a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A, met all primary/secondary endpoints at Week (Wk) 16 in patients (pts) with active non-radiographic axial spondyloarthritis (nr-axSpA) and radiographic axSpA (r-axSpA;i.e., ankylosing spondylitis), in the parallel phase 3 BE MOBILE 1 and 2 studies, respectively.[1,2]ObjectivesTo assess efficacy and safety of BKZ in these pts up to Wk 52.MethodsBE MOBILE 1 (NCT03928704) and 2 (NCT03928743) both involved a 16-wk placebo (PBO)-controlled and 36-wk maintenance period.[1,2] Pts were randomised to subcutaneous BKZ 160 mg Q4W (BKZ) or to PBO then BKZ from Wk 16 (PBO/BKZ).Results220/254 (86.6%) randomised pts with nr-axSpA and 298/332 (89.8%) with r-axSpA completed Wk 52. Efficacy was sustained to Wk 52 in both studies (Table 1). ASAS40 responses in BKZ-randomised pts increased from Wk 16 (nr-axSpA: 47.7%;r-axSpA: 44.8%;non-responder imputation [NRI]) to Wk 52 (60.9%;58.4%;NRI) with high levels of efficacy across TNFi-naïve and TNFi-IR populations (Table 1). At Wk 52, ASDAS <2.1 was achieved by 61.6% and 57.1%, and ASDAS <1.3 by 25.2% and 23.4%, of BKZ-randomised pts with nr-axSpA and r-axSpA, respectively (Figure 1). Wk 16 reductions from baseline in objective signs of inflammation (MRI, hs-CRP), and improvements in function (BASFI) and ASQoL, were maintained through 52 wks. Efficacy at Wk 52 was similar in PBO/BKZ-treated and BKZ-randomised pts (Table 1).At Wk 52, 75.0% (183/244) of pts with nr-axSpA and 75.5% (249/330) of pts with r-axSpA had ≥1 treatment-emergent adverse event (TEAE) on BKZ;the most frequent (% pts) TEAEs by preferred term (MedDRA v19.0) were nasopharyngitis (nr-axSpa: 12.3%;r-axSpA 9.1%) and upper respiratory tract infection (9.4%;6.4%);few COVID-19 infections were reported (7.0%;2.1%). Incidence (pts/100 pt years) of serious TEAEs were low (4.4;7.1);no major adverse cardiovascular events, active tuberculosis cases, serious COVID-19 infections, or deaths were reported. Most incidences of fungal infection (19.6;14.9;none serious or systemic) were Candida (12.8;8.3) and mild to moderate;two pts in both studies discontinued the study due to Candida infections. Incidence of IBD (1.0;1.0) and uveitis (1.5;2.4) were low.ConclusionAcross the axSpA spectrum, BKZ resulted in sustained efficacy to Wk 52. No new safety signals were observed, consistent with the Wk 24 safety profile.[1,2]References[1]Deodhar A. Ann Rheum Dis 2022;81:772–3;2.[2]van der Heijde D. Ann Rheum Dis 2022;81:12–3.Table 1.Efficacy at Wk 52Mean (SE), unless statedBE MOBILE 1BE MOBILE 2PBO→BKZ N=126BKZ N=128PBO→BKZ N=111BKZ N=221ASAS40 [NRI] n (%)64 (50.8)78 (60.9)76 (68.5)129 (58.4)ASAS40 in TNFi-naïve [NRI] n (%)58 (53.2)a73 (61.9)b67 (71.3)c108 (58.7)dASAS40 in TNFi-IRe [NRI] n (%)6 (35.3)f5 (50.0)g9 (52.9)f21 (56.8)hASAS20 [NRI] n (%)88 (69.8)94 (73.4)89 (80.2)158 (71.5)ASAS PR [NRI] n (%)38 (30.2)38 (29.7)41 (36.9)66 (29.9)ASAS 5/6 [NRI] n (%)65 (51.6)71 (55.5)74 (66.7)124 (56.1)BASDAI CfB [MI]–3.5 (0.2)–3.9 (0.2)–4.0 (0.2)–3.6 (0.1)BASFI CfB [MI]–2.6 (0.2)–3.0 (0.2)–2.8 (0.2)–2.8 (0.1)ASDAS-MI [NRI] n (%)37 (29.4)47 (36.7)49 (44.1)71 (32.1)Nocturnal spinal pain CfB [MI]–4.1 (0.2)–4.3 (0.3)–4.6 (0.3)–4.1 (0.2)ASQoL CfB [MI]–5.3 (0.4)–5.9 (0.4)–5.6 (0.4)–5.7 (0.3)SF-36 PCS CfB [MI]11.4 (0.9)12.2 (0.9)12.3 (0.9)12.0 (0.6)BASMI CfB [MI]–0.4 (0.1)–0.6 (0.1)–0.7 (0.1)–0.7 (0.1)Total resolution of enthesitisi [NRI] n (%)41 (44.6)j51 (54.3)c31 (46.3)k67 (50.8)lASDAS-CRP CfB [MI]–1.6 (0.1)–1.8 (0.1)–1.9 (0.1)–1.7 (0.1)SPARCC MRI SIJ score CfB [OC]mMean (SD)–6.4 (10.7)n–7.6 (10.5)o–2.8 (6.1)p–4.7 (8.2)qBerlin MRI spine score CfB [OC]mMean (SD)–0.4 (2.0)k–0.7 (2.5)r–2.1 (3.4)p–2.4 (3.9)shs-CRP, mg/L [MI] Median2.21.72.02.3RS. n: a109, b118, c94, d184;eMax 1 TNFi;n: f17, g10, h37;iMASES=0 in pts with MASES >0 at BL;n: j92, k67;l132;mMRI sub-study;n: n70, o82, p48, q90, r79, s89.AcknowledgementsThis study was funded by UCB Ph rma. Medical writing support was provided by Costello Medical, funded by UCB Pharma.Disclosure of InterestsXenofon Baraliakos Speakers bureau: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer and UCB Pharma, Paid instructor for: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer and UCB Pharma, Consultant of: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer and UCB Pharma, Atul Deodhar Speakers bureau: Janssen, Novartis and Pfizer, Consultant of: AbbVie, Amgen, Aurinia, BMS, Eli Lilly, Janssen, MoonLake, Novartis, Pfizer and UCB Pharma, Grant/research support from: AbbVie, BMS, Celgene, Eli Lilly, MoonLake, Novartis, Pfizer and UCB Pharma, Désirée van der Heijde Consultant of: AbbVie, Bayer, BMS, Cyxone, Eisai, Galapagos, Gilead, GSK, Janssen, Eli Lilly, Novartis, Pfizer and UCB Pharma, Employee of: Director of Imaging Rheumatology BV, Marina Magrey Consultant of: AbbVie, Eli Lilly, Novartis, Pfizer and UCB Pharma, Grant/research support from: AbbVie and UCB Pharma, Walter P Maksymowych Consultant of: AbbVie, BMS, Boehringer-Ingelheim, Celgene, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer and UCB Pharma, Grant/research support from: AbbVie and Pfizer;educational grants from AbbVie, Janssen, Novartis and Pfizer, Employee of: Chief Medical Officer for CARE ARTHRITIS, Tetsuya Tomita Speakers bureau: AbbVie, Astellas, BMS, Eisai, Eli Lilly, Janssen, Kyowa Kirin, Mitsubishi-Tanabe, Novartis and Pfizer, Consultant of: AbbVie, Eli Lilly, Gilead, Novartis and Pfizer, Huji Xu Speakers bureau: AbbVie, Janssen, Novartis, Pfizer and UCB Pharma, Consultant of: AbbVie, Beigene, BioMap, IASO, Pfizer and UCB Pharma, Employee of: Clinical investigator for Peking-Tsinghua Center for Life Sciences, Marga Oortgiesen Shareholder of: UCB Pharma, Employee of: UCB Pharma, Ute Massow Employee of: UCB Pharma, Carmen Fleurinck Employee of: UCB Pharma, Alicia Ellis Employee of: UCB Pharma, Thomas Vaux Employee of: UCB Pharma, julie smith Employee of: UCB Pharma, Alexander Marten Employee of: UCB Pharma, Lianne S. Gensler Consultant of: AbbVie, Acelyrin, Eli Lilly, Fresenius Kabi, Janssen, Novartis, Pfizer and UCB Pharma, Grant/research support from: Novartis and UCB Pharma paid to institution.

The Therapeutic Impact of Plant-Based and Nutritional Supplements on Anxiety, Depressive Symptoms and Sleep Quality among Adults and Elderly: A Systematic Review of the Literature.

BACKGROUND: The emerging research in the literature continues to forecast a drastic and alarming increase in negative mental health and sleep health outcomes among populations, especially after the COVID-19 pandemic, which significantly influenced people's way of life. With mental health pharmaceutical interventions continuing to be stigmatized and inaccessible among populations, natural supplements provide an opportunity for intervention. OBJECTIVE: This study sought to conduct a systematic review of the literature on the most recent comprehensive evidence for which nutritional supplements have the greatest therapeutic impact on symptoms of anxiety, depression, and insomnia. METHODS: A systematic search of the literature, utilizing several databases, including PubMed and Web of Science, was conducted on 29 April 2022. We used developed keywords and MeSH terms for the search. The study eligibility criteria included (1) a randomized control trial; (2) investigating a plant-based therapeutic or natural supplement as the intervention; (3) measuring at least one health outcome of the following: anxiety symptoms, depressive symptoms, or sleep health outcomes; (4) utilizing validated measurement tools to measure the outcome of interest; (5) written in the English language; (6) peer reviewed; and (7) focused on adults and elderly populations. MAIN RESULTS: Following the PRISMA guidelines, 76 studies were included in this review. We used the revised Risk of Bias tool (RoB2) to assess the quality of all included randomized control trials. A qualitative data synthesis was conducted. Overall, we found several valuable insights from the evidence in the literature, including evidence that demonstrates the benefits of probiotics and vitamin B complexes on anxiety symptoms, depressive symptoms, and sleep quality. Implication of Key Findings: This review provides the most updated findings in the literature on the topic, including an abundance of research that was published in the past 5 years. Given the expected rise in negative mental and sleep health outcomes following the pandemic, the supplements and therapeutics identified in this study should be the target of intervention measures to increase their accessibility and affordability and allow them to be incorporated into clinical guidelines of treatment. PROSPERO registration number: CRD42022361130.

Macroeconomic expectations and consumer sentiment during the COVID-19 pandemic: The role of others' beliefs.

This paper investigates the effect of information about cross-country ratings of the government's and the public's reaction to the COVID-19 pandemic on consumers' macroeconomic expectations and sentiment. We conduct consumer surveys with randomized control trials (RCTs) in two waves in Thailand and Vietnam. The information treatments have the strongest effect when the information shown contradicts consumers' prior beliefs. In the first survey, conducted when the first lockdown was eased, treatment effects are stronger in Vietnam, causing more optimistic expectations and sentiment. In the second survey, conducted at the start of the second wave of infections, treatment effects are stronger in Thailand, causing a more pessimistic outlook.

Results from a test-and-treat study for influenza among residents of homeless shelters in King County, WA: A stepped-wedge cluster-randomized trial.

BACKGROUND: Persons experiencing homelessness face increased risk of influenza as overcrowding in congregate shelters can facilitate influenza virus spread. Data regarding on-site influenza testing and antiviral treatment within homeless shelters remain limited. METHODS: We conducted a cluster-randomized stepped-wedge trial of point-of-care molecular influenza testing coupled with antiviral treatment with baloxavir or oseltamivir in residents of 14 homeless shelters in Seattle, WA, USA. Residents ≥3 months with cough or ≥2 acute respiratory illness (ARI) symptoms and onset <7 days were eligible. In control periods, mid-nasal swabs were tested for influenza by reverse transcription polymerase chain reaction (RT-PCR). The intervention period included on-site rapid molecular influenza testing and antiviral treatment for influenza-positives if symptom onset was <48 h. The primary endpoint was monthly influenza virus infections in the control versus intervention periods. Influenza whole genome sequencing was performed to assess transmission and antiviral resistance. RESULTS: During 11/15/2019-4/30/2020 and 11/2/2020-4/30/2021, 1283 ARI encounters from 668 participants were observed. Influenza virus was detected in 51 (4%) specimens using RT-PCR (A = 14; B = 37); 21 influenza virus infections were detected from 269 (8%) intervention-eligible encounters by rapid molecular testing and received antiviral treatment. Thirty-seven percent of ARI-participant encounters reported symptom onset < 48 h. The intervention had no effect on influenza virus transmission (adjusted relative risk 1.73, 95% confidence interval [CI] 0.50-6.00). Of 23 influenza genomes, 86% of A(H1N1)pdm09 and 81% of B/Victoria sequences were closely related. CONCLUSION: Our findings suggest feasibility of influenza test-and-treat strategies in shelters. Additional studies would help discern an intervention effect during periods of increased influenza activity.

Ginger supplement significantly reduced length of hospital stay in individuals with COVID-19.

BACKGROUND: Evidence from previous studies has suggested that ginger extract exhibits the potential as an alternative treatment for Coronavirus disease 2019 (COVID-19). Here, we want to investigate whether ginger supplement improves the clinical manifestation of hospitalized COVID-19 individuals. METHODS: A total of 227 hospitalized individuals with COVID-19 were randomized to either the control (n = 132) or intervention group (n = 95). The intervention group took ginger supplement orally at the dosage of 1.5 g twice daily, until they were discharged from the hospital. Both groups received the same standard of general medical care during hospitalization, and the length of stay was recorded and compared between groups. RESULTS: Among all participants, a significant reduction in hospitalization time (the difference between the treatment and control groups was 2.4 d, 95% CI 1.6-3.2) was detected in response to the ginger supplement. This effect was more pronounced in men, participants aged 60 years or older, and participants with pre-existing medical conditions, relative to their counterparts (P-interactions < 0.05 for all). CONCLUSION: Ginger supplement significantly shortened the length of stay of hospitalized individuals with COVID-19. TRIAL REGISTRATION: The trial was registered on the Chinese Clinical Trial Registry (ChiCTR2200059824).

The effect of a short, animated story-based video on COVID-19 vaccine hesitancy: A study protocol for an online randomized controlled trial.

Introduction: Exposure to a high volume of vaccine misinformation on social media can have a negative effect on vaccine confidence and rates. To counteract misinformation, we designed a collage of three short, animated story-based (SAS) videos to convey scientifically informed and accessible information about COVID-19 vaccine applicable to a social media context. Methods and analysis: We will conduct an online randomized controlled trial primarily to: (1) determine the effectiveness of SAS videos in improving COVID-19 vaccine knowledge; (2) evaluate the effectiveness of SAS videos in increasing behavioral intent for COVID-19 vaccination; and (3) quantify people's interest in watching SAS videos about the COVID-19 vaccine. We also aim to identify barriers and facilitators to COIVD-19 vaccinations that have been shown to minimize vaccine hesitancy between vaccinated and unvaccinated populations. Using a web-based recruitment platform, a total of 10,000 adults from the United States will be recruited and randomly assigned to (1) a SAS video collage arm, (2) an attention placebo control video arm, or (3) no intervention arm (1:1:1). Furthermore, we will measure behavioral intent to obtain information on vaccination regarding COVID-19. At the end of the trial, participants randomized to arm 2 and arm 3 will be given the option of watching one of the intervention videos voluntarily to assess participant engagement with SAS videos. Finally, we will assess individual factors associated with vaccine hesitancy - hope, optimism, COVID-19 perceived risks and benefits, self-efficacy, perceived social norms, and trust - and compare vaccinated and unvaccinated participants across the three arms. Discussions: Evidence-based information from official channels can be complex and inaccessible to the general public, whereas false information on social media is frequently shared in brief postings, images, or videos that can easily reach the general public, thereby rapidly disseminating (mis-)information. To avoid the spread of misinformation, social media may be used to deliver evidence-based and emotionally compelling information in a readily accessible format in order to pre-empt misinformation. Our findings may help inform future SAS efforts addressing COVID-19 and other important public health challenges. Ethics and dissemination: The study was approved by the Heidelberg University Hospital's Ethics Committee (S-163/2022). The trial was registered with German Clinical Trials Register (www.drks.de) on 5 January 2022: number DRKS00027938. Findings of the study will be published in peer-reviewed scientific publications and possibly presented at scientific conferences.

Health Care Workers' Need for Headspace: Findings From a Multisite Definitive Randomized Controlled Trial of an Unguided Digital Mindfulness-Based Self-help App to Reduce Healthcare Worker Stress.

BACKGROUND: Health care workers experience high stress. Accessible, affordable, and effective approaches to reducing stress are lacking. In-person mindfulness-based interventions can reduce health care worker stress but are not widely available or accessible to busy health care workers. Unguided, digital, mindfulness-based self-help (MBSH) interventions show promise and can be flexibly engaged with. However, their effectiveness in reducing health care worker stress has not yet been explored in a definitive trial. OBJECTIVE: This study aimed to investigate the effectiveness of an unguided digital MBSH app (Headspace) in reducing health care worker stress. METHODS: This was a definitive superiority randomized controlled trial with 2182 National Health Service staff in England recruited on the web and allocated in a 1:1 ratio to fully automated Headspace (n=1095, 50.18%) or active control (Moodzone; n=1087, 49.82%) for 4.5 months. Outcomes were subscales of the Depression, Anxiety, and Stress (primary outcome) Scale short form; Short Warwick Edinburgh Mental Well-being Scale; Maslach Burnout Inventory; 15-item Five-Facet Mindfulness Questionnaire minus Observe items; Self-Compassion Scale-Short Form; Compassionate Love Scale; Penn State Worry Questionnaire; Brooding subscale of the Ruminative Response Scale; and sickness absence. RESULTS: Intention-to-treat analyses found that Headspace led to greater reductions in stress over time than Moodzone (b=-0.31, 95% CI -0.47 to -0.14; P<.001), with small effects. Small effects of Headspace versus Moodzone were found for depression (b=-0.24, 95% CI -0.40 to -0.08; P=.003), anxiety (b=-0.19, 95% CI -0.32 to -0.06; P=.004), well-being (b=0.14, 95% CI 0.05-0.23; P=.002), mindfulness (b=0.22, 95% CI 0.09-0.34; P=.001), self-compassion (b=0.48, 95% CI 0.33-0.64; P<.001), compassion for others (b=0.02, 95% CI 0.00-0.04; P=.04), and worry (b=-0.30, 95% CI -0.51 to -0.09; P=.005) but not for burnout (b=-0.19, -0.04, and 0.13, all 95% CIs >0; P=.65, .67, and .35), ruminative brooding (b=-0.06, 95% CI -0.12 to 0.00; P=.06), or sickness absence (γ=0.09, 95% CI -0.18 to 0.34). Per-protocol effects of Headspace (454/1095, 41.46%) versus Moodzone (283/1087, 26.03%) over time were found for stress, self-compassion, and compassion for others but not for the other outcomes. Engagement (practice days per week) and improvements in self-compassion during the initial 1.5-month intervention period mediated pre- to postintervention improvements in stress. Improvements in mindfulness, rumination, and worry did not mediate pre- to postintervention improvements in stress. No serious adverse events were reported. CONCLUSIONS: An unguided digital MBSH intervention (Headspace) can reduce health care workers' stress. Effect sizes were small but could have population-level benefits. Unguided digital MBSH interventions can be part of the solution to reducing health care worker stress alongside potentially costlier but potentially more effective in-person mindfulness-based interventions, nonmindfulness courses, and organizational-level interventions. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN15424185; https://tinyurl.com/rv9en5kc.

The effects of family-centered empowerment model on depression, anxiety, and stress of the family caregivers of patients with COVID-19: a randomized clinical trial.

BACKGROUND: Taking care of patients with Covid-19 is regarded as a challenging task for family caregivers. Hence, a Family-Centered Empowerment Model (FCEM) should help them achieve greater psychological strength throughout the home healthcare process. METHODS: This study is a randomized clinical trial with two groups; besides, pre-test and post-test designs were conducted based on the CONSORT checklist from April to July 2020, in Iran. Seventy family caregivers were randomly assigned to FCEM (n = 35) and control (n = 35) groups. Then, four stages of FCEM in four online sessions were provided to the participants of the intervention group via WhatsApp messenger. The procedure started at the patient's discharge and continued for two weeks. The demographic information questionnaire and Depression Anxiety Stress Scale (DASS-21) were employed before and five days after the FCEM sessions to gather the required data. RESULTS: The sample was made up of 55.8% women and 44.2% men caregivers, with a mean age of 42.5 years. The results demonstrated a substantial difference in the average score of stress (p = 0.023), anxiety (p = 0.003), and depression (p = 0.012). CONCLUSIONS: The combination of a face-to-face orientation session and online methods of FCEM is likely to lower stress, anxiety, and depression in family caregivers, which can be contributed to the practicability, simplicity, and effectiveness of this home health intervention. TRIAL REGISTRATION: This study (no. IRCT20180429039463N2 ) was registered in the Iranian Registry of Clinical Trials on 10/04/2020.

Impact of Steam Inhalation, Saline Gargling, and Povidone-Iodine Gargling on Clinical Outcome of COVID-19 Patients in Bengaluru, Karnataka: A Randomized Control Trial.

Context: In the absence of any specific treatment available for COVID-19, people started practicing traditional nonpharmacological preventive home remedies such as salt water gargling and steam inhalation. The available research evidence on some of these measures opines that steam inhalation, saline gargling, and povidone-iodine gargling does have virucidal properties and do provide symptomatic relief. Aims: The aim is to test this hypothesis, and the present trial was undertaken with an objective to assess the effect of steam inhalation, saline gargling, and povidone-iodine gargling among the COVID-19-positive patients with respect to early test negativity and clinical recovery. Methodology: Open-labeled, parallel, randomized controlled trial was conducted among asymptomatic or mild COVID-19-positive patients in Bangalore from September 2020 to February 2021. In each group of steam inhalation, saline gargling, povidone-iodine gargling, and control, twenty participants were allocated. Daily follow-up was done for 21 days to assess early test negativity and clinical recovery. Trial Registry Number: Clinical Trial Registry India/2020/09/027687. Results: Among 80 participants recruited, 65 (81.3%) were symptomatic. Early test negativity was seen in povidone-iodine gargling group of 6 days (KaplanMeier survival curve, BreslowGeneralized Wilcoxon test P = 0.7 as per the intention-to-treat and as per-protocol P = 0.8). Significant clinical recovery was seen in saline gargling group (4 days, P = 0.01). Conclusion: Povidone-iodine gargling was effective in providing early test negativity, whereas saline gargling was effective in early clinical recovery.

A smartphone application of diabetes coaching intervention to prevent the onset of complications and to improve diabetes self-management: A randomized control trial.

BACKGROUND AND AIM: Diabetes mellitus (DM) has been a worldwide public health problem during the last two decades. To examine the effect of a smartphone application of diabetes coaching intervention on improving self-management behaviors and preventing onset diabetes complications. METHODS: A randomized control trial, two groups, pre-test, and post-test design with a non-equivalent control group was conducted. The intervention group received a 12-week smartphone application of diabetes coaching intervention to improve diabetes self-management behaviors and to prevent onset diabetes complications. While the control group received the usual care from the community health centers. The smartphone application consisted of narrative App-based coaching, a printed user guide, mindfulness-based coaching; skill-based coaching, and a small App-interaction. RESULTS: After implementation, the self-management behaviors among the experimental group were improved than the control group in terms of dietary control, physical exercise, blood glucose monitoring, medication adherence, and screening of complications. The clinical outcomes were also significantly improved among the experimental group and to the control group. CONCLUSIONS: A smartphone application-based diabetes coaching intervention was feasible to apply as a nationwide program to promote diabetes self-management (DSM) during the covid-19 pandemic.

A randomized, double-blind, placebo-controlled trial of intravenous alpha-1 antitrypsin for ARDS secondary to COVID-19.

Background: Patients with severe coronavirus disease 2019 (COVID-19) develop a febrile pro-inflammatory cytokinemia with accelerated progression to acute respiratory distress syndrome (ARDS). Here we report the results of a phase 2, multicenter, randomized, double-blind, placebo-controlled trial of intravenous (IV) plasma-purified alpha-1 antitrypsin (AAT) for moderate to severe ARDS secondary to COVID-19 (EudraCT 2020-001391-15). Methods: Patients (n = 36) were randomized to receive weekly placebo, weekly AAT (Prolastin, Grifols, S.A.; 120 mg/kg), or AAT once followed by weekly placebo. The primary endpoint was the change in plasma interleukin (IL)-6 concentration at 1 week. In addition to assessing safety and tolerability, changes in plasma levels of IL-1ß, IL-8, IL-10, and soluble tumor necrosis factor receptor 1 (sTNFR1) and clinical outcomes were assessed as secondary endpoints. Findings: Treatment with IV AAT resulted in decreased inflammation and was safe and well tolerated. The study met its primary endpoint, with decreased circulating IL-6 concentrations at 1 week in the treatment group. This was in contrast to the placebo group, where IL-6 was increased. Similarly, plasma sTNFR1 was substantially decreased in the treatment group while remaining unchanged in patients receiving placebo. IV AAT did not definitively reduce levels of IL-1ß, IL-8, and IL-10. No difference in mortality or ventilator-free days was observed between groups, although a trend toward decreased time on ventilator was observed in AAT-treated patients. Conclusions: In patients with COVID-19 and moderate to severe ARDS, treatment with IV AAT was safe, feasible, and biochemically efficacious. The data support progression to a phase 3 trial and prompt further investigation of AAT as an anti-inflammatory therapeutic. Funding: ECSA-2020-009; Elaine Galwey Research Bursary.

Human Papillomavirus vaccination clinical decision support for young adults in an upper midwestern healthcare system: a clinic cluster-randomized control trial.

INTRODUCTION: Human papillomavirus (HPV) vaccination rates are low in young adults. Clinical decision support (CDS) in primary care may increase HPV vaccination. We tested the treatment effect of algorithm-driven, web-based, and electronic health record-linked CDS with or without shared decision-making tools (SDMT) on HPV vaccination rates compared to usual care (UC). METHODS: In a clinic cluster-randomized control trial conducted in a healthcare system serving a largely rural population, we randomized 34 primary care clinic clusters (with three clinics sharing clinicians randomized together) to: CDS; CDS+SDMT; UC. The sample included young adults aged 18-26 due for HPV vaccination with a study index visit from 08/01/2018-03/15/2019 in a study clinic. Generalized linear mixed models tested differences in HPV vaccination status 12 months after index visits by study arm. RESULTS: Among 10,253 patients, 6,876 (65.2%) were due for HPV vaccination, and 5,054 met study eligibility criteria. In adjusted analyses, the HPV vaccination series was completed by 12 months in 2.3% (95% CI: 1.6%-3.2%) of CDS, 1.6% (95% CI: 1.1%-2.3%) of CDS+SDMT, and 2.2% (95% CI: 1.6%-3.0%) of UC patients, and at least one HPV vaccine was received by 12 months in 13.1% (95% CI: 10.6%-16.1%) of CDS, 9.2% (95% CI: 7.3%-11.6%) of CDS+SDMT, and 11.2% (95% CI: 9.1%-13.7%) of UC patients. Differences were not significant between arms. Females, those with prior HPV vaccinations, and those seen at urban clinics had significantly higher odds of HPV vaccination in adjusted models. DISCUSSION: CDS may require optimization for young adults to significantly impact HPV vaccination. TRIAL REGISTRATION: clinicaltrials.gov NCT02986230, 12/6/2016.

Aspirin as a Treatment for ARDS: A Randomized, Placebo-Controlled Clinical Trial.

BACKGROUND: There is no pharmacologic treatment for ARDS. Platelets play an important role in the pathophysiology of ARDS. Preclinical, observational, and clinically relevant models of ARDS indicate aspirin as a potential therapeutic option. RESEARCH QUESTION: Is enteral aspirin (75 mg, once daily) safe and effective in improving surrogate outcomes in adult patients with ARDS? STUDY DESIGN AND METHODS: This randomized, double-blind (patient and investigator), allocation-concealed, placebo-controlled phase 2 trial was conducted in five UK ICUs. Patients fulfilling the Berlin definition of ARDS were randomly assigned at a 1:1 ratio to receive enteral aspirin (75 mg) or placebo, for a maximum of 14 days, using a computer-generated randomization schedule, with variable block size, stratified by vasopressor requirement. The primary end point was oxygenation index (OI) on day 7. Secondary outcomes included safety parameters and other respiratory physiological markers. Analyses were by intention to treat. RESULTS: The trial was stopped early, due to slow recruitment, after 49 of a planned 60 patients were recruited. Twenty-four patients were allocated to aspirin and 25 to placebo. There was no significant difference in day 7 OI [aspirin group: unadjusted mean, 54.4 (SD 26.8); placebo group: 42.4 (SD 25); mean difference, 12.0; 95% CI, -6.1 to 30.1; P = .19]. Aspirin did not significantly impact the secondary outcomes. There was no difference in the number of adverse events between the groups (13 in each; OR, 1.04; 95% CI, 0.56-1.94; P = .56). INTERPRETATION: Aspirin was well tolerated but did not improve OI or other physiological outcomes; a larger trial is not feasible in its current design. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02326350; URL: www. CLINICALTRIALS: gov.

Non-invasive Vagus Nerve Stimulation for COVID-19: Results From a Randomized Controlled Trial (SAVIOR I).

Background: Severe coronavirus disease 2019 (COVID-19) is characterized, in part, by an excessive inflammatory response. Evidence from animal and human studies suggests that vagus nerve stimulation can lead to reduced levels of various biomarkers of inflammation. We conducted a prospective randomized controlled study (SAVIOR-I) to assess the feasibility, efficacy, and safety of non-invasive vagus nerve stimulation (nVNS) for the treatment of respiratory symptoms and inflammatory markers among patients who were hospitalized for COVID-19 (ClinicalTrials.gov identifier: NCT04368156). Methods: Participants were randomly assigned in a 1:1 allocation to receive either the standard of care (SoC) alone or nVNS therapy plus the SoC. The nVNS group received 2 consecutive 2-min doses of nVNS 3 times daily as prophylaxis. Efficacy and safety were evaluated via the incidence of specific clinical events, inflammatory biomarker levels, and the occurrence of adverse events. Results: Of the 110 participants who were enrolled and randomly assigned, 97 (nVNS, n = 47; SoC, n = 50) had sufficient available data and comprised the evaluable population. C-reactive protein (CRP) levels decreased from baseline to a significantly greater degree in the nVNS group than in the SoC group at day 5 and overall (i.e., all postbaseline data points collected through day 5, combined). Procalcitonin level also showed significantly greater decreases from baseline to day 5 in the nVNS group than in the SoC group. D-dimer levels were decreased from baseline for the nVNS group and increased from baseline for the SoC group at day 5 and overall, although the difference between the treatment groups did not reach statistical significance. No significant treatment differences were seen for clinical respiratory outcomes or any of the other biochemical markers evaluated. No serious nVNS-related adverse events occurred during the study. Conclusions: nVNS therapy led to significant reductions in levels of inflammatory markers, specifically CRP and procalcitonin. Because nVNS has multiple mechanisms of action that may be relevant to COVID-19, additional research into its potential use earlier in the course of COVID-19 and its potential to mitigate some of the symptoms associated with post-acute sequelae of COVID-19 is warranted.

A Group-Facilitated, Internet-Based Intervention to Promote Mental Health and Well-Being in a Vulnerable Population of University Students: Randomized Controlled Trial of the Be Well Plan Program.

BACKGROUND: A growing literature supports the use of internet-based interventions to improve mental health outcomes. However, most programs target specific symptoms or participant groups and are not tailored to facilitate improvements in mental health and well-being or do not allow for needs and preferences of individual participants. The Be Well Plan, a 5-week group-facilitated, internet-based mental health and well-being group intervention addresses these gaps, allowing participants to select a range of activities that they can tailor to their specific characteristics, needs, and preferences. OBJECTIVE: This study aims to test whether the Be Well Plan program was effective in improving primary outcomes of mental well-being, resilience, anxiety, and depression compared to a waitlist control group during the COVID-19 pandemic; secondary outcomes included self-efficacy, a sense of control, and cognitive flexibility. The study further seeks to examine participants' engagement and satisfaction with the program. METHODS: A randomized controlled trial (RCT) was conducted with 2 parallel arms, an intervention and a waitlist control group. The intervention involved 5 weekly 2-hour sessions, which were facilitated in group format using Zoom videoconferencing software. University students were recruited via social media posts, lectures, emails, flyers, and posters. RESULTS: Using an intentional randomization 2:1 allocation strategy, we recruited 215 participants to the trial (n=126, 58.6%, intervention group; n=89, 41.4%, waitlist control group). Of the 126 participants assigned to the intervention group, 75 (59.5%) commenced the program and were included in modified intention-to-treat (mITT) analyses. mITT intervention participants attended, on average, 3.41 sessions (SD 1.56, median 4); 55 (73.3%) attended at least 4 sessions, and 25 (33.3%) attended all 5 sessions. Of the 49 intervention group participants who completed the postintervention assessment, 47 (95.9%) were either very satisfied (n=31, 66%) or satisfied (n=16, 34%). The mITT analysis for well-being (F1,162=9.65, P=.002, Cohen d=0.48) and resilience (F1,162=7.85, P=.006, Cohen d=0.44) showed significant time × group interaction effects, suggesting that both groups improved over time, but the Be Well Plan (intervention) group showed significantly greater improvement compared to the waitlist control group. A similar pattern of results was observed for depression and anxiety (Cohen d=0.32 and 0.37, respectively), as well as the secondary outcomes (self-efficacy, Cohen d=0.50; sense of control, Cohen d=0.42; cognitive flexibility, Cohen d=0.65). Larger effect sizes were observed in the completer analyses. Reliable change analysis showed that the majority of mITT participants (58/75, 77.3%) demonstrated a significant reliable improvement in at least 1 of the primary outcomes. CONCLUSIONS: The Be Well Plan program was effective in improving mental health and well-being, including mental well-being, resilience, depression, and anxiety. Participant satisfaction scores and attendance indicated a high degree of engagement and satisfaction with the program. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry ACTRN12621000180819; https://tinyurl.com/2p8da5sk.

Herbal medications and natural products for patients with covid-19 and diabetes mellitus: Potentials and challenges.

Background: The presence of diabetes mellitus (DM) among COVID-19 patients is associated with increased hospitalization, morbidity, and mortality. Evidence has shown that hyperglycemia potentiates SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection and plays a central role in severe COVID-19 and diabetes comorbidity. In this review, we explore the therapeutic potentials of herbal medications and natural products in the management of COVID-19 and DM comorbidity and the challenges associated with the preexisting or concurrent use of these substances. Methods: Research papers that were published from January 2016 to December 2021 were retrieved from PubMed, ScienceDirect, and Google Scholar databases. Papers reporting clinical evidence of antidiabetic activities and any available evidence of the anti-COVID-19 potential of ten selected natural products were retrieved and analyzed for discussion in this review. Results: A total of 548 papers (73 clinical trials on the antidiabetic activities of the selected natural products and 475 research and review articles on their anti-COVID-19 potential) were retrieved from the literature search for further analysis. A total of 517 articles (reviews and less relevant research papers) were excluded. A cumulative sum of thirty-one (31) research papers (20 clinical trials and 10 others) met the criteria and have been discussed in this review. Conclusion: The findings of this review suggest that phenolic compounds are the most promising phytochemicals in the management of COVID-19 and DM comorbidity. Curcumin and propolis have shown substantial evidence against COVID-19 and DM in humans and are thus, considered the best potential therapeutic options.