Observer-blinded Study Research Articles

168. Safety, Reactogenicity, and Immunogenicity of mRNA-1345, an Investigational Respiratory Syncytial Virus Vaccine, in Participants Aged 2 to < 18 Years at High Risk of Severe Disease

Abstract Background Respiratory syncytial virus (RSV) is the primary cause of lower respiratory tract disease in children aged < 5 years and causes substantial burden in those at high risk aged 5-18 years. No active RSV vaccine is currently available for children. Here, we present interim safety and immunogenicity of a single injection of the mRNA-based vaccine, mRNA-1345, in participants aged 2 to < 18 years at high risk for severe RSV disease. Methods This phase 2, randomized, observer-blind study enrolled participants into 2 age cohorts (2 to < 5 years and 5 to < 18 years). Participants aged 2 to < 5 years were healthy or had stable, chronic conditions increasing risk for RSV disease, and were randomized (1:1:1:1) to receive a single mRNA-1345 injection (7.5, 15, or 30 μg) or placebo. Participants aged 5 to < 18 years had chronic conditions that increased disease risk and were randomized (1:1:1) to receive a single mRNA-1345 injection (15, 30, or 50 μg). Safety and reactogenicity were primary objectives. The secondary objective was immunogenicity, measured by serum RSV neutralizing antibodies (nAb) against RSV-A and RSV-B, and RSV prefusion F (preF)-binding antibodies (bAb). Interim results through Day 29 are reported. Results At data cutoff, 162 participants aged 2 to < 5 years (mean 2.9 ± 0.8 years) and 184 participants aged 5 to < 18 years (mean 11.4 ± 3.8 years) had received a vaccination. In both cohorts, solicited adverse reactions were primarily Grade 1-2 in severity; injection site pain, headache, and fatigue were most frequently reported (Figure 1). No deaths occurred and no adverse events (AEs) led to study discontinuation; 1 unrelated serious AE and 1 AE of special interest were reported. At Day 29, a single mRNA-1345 injection increased RSV nAb titers from baseline by 5.9- to 12.7-fold (RSV-A) and 4.3- to 8.9-fold (RSV-B) in those aged 2 to < 5 years, and by 8.2- to 15.8-fold (RSV-A) and 4.7- to 8.0-fold (RSV-B) in those aged 5 to < 18 years (Figure 2). Similarly, vaccination increased RSV preF bAb concentrations at Day 29 for both cohorts (Figure 2). Conclusion A single injection of mRNA-1345 was well tolerated, raised no safety concerns, and increased both nAb and bAb immune responses in participants aged 2 to < 18 years. These findings support further development of mRNA-1345 for the pediatric population. Disclosures Sabine Schnyder Ghamloush, MD, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds (Public Company) Hui Qian, PhD, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds (Public Company) HuiLing Chen, PhD, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds (Public Company) Joseph Whitten, MD, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds (Public Company) Sonia K. Stoszek, PhD, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds (Public Company) Matthew D. Snape, MBBS, MD, FRCPCH, FPM, FMedSci, Moderna, Inc.: Emplolyee|Moderna, Inc.: Stocks/Bonds (Public Company)

Preoperative Analgesia Efficacy of Liposomal Bupivacaine Following Pericapsular Nerve Group (PENG) Block in Patients with Hip Fracture: A Randomized Controlled Observer-Blinded Study.

Single-injection pericapsular nerve group (PENG) block with ropivacaine provides clear analgesic effects in preoperative pain management for hip fractures. However, it suffers from insufficient duration, failing to meet the needs of most patients. This single-center, randomized controlled, observer-blinded trial utilizes a novel combination of liposomal bupivacaine (LB) single-injection PENG block to examine its efficacy, duration, and safety in preoperative analgesia for hip fractures, aiming to develop a new preoperative analgesic protocol. Sixty-six patients with hip fractures received ultrasound-guided single-injection PENG block with LB or ropivacaine after admission. The primary outcome was the static and dynamic pain scores measured at 48h post-block. Pain scores at 12, 24, 36, 60, and 72h post-block, rescue analgesia rate, time to first opioid, additional morphine consumption, and adverse events were assessed as the secondary outcomes. LB versus ropivacaine group at 48h post-block, with a median interquartile range (IQR) of 2 (1.0-2.0) versus 3 (2.0-3.0) at static pain score and 2 (1.75-3.0) versus 4 (4.0-5.0) at dynamic pain score. LB group had lower dynamic and static pain scores at other observation points except for the static pain score at 72h, lower pain intensity [sum of pain intensity difference (SPID)0-24, SPID0-48 and SPID0-72], longer time to first opioid, lower additional morphine consumption, and lower incidence of nausea and vomiting. No significant inter-group differences were detected in other secondary outcomes. For preoperative analgesia of hip fractures, LB single-injection PENG block had a similar analgesic intensity and safety as ropivacaine but provided a longer duration of analgesia, reaching 48h and even extending beyond 60h, which reduced opioid consumption and extended time to the first opioid. The protocol was registered in www.chictr.org.cn under the identifier ChiCTR2300072939.

ChatGPT (GPT-4) versus doctors on complex cases of the Swedish family medicine specialist examination: an observational comparative study

BackgroundRecent breakthroughs in artificial intelligence research include the development of generative pretrained transformers (GPT). ChatGPT has been shown to perform well when answering several sets of medical multiple-choice questions. However,...

Point-of-Care Lung Ultrasound to Evaluate Lung Isolation During One-Lung Ventilation in Children: A Blinded Observational Feasibility Study.

Minimally invasive thoracic surgical techniques require effective lung isolation using one-lung ventilation (OLV). Verification of lung isolation may be confirmed by auscultation, visual confirmation using fiberoptic bronchoscopy (FOB), or more recently, point-of-care ultrasound (POCUS). The aim of this study was to prospectively compare lung ultrasound with clinical auscultation to confirm OLV before thoracic surgery in pediatric patients. This prospectively blinded feasibility study included 40 patients ranging in age from 0 to 20 years. After confirmation of lung separation by the primary anesthesia team using FOB, the sonographer and the auscultator, both blinded to the laterality of surgery and lung separation, entered the operating room. The sonographer evaluated for pleural lung sliding and the auscultator listened for breath sounds. Successful lung separation was definitively confirmed by direct visualization of lung collapse during the operation. In confirming effective single-lung ventilation, lung ultrasound had a diagnostic accuracy of 95% (95% confidence interval [CI], 82.7%-98.5%). In contrast, auscultation could only reliably confirm lung isolation with 68% accuracy (95% CI, 51.5%-80.4%). The McNemar test showed a statistically significant difference between the use of lung ultrasound and auscultation (P < .001). The median time to perform ultrasonography was 67 seconds (interquartile range [IQR], 46-142) and the median time to perform auscultation was 21 seconds (IQR, 10-32). Based on the initial results of our feasibility trial, lung ultrasound proved to be a fast and reliable method to verify single-lung ventilation in pediatric patients presenting for thoracic surgery with a high degree of diagnostic accuracy.

Circulating Chromogranin A as a Surveillance Biomarker in Patients with Carcinoids-The CASPAR Study.

Gastroenteropancreatic neuroendocrine tumors (GEP-NET) are relatively indolent but can be more aggressive. The current recommendations for using serum chromogranin A (CgA) for patients with GEP-NET are equivocal. This study was designed to validate an automated CgA immunofluorescence assay for monitoring disease progression in patients with GEP-NET. A prospective, multicenter, blinded observational study was designed to validate an automated CgA immunofluorescence assay for monitoring disease progression in patients with GEP-NET. Tumor progression was evaluated with RECIST 1.1 by CT/MRI. An increase ≥50% above the prior CgA concentration to a value >100 ng/mL in the following CgA concentration was considered positive. A total of 153 patients with GEP-NET were enrolled. Using the prespecified cut-off of CgA change for tumor progression, specificity was 93.4% (95% confidence interval, 90.4%-95.5%; P < 0.001), sensitivity 34.4% (25.6%-44.3%), positive predictive value 57.9% (45.0-69.8), negative predictive value 84.3% (80.5-87.6), and AUC 0.73 (0.67-0.79). Changes in serial measurements of serum CgA had a favorable specificity and negative predictive value, making this test a useful adjunct to routine radiographic monitoring.

Safety and Immunogenicity of an Adjuvanted Clostridioides difficile Vaccine Candidate in Healthy Adults: A Randomized Placebo-Controlled Phase 1 Study.

This study investigated the safety, reactogenicity, and immunogenicity in healthy subjects of a Clostridioides difficile vaccine candidate with/without adjuvant, targeting toxins A and B. In this first-in-human, phase 1, observer-blind study, subjects aged 18-45 years were randomized to receive F2 antigen (n = 10) or placebo (n = 10), and subjects aged 50-70 years to receive F2 antigen plus AS01 adjuvant (n = 45), F2 antigen (n = 45), or placebo (n = 30) in 2 doses 1 month apart. A subcohort (n = 40) received a third dose 15 months later. Solicited adverse events (AEs) were recorded for 7 days and unsolicited AEs for 30 days after each dose. Immunogenicity was assessed at baseline and after each dose. Solicited AEs were transient and most frequent in subjects receiving F2 antigen plus AS01. No serious AEs were considered related to study vaccine. Immunogenicity was substantially higher in subjects receiving F2 antigen plus AS01 than subjects receiving F2 antigen alone. A third dose increased the immune response in subjects with baseline neutralization titers below the assay lower limit of quantitation. The GSK C. difficile vaccine candidate was immunogenic, especially when given with AS01, and was well tolerated with an acceptable safety profile. NCT04026009.

Decreasing brain activity caused by acute administration of ketamine and alcohol - A randomized, controlled, observer-blinded experimental study.

Substance abuse is a major public health problem. In recent years, ketamine, which is a parenteral anesthetic, has been consumed increasingly as an illicit drug together with alcohol, although little is known of how this association alters brain activity. The present study investigated the influence of progressive doses of ketamine, associated with alcohol, on electrophysiological activity. For this, 72 late-adolescent (8-10-week-old) male Wistar rats received either ketamine only, at low (10mg/kg), intermediate (20mg/kg) or high (30mg/kg) doses via intraperitoneal injection, or alcohol (2mL/100g) via oral gavage followed by ketamine (at low, intermediate, and high doses). Electroencephalograms (EEG) and electromyographic recordings were obtained 5min after the final application of the drug. When administered alone, ketamine resulted in an increase in delta, theta, beta, and gamma brainwaves, with a more pronounced effect being detected at the highest dose (30mg/kg) in the case of the delta, beta, and gamma waves. The amplitude of the alpha brainwaves was reduced at all doses of ketamine, but less intensively at the highest dose. When administered alone, alcohol reduced all the brainwaves, with the reduction in the alpha waves being exacerbated by ketamine at all doses, and that of the theta and beta waves being boosted at the lowest dose. The intermediate dose of ketamine (20mg/kg) reverted the alcohol-induced reduction in the theta and gamma waves, whereas the high dose increased delta, theta, beta, and gamma bandpower. Overall, then, while ketamine enhances the depressant effects of alcohol on the alpha brainwave at all doses, a low dose intensified this effect on the theta and beta 175 waves, whereas a high dose produces neuronal hyperexcitability in the theta and 176 gamma bandpower.

Transcutaneous carbon dioxide monitoring in children undergoing rigid bronchoscopy: a prospective blinded observational study.

Anesthetic management during rigid bronchoscopy in children can be challenging, and continuous end-tidal carbon dioxide (EtCO2) monitoring is often unachievable. Transcutaneous carbon dioxide (TcCO2) monitoring is strongly correlated with the partial pressure of carbon dioxide (PaCO2) and EtCO2. We aimed to investigate the incidence of hypercapnia in children undergoing rigid bronchoscopy. We enrolled patients aged < 18yr scheduled for rigid bronchoscopy in a prospective observational study. We recorded TcCO2 values from anesthesia induction to the postanesthesia care unit (PACU) stay. We ended monitoring when TcCO2 reached values ≤ 50mm Hg. The operating room (OR) team was blinded to the TcCO2. The outcome of primary interest was the incidence of hypercapnia (TcCO2 > 50mm Hg) in the OR. Other outcomes were the incidences of hypercapnia in the PACU and severe hypercapnia (TcCO2 > 90mm Hg), factors possibly related to hypercapnia (patient, surgery, or anesthesia factors), and the incidence of perioperative adverse events. A total of 30 patients were enrolled. The median [interquartile range (IQR)] age was 3.5 [1.5-8.0] yr. The incidence of hypercapnia was 100% in the OR and 60% in the PACU. Five cases (17%) presented with severe hypercapnia in the OR. The highest median [IQR] TcCO2 was 69 [61-79] mm Hg. The most common adverse event was oxygen desaturation (57%, 17/30). Patients with severe hypercapnia had long stays in the PACU. Hypercapnia was a frequent event in children undergoing rigid bronchoscopy and severe hypercapnia was associated with a long PACU stay. Further studies are needed to assess the utility of TcCO2 monitoring in guiding ventilatory interventions during these cases.

CLOVER (CLOstridium difficile Vaccine Efficacy tRial) Study: A Phase 3, Randomized Trial Investigating the Efficacy and Safety of a Detoxified Toxin A/B Vaccine in Adults 50 Years and Older at Increased Risk of Clostridioides difficile Infection.

Clostridioides difficile infection (CDI) causes substantial mortality and healthcare burden. We assessed the detoxified toxin-A/B PF-06425090 vaccine for primary CDI prevention. This phase 3 observer-blinded study randomized (1:1) ≥50-year-olds at increased CDI risk (N = 17 535) to receive 3 PF-06425090 or placebo doses (0, 1, and 6 months). Primary end points were first CDI episode (≥3 unformed stools within 24 hours; central laboratory-confirmed toxin A/B positive) ≥14 days post-dose 3 (PD3; first primary) and post-dose 2 (PD2; second primary). CDI duration, need for CDI-related medical attention (secondary end points), and antibiotic use (post hoc analysis) PD3 were evaluated. Tolerability and safety were assessed. The primary end point was not met (17 PF-06425090 and 25 placebo recipients had first CDI episode ≥14 days PD3 [vaccine efficacy (VE) = 31.0% (96.4% confidence interval [CI], -38.7% to 66.6%)]; 24 PF-06425090 and 34 placebo recipients had first CDI episode ≥14 days PD2 [VE = 28.6% (96.4% CI, -28.4% to 61.0%)]. Median CDI duration was lower with PF-06425090 (1 day) versus placebo (4 days; 2-sided nominal P = .02). Of participants with first CDI episode, 0 PF-06425090 and 11 placebo recipients sought CDI-related medical attention (post hoc analysis estimated VE = 100%; 95% CI, 59.6% to 100.0%) and 0 PF-06425090 and 10 placebo recipients required antibiotic treatment (VE = 100%; 95% CI, 54.8% to 100.0%). Local reactions were more frequent in PF-06425090 recipients, and systemic events were generally similar between groups; most were mild to moderate. Adverse event rates were similar between groups. Three PF-06425090 doses were safe and well tolerated. Although the primary end point was not met, PF-06425090 reduced symptom duration, CDI that required medical attention, and CDI-directed antibiotic treatment, highlighting its potential to reduce CDI-associated healthcare burden. NCT03090191.

Frequency and risk factors for the development of emergence delirium in children during correction of various forms of strabismus: a prospective observational blinded study

Frequency and risk factors for the development of emergence delirium in children during correction of various forms of strabismus: a prospective observational blinded study

Cold atmospheric plasma therapy for Malassezia folliculitis: Laboratory investigations and a randomized clinical trial.

Current treatment options for Malassezia folliculitis (MF) are limited. Recent research has demonstrated the inhibitory effect of cold atmospheric plasma (CAP) on the growth of Malassezia pachydermatis in vitro, suggesting CAP as a potential therapeutic approach for managing MF. The objective of our study is to assess the in vitro antifungal susceptibility of Malassezia yeasts to CAP. Additionally, we aim to evaluate the efficacy and tolerability of CAP in treating patients with MF. We initially studied the antifungal effect of CAP on planktonic and biofilm forms of Malassezia yeasts, using well-established techniques such as zone of inhibition, transmission electron microscopy, colony count assay and 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide salt assay. Subsequently, a randomized (1:1 ratio), active comparator-controlled, observer-blind study was conducted comparing daily CAP therapy versus itraconazole 200mg/day for 2weeks in 50 patients with MF. Efficacy outcomes were measured by success rate, negative microscopy rate and changes in Dermatology Life Quality Index (DLQI) and Global Aesthetic Improvement Scale (GAIS) scores. Safety was assessed by monitoring adverse events (AEs) and local tolerability. In laboratory investigations, CAP time-dependently inhibited the growth of Malassezia yeasts in both planktonic and biofilm forms. Forty-nine patients completed the clinical study. At week 2, success was achieved by 40.0% of subjects in the CAP group versus 58.3% in the itraconazole group (p=0.199). The negative direct microscopy rates of follicular samples were 56.0% in the CAP group versus 66.7% in the itraconazole group (p=0.444). No significant differences were found in the proportion of subjects achieving DLQI scores of 0/1 (p=0.456) or in the GAIS responder rates (p=0.588) between the two groups. Three patients in the CAP group and one patient in the itraconazole group reported mild AEs. CAP demonstrated significant antifungal activity against Malassezia yeasts in vitro and exhibited comparable efficacy to itraconazole in treating MF patients. Without the associated adverse effects of oral antifungal drugs, CAP can be considered a promising and safe treatment modality for MF.

Safety and Immunogenicity of mRNA-1010, an Investigational Seasonal Influenza Vaccine, in Healthy Adults: Final Results From a Phase 1/2 Randomized Trial.

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

Efficacy, reactogenicity, and safety of the adjuvanted recombinant zoster vaccine for the prevention of herpes zoster in Chinese adults ≥ 50 years: A randomized, placebo-controlled trial

ABSTRACT Phase III multi-country studies (ZOE-50/70) demonstrated that the adjuvanted recombinant zoster vaccine (RZV) was well tolerated and prevented herpes zoster (HZ) in healthy ≥ 50-year-olds, with a vaccine efficacy (VE) > 90% across age groups. These pivotal trials did not enroll participants from mainland China where RZV is licensed, therefore similar clinical data are missing for this population. In this phase IV observer-blind study (NCT04869982) conducted between 2021 and 2023 in China, immunocompetent and medically stable ≥ 50-year-olds were randomized 1:1 to receive two RZV or placebo doses, 2 months apart. This study assessed the VE (overall, as confirmatory objective, and descriptively by age category [50–69-year-olds/≥ 70-year-olds]), reactogenicity, and safety of RZV in this Chinese population. Of the 6138 enrolled participants, 99.2% completed the study. During a mean follow-up period of 15.2 (±1.1) months, 31 HZ episodes were confirmed (RZV = 0; placebo = 31) for an incidence rate of 0.0 vs 8.2 per 1000 person-years and an overall VE of 100% (89.82–100). The descriptive VE was 100% (85.29–100) for 50–69-year-olds and 100% (60.90–100) for ≥ 70-year-olds. Solicited adverse events (AEs) were more frequent in the RZV vs the placebo group (median duration: 1–3 days for both groups). Pain and fatigue were the most frequent local and general AEs (RZV: 72.1% and 43.4%; placebo: 9.2% and 5.3%). The frequencies of unsolicited AEs, serious AEs, potential immune-mediated diseases, and deaths were similar between both groups. RZV is well tolerated and efficacious in preventing HZ in Chinese ≥ 50-year-olds, consistent with efficacy studies including worldwide populations with similar age and medical characteristics.

Efficacy of apremilast in hyperkeratotic hand and foot dermatitis: results from a randomized observer-blinded comparative study.

Hyperkeratotic hand and foot dermatitis significantly affects quality of life. Some patients respond suboptimally to topical corticosteroids and have multiple recurrences. Our aim was to compare the efficacy and safety profile of apremilast and topical corticosteroid versus corticosteroid alone in hyperkeratotic hand and foot dermatitis. This randomized controlled study involved 77 patients treated for 3 months. GroupA (39 patients) received mometasone furoate 0.1% cream with oral apremilast 30 mg twice daily, and Group B (38 patients) received mometasone alone. They were assessed monthly using the Hand Eczema Clinical Severity Index (HECSI) and Visual Analogue Scale (VAS) scores for pruritus. Investigator Global Assessment (IGA) and Quality of Life in Hand Eczema Questionnaire (QOLHEQ) were conducted at the end of 3 months. The HECSI, VAS score, and QOLHEQ showed a significant decrease in both groups from baseline to the third month. Intergroup comparisons of HECSI failed to reach the significance level. When compared, patients receiving apremilast had significantly better improvement in the third month according to the Patient Global Assessment (PGA) and Investigator Global Assessment (IGA). They also had a smaller number of flares. Adding apremilast to topical corticosteroid leads to better patient and physician-perceived improvement and reduces the number of flares in hyperkeratotic hand eczema.

Association of Pelvic Organ Prolapse and Changes in Bone Imaging Biomarkers in Postmenopausal Women with Low Bone Mineral Density

Background: To test the hypothesis that pelvic organ prolapse (POP) and osteoporosis are both manifestations of a connective tissue disorder, we evaluated whether there is an association between presence of POP and bone imaging biomarkers in postmenopausal women with low bone mineral density (BMD). Methods: A blind analytical, observational, and prospective cross-sectional study recruited 89 postmenopausal women with low BMD. Women were divided into those with absent/minimal or with moderate-to-severe POP. An X-ray of the spine was performed followed by a computational image analysis to quantify textural features on each vertebral body. Statistical analysis with a stepwise binary logistic regression model was used. Results: After 10 steps, the final model showed significance (p &lt; 0.05) in the Omnibus coefficients test. The model classification results were high with over 80% success rates for both groups and an accuracy of 83%. The verification table showed that 39 of the 46 non-prolapsed patients were classified correctly, while 7 women were classified as having prolapsed. Among the 43 patients that had prolapsed, 35 patients were correctly classified while 8 were wrongly classified. The logistic regression analysis confirmed that both groups (prolapsed and non-prolapsed patients) can be differentiated using bone biomarkers on plain films. Most of the significant changes were found on the dorsal vertebrae. Conclusions: Pelvic organ prolapse is related to changes in bone imaging biomarkers, besides BMD. These results support the hypothesis that both pelvic prolapse and osteoporosis have a common causal origin.

Immunogenicity and safety of a bivalent (omicron BA.5 plus ancestral) SARS-CoV-2 recombinant spike protein vaccine as a heterologous booster dose: interim analysis of a phase 3, non-inferiority, randomised, clinical trial

SARS-CoV-2 variants evade immunity despite vaccination with prototype COVID-19 vaccines or previous infection. The 2019nCoV-311 (part 2) study is evaluating immune responses after two booster doses of a vaccine containing the omicron BA.5 subvariant spike protein in adults previously vaccinated with a prototype mRNA vaccine. This interim analysis reports on day 28 immunogenicity and safety outcomes after one booster dose. In this phase 3, randomised, observer-blinded study conducted at 35 sites in Australia, medically stable, previously COVID-19-vaccinated (mRNA-based; ≥three doses) adults aged 18 years or older were enrolled and randomly allocated (1:1:1; via an interactive web response system) to receive two doses of bivalent (NVX-CoV2373 + NVX-CoV2540; bivalent group), authorised prototype (NVX-CoV2373; prototype group), or BA.5 (NVX-CoV2540; BA.5 group) vaccine. Only blinded personnel performed study assessments or had participant contact to collect data after study vaccination. Participants received vaccines containing 5 μg SARS-CoV-2 recombinant spike protein and 50 μg Matrix-M adjuvant, administered via a 0·5 mL intramuscular injection (2·5 μg of NVX-CoV2373 plus 2·5 μg of NVX-CoV2540 for the bivalent vaccine, prepared on-site as a 1:1 mixture). The coprimary endpoints include day 28 neutralising antibody geometric mean titre (GMT) ratios (GMTRs) to omicron BA.5 and the ancestral strain, and seroresponse rates to BA.5, in the bivalent and prototype groups. These endpoints were calculated in the per-protocol analysis set, which was defined as participants who had received a vaccine dose, had baseline and day 28 immunogenicity data, and were PCR-negative for SARS-CoV-2, with no major protocol deviations. The primary objective was to determine the primary outcome (antibody responses), which consisted of three comparisons: superiority of the bivalent versus prototype vaccine for neutralising antibody GMT to BA.5 (ie, lower bound of the GMTR 95% CI >1·0); non-inferiority of neutralising antibody seroresponse rate to BA.5 (ie, lower bound of the seroresponse rate 95% CI >-5%); and non-inferiority of neutralising antibody GMT to the ancestral strain (ie, lower bound of GMTR 95% CI >0·67). This trial was registered at ClinicalTrials.gov, number NCT05372588. Between March 22, 2023 and May 2, 2023, 837 participants were screened for eligibility and 766 were randomly allocated to receive the BA.5 (n=255), prototype (n=252), or bivalent (n=259) vaccine. After accounting for exclusions due to participants being baseline SARS-CoV-2-positive, having previous infection, or protocol deviations, the per-protocol analysis set included 694 participants (236 in BA.5 group, 227 in prototype group, and 231 in bivalent group). In this interim analysis (maximum follow-up 35 days after the first dose), the bivalent group, compared with the prototype group, had superior neutralising antibody responses to BA.5 (GMT 1017·8 [95% CI 891·0-1162·6] vs 515·1 [450·4-589·0]; GMTR 2·0 [1·69-2·33]) and a non-inferior seroresponse rate to BA.5 at day 28 (39·8% [33·5-46·5] vs 12·3% [8·4-17·3]; difference 27·5% [19·8-35·0]). The bivalent group also had non-inferior neutralising antibody responses to the ancestral strain (GMTR 1·0 [0·84-1·20]), compared with the prototype group. All vaccines were similarly well tolerated. All three coprimary endpoints were met in part 2 of the ongoing 2019nCoV-311 study. These data support the development of monovalent and/or bivalent vaccines for the most currently circulating variants, to optimise protection. With no new safety findings, further investigation of omicron-based subvariant vaccines is supported by the evidence. Novavax.

Comparable safety and non-inferior immunogenicity of the SARS-CoV-2 mRNA vaccine candidate PTX-COVID19-B and BNT162b2 in a phase 2 randomized, observer-blinded study

In the aftermath of the COVID-19 pandemic, the evolution of the SARS-CoV-2 into a seasonal pathogen along with the emergence of new variants, underscores the need for dynamic and adaptable responses, emphasizing the importance of sustained vaccination strategies. This observer-blind, double-dummy, randomized immunobridging phase 2 study (NCT05175742) aimed to compare the immunogenicity induced by two doses of 40 μg PTX-COVID19-B vaccine candidate administered 28 days apart, with the response induced by two doses of 30 µg Pfizer-BioNTech COVID-19 vaccine (BNT162b2), administered 21 days apart, in Nucleocapsid-protein seronegative adults 18–64 years of age. Both vaccines were administrated via intramuscular injection in the deltoid muscle. Two weeks after the second dose, the neutralizing antibody (NAb) geometric mean titer ratio and seroconversion rate met the non-inferiority criteria, successfully achieving the primary immunogenicity endpoints of the study. PTX-COVID19-B demonstrated similar safety and tolerability profile to BNT162b2 vaccine. The lowest NAb response was observed in subjects with low-to-undetectable NAb at baseline or no reported breakthrough infection. Conversely, participants who experienced breakthrough infections during the study exhibited higher NAb titers. This study also shows induction of cell-mediated immune (CMI) responses by PTX-COVID19-B. In conclusion, the vaccine candidate PTX-COVID19-B demonstrated favourable safety profile along with immunogenicity similar to the active comparator BNT162b2 vaccine.

543 - Early repigmentation of stable vitiligo through point-of-care melanocyte transfer using non-cultured autologous skin cell suspension

Abstract Introduction Vitiligo is an acquired depigmenting skin condition characterized by the loss of skin pigmentation, impacting 0.5% to 2% of the global population.1–3 Vitiligo presents as distinct depigmented patches resulting from autoimmune melanocyte destruction. Individuals with visual vitiligo lesions often experience negative body image, diminished self-confidence, discomfort, and overall lower quality of life (QoL).4 While there are medical treatment options available, these can be associated with poor efficacy and low medication compliance.4 Residual lesions after treatment may require surgical intervention which allows for melanocyte transplantation from an area that is pigmented to one that is lacking functional melanocytes. Through a point-of-care device, a non-cultured autologous skin cell suspension (ACSC) can be prepared using a small skin sample; the ASCS contains healthy melanocytes and is immediately applied onto skin treated with ablative laser to aid in the repigmentation of affected areas. Objective The objective of this study was to evaluate the one-time application of ASCS, with a 1:20 donor to treatment site expansion ratio, for the safe and effective repigmentation of stable vitiligo lesions. Methods A randomized, within-subject controlled, central observer-blinded study was conducted to compare the clinical performance of laser ablation, ASCS, and NB-UVB to NB-UVB alone for repigmentation of stable vitiligo lesions in adults. Subjects received NB-UVB phototherapy on both ASCS-treated and controlled lesions as per recommended by the Vitiligo Working Group. Repigmentation of ASCS-treated and control lesions were categorized by a Central Review Committee (CRC) of blinded dermatologists as one of the following: 0%-25%, 26%-50%, 51%-79%, or 80-100%. The primary effectiveness endpoint was defined as the proportion of lesions achieving ≥80% repigmentation for ASCS-treated versus control areas at Week 24. Early regimentation was assessed at Weeks 4 and 12 as a post hoc analysis. Results A significantly higher proportion of the ASCS-treated areas (36.0%, n = 9) compared to control-treated areas (0.0%) attained ≥80% repigmentation at Week 24 (P = 0.012). At Week 4, 30.4% (n = 7/23) of ASCS-treated areas had ≥26% repigmentation compared to 4.3% (n = 1/23) in the control areas. At Week 12, 56.5% (n = 13/23) of ASCS-treated areas had ≥26% repigmentation compared to 21.7% (n = 5/23) in the control areas. At Week 24, 64% (n = 16/25) of ASCS-treated areas had ≥26% repigmentation compared to 28% (n = 7/25) in the control areas. Conclusion A one-time treatment of ASCS, with the addition of NB-UVB, can result in excellent repigmentation results by 24 weeks, with most subjects seeing ≥26% repigmentation as early as 4 to 12 weeks.

Prognostic value of PSMA-extracellular vesicles in oligometastatic castration-sensitive prostate cancer treated with stereotactic ablative radiotherapy: A multi-center observational study.

191 Background: Two randomized clinical trials have demonstrated that SABR can prolong time to progression in oligometastatic castration-sensitive prostate cancer (omCSPC) patients. However, there is a need for predictive tools to identify patients who will benefit from SABR alone or with systemic therapy. We investigated the prognostic value of PSMA-positive extracellular vesicles (PSMA+EVs) in a blinded observational study using blood samples from three independent patient cohorts. Methods: We obtained plasma samples from 157 omCSPC patients treated with SABR from the ORIOLE cohort (N=30, JHU) and STOMP-like cohorts (N=80, UGhent; N=47, Iridium Net). Baseline PSMA+EV levels (EV/ml) were measured by nanoscale flow cytometry. Primary clinical endpoints were biochemical progression (bPFS) and radiographic progression (rPFS). Optimal cutoffs for PSA (ng/ml) and PSMA+EV (EVs/ml) were defined as the point with the most significant log-rank test split. Kaplan-Meier curves and univariate Cox regression models were used to determine the association of PSMA+EV levels with clinical outcomes. Results: Twenty percent of patients (N=157 total) were diagnosed with bone scan, 79% with PET imaging, and 1% with other modalities. Ninety-four percent of patients presented with ≤3 metastases on imaging. In the pooled STOMP-like cohorts, median bPFS was 27.9 and 18.0 months for PSMA+EV low and high groups, respectively (p=0.039). Median rPFS was 36.0 versus 27.0 months (p=0.029). In the ORIOLE cohort, median bPFS was 24.3 and 5.9 months in PSMA+EV low and high, respectively (p=0.021). Median rPFS was 36.0 versus 11.1 months (p=0.019). High baseline PSMA+EV levels were associated with higher risk of both biochemical and radiographic progression (Table). Combination of baseline PSA low and PSMA+EV low outperformed either biomarker alone and better predicted risk of disease progression after SABR. Conclusions: While prospective biomarker-guided trials are warranted, a PSMA+EV blood test can aid patient selection by identifying omCSPC patients who may have durable responses to SABR without ADT. [Table: see text]

When Nurses in an Emergency Situation Look for a Medical Item But Fail to See It.

Emergency department nurses may fail to see medical items in emergency cart drawers, such as syringes and tubes, while handling emergency situations, which can often contribute to a delay in managing the case. This is a phenomenon known as Looked-but-failed-to-see (LBFTS) and occurs when the observer fails to detect a visible visual stimulus among various other stimuli. LBFTS is a group of human errors, including inattentional blindness (IB), satisfaction of search, and biased search processes, and is associated with constraints on human visual processing. LBFTS has been studied extensively in the fields of aviation, military, radiology, and road safety; however, the role of LBFTS in hospital ED has generally been overlooked. Hence, a key aim of this study was to investigate the possibility of the occurrence of LBFTS among ED nurses while searching for a particular medical item during a real-life emergency. An observational cross-sectional blinded study was conducted to determine the occurrence of LBFTS in a real-life visual search task during resuscitation cases in ED. The A-B-C (antecedent-behavior-consequence) observation and recording naturalistic observation technique was used. A total of 45 ED nurses who were assigned to either the crash cart or the intubation trolley at the time of data collection agreed to participate and were included in the analysis. The results revealed that LBFTS accounted for 66% of the cases where emergency items were brought from another location. Participants missed seeing an item, although the item was directly in front of their eyes. Factors such as the perception of cognitive workload at the time of data collection positively impacted the increase in LBFTS (P = .021). Taken together, the results of the present study and recent visual studies support the occurrence of LBFTS among nurses working in ED. Devising successful strategies to reduce this phenomenon could translate directly into saved lives.