Trauma-focused therapy in early intervention for psychosis settings: Results of a feasibility RCT of 'EMDR for psychosis'

Aims: Trauma is particularly prevalent amongst Early Intervention (EI) patients and is associated with adverse clinical and prognostic outcomes. To determine the feasibility of a large-scale randomized controlled trial (RCT) of an 'EMDR for psychosis' intervention for trauma survivors with active psychotic symptoms supported by EI services, we conducted a single-blind RCT comparing 16 sessions of EMDRp + TAU versus TAU only. Method(s): EMDRp therapy and trial assessments were completed both in-person and remotely during the COVID-19 pandemic, and key feasibility outcomes (recruitment & retention, therapy attendance/ engagement, adherence to EMPRp treatment protocol, and the 'promise of efficacy' of EMDRp on relevant clinical outcomes) were examined at 6- and 12-month post-randomization assessments. Results and Conclusion(s): 60 participants (100% of the recruitment target) received TAU or EMDR + TAU. The feasibility criteria examined in this trial were fully met, and EMDRp was associated with promising signals of efficacy on a range of valuable post-treatment outcomes, including improved psychotic symptoms (PANSS), subjective recovery (QPR), post-traumatic symptoms (PCL-5;ITQ), depression (PHQ-9), anxiety (GAD-7) and general health status (EQ-5D-VAS) at the 6-month assessment. Signals of efficacy at 12-month were less pronounced, but remained robust for trauma symptoms and general health status. The findings will be discussed with relevance to future clinical trials of trauma-focused therapy in clients with early psychosis, and the provision of more tailored trauma therapies for EI service users.

Comparative effectiveness and safety of a pharmacist-managed protocol for the transition from intravenous to subcutaneous insulin

Purpose: To evaluate the effectiveness and safety of a pharmacist-managed protocol for transitioning critically ill patients from intravenous (iv) to subcutaneous insulin compared with a provider-managed process. Method(s): This single-center, retrospective, observational study included patients admitted to the medical or surgical/trauma intensive care unit who received a continuous infusion of iv insulin from January 2019 to April 2021. Patients were excluded if they were less than 18 years of age, pregnant, incarcerated, or received iv insulin for the diagnosis of diabetic ketoacidosis, hyperglycemic hyperosmolar state, calcium channel blocker or beta blocker overdose, or hypertriglyceridemia. The primary outcome was the percentage of blood glucose (BG) concentrations within the target range of 70-150 mg/dL from 0 to 48 h following transition to subcutaneous insulin. Secondary outcomes included percentage of BG concentrations within goal range following transition at 0-12 h and 12-24 h, incidence of hypo- and hyperglycemia, and percentage of patients requiring dose adjustments after initial transition. Result(s): A total of 110 unique patients were included with 70 patients in the provider-managed group and 40 patients in the pharmacist-managed group. On average, pharmacists transitioned patients to 63% basal insulin based on their 24-h total day dose of insulin. The pharmacist-managed group achieved glycemic control in 53% of transitions at 12 h, 40% at 24 h, and 47% from 0 to 48 h, while the provider group achieved glycemic control in 25% of transitions at 12 h, 12% at 24 h, and 18% from 0 to 48 h (p < 0.001 for all time points). As for safety end points, the pharmacist-managed group demonstrated lower rates of hypoglycemia (p = 0.001), severe hypoglycemia (p = 0.332), hyperglycemia (p < 0.001), and severe hyperglycemia (p < 0.001) compared with the provider-managed group. Conclusion(s): Pharmacists can effectively and safely transition critically ill patients from iv to subcutaneous insulin utilizing a standardized protocol.Copyright © 2023 Pharmacotherapy Publications, Inc.

Tolerance of ETD001, a long-acting inhaled epithelial sodium channel blocker, in humans

Background: To assess the safety, tolerability, and pharmacokinetic (PK) profile in humans of the novel inhaled epithelial sodium channel blocker ETD001. Method(s): Inhaled ETD001 or placebo, delivered via nebulizer, have been administered in a 3:1 ratio to 96 healthy subjects in a blinded, first-inhuman clinical trial (ClinicalTrials.gov Identifier: NCT04926701). The study consisted of two parts. Part A evaluated single ascending doses (SADs) up to 10.8 mg, and Part B evaluated multiple ascending doses (MADs) up to 3.1 mg once daily (QD) for 7 days and 4.65 mg twice daily (BID) for 14 days. Safety was assessed by monitoring for adverse events (AEs), laboratory safety tests (including blood potassium monitoring), vital signs, 12-lead electrocardiogram (ECG), and spirometry. Systemic exposurewas assessed using serial pharmacokinetic blood draws. Result(s): Therewere no serious AEs. Twenty-four subjects reported 38 AEs, all of mild to moderate intensity and all resolved. There were no clinically relevant changes in laboratory safety tests, vital signs, ECGs, or spirometry measurements. All blood potassium assessments were within normal range at all doses. Three subjects withdrew in Part B;all withdrawals were considered unrelated to study drug: one on day 6 from the 3.1-mg QD cohort for personal reasons, one after the first dose of the 3.1-mg BID cohort because of vasovagal syncope at time of venipuncture triggering atrial fibrillation that spontaneously resolved, and one on Day 4 of the 3.1- mg BID cohort because of a positive COVID-19 test. Pharmacokinetic parameters were approximately dose proportional in Part A, with peak concentrations 1 to 2 hours after dose and exposure out to 12 to 24 hours at all doses, indicating good lung retention. Part B plasma concentrations displayed dose-independent kinetics and showed minimal accumulation, with a mean of 1.11-fold observed over 14 days. Conclusion(s): ETD001 was well tolerated at single doses up to 10.8 mg and multiple doses of 3.1 mg QD for 7 days and 4.65 mg BID for 14 days. The wide safety margin is predicted to enable doses capable of durable target engagement in the lung, which are expected to enhance mucociliary clearance in people with cystic fibrosis.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

A Sham-Controlled Randomized Trial of Low Intensity Shockwave Therapy for Erectile Dysfunction

INTRODUCTION AND OBJECTIVE: We performed a shamcontrolled, randomized prospective trial in men with ED using an electrohydraulic shockwave device FDA cleared for connective tissue activation and improved blood flow. METHOD(S): This single-blind study was performed in men with ED naive to acoustic wave and shockwave therapy. Patients were randomized to treatment and assigned to active low intensity shockwave therapy (LiSWT) (4 Hz, 0.12 mJ/mm2) or sham treatment, 2:1. Arm 1 consisted of 3 treatments of 5000 shocks every 3 weeks. Arm 2 consisted of 5000, 3000, and 3000 shocks during weeks 1, 2, and 3, respectively, followed by an identical cycle of treatment 3 weeks later. Doppler ultrasound and grayscale imaging with a 15.4 MHz probe were performed under pharmacologic erection at weeks 20 and 32. Subjects completing sham treatment were unblinded and crossed over to the opposite arm for active treatment. Post-treatment end diastolic velocity (EDV) and peak systolic velocity (PSV) were measured, and visual grading scores were used to assess extent of hypoechoic regions in the corpora cavernosa. Data were analyzed by 2-way repeated measures ANOVA with Geisser-Greenhouse correction. Pairwise comparisons were performed to baseline used Dunnett's multiple comparison test. Missing data were imputed by "last observation carried forward". RESULT(S): Although powered for 60, recruitment was limited due to COVID and 36 subjects (22 active, 14 sham) were randomized. Sham treatments showed no significant changes in outcome measures. The number of subjects with improved visual grading scores in the proximal region was consistently higher in active LiSWT vs sham (Arm 1=88.9% vs. 11.1%;Arm 2=40.0% vs. 20.0%, respectively) with statistical significance in Arm 1 at weeks 20 (p=0.005) and 32 (p=0.001). Sham subjects rolled over to active LiSWT also had improved grayscale ratings (Arm 1=33.3% vs. 11.1%;Arm 2=40.0% vs. 20.0%). After LiSWT, greater numbers of patients had higher PSV, lower EDV, or no worsening of blood flow parameters relative to baseline. Decrease in EDV was statistically significant in active treatment Arm 2 at Week 32 (p=0.003). Mean IIEF-EF scores were nominally higher in subjects in active treatment who had improved visual grading scores vs those with no improvement. Adverse events were transient. CONCLUSION(S): Flaccid penile LiSWT appears to be safe and efficacious for treating ED based on statistically significant changes from baseline between sham and active treatments in primary outcome measures.

METFORMIN REDUCED SARS-CoV-2 VIRAL LOAD IN A PHASE 3 RANDOMIZED CLINICAL TRIAL

Background: Metformin has in vitro activity against SARS-CoV-2. In a published phase 3, quadruple-blinded, placebo-controlled randomized trial of outpatient COVID-19 therapy, metformin resulted in a 42% reduction in ER visits/hospitalizations/deaths by day 14, 58% reduction in hospitalizations/ death by day 28, and 42% reduction in Long Covid through 10 months. This analysis presents the results of viral load sampling performed during that clinical trial. Method(s): Covid-Out trial (NCT04510194) enrolled adults aged 30 to 85 within 3 days of a documented SARS-CoV-2 infection and < 7 days after symptom onset. The trial randomized 1323 participants to metformin (1000mg/day days 2-5;1500mg/day days 6 to 14), ivermectin, fluvoxamine, and/or exact-matching placebo in a 2x3 factorial trial design. Nasal swabs for viral load were an optional component, self-collected from the anterior nares on day 1, 5, and 10. Viral loads were measured via RT-qPCR using N1 and N2 targets in the SARSCoV- 2 nucleocapsid protein, with relative Ct values converted to absolute copy number via calibration to droplet digital PCR. A linear Tobit regression model was used to assess change over time while accounting for left censoring due to the viral load limit of detection. Results were adjusted for other treatment allocations within the factorial design, vaccination status, and baseline viral load. Repeated measures were accounted for using clustered standard errors within participants. Result(s): Samples were available from n = 945, 871, and 775 participants on days 1, 5, and 10, respectively. The mean change from baseline to followup was -0.64 log10 copies/mL (95%CI, -1.16 to -0.13) for metformin versus placebo, which equates to a 4.4-fold greater decrease. The mean change in SARS-CoV-2 from baseline to day 5 was -0.48 log10 copies/mL, and was -0.81 log10 copies/mL from baseline to day 10. The anti-viral effect increased with increased metformin dosing days 6-14. The antiviral effect was larger in those unvaccinated (mean -0.95 log copies/mL) than vaccinated (mean -0.39 log copies/mL). There was no change in viral load vs. placebo for ivermectin or fluvoxamine. Conclusion(s): Metformin lowered SARS-CoV-2 viral load in this quadrupleblinded, randomized clinical trial. The temporal relationship to dose titration suggests a dose-dependent effect. The magnitude of antiviral effect was similar to nirmatrelvir at day 5, greater than nirmatrelvir at day 10. Metformin is safe, widely available, and has few contraindications.

Clinical Features and Risk Factors for Mortality in Patients with Stenotrophomonas maltophilia Infection

Introduction: It is important to know the risk factors for death in reducing mortality in patients with Stenotrophomonas maltophilia infections. The purpose of this study was to examine the risk factors associated with mortality in hospitalized patients with S. maltophilia infections. Material(s) and Method(s): Patients with S. maltophilia infections aged 18 years and older who were hospitalized in Haseki Research and Training between January 1, 2017, and April 30, 2022, were included in the study. The patients were divided into two groups, non-survivors and survivors, and the clinical features and laboratory parameters of the groups were compared. Mortality risk factors were analyzed by logistic and Cox regression analyses. Result(s): A total of 75 patients with S. maltophilia infections were included. The mortality rate was 38.6% (n= 29). Advanced age (OR= 1.05, 95% CI= 1.012-1.085, p= 0.009), COVID-19 pneumonia (OR= 9.52, 95% CI= 1.255-72.223, p= 0.029), and presence of central venous catheter (CVC) (OR= 18.25, 95% CI= 2.187-152.323, p= 0.007) were risk factors for death. Conclusion(s): Physicians should be aware of the potential risk of S. maltophilia infections for mortality, particularly in patients with predefined risk factors such as advanced age, the presence of CVC, and COVID-19. Performing CVC care in accordance with infection prevention and control measures and timely removal of CVC may be beneficial in reducing deaths due to S. maltophilia infection.Copyright © 2023 Bilimsel Tip Yayinevi. All rights reserved.

Efficacy of N-acetyl Cysteine in Severe COVID-19 Patients: A Randomized Controlled Phase III Clinical Trial

Background: Today, various drugs have been investigated as the primary or complementary treatment for coronavirus disease 2019 (COVID-19). N-acetylcysteine (NAC) has been used as a mucolytic in pulmonary diseases. This drug apparently contributes to the retrieval of the intracellular antioxidant system. Objective(s): This study aimed to determine the efficacy of NAC in severe COVID-19 patients admitted to the intensive care unit (ICU). Method(s): This single-blinded randomized controlled phase III clinical trial included 40 patients with confirmed COVID-19 (based on polymerase chain reaction) admitted to the Shahid Mohammadi Hospital's ICU, Bandar Abbas, Iran, in 2020. All cases had severe COVID-19. They were allocated randomly to two equal groups. Patients in the control group received standard drug therapy based on the treatment protocol of the national COVID-19 committee, while those in the NAC group received a single dose of intravenous NAC (300 mg/kg) upon admission to the ICU in addition to standard drug treatment. Clinical status and laboratory tests were done on admission to the ICU and then 14 days later or at discharge without knowing the patient grouping. Result(s): The two groups were comparable regarding age, gender, and other baseline laboratory and clinical parameters. At the final evaluation, respiratory rate (21.25 +/- 4.67 vs. 27.37 +/- 6.99 /min) and D-dimer (186.37 +/- 410.23 vs. 1339.04 +/- 2183.87 ng/mL) were significantly lower in the NAC group (P = 0.004 and P = 0.030, respectively). Also, a lower percentage of patients in the NAC group had lactate dehydrogenase (LDH) <= 245 U/L (0% vs. 25%, P = 0.047). Although the length of ward and ICU stay was shorter in the NAC group than in controls, the difference was statistically insignificant (P = 0.598 and P = 0.629, respectively). Mortality, on the other hand, was 75% in the control group and 50% in the NAC group, with no statistically significant difference (P = 0.102). Concerning the change in the study parameters, only the decrease in diastolic blood pressure (DBP) was significantly higher with NAC (P = 0.042). The intubation and mechanical ventilation rates were higher, while oxygen with mask and nasal oxygen rates were lower with NAC, but the difference was statistically insignificant. Conclusion(s): Based on the current research, NAC is related to a significant decrease in RR, D-dimer, and DBP in severe COVID-19. Also, LDH was significantly lower in the NAC group than in the controls. More research with larger sample sizes is needed to validate the current study results.Copyright © 2023, Author(s).

The application value of low-dose CT scan in pregnant women with COVID-19.

Objective: To explore the value of low-dose CT in pregnancy with COVID-19. Method(s): A retrospective analysis was performed on the clinical characteristics, laboratory tests, and chest CT findings of 12 pregnant women with COVID-19 diagnosed by nucleic acid testing in the Renmin Hospital of Wuhan University from January 20, 2020 to February 16, 2020. Two radiologists blinded to the reconstruction algorithm independently scored subjective image quality on a 5-point Likert scale. Image quality score >= 3 was acceptable in clinics. The CT radiation doses were recorded, including CT volume dose index (CTDIvol), dose length product (DLP), and effective radiation dose (E). Two radiologists observed the distribution, shape, density, and other characteristics of lung lesions, and they also decided whether hilar, mediastinal lymphadenopathy, and pleural changed. Result(s): A total of 12 pregnant women with COVID-19, 8 had cough, 4 had fever, 2 had chest tightness, and 1 had dyspnea and diarrhea each. The CT image quality score of all patients was 3-4, with an average of 3.46, which fully met the clinical diagnosis requirements. The CTDIvol value was 1.13-4.31 mGy, with an average of 3.02 mGy. The DLP value was 34.48-75.29 mGy*cm, with an average of 55.48 mGy*cm. The Evalue was 0.48-1.05 mSv, with an average of 0.78 mSv. In all cases, chest CT examination showed abnormal manifestations after clinical symptoms, including unilateral lung lesions in 5 cases and bilateral lung lesions in 7 cases, 1 case of ground-glass opacity, 1 case of solidification, 7 cases of ground-glass and consolidation, 1 case of strip opacity, ground-glass, and consolidation and strip cable shadow coexisted in 2 cases. Conclusion(s): The application of low-dose CT scan in pregnant women with COVID-19 is completely feasible. CT mainly manifested as bilateral lung patchy and flaky ground-glass opacity with consolidation. Active and effective treatment can help recover and improve prognosis.Copyright © 2020 by the Chinese Medical Association.

Virtual reality intervention alleviates dyspnea in patients recovering from COVID pneumonia

Immersive virtual reality (iVR)-based digital therapeutics (DTx) are gaining clinical attention in the field of pain management. Based on known analogies between pain and dyspnea, we investigated the effects of visualrespiratory feedback, on persistent dyspnea in patients recovering from COVID-19 pneumonia. We performed a controlled, randomized, single-blind, cross-over clinical study to evaluate an iVR-based intervention to alleviate dyspnea in patients recovering from COVID-19 pneumonia. Included patients reported persistent dyspnea and preserved cognitive function. Assignment was random and concealed. Patients received synchronous (intervention) or asynchronous (control) feedback of their breathing, embodied via a gender-matched virtual body. Outcomes were assessed using questionnaires and breathing recordings. Twenty-six patients were enrolled (27% women;age: median=55, interquartile range (IQR)=18). The median (IQR) rating on a 7-point Likert-scale of breathing comfort improved from 1(2) at baseline, to 2(1) for synchronous feedback, but remained unchanged at 1(1.5) for asynchronous feedback (p<0.05) between iVR conditions) Moreover, 91.2% of all patients were satisfied with the intervention (p<0.0001) and 66.7% perceived it as beneficial for their breathing (p<0.05). Based on these findings, our iVR-based DTx presents a feasible and safe respiratory rehabilitation tool that improves breathing comfort in patients recovering from COVID-19 infection presenting with persistent dyspnea. Future research should investigate the DTx's generalizability to persistent dyspnea with other etiologies and its potential for preventing chronification.

A Placebo-Controlled, Single-Blind Extension Study Evaluating The Safety And Efficacy Of Lorecivivint In Subjects With Structurally Advanced Osteoarthritis Of The Knee (Oa-07): Radiographic And Pain Outcomes At 24 And 30 Month

Purpose: Knee osteoarthritis (OA) is a common joint disorder associated with pain, disability, and joint damage. An unmet need remains for safe, efficacious treatments for symptoms and disease modification. Lorecivivint (LOR), a novel intra-articular (IA) CLK/DYRK inhibitor thought to modulate Wnt and inflammatory pathways, has previously appeared safe, demonstrated patient-reported outcome (PRO) improvements compared with placebo (PBO), and maintenance of radiographic medial joint space width (mJSW). A LOR trial, OA-11, enrolled participants with structurally advanced (mJSW 1.5-4 mm) knee OA. OA-11 did not meet its primary endpoint;however, greater treatment effects were observed in subjects with less advanced/earlier (Kellgren Lawrence [KL] grade 2) OA. Additionally, the COVID pandemic potentially confounded pain reporting and expected mJSW progression. An ongoing 4-year extension study, OA-07 (NCT04520607), continues to evaluate LOR safety and efficacy with primary and secondary efficacy outcomes of mJSW (mm) and Pain Numerical Rating Scale (NRS [0-10]) respectively. Data up to 30 months from this study are reported. Method(s): Subjects who completed OA-11, a 13-month Phase 3 LOR trial, were enrolled into OA-07, an extension study designed to evaluate safety and efficacy of long-term LOR treatment. During the single-blinded Year 1 of OA-07, subjects received repeat injection according to their randomized treatment received in OA-11 (LOR or PBO). In Year 2 and annually thereafter, all subjects (LOR and PBO) received an open-label 0.07 mg IA LOR injection. OA-07 commenced in July 2020 and is planned to continue over a 4-year period with clinic visits every six months. Result(s): 277 subjects (mean age 61.0 +/- 8.2 years, BMI 31.8 +/- 4.9 kg/m2, female 62.8%, KL3 45.5%, 67.1% bilaterally symptomatic, mean baseline mJSW 2.63 +/- 0.69 mm, 68.6% mJSW < 3 mm) were enrolled. LOR appears safe and well-tolerated, consistent with its previously observed safety profile. At 24 months, the LOR treatment arm shows reduced mJSW loss compared to placebo, LOR -0.13 (+/- 0.06) mm (n=103) vs. PBO -0.22 (+/- 0.05) mm (n=112) (DELTA=0.10 mm, 95% CI [-0.05, 0.25], P=0.199, Figure 1A) for Full Analysis Set (FAS) and LOR +0.02 (+/- 0.07) mm (n=61) vs. PBO -0.15 (+/- 0.07) mm (n=63) (DELTA=0.17 mm, 95% CI [-0.02, 0.37], P=0.077, Figure 1B) for KL2. Average change from OA-07 baseline to 24 months in Pain NRS is -0.25 (+/- 0.19) for LOR (n=121) compared to 0.11 (+/- 0.19) for placebo (n=130) (DELTA=-0.36, 95% CI [-0.89, 0.17], P=0.179, Figure 2A). For WOMAC Function, LOR (n=96) change from baseline was -5.33 (+/- 1.84) vs PBO (n=104) -0.43 (+/-1.76), (DELTA=-4.90, 95% CI [-9.92, 0.13], P=0.056, Figure 2B);for WOMAC Pain, LOR (n=96) change from baseline of -4.80 (+/-1.87) vs PBO (n=106) 0.38 (+/-1.78), (DELTA=-5.18, 95% CI [-10.28, -0.08], P=0.047, Figure 2C). At 30 months (Figure 2A), unblinded IA injection of LOR (n=60) shows additional Pain NRS improvements with change from OA-07 baseline of -0.57 (+/-0.39) and cross-over to LOR from PBO (n=76) shows an improvement of -0.37 (+/-0.26). Larger improvements in PROs were observed in the KL2 subgroup, with month 24 improvements for LOR over PBO (DELTA= -0.48 (95% CI -1.20, 0.23), P=0.183 in Pain NRS, (DELTA -6.05 (95% CI -12.87, 0.78), P=0.082 in WOMAC Function, and (DELTA -6.58 (95% CI -13.18, 0.02), P=0.051, in WOMAC Pain. Conclusion(s): LOR continues to appear safe and well tolerated. A potential benefit of LOR 0.07 mg compared with PBO in mJSW is observed 12 months after OA-07 baseline injection. Potential LOR benefit compared to PBO is also seen across PROs. Within this structurally advanced knee OA cohort, both mJSW and PROs treatment effects appear enhanced in earlier/ less advanced KL2 knee OA subjects relative to those with more advanced KL3 graded knees. This study is ongoing. [Formula presented] [Formula presented]Copyright © 2023

OPTIMA, a prospective randomized trial to validate the clinical utility and cost-effectiveness of gene expression test-directed chemotherapy decisions in high clinical risk early breast cancer

Background: Multi-parameter tumor gene expression assays (MPAs) are used to estimate individual patient risk and guide chemotherapy use in hormone-sensitive, HER2-negative early breast cancer. The TAILORx trial supports MPA use in a node-negative population. Evidence for MPA use in postmenopausal node-positive breast cancer has been provided by the RxPONDER trial interim analysis but this relies on the absence of superiority in an analysis where >50% of events were unrelated to breast cancer. There is much uncertainty about MPA use for premenopausal patients. OPTIMA (Optimal Personalised Treatment of early breast cancer usIng Multi-parameter Analysis) (ISRCTN42400492) is a prospective international randomized controlled trial designed to validate MPAs as predictors of chemotherapy sensitivity in a largely node-positive breast cancer population. Method(s): OPTIMA is a partially blinded study with an adaptive two-stage design. The trial recruits women and men age 40 or older with resected ER-positive, HER2-negative invasive breast cancer and up to 9 involved axillary lymph nodes. Randomization is to standard management (chemotherapy and endocrine therapy) or to MPA-directed treatment using the Prosigna (PAM50) test. Those with a Prosigna tumor Score (ROR-PT) >60 receive standard management whilst those with a low score (<=60) tumor are treated with endocrine therapy alone. Endocrine therapy for premenopausal women includes ovarian suppression for all participants unless they experience a chemotherapy-induced menopause. Adjuvant abemaciclib is permitted. The trial will be analyzed for (1) non-inferiority of recurrence according to randomization and (2) cost-effectiveness. The key secondary outcome is non-inferiority of recurrence for patients with low ROR-PT score tumors. The efficacy analyses will be performed Per Protocol using Invasive Breast Cancer Free Survival (IBCFS) as the primary outcome measure to limit the risk of a false non-inferiority conclusion. Recruitment of 4500 patients over 8 years will permit demonstration of up to 3% non-inferiority of test-directed treatment with at least 83% power, assuming 5-year IBCFS is 87% with standard management. An integrated qualitative recruitment study addresses challenges to consent and recruitment, building on experience from the feasibility study which found that a multidisciplinary approach is important for recruitment success. OPTIMA is strongly supported by a patient group which has helped design all patient documents and which is represented on the TMG. Result(s): The OPTIMA main trial opened in January 2017 and has continued to recruit throughout the COVID-19 pandemic. Overall recruitment as of 1 July 2022 was 2814 (2593 from UK, 221 from Norway). Patient characteristics are well balanced between the trial arms. Currently 95% of randomized participants are eligible for inclusion in the PP analysis. 66% of the MPA-directed arm participants have been allocated to endocrine therapy only. The test failure rate is < 1%. Conclusion(s): OPTIMA will provide robust unbiased evidence on test-directed chemotherapy safety for both postmenopausal and premenopausal women with 1-3 involved nodes as well as for patients with 4-9 involved nodes and for patients treated with abemaciclib.

Acupuncture for olfactory dysfunction in infected COVID-19 patients: Study protocol for a randomized, sham-controlled clinical trial

Background: Olfactory dysfunction (OD) is a common symptom of Corona Virus Disease 2019 (COVID-19). It is defined as the reduced or distorted ability to smell during sniffing (orthonasal olfaction) and represents one of the early symptoms in the clinical course of COVID-19 infection. A large online questionnaire-based survey has shown that some post-COVID-19 patients had no improvement 1 month after discharge from the hospital. Objective: To explore the efficacy of acupuncture for OD in COVID-19 infected patients and to determine whether acupuncture could have benefits over sham acupuncture for OD in post-COVID-19 patients. Methods: This is a single-blind, randomized controlled, cross-over trial. We plan to recruit 40 post-COVID-19 patients with smell loss or smell distortions lasting for more than 1 month. Qualified patients will be randomly allocated to the intervention group (real acupuncture) or the control group (sham acupuncture) at a 1:1 ratio. Each patient will receive 8 sessions of treatment over 4 weeks (Cycle 1) and a 2-week follow-up. After the follow-up, the control group will be subjected to real acupuncture for another 4 weeks (Cycle 2), and the real acupuncture group will undergo the 4-week sham acupuncture. The primary outcomes will be the score changes on the questionnaire of olfactory functioning and olfaction-related quality of life at week 6, 8, 12, and 14 from the baseline. The secondary outcomes will be the changes in the olfactory test score at week 6 and 12 from the baseline measured by using the Traditional Chinese version of the University of Pennsylvania Smell Identification Test (UPSIT-TC). Discussion: The results of this trial will help to determine the effectiveness of acupuncture for OD in post-COVID-19 patients. This may provide a new treatment option for patients.

The impact of Virtual Individual Cognitive Stimulation Therapy (V-iCST) on cognition, quality of life, mood, and communication in dementia: a feasibility randomized controlled trial

Background: The COVID-19 pandemic has led to the suspension of community-based dementia services worldwide, where evidence-based interventions for dementia, like Cognitive Stimulation Therapy (CST), were delivered. Treatment access is paramount during the pandemic and beyond for people with dementia to maintain functioning and well-being. This study aimed to evaluate the feasibility and acceptability of a virtual, 14-session program of Individual Cognitive Stimulation Therapy (V-iCST) in the UK. Method(s): A single-blind feasibility randomized controlled trial (RCT) was conducted in the UK. Thirty-four people with mild to moderate dementia were recruited from dementia organizations and networks. Seventeen were randomly assigned to receive V-iCST (14, 45-min sessions) and 17 to treatment as usual (TAU) over seven weeks. Feasibility and acceptability data, for example, recruitment, attrition, attendance, adverse effects, and fidelity, were collected. Outcome measures on cognitive function, quality of life (QoL), mood, and communication were collected pre and post-test. Analysis of covariance was used to compare changes in V-iCST and TAU. Result(s): We have successfully completed recruitment. Results on feasibility, acceptability, and preliminary efficacy will be available at the conference. Conclusion(s): We hypothesize that V-iCST is feasible and acceptable and will have positive effects on cognitive, QoL, mood, and communication. Findings will be available at the conference. Copyright © 2022 the Alzheimer's Association.

Single Blind Randomized Controlled Trial Comparing BNT162b2 vs JNJ-78436735 Vaccine as an Additional Dose After Two Doses of BNT162b2 Vaccine in Solid Organ Transplant (SOT) Recipients

Purpose: Even though a high efficacy and immunogenicity of COVID-19 vaccines have been reported in the general population, vaccine immunogenicity is suboptimal in SOT recipients and breakthrough SARS-CoV-2 infection has already been reported in this immunocompromised population. Thus, several approaches including booster dose administration was investigated and showed better outcome. However, as a booster, mix and match method has not been investigated enough yet. The aim and objectives of this study is to check the immunogenicity after third dose of the SARSCoV- 2 vaccines either with adenovirus vector vs. mRNA vaccine. Method(s): This is a single center, single blinded (patient blinded), randomized controlled trial comparing BNT 162b2 and JNJ-78436735 as a third dose after completion of two doses of BNTT 162b2 vaccine in SOT recipients. We included adult SOT recipients with functional graft on at least one immunosuppressive medication. Also, the participants should have completed two doses of BNT162b2 vaccination at least 28 days prior to the third dose. As a primary end point, we are going to check the anti-spike protein of SARS-CoV-2 IgG positive rate in one month after vaccination. Result(s): We have finished the enrollment and there were 60 SOT recipients including 39 kidney, 11 liver, 4 lung, 2 heart and 4 combined organ transplant recipients. Already, 58 recipients completed the follow up blood test visit. Median age of the enrolled recipients was 56.7 (IQR 51 - 63) and 22 (37.9%) were female. As a maintenance immunosuppression, 52 (89.7%), 45 (77.5%) and 26 (44.8%) recipients received tacrolimus, mycophenolate and prednisone, respectively. Conclusion(s): Immunogenicity data will be analyzed once the follow up blood test result are finished. Adverse events and the rate of COVID-19 also will be reported.

REIMAGINING CARE AFTER THE ICU: LEVERAGING TELEMEDICINE FOR PATIENTS WITH COVID-19 IN THE ICU

SESSION TITLE: What Lessons Will We Take From the Pandemic? SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/19/2022 11:15 am - 12:15 pm PURPOSE: Post-intensive care syndrome (PICS) affects 50% of ICU survivors leading to significant healthcare utilization. COVID-19 survivors are at higher risk for developing PICS given the prolonged duration of critical illness. The aim of this study was to determine the feasibility and acceptability of using telemedicine (TM) for the transitional care (TC) of post ICU COVID-19 survivors. METHODS: This prospective randomized un-blinded controlled study was conducted from July 2021 to January 2022. Adults admitted to the ICU with a diagnosis of acute respiratory distress syndrome secondary to COVID-19 infection and discharged home were included. Those who lacked communication and internet services, and had pre-morbid conditions preventing independent self-care were excluded. 40 patients were recruited with 20 patients in each arm. The study group (SG) underwent a telemedicine (TM) visit within 2 weeks of discharge, where vital signs logs (VSL), virtual six-minute walk test (v6MWT), and EuroQoL 5-Dimension (EQ-5D) questionnaire were reviewed. The control group (CG) received a TM visit within 6 weeks of discharge and completed the EQ-5D questionnaire. This study was approved by the WVU IRB (#2104284924). RESULTS: Both groups had similar baseline characteristics. Completion rate of the VSL and v6MWT was 50% in the SG. 39% of SG came off oxygen supplementation compared to 33% in the CG. There was less anxiety/depression, increased request, and compliance to follow-up in pulmonary clinic noted in SG compared to CG, however this difference was not statistically significant. All readmissions were non- preventable (n=3;2 CG, 1 SG). 100% survival rate was noted in both groups at 30-days. 5% of patients were lost to follow up in both groups due to non-working communication devices and lack of response despite multiple attempts made for the TM visit. 67% (2/3) of primary care physicians (PCP) felt that this intervention helped establish continuity of care. 83% (5/6) of participants felt that an intensivist led TC visit provided closure for their ICU hospitalization. CONCLUSIONS: There was no significant difference noted in outcomes between the 2 groups, however, this is likely due to underpowered sample sizes. This form of TC is well received by both PCP and patients in screening and mitigation of PICS. CLINICAL IMPLICATIONS: This pilot study is the first in the region to show the acceptability and feasibility of using TM for the TC of ICU COVID survivors. It is vital to ensure ICU survivors receive targeted multidisciplinary management to prevent PICS. TM can be utilized in the future for the TC of all ICU survivors. DISCLOSURES: No relevant relationships by Ariful Alam No relevant relationships by Bathmapriya Balakrishnan No relevant relationships by Lucas Hamrick No relevant relationships by Sunil Sharma Consultant relationship with Res Med Please note: 7/2021-Present Added 03/31/2022 by Robert Stansbury, value=Consulting fee No relevant relationships by Jesse Thompson

USING THE TEAR FILM IMAGER FOR COVID19 DETECTION-A PILOT STUDY

Purpose : <div style='direction: ltr;'>A key challenge in limiting the spread of Covid-19 is the absence of a fast non-invasive tool to detect infected individuals in the general population. Using polymerase chain reaction (PCR) testing, it has been demonstrated that SARS-CoV-2 is present in the tear film of patients with ocular symptoms. The presence of virions in or next to the lipid layer of the tear film would theoretically cause a measurable interruption of the normal tear bi-layer structure. The goal of this pilot study is to test the hypothesis that a specialized version of Tear Film Imager (vTFI) could be used for detection of infected individuals, in a quick, non-invasive manner. It is important to note that vTFI findings are not specific to SARS-Cov-2, and similar enveloped virions might cause a comparable disturbance.</div> Methods : <div style='direction: ltr;'>In our pilot study, twenty eyes of ten patients that were hospitalized due to Covid-19 infection in a designated quarantine department were compared to twenty eyes of ten healthy control patients. The study was approved by the Wolfson medical center's Institutional Review Board. All participants had a nasopharyngeal PCR swab confirming infection status up to 72 hours prior to examination by vTFI. Any patients with chronic viral infection (i.e. HIV, HBV etc'), corneal abnormalities, or corneal/refractive surgery were excluded to ensure uniformity of the data and focus on virion detection</div> Results : <div style='direction: ltr;'>Using vTFI 16 out of 20 healthy eyes correctly tested negative. 15 out of 20 Covid-positive eyes were correctly identified positive using TFI. In total 70% of the control group were correctly categorized by TFI algorithm as healthy (positive if one eye positive) and 80% of the Covid-infected individuals were positively identified.</div> Conclusions : <div style='direction: ltr;'>Identification of Covid-19 status from the tear film layer using ultra-fast non-invasive vTFI shows promise and a larger sample blinded study should be performed to assess its implementation in an outpatient setting. Being a nonspecific test, the use of vTFI is not dependent on special primers and may offer a modality for diagnosing individuals suspected of being infected with other emerging pathogens. </div>.

Virtual Interactive Surgical Skills Classroom: A Parallel-Designed, Non-Inferiority, Adjudicator-Blinded, Randomised Controlled Trial (VIRTUAL)

Introduction: Virtual classroom training (VCT) is a novel educational method that permits accessible, distanced interactive expert instruction. We aimed to evaluate the efficacy of VCT in comparison to face-to-face training (FFT) and non-interactive computer-based learning (CBL) for basic surgical skills training. Method: 72 participants recruited from five London medical schools underwent stratified block randomisation into three equal intervention groups based on subjective and objective suturing experience. VCT was delivered via the BARCO weConnect platform and FFT was provided by expert instructors. Optimal student-to-teacher ratio was used, 12:1 for VCT and 4:1 for FFT. The assessed task was interrupted suturing with hand-tied knots. The primary outcome was post-intervention Objective Structured Assessment of Technical Skills (OSATS) score, adjudicated by two blinded experts and adjusted for baseline proficiency. Results: VCT was non-inferior to FFT (adjusted difference 0.44, 95% CI: -0.54 to 1.75, delta 0.675), VCT was superior to CBL (adjusted difference 1.69, 95% CI 0.41 to 2.96) and FFT was superior to CBL (adjusted difference 1.25, 95% CI 0.20 to 2.29). FFT alone was associated with student travel expenses (mean £4.88, SD 3.70). Instructor hours used per student for VCT and FFT were 0.25 and 0.75, respectively. Conclusions: VCT has a similar educational benefit to FFT and is a suitable modality of high-quality surgical skills education. VCT provides greater accessibility and resource efficiency compared to FFT. VCT satisfies the requirement for social distancing during the COVID-19 pandemic and is better than non-interactive CBL. VCT has the potential to improve global availability and accessibility of surgical skills training.

WITHDRAWING METHOTREXATE after BOTH VERSUS only SECOND DOSE of the CHADOX1 NCOV-19 VACCINE in PATIENTS with AUTOIMMUNE INFLAMMATORY ARTHRITIS: TWO INDEPENDENT RANDOMIZED CONTROLLED TRIALS (MIVAC i and II)

Background: Pausing methotrexate (MTX) for two to four weeks, improved immunogenicity of infuenza vaccination in patients with rheumatoid arthritis (RA), albeit a risk of disease fare (1). This guided the framing of guidelines on MTX withdrawal for COVID-19 vaccination (2). However, evidence for MTX withdrawal for COVID-19 vaccination is limited to observational studies only. Objectives: To compare the efficacy and safety of holding MTX after each (MIVAC 1) and only after the second dose (MIVAC II) of the ChAdOx1 vaccine versus continuation of MTX in two randomized controlled trials (RCTs). Methods: Two single centre, investigator-blinded, RCTs were conducted in patients with RA or Psoriatic arthritis (PsA) on stable doses of MTX without prior COVID-19 (CTRI reg. no. MIVAC I: CTRI/2021/07/03463 & MIVAC II: CTRI/2021/07/035307). In MIVAC I, unvaccinated patients were randomised (1:1) to hold or continue MTX for two weeks after each dose of the vaccine. MIVAC II included patients who had continued MTX during the frst dose of ChA-dOx1 and were randomised (1:1) to hold or continue MTX for 2 weeks after the second vaccine dose. The primary outcome for both the trials was the anti-Receptor Binding Domain (RBD) antibody titres measured four weeks after the second vaccine dose (per protocol analysis). Secondary outcome was the fare rate, defned as an increase in disease activity scores (DAS28/cDAPSA) or physician intent to hike DMARDs. Results: 250 patients were randomized for MIVAC 1 and 178 for MIVAC II and after due exclusions, 158 and 157 were eligible for analysis respectively (Figure 1). In MIVAC I, median anti-RBD titres were signifcantly high in the MTX hold group [2484 (1050-4388) versus 1147(433-2360), p=0.001] but the fare rate was higher in the hold group [20 (25%) versus 6(8%) p=0.005] compared to continue group. In MIVAC II median anti-RBD titres were signifcantly high for the MTX hold group [2553 (1792-4823) versus 990 (356-2252), p=0.001] when compared to continue group but there was no difference in the fare rate between the groups [9(11.8%) and 4(7.9%), p=0.15] (Table 1). Since both were parallel studies in similar population, MTX hold arms across both the trials were compared for anti-RBD titres and fare. There was no difference in the anti-RBD titres [p=0.2] between the groups. In MIVAC I, 29(36.25%) patients had reported fare (19 in either frst or second dose, 10 for both doses) when compared to MIVAC II where only 9(11.84%) patients had reported fare after the second dose (P <0.001). Conclusion: Holding MTX after both the doses or only after the second dose of ChAdOx1 yields higher anti-RBD antibody titres as compared to continuing MTX. Comparing across the trials, holding MTX only after the second dose appears to be non-inferior to holding MTX after both doses of the vaccine with a lesser risk of fare.

A RANDOMIZED CLINICAL TRIAL of 2-WEEK METHOTREXATE DISCONTINUATION in RHEUMATOID ARTHRITIS PATIENTS VACCINATED with INACTIVATED SARS-COV-2 VACCINE

Background: Patients with rheumatoid arthritis (RA) on methotrexate have reduced vaccine responses. Temporary discontinuation has improved immuno-genicity of anti-infuenza vaccine, but this strategy has not been evaluated in anti-SARS-CoV-2 vaccines. Objectives: To evaluate the effect on immunogenicity and safety of 2-week methotrexate (MTX) discontinuation after each dose of the Sinovac-CoronaVac vaccine versus MTX maintenance in rheumatoid arthritis (RA) patients. Methods: This was a single-center, prospective, randomized, investigator-blinded, intervention study (#NCT04754698, CoronavRheum), including adult RA patients (stable CDAI≤10, prednisone ≤7.5mg/day), randomized (1:1) to withdraw MTX (MTX-hold) for 2 weeks after each vaccine dose or maintain MTX (MTX-maintain), evaluated at D0, D28 and D69. Co-primary outcomes were anti-SARS-CoV-2 S1/S2 IgG seroconversion(SC) and neutralizing antibody (NAb) positivity at D69. Secondary outcomes were geometric mean titers (GMT) and fare rates. For immunogenicity analyses, we excluded patients with baseline positive IgG/NAb, and, for safety reasons, those who fared at D28 (CDAI>10) and did not withdraw MTX twice. Results: Randomization included 138 patients with 9 exclusions (5 COVID-19, 4 protocol violations). Safety evaluation included 60 (MTX-hold) and 69 (MTX-maintain) patients. Further exclusions: 27 patients [13 (21.7%) vs. 14 (20.3%), p=0.848] with positive baseline IgG/NAb and 10 patients (21.3%) in MTX-hold with CDAI>10 at D28. At D69, MTX-hold (n=37) had a higher rate of seroconversion than MTX-maintain (n=55) group [29 (78.4%) vs 30 (54.5%), p=0.019], with parallel augmentation in GMT [34.2 (25.2-46.4) vs 16.8 (11.9-23.6), p=0.006]. No differences were observed for NAb positivity [23 (62.2%) vs 27 (49.1%), p=0.217]. At D28 fare, rates were comparable in both groups (CDAI, p=0.122;DAS28-CRP, p=0.576), whereas CDAI>10 was more frequent in MTX-hold at D69 (p=0.024). Conclusion: We provide novel data that 2-week MTX withdrawal after each Sinovac-CoronaVac vaccine dose improves anti-SARS-CoV-2 IgG response. The increased fare rates after second MTX withdrawal may be attributed to the short-term interval between vaccine doses. This strategy requires close surveillance and shared decision making due to the possibility of fares.

DIGITALLY ENHANCED TREAT-TO-TARGET and SHARED DECISION-MAKING APPROACH with A DIGITAL HEALTH APPLICATION: INTERIM RESULTS from A RANDOMIZED CONTROLLED TRIAL

Background: Digital health applications (DHA) became indispensable patient companions accelerated by the current COVID pandemic [1]. In 2020, for the frst time worldwide, a regulatory framework to reimburse DHA was established in Germany. To get listed as a DHA, preliminary evidence needs to be generated-next to fulflling highest standards in quality and safety. The DHA ABATON RA consists of two parts;1) digital shared-decision-making (SDM) including choosing an appropriate electronic patient reported outcome (ePRO) instrument and the respective ePRO target for the next visit, 2) remote patient monitoring and ePRO tracking by the patient. Hereby, ABATON RA supports a digitally guided Treat-to-Target (T2T) approach. Objectives: The objective of this study is to evaluate a potentially benefcial effect for the patient by using ABATON RA. Methods: Three-armed, partially blinded multicenter trial (RCT) including RA patients who regularly use a smartphone. Patients attend 3 visits, 3 months apart (T0, T3, T6), with one follow-up visit (T9). Intervention group (IG): Patients use ABATON RA. Via SDM patients and rheumatologists choose a specifc ePRO and respective treatment target for the next visit in three months, e.g. RAID ≤4. Control group (CG): Standard of care treatment (no DHA). Placebo group (PG): Usage of a placebo version of ABATON RA providing only Regensburger Insomnie Skala (RIS) and Epworth Sleepiness Scale (ESS) as ePROs. No SDM is conducted and ePRO results are not presented to HCP. Results: This interim analysis evaluated the frst 38 patients that completed T3. IG: 13 patients (Av. age 55.9, 61.5% females);PG: 12 (Av. age 50.7, 66.7% females);CG: 13 (Av. age 56.1, 76.9% females). We observe a signifcant improvement in the mean over time in a pairwise comparison within the intervention group for the following: Pt-GA mean difference of 2.98 (p = 0.025, partial η2 = 0.353), pain mean difference of 1.46 (p = 0.049, partial η2 = 0.286) whereas all pairwise comparisons for the two parameters were non-signifcant in PG and CG. The patient reactions assessment (PRA) score, measuring patient perceived quality of the patient-provider relationship, increased by a mean of 4.15 points in IG, compared to a slight decrease of 1.92 for PG and 2.77 for CG. Conclusion: These preliminary fndings show benefcial differences among the groups in favor of IG: 1) for quality of life and 2) the physician-patient-relationship. A digitally enhanced therapy is non-inferior to the gold-standard of exclusive in-person treatment. Patients seem willing and able to get involved in an enhanced treat-to-target and shared decision-making approach.