Time Points Baseline Research Articles

Protocol for a Pilot Study on the Neurocardiac Mechanism of an Interoceptive Compassion-Based Heart-Smile Training for Depression.

Heart-Smile Training (HST) is an interoceptive compassion-based behavioral intervention that in case reports has been beneficial for depression. Interoception refers to the awareness and regulation of physiological signals from inside the body. Depressed patients often have diminished interoceptive awareness and often experience disconnection from bodily needs and sensations. In addition to interoceptive dysfunction, depression often involves negative self-evaluation and self-critical rumination. HST is a compassion-based meditation training program that explicitly cultivates interoceptive awareness of the heart area. This study aims to investigate the possible neurocardiac mechanisms engaged through HST for depression patients. We plan to enroll 50 subjects to be randomized into a 4-week HST intervention group and a waitlist group. A battery of psychological questionnaires will be administered at baseline and post-intervention timepoints, and electroencephalography (EEG) will be collected during compassion meditation guided by pre-recorded audio. The primary clinical outcome measures are on the feasibility of the intervention and research procedures, the primary mechanistic outcome measure is the post-intervention change in Heartbeat Evoked Potential (HEP) amplitude. Secondary outcome measures include changes in depression severity and EEG gamma spectral activity. Exploratory outcome measures include effects of HST on skin conductance response, heart rate variability, EEG spectral properties in other frequency bands, as well as a list of psychological questionnaires that measure depression and anxiety symptoms, emotion regulation, mindfulness, interoceptive awareness, self-compassion, gratitude, sleep quality, quality of life and social connectedness. Results not yet available. This is the first study on the feasibility and interoceptive neurocardiac mechanism of HST. Our findings will provide frontier knowledge on the physiological working mechanism of behavioral interventions with an interoception-based meditative approach. https://clinicaltrials.gov/study/NCT05564533.

The Effects of Cognitive Ability, Mental Health, and Self-Quarantining on Functional Ability of Older Adults During the COVID-19 Pandemic: Results From the Canadian Longitudinal Study on Aging.

Determine whether levels of anxiety and depression, cognitive ability, and self-quarantining during and prior to the pandemic predict decreases in perceived functional ability. Longitudinal data collected from the Canadian Longitudinal Study on Aging (CLSA) COVID-19 Questionnaire Study (2020) and core CLSA study (Follow-Up 1; 2014-2018). 17541 CLSA participants. Self-quarantining behaviours from questionnaires administered at Baseline (April 2020), Monthly, and Exit (December 2020) time points of the CLSA COVID-19 Questionnaire Study, levels of anxiety and depression at Baseline, perceived change in functional ability at Exit, and performance on neuropsychological tests (Rey Auditory Verbal Learning Task, Mental Alternation Task, Animal Fluency Test) and functional ability (Older Americans Resources and Services [OARS] Multidimensional Assessment Questionnaire) from the core CLSA study. Greater cognitive ability pre-pandemic (B = -.003, P < .01), higher levels of anxiety (B = -.024, P < .01) and depressive symptoms (B = -.110, P < .01) at Baseline, and higher frequency of engaging in self-quarantining throughout the COVID-19 survey period (B = -.098, P < .01) were associated with perceived loss in functional ability at Exit. Self-quarantining behaviour was associated with perceived loss in functional ability only at average and high levels of depressive symptoms (B = -.013, P < .01). Older adults with higher cognitive and lower functional ability prior to the pandemic were at greater risk of decreased perceived functional ability during the first year of the pandemic, as were those who experienced greater levels of anxiety and depressive symptoms during the pandemic. Strategies/interventions to preserve functional ability in older adults with cognitive independence prior to future pandemics are warranted.

Conservative treatment outcome for Achilles tendon re-rupture occurring in the subacute phase after primary repair.

Until now, a treatment protocol for Achilles tendon re-rupture (ATRR) occurring in the postoperative period 5-12weeks following primary Achilles tendon repair has not been established. We refer to this time frame as the subacute postoperative phase, and the objective of this study was to assess the efficacy of conservative treatment for subacute ATRR in this phase. We conducted a retrospective review of 390 cases (385 patients) who had undergone primary Achilles tendon repair using the 4-strand Krachow method between January 2010 and August 2021. All patients were subjected to more than 12months of follow-up and were categorized into two groups based on the presence of subacute ATRR: Group 1 comprised 370 cases without ATRR, while Group 2 comprised 20 cases with ATRR. Following confirmation of ATRR, we immediately applied a below-knee cast in an ankle plantar flexed position (25°-30°), followed by bracing according to the same rehabilitation plan used for the primary repair. After administering conservative treatment to the patients with ATRR, we compared several outcome parameters between the two groups, including isokinetic plantar flexion power measured using a dynamometer, time required for a single heel raise (t-SHR), time needed for ten repetitive SHRs (t-SHR10), Achilles Tendon Total Rupture Score (ATRS), and Foot and Ankle Ability Measure (FAAM) scores. The baseline timepoints for Groups 1 and 2 were the dates of the primary repair and the re-injury event. After primary Achilles tendon repair, subacute ATRR occurred in 5.1% of patients. There were no significant differences between the groups in terms of t-SHR and t-SHR10 (P = 0.281, 0.486). Similarly, the isokinetic dynamometer measurements revealed no significant differences in peak torque for plantar flexion at angular velocities of 30°/s and 120°/s, both in absolute values and as a percentage of the contralateral side, between the groups (P > 0.05 for each). However, ATRSs were significantly lower in Group 2 compared to Group 1 before 6months (P < 0.05), as were FAAM-Activities of Daily Living scores at 6months (P < 0.05). After 12months, there were no significant differences in these scores between the two groups (both P > 0.05). Conservative treatment for subacute ATRR following primary Achilles tendon repair yields clinical outcomes comparable to those without ATRR. Therefore, we recommend that surgeons consider relying on the patient's natural healing capabilities rather than opting for aggressive surgical interventions, as expediting such operations may be unnecessary for subacute injuries.

Effectiveness and tolerance of multicorrective topical treatment for infraorbital dark circles and puffiness.

Treatment of infraorbital dark circles and under-eye puffiness is challenging due to its multifactorial nature and lack of broadly applicable, effective treatments. A daily skincare treatment option that is multimodal, effective, and tolerable across a broad patient population is an unmet need. A multicorrective topical eye cream (MTEC) formulated with Tetrahexyldecyl (THD) ascorbate (vitamin C), prebiotic Inula Helenium, bioavailable peptides, botanical extracts, chrysin, and caffeine is hypothesized to improve the appearance of infraorbital dark circles and under-eye puffiness by targeting microvasculature congestion and permeability, melanin accumulation and hemoglobin degradation-related pigmentation, and skin health. An IRB approved, open-label, 12-week clinical study set out to evaluate the efficacy and tolerability of the MTEC across a broad patient population including varying ethnicities and Fitzpatrick Skin Types (FST). Female subjects (n = 40) ages 35-60 years old, with moderate-to-severe under-eye dark circles, moderate under-eye puffiness, and mild-to-moderate fine lines were enrolled into the study. Objective (Chromameter, VISIA® imaging, and Laser Doppler) and subjective assessments (clinical grading and self-assessment questionnaire) were conducted at baseline and post-baseline timepoints. Thirty-seven subjects completed the study, and the MTEC efficaciously demonstrated short-term and long-term improvements in objective and subjective assessments across a broad patient population. Specifically, the MTEC demonstrated significant improvement of infraorbital dark circles, mainly by the reduction in microvasculature congestion and permeability, melanin, and hemoglobin degradation-related pigmentation. Topical application of the MTEC may offer an effective and tolerable treatment option for infraorbital dark circles and puffiness.

Gut microbiome predictors of Escherichia coli sequence type 131 colonization and loss

Escherichia coli sequence type 131 (ST131), specifically its fluoroquinolone-resistant H30R clade (ST131-H30R), is a global multidrug-resistant pathogen. The gut microbiome's role in ST131-H30R intestinal carriage is undefined. Veterans and their household members underwent longitudinal fecal swab surveillance for ST131 in 2014-2018. The fecal microbiome was characterized by 16S rRNA qPCR and sequencing. We evaluated associations between ST131-H30R carriage and gut microbiome at baseline by random forest models to identify the most informative gut bacterial phyla and genera attributes for ST131 and ST131-H30R carriage status. Next, we assessed longitudinal associations between fecal microbiome and ST131-H30R carriage using a mixed-effects logistic regression with longitudinal measures. Of the 519 participants, 78 were carriers of ST131, among whom 49 had ST131-H30R. At the baseline timepoint, H30R-positive participants had higher proportional abundances of Actinobacteria phylum (mean: 4.9% vs. 3.1%) than ST131-negative participants. H30R-positive participants also had higher abundances of Collinsella (mean: 2.3% vs. 1.1%) and lower abundances of Alistipes (mean: 2.1% vs. 2.6%) than ST131-negative participants. In the longitudinal analysis, Collinsella abundance correlated positively with ST131-H30R carriage status and negatively with the loss of ST131-H30R. Conversely, Alistipes corresponded with the loss and persistent absence of ST131-H30R even in the presence of a household exposure. Abundances of specific fecal bacteria correlated with ST131-H30R carriage, persistence, and loss, suggesting their potential as targets for microbiome-based strategies to reduce carriage of ST131-H30R, a significant risk factor for invasive infections. This work was supported in part by National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers R21AI117654 and UM1AI104681 and the Office of Research and Development, Department of Veterans Affairs. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Department of Veterans Affairs.

Nebulized dexmedetomidine for attenuating hemodynamic response to laryngoscopy and endotracheal intubation in adult patients undergoing surgeries under general anaesthesia: a systematic review and meta-analysis of randomized controlled trials

BackgroundSympathetic stimulation associated with laryngoscopy and endotracheal intubation (ETI) may lead to adverse cardio-/cerebro-vascular events in susceptible patients. Nebulization is a novel route for dexmedetomidine administration providing a large surface area for absorption while avoiding bradycardia and hypotension associated with intravenous route. We aimed to evaluate the efficacy and safety of dexmedetomidine nebulization for attenuating hemodynamic response to ETI in adult patients undergoing surgery under general anaesthesia.MethodsThis systematic review was registered prospectively in the International Prospective Register of Systematic Reviews (CRD42023403624). PubMed, Embase (OvidSP), Cochrane library, Scopus (Elsevier), Web of Science (Clarivate) and Google Scholar were systematically searched from database inception until March 31, 2023. Two reviewers independently screened titles, abstracts and then full text against pre-specified eligibility criteria. Randomized controlled trials (RCTs) assessing effect of dexmedetomidine nebulization on hemodynamic response to ETI in adult patients undergoing surgeries under general anaesthesia were included. All studies reporting heart rate and systolic blood pressure at baseline and various time points after ETI were included. A pre-piloted data extraction form, Cochrane revised risk-of-bias tool (ROB 2) tool, GRADE approach and RevMan 5.4.1 (Cochrane Collaboration, Copenhagen, Denmark) were used for data extraction, risk of bias assessment, rating certainty of evidence and data synthesis respectively. Mean difference and relative risk with 95% Confidence Interval (CI) were used for continuous and dichotomous variables respectively.ResultsSix RCTs randomized 480 patients with ASA I/II patients aged < 60 years of age and undergoing elective surgeries to receive either dexmedetomidine (n = 240) or saline nebulization (n = 240). Except for one RCT which used 2 μg/kg, all other RCTs used dexmedetomidine dose of 1 μg /kg. Heart rate, systolic, diastolic and mean blood pressure were significantly lower in the dexmedetomidine group at all the measured time points after laryngoscopy and ETI with the only exception being systolic blood pressure at 3 min [mean difference -13.86 (95% CI -30.01 to 2.99), p = 0.09]. Bradycardia and hypotension as adverse effects were absent across the included studies. However, only one-third of the included studies had a low risk of bias and strength of evidence was very low according to the GRADE assessment.ConclusionsCompared to placebo, premedication with dexmedetomidine nebulization was associated with lower HR and BP following ETI without any risk of bradycardia and hypotension. However, the strength of evidence was very poor and came from just one country. Future well designed and conducted studies in different populations are warranted.Trial registrationPROSPERO Registration number: CRD42023403624

Effect of albumin substitution on pharmacokinetics of piperacillin/tazobactam in patients with severe burn injury admitted to the ICU.

Pathophysiological changes in severely burned patients alter the pharmacokinetics (PK) of anti-infective agents, potentially leading to subtherapeutic concentrations at the target site. Albumin supplementation, to support fluid resuscitation, may affect pharmacokinetic properties by binding drugs. This study aimed to investigate the PK of piperacillin/tazobactam in burn patients admitted to the ICU before and after albumin substitution as total and unbound concentrations in plasma. Patients admitted to the ICU and scheduled for 4.5 g piperacillin/tazobactam administration and 200 mL of 20% albumin substitution as part of clinical routine were included. Patients underwent IV microdialysis, and simultaneous arterial plasma sampling, at baseline and multiple timepoints after drug administration. PK analysis of total and unbound drug concentrations under steady-state conditions was performed before and after albumin supplementation. A total of seven patients with second- to third-degree burns involving 20%-60% of the total body surface were enrolled. Mean (SD) AUC0-8 (h·mg/L) of total piperacillin/tazobactam before and after albumin substitution were 402.1 (242)/53.2 (27) and 521.8 (363)/59.7 (32), respectively. Unbound mean AUC0-8 before and after albumin supplementation were 398.9 (204)/54.5 (25) and 456.4 (439)/64.5 (82), respectively. Albumin supplementation had little impact on the PK of piperacillin/tazobactam. After albumin supplementation, there was a numerical increase in mean AUC0-8 of total and unbound piperacillin/tazobactam, whereas similar Cmax values were observed. Future studies may investigate the effect of albumin supplementation on drugs with a higher plasma protein binding.

Improving the Well-Being of People With Advanced Cancer and Their Family Caregivers: Protocol for an Effectiveness-Implementation Trial of a Dyadic Digital Health Intervention (FOCUSau).

Advanced cancer significantly impacts patients' and family caregivers' quality of life. When patients and caregivers are supported concurrently as a dyad, the well-being of each person is optimized. Family, Outlook, Communication, Uncertainty, Symptom management (FOCUS) is a dyadic, psychoeducational intervention developed in the United States, shown to improve the well-being and quality of life of patients with advanced cancer and their primary caregivers. Originally, a nurse-delivered in-person intervention, FOCUS has been adapted into a self-administered web-based intervention for European delivery. The aims of this study are to (1) adapt FOCUS to the Australian context (FOCUSau); (2) evaluate the effectiveness of FOCUSau in improving the emotional well-being and self-efficacy of patients with advanced cancer and their primary caregiver relative to usual care control group; (3) compare health care use between the intervention and control groups; and (4) assess the acceptability, feasibility, and scalability of FOCUSau in order to inform future maintainable implementation of the intervention within the Australian health care system. FOCUS will be adapted prior to trial commencement, using an iterative stakeholder feedback process to create FOCUSau. To examine the efficacy and cost-effectiveness of FOCUSau and assess its acceptability, feasibility, and scalability, we will undertake a hybrid type 1 implementation study consisting of a phase 3 (clinical effectiveness) trial along with an observational implementation study. Participants will include patients with cancer who are older than 18 years, able to access the internet, and able to identify a primary support person or caregiver who can also be approached for participation. The sample size consists of 173 dyads in each arm (ie, 346 dyads in total). Patient-caregiver dyad data will be collected at 3 time points-baseline (T0) completed prerandomization; first follow-up (T1; N=346) at 12 weeks post baseline; and second follow-up (T2) at 24 weeks post baseline. The study was funded in March 2022. Recruitment commenced in July 2024. If shown to be effective, this intervention will improve the well-being of patients with advanced cancer and their family caregivers, regardless of their location or current level of health care support. ClinicalTrials.gov NCT06082128; https://clinicaltrials.gov/study/NCT06082128. PRR1-10.2196/55252.

Anti-Peptidylarginine Deiminase 4 Autoantibodies and Disease Duration as Predictors of Treatment Response in Rheumatoid Arthritis.

Given that autoantibodies to peptidylarginine deiminase 4 (PAD4) are associated with erosive disease in established rheumatoid arthritis (RA), this study was conducted to compare the clinical and prognostic use of anti-PAD4 antibodies in patients with early and established RA. Sera from patients with early (duration <2 years; n=422) or established (duration ≥2 years; n=359) RA from two randomized clinical trials of tofacitinib ± methotrexate compared with adalimumab + MTX or MTX alone were evaluated for the presence of anti-PAD4 and anti-PAD3/4 antibodies at baseline and posttreatment time points. Summary statistics were calculated for demographic, clinical, and serological characteristics, and generalized estimating equations were used to model clinical outcomes by disease duration according to anti-PAD4 status. Anti-PAD4 antibodies were present in 22% and 40% of patients with early and established RA, respectively, stable following treatment, and associated with baseline joint damage only in established RA. In early RA, baseline anti-PAD4 antibodies were associated with a greater improvement in disease activity score 28-joint count using C-reactive protein levels after treatment compared with individuals with negative anti-PAD4 (P = 0.049). Tofacitinib ± MTX was more broadly efficacious than MTX alone at improving clinical outcomes in early and established RA, irrespective of anti-PAD4 status (P < 0.05 for all), whereas adalimumab + MTX exhibited differential benefits in achieving disease activity score remission in early RA (P = 0.036) and American College of Rheumatology 20 responses in established RA (P = 0.002). Differences in prevalence, clinical associations, and treatment-response outcomes according to anti-PAD4 antibody status in early and established RA suggests the existence of a therapeutic window to prevent the accumulation of irreversible joint damage in early patients with RA with anti-PAD4 antibodies.

Functional and Multi-Omics Signatures of Mitapivat Efficacy upon Activation of Pyruvate Kinase in Red Blood Cells from Patients with Sickle Cell Disease

2,3-diphosphoglycerate (DPG) in red blood cells (RBCs) stabilizes deoxyhemoglobin to promote hemoglobin (Hb) oxygen off-loading and counteract hypoxia. In sickle cell disease (SCD), mutation of glutamate 6 to valine in the beta chain of Hb results in HbS that polymerizes, causing RBCs to sickle upon deoxygenation in the tissues. Elevated DPG promotes sickling by stabilizing HbS fibers. DPG is an intermediate substrate in the glycolytic pathway in which pyruvate kinase (PK) is a rate-limiting enzyme. In a previous Phase 1 study (NCT04000165, Xu et al, 2022), we established proof-of-concept for activating PK as a viable anti-sickling therapeutic approach; mitapivat, an investigational oral allosteric activator of PK, decreased DPG and increased adenosine triphosphate (ATP) levels, improved hematologic and sickling parameters in patients (pts) with SCD (HbSS). Here, we investigated the changes in the metabolome, lipidome and proteome of RBCs from patients with SCD currently enrolled in an open label, Phase 1/2 study (NCT04610866) that evaluates long-term safety and tolerability of mitapivat in pts with SCD. Fifteen pts with HbSS (aged 25 - 57 years, 10 males) were evaluated. All pts started mitapivat at 50 mg twice daily (BID), escalating after 4 wks to 100 mg BID; dose adjustments were performed for safety and tolerability, per PI discretion. At the time of data cutoff (March 23, 2023), all 15 pts completed the core period of 24 wks, 14 pts completed 48 wks ,10 pts completed 72 wks and 6 pts completed 92 wks. Leuko-depleted RBCs (LDRBCs) obtained from fresh whole blood in EDTA at baseline (V1, prior to drug initiation) and various longitudinal time points over the course of the study were flash-frozen in liquid nitrogen and kept frozen at -80°C until analysis. Clinical measurements of DPG, ATP, red cell PK (PKR) protein and activity levels, oxygen affinity (p50) and sickling kinetics (t50) were accompanied by multi-omics (metabolomics, lipidomics, proteomics) characterization of the LDRBCs. In total, 150 (6x12, 4x10, 4x8 and 1x6) timepoint samples were analyzed (Fig 1A). Multi-omics analyses were performed through a stepwise extraction of metabolites, lipids and proteins on 50 µl of packed LDRBC pellets. Extracts were separated via ultra-high-pressure liquid chromatography coupled to mass spectrometry, prior to peak picking and identification of ddMS2 data as previously described (Thomas et al 2020). Statistical analyses were conducted using MetaboAnalyst v 5.0 and Rstudio upon normalization of relative quantitative data to visit 0 levels for each variable. Network analysis and pathway analysis were performed in OmicsNet v 2.0. Mitapivat therapy had significant effects on the metabolome, lipidome and proteome of SCD RBCs. Overall, the temporal trends of omics responses to mitapivat treatment across visits was evident, especially when focusing on the top 50 metabolites/lipids or proteins by time series ANOVA. Specifically, results suggested a positive correlation between mass spectrometry-based quantitation of RBC mitapivat levels and DPG consumption, ATP accumulation, PKR activity (measured via enzymatic assays), and PKR protein levels, with internal consistency between omics data and antibody-based or enzymatic assays (Fig. 1A). The treatment also promoted activation of the Lands cycle, transient elevation of lysophosphatidylcholines and oxylipins, and depletion in free fatty acids within the first 6 months, suggestive of an effect on membrane lipid remodeling. SCD RBCs abnormally retain mitochondria; here, we showed a consistent decrease in the levels of residual mitochondrial proteins in RBCs within 4 wks of mitapivat treatment (Fig. 1B). In keeping with the predicted activation of PKR upon mitapivat treatment, we observed decreases in DPG and increases in ATP, with elevation in glycolytic fluxes, as inferred from longitudinal changes in glycolytic intermediates at the hexose and triose phosphate steps, as well as lactate. Unsupervised analyses of omics data confirmed the specificity of mitapivat on targeting late glycolysis, with glycolytic metabolites ranking as the top correlates to parameters of oxygen affinity (p50) and sickling kinetics (t50) during mitapivat treatment. Multi-omics analysis of RBCs from HbSS patients treated with mitapivat identified benefits for glycolysis, DPG consumption and ATP generation, as well as activation of the Lands cycle.

Prognostic value of circulating tumor DNA in operable non-small cell lung cancer: a systematic review and reconstructed individual patient-data based meta-analysis

BackgroundThis reconstructed individual patient data (IPD)-based meta-analysis is aimed to summarize the current findings and comprehensively investigate the predictive value of circulating tumor DNA (ctDNA) in operable non-small cell lung cancer (NSCLC).MethodsPubMed, Cochrane and Embase were searched to include potentially eligible studies. The primary outcomes included progression-free survival (DFS) by ctDNA status at baseline, postoperative, and longitudinal timepoints. The IPD-based survival data was retracted and used in reconstructed IPD-based meta-analysis. Subgroup analysis was implemented based on the baseline characteristics.ResultsTotally, 28 studies were involved, including 15 full-length articles (1686 patients) for IPD-based synthesis and 20 studies for conventional meta-analysis. The IPD-based meta-analysis discovered that patients with positive ctDNA status at the baseline (hazard ratio, HR = 3.73, 95% confidential interval, CI: 2.95–4.72), postoperative (3.96, 2.19–7.16), or longitudinal timepoints (12.33, 8.72–17.43) showed significantly higher risk of recurrence. Patients with persistent ctDNA-negative status had the lowest recurrence rate, and the negative conversion of ctDNA from baseline to postoperative timepoints was correlated with elevated DFS. Subgroup analyses suggested that stage II–III patients with ctDNA-positive status may achieve preferable therapeutic outcomes.ConclusionsPlasm ctDNA monitoring shows excellent clinical significance at the tested timepoints. Perioperative conversion of ctDNA status may indicate the therapeutic effect of radical surgery. Postoperative adjuvant therapy may be determined according to the ctDNA status.Trail registrationCRD42022304445.

506. Resistance Analyses from the Remdesivir Phase 3 REDPINE Study in Participants with Severely Reduced Kidney Function Who Were Hospitalized for COVID-19

Abstract Background Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in nonhospitalized and hospitalized adult and pediatric patients with clinical benefit demonstrated in multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from the Phase 3 REDPINE study, which demonstrated the safety of RDV in participants with severely reduced kidney function. Methods REDPINE (NCT04745351) was a double-blind, placebo-controlled trial in participants hospitalized for COVID-19 with severely reduced kidney function who were randomized 2:1 to receive RDV or placebo for 5 days. Full-genome deep sequencing of SARS-CoV-2 was performed on nasopharyngeal swab samples collected on Days 1 (baseline), 3, 5, 7, 14, 21, and/or 29. Emergent amino acid substitutions from RDV-treated participants were tested for RDV susceptibility in a SARS-CoV-2 replicon system. Results Of the 243 participants randomized and treated, 82 (RDV, 55; placebo, 27) met the resistance analysis criteria (all participants with all-cause death or invasive mechanical ventilation [IMV] through Day 29 or with SARS-CoV-2 RNA above the viral load assay lower limit of quantitation on Day 14). Sequencing data at both baseline and postbaseline timepoints were obtained from 60 participants (RDV, 41; placebo, 19). Among these, emergent amino acid substitutions in Nsp12 were observed in 8/41 (19.5%) in the RDV group and 1/19 (5.3%) in the placebo group. The proportions of participants with all-cause death or IMV through Day 29 were comparable between participants in the RDV group with emergent Nsp12 substitutions (5/8, 62.5%) or without emergent Nsp12 substitutions (30/33, 90.9%). In 4 participants in the RDV group, Nsp12 substitutions with low-level reduced susceptibility to RDV were identified in samples collected 9 days after cessation of RDV treatment (2.9- to 3.4-fold change in EC50): M794I (n = 2), C799F (n = 1), and E136V (n = 1). Three of these 4 participants had received solid organ transplants and were receiving concomitant immunosuppressive therapies during the study. Conclusion The results of resistance analyses in participants with severely reduced kidney function hospitalized for COVID-19 confirm a high barrier to clinically meaningful resistance to RDV in COVID-19 patients. Disclosures Kristen Andreatta, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Jiani Li, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Lauren Rodriguez, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Dong Han, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Simin Xu, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Jason K. Perry, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Yiannis Koullias, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Robert H. Hyland, DPhil, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Charlotte Hedskog, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds

Can photobiomodulation improve quadriceps strength and endurance outcomes in asymptomatic adults? A double-blind randomized controlled trial

AimTo explore the effect of photobiomodulation on quadriceps strength and endurance torques in asymptomatic adults. MethodsTwenty-eight asymptomatic adults were randomized to one of two interventions: photobiomodulation (n = 14) or sham (n = 14). Quadriceps strength was evaluated by maximum voluntary isometric contraction test (60°) and endurance by an elastic resistance in multiple-set knee extension/flexion repetitions using a traction dynamometer. The outcomes were measured at three time points: pre-baseline; baseline and; final assessment. The photobiomodulation was applied to the quadriceps and triceps surae muscles of each participant's dominant lower limb, using a cluster with 1 infrared laser diode and 3 led amber of 170 mW for 240 s over four consecutive days. The sham group went through the same procedures, but the equipment was off, and patients and assessors were blinded to the intervention. Reliability and minimal detectable change of the measures were obtained from the pre-baseline and baseline time points. Differences between interventions were tested by an analysis of covariance. Results and discussionThere was no difference between photobiomodulation compared to sham in maximum isometric torque (mean difference (95% CI) = 0.008 (−0.29 to 0.31) and endurance torques (mean difference (95% CI) = 0.04 (−0.03 to 0.12). The mean difference was lower than the minimal detectable change for the maximum isometric torque (1.02 Nm.kg−1) and endurance torque (0.49 Nm.kg−1). ConclusionPhotobiomodulation does not improve quadriceps strength and endurance outcomes in asymptomatic adults.

Tongue and laryngeal exercises improve tongue strength and vocal function outcomes in a Pink1-/- rat model of early Parkinson disease

Parkinson disease (PD) causes voice and swallow dysfunction even in early stages of the disease. Treatment of this dysfunction is limited, and the neuropathology underlying this dysfunction is poorly defined. Targeted exercise provides the greatest benefit for offsetting voice and swallow dysfunction, and previous data suggest the hypoglossal nucleus and noradrenergic-locus coeruleus (LC) may be involved in its early pathology. To investigate relationships between targeted exercise and neuropathology of voice and swallow dysfunction, we implemented a combined exercise paradigm that included tongue force and vocalization exercises early in the Pink1-/- rat model. We tested the hypotheses that (1) tongue and vocal exercise improves tongue force and timing behaviors and vocalization outcomes, and (2) exercise increases optical density of serotonin (5-HT) in the hypoglossal nucleus, and tyrosine hydroxylase immunoreactive (Th-ir) cell counts in the LC. At two months of age Pink1-/- rats were randomized to exercise or non-exercise treatment. Age-matched wildtype (WT) control rats were assigned to non-exercise treatment. Tongue force and timing behaviors and ultrasonic vocalizations were measured at baseline (two months) and final (four months) timepoints. Optical density of 5-HT in the hypoglossal nucleus and TH-ir cell counts in the LC were obtained. Pink1-/- rats produced greater tongue forces, faster tongue contraction, and higher-intensity vocalization following exercise. There were no differences in LC TH-ir. The non-exercised Pink1-/- group had reduced density of 5-HT in the hypoglossal nucleus compared to the WT control group. The changes to tongue function and vocalization after targeted exercise suggests exercise intervention may be beneficial in early PD.

Effectiveness of an amygdala and insula retraining program combined with mindfulness training to improve the quality of life in patients with long COVID: a randomized controlled trial protocol

BackgroundThere has been growing clinical awareness in recent years of the long-term physical and psychological consequences of the SARS-CoV-2 virus, known as Long COVID. The prevalence of Long COVID is approximately 10% of those infected by the virus. Long COVID is associated with physical and neuropsychological symptoms, including those related to mental health, psychological wellbeing, and cognition. However, research on psychological interventions is still in its early stages, in which means that available results are still limited. The main objective of this study is to evaluate the effects of a program based on amygdala and insula retraining (AIR) combined with mindfulness training (AIR + Mindfulness) on the improvement of quality of life, psychological well-being, and cognition in patients with Long COVID.MethodsThis study protocol presents a single-blind randomized controlled trial (RCT) that encompasses baseline, post-treatment, and six-month follow-up assessment time points. A total of 100 patients diagnosed with Long COVID by the Spanish National Health Service will be randomly assigned to either AIR + Mindfulness (n = 50) or relaxation intervention (n = 50), the latter as a control group. The primary outcome will be quality of life assessed using the Short Form-36 Health Survey (SF-36). Additional outcomes such as fatigue, pain, anxiety, memory, and sleep quality will also be evaluated. Mixed effects regression models will be used to estimate the effectiveness of the program, and effect size calculations will be made.DiscussionLong COVID syndrome is a clinical condition characterized by the persistence of symptoms for at least 12 weeks after the onset of COVID-19 that significantly affects people’s quality of life. This will be the first RCT conducted in Spain to apply a psychotherapy program for the management of symptoms derived from Long COVID. Positive results from this RCT may have a significant impact on the clinical context by confirming the beneficial effect of the intervention program being evaluated on improving the symptoms of Long COVID syndrome and aiding the development of better action strategies for these patients.Trial registrationClinical Trials.gov NCT05956405. Registered on July 20, 2023.

Abstract 14010: Synergistic Influence of Rivaroxaban on Platelets, Inflammation and Coagulation Biomarkers in Patients With CAD and/or PAD on Aspirin Therapy

Background: Cardiovascular benefits of 2.5 mg twice daily rivaroxaban plus aspirin therapy (RIV+ASA) has been demonstrated in patients with arterial diseases. Hypothesis: RIV+ASA is associated with reduced platelet activation and plasma inflammation and coagulation activation markers in patients with CAD and/or PAD who were on ASA. Methods: In this open-label biomarker study, patients on 81 mg/day ASA were randomized to continue ASA or RIV+ASA for 12 weeks. We assessed ADP-, α-thrombin-, and tissue factor-induced platelet aggregation (PA) using conventional aggregometry, platelet-fibrin clot strength (PFCS) by INTEM (intrinsic pathway activator) and EXTEM (extrinsic pathway activator) using thromboelastometry, shear-induced PA by platelet function analyzer-100, D-dimer and fibrinogen using coagulation analyzer, hs-CRP and interleukin-6 using ELISA method at baseline, and four weeks and 12 weeks post-randomization. Results: Data was available in 9 patients with RIV + ASA and ten patients with ASA-only therapy. Most patients were male, Caucasians, obese and older. There were no differences in baseline demographics, medications, and laboratory values between groups, except patients in RIV + ASA group had higher white blood cell counts (p=0.028) and lower baseline 2uM ADP-induced PA (p=0.03). There were no differences in other laboratory measurements between baseline and post-randomization time points within the group or at 4- and 12-week time points between groups, except D-dimer values were significantly lower at 12 weeks (p=0.038) in the RIV + ASA vs. ASA-only group. No significant adverse events were observed. Conclusions: Twelve weeks of rivaroxaban plus aspirin vs. aspirin was associated with similar levels of platelet aggregation, platelet fibrin clot strength, fibrinogen and inflammation markers, and lower d-dimer levels.

Abstract 15922: Integrative Analysis of Extracellular Vesicles in Heart Transplant Rejection: From Biomarker Discovery to Novel Immune Mechanisms

Introduction: At the forefront of post-heart transplant care is early detection of transplant rejection. However, the current gold standard for detecting acute cellular transplant rejection is recurrent invasive endomyocardial biopsies (EMB). We aimed at developing a non-invasive biomarker for acute cellular heart transplant rejection (ACR) using a plasma extracellular vesicle (EV) platform. Methods: Peripheral and coronary sinus plasma samples were prospectively collected from 183 (31.7% female) patients from 2020 to 2023 during routine surveillance EMB. A discovery cohort comprised five patients who displayed ISHLT 0-1R biopsy followed by an ISHLT 2R grade rejection event. Plasma EVs were isolated from the baseline (0-1R) and rejection (2R) time points. Subsequently, integrative analysis of plasma EV proteomic, miRNomic, and metabolomics was performed pairwise with the samples. Results: The study collected 943 sample time points from 183 patients. Of these sample collections, 43 (4.5%) cases were 2R rejections. Our proteomic analysis of the plasma EVs identified 28 proteins found explicitly during a grade 2R rejection and 87 differentially expressed proteins during a 2R rejection event. An Ingenuity Pathway Analysis (IPA) analysis of the upregulated proteins highlighted EVs mediated mTOR signaling and antigen presentation as central to rejection events. Although all patients in the discovery cohort were negative for antibody-mediated rejection (AMR), the proteomic findings also revealed increased B-cell receptor signaling, implying a mechanistic intersection of ACR and AMR. Conclusions: A distinct set of proteins were found in plasma EVs during ACR events, providing potentially specific and sensitive biomarkers to reduce the need for EMB that could be exploited for ACR diagnosis. The proteins identified formed an immune signaling network that suggests a novel role for EVs in ACR pathogenesis.

Abstract 13220: Independent Effects of Baseline Pulse Wave Velocity versus Advancing Age on Changes in Arterial Stiffness Over Time

Introduction: While arterial stiffness (AS) is a known marker of vascular ageing that prognosticates cardiovascular disease (CVD), prospective analyses of AS evolution alongside chronological age are necessary to understand factors that drive progressive AS. Using pulse wave velocity (PWV) we investigated the impact of baseline factors in predicting PWV changes over a 5-year period. Hypothesis: We hypothesized that certain baseline factors in older Asian adults are predictive of PWV trajectories later in life independent of chronological age. Methods: Participants without CVD from a community-based cohort had their clinical risk factors collected prospectively, and PWV (m/s) measured using a cuff-based oscillometric pulse wave analysis machine at baseline and 5-year timepoint. Results: This analysis included 159 participants (41.5% women, mean age 67.7 ± 10.2 years). ΔPWV (2.19 ± 2.25), the 5-year change in PWV, was associated with baseline PWV (β = -0.687, p &lt; 0.001), age (β = 0.084, p &lt; 0.001), hypertension (β=0.763, p = 0.033), weight (β = -0.042, p = 0.018) and waist circumference (β = -0.045, p = 0.018). Gender, body mass index, dyslipidemia, diabetes mellitus and lifetime smoking status were not significantly associated with ΔPWV. ΔPWV was independently associated with baseline PWV (β = -1.17, 95% CI -1.65 - -0.70, p &lt; 0.001) and age (β = 0.144, 95% CI 0.09 - 0.20, p &lt; 0.001) adjusting for weight, waist circumference and hypertension, with insignificant interaction between baseline PWV and age (p = 0.431). Participants with increases in PWV after 5 years, compared to those without PWV increase, had lower PWV (8.52 ± 1.81 vs 11.10 ± 2.44) at baseline. Conclusions: Baseline PWV was associated with changes in AS over a 5-year period independent of age and clinical risk factors. The inverse relationship between baseline PWV and ΔPWV may suggest plateauing of PWV increases at higher baseline PWV levels. In addition, high baseline PWV may not predict worsening of AS later in life.

Abstract 13041: Effects of Parity on Arterial Stiffness Persists Into Old Age, Independent of Chronological Ageing

Introduction: Persistent effects of reproductive factors on vascular ageing, over chronological ageing, as examined through objective measurements of arterial stiffness, are rarely studied. Hypothesis: We hypothesized that the effects of parity and maternal age at first birth (AFB) on vascular ageing will persist over time independent of chronological ageing, in older Asian women. Methods: Among a community-based cohort of older Asian adults without cardiovascular disease, we prospectively studied demographics, parity, AFB, and cardiovascular risk factors, at baseline and 5-year examination timepoints. Arterial stiffness was measured through pulse wave velocity (PWV) using a cuff-based auscultatoric oscillometric pulse wave analysis machine. Results: 170 women (baseline mean age 60.76±13.75 years) were included. Parity ranged from 0 to 8 (mean parity 2±1.3). AFB ranged from 18 to 44 (mean age 28±4.4) years. By regression, univariate determinants of 5-year PWV were parity (β=0.491, p=&lt;.001), αFB (β=-0.107, p=.011), baseline age (β=3.884, p=&lt;.001), body mass index (βμΙ) (β=0.147, p=.006), waist circumference (β=0.076, p=&lt;.001), diabetes (β=1.681, p=&lt;.004), hypertension (β=2.383, p=&lt;.001), dyslipidemia (β=2.220, p=&lt;.001), 5-year age (β=3.886, p=&lt;.001),waist circumference (β=0.085, p=&lt;.001), diabetes (β=1.723, p=.001), hypertension (β=2.485, p=&lt;.001). Based on multivariate regression, parity (β=0.345, 95% CI 0.105, 0.586, p=.005), but not AFB, was independently associated with 5-year PWV, independent of age. Conclusions: Parity and AFB correlated with PWV, a marker of arterial stiffness, in old age in Asian women. Accounting for chronological ageing and clinical factors across 5 years, parity exerted a persistent independent effect on arterial stiffness in older women. Other biological factors surrounding parity in these women apart from traditional cardiovascular risk factors may explain these observations.

Role of Circulating Tumor DNA As a Prognostic Biomarker in Patients with Diffuse Large B-Cell Lymphoma

Introduction: Nearly 50-60% of the patients withDiffuse large B-cell lymphoma (DLBCL) can be cured by front line chemoimmunotherapy. Current risk stratification modalities include cell-of-origin (germinal center (GCB) or non-GCB (activated B-cell [ABC])) subtyping, use of the revised International Prognostic Index (R-IPI), Ki-67 proliferation index assessment, and cytogenetic aberration detection. However, a novel approach for molecular residual disease (MRD) detection and treatment monitoring is needed to improve patient outcomes. Methods: A personalized and tumor-informed multiplex PCR assay (Signatera™ bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA in a prospective clinical cohort of patients with DLBCL. Serial ctDNA testing was performed at various time points collected at the treating physician's discretion, including pretreatment (baseline), during first-line therapy, during and post-salvage therapy, at the end of treatment, and during surveillance, up to the last clinical follow-up. ctDNA clearance was defined as change in ctDNA status (positive to negative) from the pre-treatment time point to the subsequent time point. Event-free survival (EFS) was defined as the time elapsed since the initial ctDNA clearance or PET imaging, for those without ctDNA clearance, during which the patient did not experience progression, death or treatment with salvage therapy. EFS was censored at the last date of followup if the patient was alive and without an event. Overall survival (OS) was defined as the elapsed time after primary treatment until death from any cause. Univariate and multivariable models were analyzed using Cox proportional models. Results: In this retrospective evaluation of commercial ctDNA testing in patients with stage I-IV DLBCL, a total of 50 patients (I:3, II:12, III: 4, and IV: 29;median age: 59 years) were analyzed. Patients were followed up for a median of 12.68 months (inter quartile range: 7.9-17.7 months). Of the 50 patients, 41 had pre-treatment (baseline) time points available and ctDNA was detected in 95% (39/41) of patients. Since the majority of the patients had stage IV disease, median ctDNA detection levels were observed to be high (overall median: 534 MTM/ml, range: 0-5957 MTM/ml; I median: 9.6 MTM/mL [range: 0.2-2822 MTM/mL], II median: 53 MTM/mL [range: 0.8-862 MTM/mL], III median: 368 [range: 2-940 MTM/mL], IV median: 1011 MTM/mL [range: 74-5958 MTM/mL]). Clearance of ctDNA at any point during first-line therapy was associated with improved outcomes (EFS, HR: 8.3, 95% CI: 2.56-27.0, p&amp;lt;0.0001 and OS, HR: 15.2, 95% CI: 1.53-149, p=0.0021), compared to patients who remained ctDNA-positive. Furthermore, 48% (13/27) of patients were found to clear their ctDNA upon the completion of the first cycle of treatment. On comparing baseline ctDNA levels with other clinicopathological risk factors, high ctDNA levels were observed to be strongly correlated with higher R-IPI scores (0-2 vs. 3-5; p=0.0008) and higher stage (I-II vs. III-IV; p=0.0007). Additionally, multivariate analysis determined that ctDNA clearance significantly outperformed all other clinicopathologic risk factors associated with EFS (HR: 48.8, 95% CI:1.2-2005, p=0.04). Finally, ctDNA clearance predicted complete response (CR)/no evidence of disease (NED) on average 95 days (range: 0-14.7 months) ahead of PET imaging or biopsy. Conclusions: In this study utilizing a real-world cohort of patients with stage I-IV DLBCL, ctDNA clearance during first-line therapy was prognostic for EFS and OS and preceded clinical response. ctDNA testing in patients with DLBCL may enable personalized surveillance, intervention, and/or trial options, ultimately improving patient outcomes.