Individual Time Points Research Articles

Carotid Intervention Improves Cognitive Function in Patients With Severe Atherosclerotic Carotid Disease.

Carotid revascularization procedures are effective in stroke prevention in appropriately selected patients. We sought to understand the effects of the carotid intervention on cognitive function in a well-defined cohort of prospectively recruited patients. A total of 170 consecutive patients undergoing carotid intervention for severe carotid stenosis were recruited. Patients received neuropsychometric testing preintervention, and at 1, 6, and 12 months postoperative. Patients were screened with the Mini-Mental State Examination. Rey Auditory Verbal Learning test (RAVLT) test was the primary outcome measure and multiple cognitive tests were used to evaluate executive function. Paired t test and McNemar test were performed to compare age-adjusted and education-adjusted postoperative scores at the individual time point with the preoperative scores. Our patients had a high prevalence of cardiovascular risks and 51.2% of whom were symptomatic. The usages of statin and antiplatelet were high (88.8% and 69.4%, respectively). A total of 140 patients had 1 or more postoperative neuropsychometric tests in addition to their preoperative tests were included. The average RAVLT preoperative score was lower ( z =-0.79, SD=1.3, confidence interval: -1 to -0.53) than the age-adjusted norm. We observed a significant improvement in RAVLT memory scores at 1 and 6 months postoperative compared with preoperative. We also observed significant improvement in multiple executive functions measures up to 12 months postoperative. The improvement on patients with preoperative stroke symptoms was less consistent. This prospective study showed that carotid intervention improved memory and executive function in patients with the severe carotid occlusive disease. It highlights the cognitive benefit of the carotid intervention in appropriately selected patients.

HTX-011 in Combination with Multimodal Analgesic Regimen Minimized Severe Pain and Opioid Use after Total Knee Arthroplasty in an Open-Label Study.

Total knee arthroplasty (TKA) can be associated with significant postoperative pain despite multimodal analgesic (MMA) protocols, and most patients require the use of opioids postoperatively. HTX-011 is a dual-acting local anesthetic containing bupivacaine and low-dose meloxicam in an extended-release polymer. In a prior randomized controlled trial (RCT), HTX-011 reduced pain and opioid use through 72 hours after TKA compared with bupivacaine hydrochloride. This open-label study (NCT03974932) evaluated the efficacy and safety of HTX-011 combined with an MMA regimen in patients undergoing TKA under spinal anesthesia. All patients received intraoperative HTX-011 (400 mg bupivacaine/12 mg meloxicam) in combination with an MMA regimen consisting of preoperative acetaminophen, celecoxib, and pregabalin and postoperative acetaminophen and celecoxib until discharge. Opioid rescue was allowed upon patient request for additional pain control. Pain scores, opioid consumption, discharge readiness, and adverse events were recorded. Fifty-one patients were treated. Compared with the prior RCT, HTX-011 with this MMA regimen further lowered pain scores and reduced opioid use. Mean patient-reported pain scores remained in the mild range, and 82% of patients or more did not experience severe pain at any individual time point through 72 hours after surgery. Mean total opioid consumption was low over 72 hours: 24.8 morphine milligram equivalents (1-2 tablets of oxycodone 10 mg/day). Approximately 60% of patients were ready for discharge by 12 hours, and 39% were discharged without an opioid prescription and did not call back for pain management. The treatment regimen was well tolerated, and no added risk was observed with the addition of MMA. HTX-011 with an MMA regimen reduced postoperative pain and opioid use following TKA.

An Evaluation of Anomaly Detection and Diagnosis in Multivariate Time Series.

Several techniques for multivariate time series anomaly detection have been proposed recently, but a systematic comparison on a common set of datasets and metrics is lacking. This article presents a systematic and comprehensive evaluation of unsupervised and semisupervised deep-learning-based methods for anomaly detection and diagnosis on multivariate time series data from cyberphysical systems. Unlike previous works, we vary the model and post-processing of model errors, i.e., the scoring functions independently of each other, through a grid of ten models and four scoring functions, comparing these variants to state-of-the-art methods. In time-series anomaly detection, detecting anomalous events is more important than detecting individual anomalous time points. Through experiments, we find that the existing evaluation metrics either do not take events into account or cannot distinguish between a good detector and trivial detectors, such as a random or an all-positive detector. We propose a new metric to overcome these drawbacks, namely, the composite F-score (Fc1), for evaluating time-series anomaly detection. Our study highlights that dynamic scoring functions work much better than static ones for multivariate time series anomaly detection, and the choice of scoring functions often matters more than the choice of the underlying model. We also find that a simple, channel-wise model-the univariate fully connected auto-encoder, with the dynamic Gaussian scoring function emerges as a winning candidate for both anomaly detection and diagnosis, beating state-of-the-art algorithms.

Longitudinal variation in SARS-CoV-2 antibody levels and emergence of viral variants: a serological analysis

BackgroundSerological assays are being used to monitor antibody responses in individuals who had SARS-CoV-2 infection and those who received a COVID-19 vaccine. We aimed to determine whether such assays can predict neutralising antibody titres as antibody levels wane and viral variants emerge.MethodsWe measured antibody levels in serum samples from a cohort of 112 participants with SARS-CoV-2 infection using ten high-throughput serological tests and functional neutralisation assays. Serum samples were taken at baseline and at up to four subsequent visits. We assessed the effects of time and spike protein sequence variation on the performance and predictive value of the various assays. We did correlation analyses for individual timepoints using non-parametric Spearman correlation, and differences between timepoints were determined by use of a two-tailed Wilcoxon matched-pairs signed rank test.FindingsNeutralising antibody titres decreased over the first few months post-infection but stabilised thereafter, at about 30% of the level observed shortly after infection. Serological assays commonly used to measure antibodies against SARS-CoV-2 displayed a range of sensitivities that declined to varying extents over time. Quantitative measurements generated by serological assays based on the spike protein were better at predicting neutralising antibody titres than those based on nucleocapsid, but performance was variable, and manufacturer positivity thresholds were not able to predict the presence or absence of detectable neutralising activity. Although we observed some deterioration in correlation between serological measurements and functional neutralisation activity, some assays maintained an ability to predict neutralising titres, even against variants of concern.InterpretationThe ability of high-throughput serological assays to predict neutralising antibody titres is likely to be crucial for evaluation of immunity at the population scale. These data can facilitate the selection of the most suitable assays as surrogates of functional neutralising activity and suggest that such measurements might be useful in clinical practice.FundingUS National Institutes of Health and National Health Service Research Scotland BioResource.

Immune disease risk variants regulate gene expression dynamics during CD4+ T cell activation

During activation, T cells undergo extensive gene expression changes that shape the properties of cells to exert their effector function. Understanding the regulation of this process could help explain how genetic variants predispose to immune diseases. Here, we mapped genetic effects on gene expression (expression quantitative trait loci (eQTLs)) using single-cell transcriptomics. We profiled 655,349 CD4+ T cells, capturing transcriptional states of unstimulated cells and three time points of cell activation in 119 healthy individuals. This identified 38 cell clusters, including transient clusters that were only present at individual time points of activation. We found 6,407 genes whose expression was correlated with genetic variation, of which 2,265 (35%) were dynamically regulated during activation. Furthermore, 127 genes were regulated by variants associated with immune-mediated diseases, with significant enrichment for dynamic effects. Our results emphasize the importance of studying context-specific gene expression regulation and provide insights into the mechanisms underlying genetic susceptibility to immune-mediated diseases.

Young Healthy Men and Women Have Similar Arterial Stiffness at Rest and Post‐Acute Inflammation

The cardioprotective effects of estrogen on arterial function and inflammation are well‐documented; however, it is unclear whether arterial stiffness and compliance vary between healthy premenopausal women and age‐matched men following an acute inflammation. The objective of the current study was to evaluate central and local arterial stiffness and compliance at rest and in response to an acute inflammatory stimulus, specifically, when estrogen levels are thought to be similar between young healthy women and men. It was hypothesized that sustained effects of estrogen throughout the lower‐hormone phase of a natural menstrual or oral contraceptive pill cycle would induce lower central and local stiffness and higher compliance in women as compared to men at rest and in response to an acute inflammatory stimulus. Concentrations of interleukin‐6 (IL‐6) and assessments of central and local arterial stiffness and compliance were obtained from 29 young healthy adults (21±3 y; female, n=15) at baseline (BL), and 24‐ (24H) and 48‐hours (48H) following administration of a seasonal influenza vaccine. To capture the lower‐hormone phases of female participants, women were assessed within the early follicular phase if naturally menstruating or the placebo pill phase if using oral contraceptives. Central stiffness was assessed via carotid‐to‐femoral pulse wave velocity (cfPWV) and local stiffness was measured using ultrasonography at the carotid artery to obtain β‐stiffness, elastic modulus (Ep) and arterial compliance (AC). IL‐6 concentrations were expressed as change‐values from BL and were compared between sexes and timepoints (24H‐BL vs. 48H‐BL). Indices of central and local stiffness and AC were compared between sexes and individual timepoints (BL vs. 24H vs. 48H). Men and women exhibited similar changes in concentrations of IL‐6 (effect of sex: P=0.60), with significant elevations at 24H‐BL as compared to 48H‐BL (effect of time: P=0.0002), indicating that the influenza vaccine successfully induced an acute inflammatory response in both groups. However, there were no effects of sex or time on cfPWV, β‐stiffness or Ep (P>0.05 for all). While men displayed greater AC as compared to women at BL (1.09±0.25 vs. 0.88±0.17 mm2/kPa, P=0.01), there were no sex‐differences at 24H and 48H (P=0.10 and 0.70, respectfully), suggesting that the women were able to compensate for their lower resting AC values when exposed to an acute inflammatory stimulus. In conclusion, when estrogen levels are similar between young healthy women and men, there are no sex‐differences in central or local arterial stiffness at rest nor in response to an acute inflammatory stimulus.

Comparative Analysis of RNA-Extraction Approaches and Associated Influences on RT-qPCR of the SARS-CoV-2 RNA in a University Residence Hall and Quarantine Location.

Wastewater-based epidemiology (WBE) provides an early warning and trend analysis approach for determining the presence of COVID-19 in a community and complements clinical testing in assessing the population level, even as viral loads fluctuate. Here, we evaluate combinations of two wastewater concentration methods (i.e., ultrafiltration and composite supernatant–solid), four pre-RNA extraction modifications, and three nucleic acid extraction kits using two different wastewater sampling locations. These consisted of a quarantine facility containing clinically confirmed COVID-19-positive inhabitants and a university residence hall. Of the combinations examined, composite supernatant–solid with pre-RNA extraction consisting of water concentration and RNA/DNA shield performed the best in terms of speed and sensitivity. Further, of the three nucleic acid extraction kits examined, the most variability was associated with the Qiagen kit. Focusing on the quarantine facility, viral concentrations measured in wastewater were generally significantly related to positive clinical cases, with the relationship dependent on method, modification, kit, target, and normalization, although results were variable-dependent on individual time points (Kendall’s Tau-b (τ) = 0.17 to 0.6) or cumulatively (Kendall’s Tau-b (τ) = −0.048 to 1). These observations can support laboratories establishing protocols to perform wastewater surveillance and monitoring efforts for COVID-19.

Longitudinal Analysis of Amplitude-Integrated Electroencephalography for Outcome Prediction in Hypoxic-Ischemic Encephalopathy

To investigate the prognostic accuracy of longitudinal analysis of amplitude-integrated electroencephalography (aEEG) background activity to predict long-term neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy (HIE) receiving therapeutic hypothermia. This single-center observational study included 149 neonates for derivation and 55 neonates for validation with moderate-severe HIE and of gestational age ≥35weeks at a tertiary neonatal intensive care unit. Single-channel aEEG background pattern, sleep-wake cycling, and seizure activity were monitored over 84hours during therapeutic hypothermia and rewarming, then scored for each 6-hour interval. Neurodevelopmental outcome was assessed using the Bayley Scales of Infant Development, Second Edition. Favorable outcome was defined as having both a Mental Development Index (MDI) score and Psychomotor Development Index (PDI) score ≥70, and adverse outcome was defined as either an MDI or a PDI <70 or death. Regression modeling for longitudinal analysis of repeatedly measured data was applied, and area under the receiver operating characteristic curve (AUC) was calculated. Longitudinal aEEG background analysis combined with sleep-wake cycling score had excellent predictive value (AUC, 0.90; 95% CI, 0.85-0.95), better than single aEEG scores at any individual time point. The model performed well in the independent validation cohort (AUC, 0.87; 95% CI, 0.62-1.00). The reclassification rate of this model compared with the conventional analysis of aEEG background at 48hours was 18% (24 patients); 14% (18 patients) were reclassified correctly. Our results were used to develop a user-friendly online outcome prediction tool. Longitudinal analysis of aEEG background activity and sleep-wake cycling is a valuable and accurate prognostic tool.

Dexamethasone Does Not Provide Additional Clinical Analgesia Effect to Local Wound Infiltration: A Comprehensive Systematic Review and Meta-Analysis.

Objective: Although the use of dexamethasone as an adjunct agent is associated with alleviating pain and prolonging analgesic duration in local wound infiltration (LWI), efficacy and safety of dexamethasone infiltration have not been fully explored. The study sought to quantify the pooled effects of dexamethasone infiltration on postoperative pain, analgesic consumption, and side effects through a review of randomized controlled trials (RCTs). Approach: RCTs comparing dexamethasone + LWI with LWI alone were retrieved from seven electronic databases. Co-primary outcomes were rest pain scores and cumulative morphine equivalent consumption within 24 h postoperatively. The study followed PRISMA, AMSTAR, and the Cochrane Collaboration. Results: Eight trials comprising 609 patients were included in the final analysis. Results indicated that dexamethasone infiltration effects were only statistical but not clinically significant at individual time points of rest pain and patient satisfaction scores. Notably, the effect of dexamethasone infiltration therapy on other pain-related parameters, including cumulative morphine consumption (mean difference, -9.05 mg; 95% CI: -22.47 to 4.37), was not significantly different compared with the control group. Analysis showed no significant differences in safety indicators between the two groups. The overall quality of evidence was high to very low. Innovation: Although statistically significant effects of dexamethasone infiltration were observed for some outcomes of postoperative wound pain, the overall benefits were below the expected minimal clinically important difference. Conclusions: In summary, the current evidence does not support routine clinical use of dexamethasone in LWI. However, further studies should explore the clinical value of preemptive analgesia and safety of a combination of dexamethasone with ropivacaine for LWI.

Efficacy of Liposomal Bupivacaine for Sternotomy Pain After Cardiac Surgery: A Retrospective Analysis.

Multimodal analgesia is a cornerstone of postoperative pain management. Different formulations of local anesthetics are available. Data to support these treatment options are limited. To determine the efficacy of liposomal bupivacaine compared with bupivacaine or ropivacaine in patients undergoing sternotomy for coronary artery bypass graft (CABG) and/or valve surgery. Single-center, retrospective, observational study at a community teaching hospital. Patients included were 18 years of age or older undergoing CABG and/or valve surgery via median sternotomy and received either liposomal bupivacaine or an active comparator. The primary outcome was opioid utilization in morphine milligram equivalent (MME) from 0 to 72 hours. A total of 376 patients were included, 223 in the liposomal bupivacaine arm and 153 in the active comparator arm. There was no difference in the MME use from 0 to 72 hours among patients in the liposomal bupivacaine group compared with the comparator group (114.2 mg [75.55] vs 107.6 mg [68.4], P = 0.38). After Bonferroni correction, there was no difference in pain scores at individual time points. At 24- and 48-hour post-op, pain scores were higher with liposomal bupivacaine at 4.4 (2.7) vs 3.5 (2.8) (P = 0.01) and 3.1 (2.9) vs 2.4 (2.6) (P = 0.02). Based on these findings and previous studies, liposomal bupivacaine should not be routinely used for CABG and/or valve surgery through a median sternotomy given lack of superiority. This helps inform surgical practice to the role of anesthetics as part of the multimodal analgesia regimen.

Outcomes of Distal Femoral Osteotomy for Valgus Malalignment: A Systematic Review and Meta-analysis of Closing Wedge Versus Opening Wedge Techniques

Background: Valgus knee deformity increases the risk for lateral articular chondral damage, contributing to earlier onset and accelerated progression of osteoarthritis. Distal femoral osteotomy (DFO) unloads the lateral joint compartment and can be performed using closing wedge (CW) or opening wedge (OW) techniques. Purpose: To perform a systematic review and meta-analysis for patients with valgus knee deformity undergoing DFO to determine differences in patient-reported outcome measures (PROMs), complications, and survival rates, comparing CW versus OW DFO. Study Design: Systematic review, Level of evidence, 4. Methods: A literature review was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines utilizing PubMed, Cochrane Database, Ovid/MEDLINE, and Scopus. Inclusion criteria consisted of studies reporting outcomes in patients undergoing CW or OW DFO for the treatment of valgus knee deformities with symptomatic lateral compartment pathology with a minimum 2-year follow-up. PROMs and complications were analyzed using random-effects modeling to identify differences in outcomes as a function of surgical technique. Long-term survival data, defined as conversion to total knee arthroplasty, were analyzed using a multiple metaregression model as a function of individual study follow-up time points and surgical technique. Results: In total, we included 23 retrospective studies (n = 619 knees), of which 10 studies (n = 271 knees) reported outcomes after CW DFO and 13 studies (n = 348 knees) reported on OW DFO outcomes. Good to excellent clinical outcomes were reported in PROMs when compared with preoperative values with both techniques, while no significant differences between techniques were appreciated on functional Knee Society Scores and Tegner scores. No significant differences were appreciated in the incidence of complications reported in patients undergoing CW (20%) versus OW (33%) DFO (P = .432). Pain requiring hardware removal was the most commonly reported complication in both groups. The survival rate for CW DFO was 81.5% (mean follow-up, 8.8 ± 4.3 years) compared with 90.5% for OW DFO (mean follow-up, 4.5 ± 1.5 years). Multiple metaregression demonstrated that patient follow-up (P < .001) was significantly associated with knee survival, while surgical technique (P = .810) was not a predictor of clinical failure. Conclusions: Both CW and OW DFO techniques were associated with good to excellent clinical outcomes with no significant differences in PROMs based on technique. Pain requiring hardware removal was the most common complication in both techniques, while long-term survivability was found to be a function of follow-up and not surgical technique. Technique selection should be based on shared patient-physician decision making with an emphasis on surgeon preference and technique familiarity.

A new blood-based RNA signature (R9), for monitoring effectiveness of tuberculosis treatment in a South Indian longitudinal cohort

SummaryTuberculosis (TB) treatment involves a multidrug regimen for six months, and until two months, it is unclear if treatment is effective. This delay can lead to the evolution of drug resistance, lung damage, disease spread, and transmission. We identify a blood-based 9-gene signature using a computational pipeline that constructs and interrogates a genome-wide transcriptome-integrated protein-interaction network. The identified signature is able to determine treatment response at week 1–2 in three independent public datasets. Signature-based R9-score correctly detected treatment response at individual timepoints (204 samples) from a newly developed South Indian longitudinal cohort involving 32 patients with pulmonary TB. These results are consistent with conventional clinical metrics and can discriminate good from poor treatment responders at week 2 (AUC 0.93(0.81–1.00)). In this work, we provide proof of concept that the R9-score can determine treatment effectiveness, making a case for designing a larger clinical study.

Angle specific analysis of hamstrings and quadriceps isokinetic torque identify residual deficits in soccer players following ACL reconstruction: a longitudinal investigation

ABSTRACT Analysing the isokinetic curve is important following ACL reconstruction as there may be deficits in torque production at specific points throughout the range of motion. We examined isokinetic (60°.s-1) torque-angle characteristics in 27 male soccer players (24.5 ± 3.9 years) at 3 time-points (17 ± 5; 25 ± 6; and 34 ± 7 weeks post-surgery). Extracted data included knee flexor and extensor peak torque, conventional hamstrings: quadriceps (H/Q) ratio, and angle-specific torque using Statistical Parametric Mapping (SPM). There were significant involved limb increases in extension peak torque at each assessment (p<0.001); however, asymmetry favouring the un-involved limb was observed (p<0.01). Flexion peak torque was greater on the un-involved limb at assessments 1 and 2 only (p<0.05). The angle of peak torque was not significantly different at individual time-points or within-limbs across the 3 assessments. SPM revealed involved limb angle-specific reductions in extension torque across the full range of motion at time-points 1 and 2 (p<0.001) but only in angles [51-80°] at assessment 3 (p<0.05). Between limb H/Q angle differences [33-45°] were shown at assessments 2 and 3. The ratio ranged from 1.60-0.74 depending on the angle tested. Angle-specific moment curves are useful for monitoring patterns of strength development during rehabilitation.

Evaluation of the Efficacy of a Smoking Cessation Intervention for Cervical Cancer Survivors and Women With High-Grade Cervical Dysplasia: Protocol for a Randomized Controlled Trial.

BackgroundThe prevalence of smoking among cervical cancer survivors is strikingly high, yet no smoking cessation interventions to date have specifically targeted this population. This paper describes the study design, methods, and data analysis plans for a randomized clinical trial designed to evaluate the efficacy of a theoretically and empirically based Motivation And Problem Solving (MAPS) approach for promoting and facilitating smoking cessation among cervical cancer survivors. MAPS is a comprehensive, dynamic, and holistic intervention that incorporates empirically supported cognitive behavioral and social cognitive theory–based treatment strategies within an overarching motivational framework. MAPS is designed to be appropriate for all smokers regardless of their motivation to change and views motivation as dynamically fluctuating from moment to moment throughout the behavior change process.ObjectiveThis 2-group randomized controlled trial compares the efficacy of standard treatment to MAPS in facilitating smoking cessation among women with a history of high-grade cervical dysplasia or cervical cancer.MethodsParticipants (N=202) are current smokers with a history of high-grade cervical dysplasia or cervical cancer recruited nationally and randomly assigned to one of two treatment conditions: (1) standard treatment (ST) or (2) MAPS. ST consists of repeated letters referring participants to their state’s tobacco cessation quitline, standard self-help materials, and free nicotine replacement therapy when ready to quit. MAPS has all ST components along with 6 proactive telephone counseling sessions delivered over 12 months. The primary outcome is abstinence from tobacco at 18 months. Secondary outcomes include abstinence over time across all assessment points, abstinence at other individual assessment time points, quit attempts, cigarettes per day, and use of state quitlines. Hypothesized treatment mechanisms and cost-effectiveness will also be evaluated.ResultsThis study was approved by the institutional review boards at the University of Texas MD Anderson Cancer Center, the University of Oklahoma Health Sciences Center, and Moffitt Cancer Center. Participant enrollment concluded at Moffitt Cancer Center in January 2020, and follow-up data collection was completed in July 2021. Data analysis is ongoing.ConclusionsThis study will yield crucial information regarding the efficacy and cost-effectiveness of a MAPS approach for smoking cessation tailored to the specific needs of women with a history of high-grade cervical dysplasia or cervical cancer. Findings indicating that MAPS has substantially greater efficacy than existing evidence-based tobacco cessation treatments would have tremendous public health significance.Trial RegistrationClinicalTrials.gov NCT02157610; https://clinicaltrials.gov/ct2/show/NCT02157610International Registered Report Identifier (IRRID)DERR1-10.2196/34502

Evaluation of the impact of transgenic maize BT799 on growth, development and reproductive function of Sprague-Dawley rats in three generations

BT799 was Bacillus thuringiensis-genetic modified (GM) maize, and Sprague-Dawley (SD) rats were treated with different diet formulations containing BT799 maize grain (33% and 66%) or its non-transgenic Zhengdan 958 (ZD958, 33% and 66%). The feeding lasted for 10 (P)/14 (F1 and F2) weeks. The reproductive capacity and pathological responses were detected in each generation of rats fed with BT799 and ZD958. During the growth and development of parental rats, each group showed the same trend in body weight gain and food intake, with a few fluctuations at individual time points. No statistically significant difference was observed in reproductive data (copulation index, fertility index, and live birth rate) of rats fed with transgenic maize compared with non-transgenic maize. We observed some apparent changes in reproductive data (sperm numbers and motility) and pathological responses (organ relative weights, hematological parameters, serum chemistry parameters, and sex hormone levels) among rats fed with BT799 maize grain. However, these differences were within the laboratory's historical normal range of control SD rats and not maize grain dose-dependent. These changes were not considered to be adverse or toxic. No significant difference in macroscopic or histological adverse effects was observed between rats consuming transgenic BT799 diet and non-transgenic diet. In conclusion, the long-term intake of BT799 maize was as safe as the corresponding non-transgenic maize for three-generation SD rats.

1039. Rapid Restoration of Bile Acid Compositions After Treatment with RBX2660 for Recurrent Clostridioides difficile Infection—Results from the PUNCH CD3 Phase 3 Trial

BackgroundMicrobiota-based treatments are increasingly evaluated as a strategy to reduce recurrence of Clostridioides difficile infection (rCDI), and their proposed mechanisms include restoration of the microbiota and microbiota-mediated functions, including bile acid metabolism. RBX2660—a broad-consortium investigational live biotherapeutic—has been evaluated in >600 participants in 6 clinical trials, with consistent reduction of rCDI recurrence. Here we report that fecal bile acid compositions were significantly restored in treatment-responsive participants in PUNCH CD3—a Phase 3 randomized, double-blinded, placebo-controlled trial of RBX2660.MethodsPUNCH CD3 participants received a single dose of RBX2660 or placebo between 24 to 72 hours after completing rCDI antibiotic treatment. Clinical response was the absence of CDI recurrence at eight weeks after treatment. Participants voluntarily submitted stool samples prior to blinded study treatment (baseline), 1, 4 and 8 weeks, 3 and 6 months after receiving study treatment. A liquid chromatography tandem mass spectrometry method was developed to extract and quantify 33 bile acids from all participant fecal samples received up to the 8-week time point. Mean bile acid compositions were fit to a Dirichlet multinomial distribution and compared across time points and between RBX2660- and placebo-treated participants.ResultsClinically, RBX2660 demonstrated superior efficacy versus placebo (70.4% versus 58.1%). RBX2660-treated clinical responders’ bile acid compositions shifted significantly from before to after treatment. Specifically, primary bile acids predominated before treatment, whereas secondary bile acids predominated after treatment (Figure 1A). These changes trended higher among RBX2660 responders compared to placebo responders. Importantly, median levels of lithocholic acid (LCA) and deoxycholic acid (DCA) showed large, significant increases after treatment (Figure 1B). A. Bile acid compositions before (BL) and up to 8 weeks after RBX2660 treatment among treatment responders. Compositions are shown as the fraction of total bile acids classified as primary or secondary conjugated or deconjugated bile acids. B. Concentrations of lithocholic acid (LCA) and deoxycholic acid (DCA) among RBX2660 treatment responders, shown with individual samples and time point group median with interquartile ranges.ConclusionAmong PUNCH CD3 clinical responders, RBX2660 significantly restored bile acids from less to more healthy compositions. These clinically correlated bile acid shifts are highly consistent with results from a prior trial of RBX2660.Disclosures Romeo Papazyan, PhD, Ferring Research Institute (Employee) Bryan Fuchs, PhD, Ferring Pharmaceuticals (Employee) Ken Blount, PhD, Rebiotix Inc., a Ferring Company (Employee)

Participant followup rate can bias structural imaging measures in longitudinal studies

Longitudinal MRI analysis is essential to accurately describe neuroanatomical changes over time. Loss of participants to followup (dropout) in longitudinal studies is inevitable and can lead to great difficulty in interpretation of statistical results if dropout is correlated with a study outcome or exposure. Beyond this, technical aspects of longitudinal MRI analysis require specialised processing pipelines to improve reliability while avoiding bias towards individual timepoints. In this article we test whether there is an additional problem that must be considered in longitudinal imaging studies, namely whether dropout has an impact on the function of FreeSurfer, a popular software pipeline used to estimate important structural brain metrics.We find that the number of acquisitions available per individual can impact the estimation of cortical thickness and brain volume using the FreeSurfer longitudinal pipeline, and can induce group differences in brain metrics. The effect on trajectories of brain metrics is smaller than the effect on brain metrics.

Mycobacterium leprae Infection in Ticks and Tick-Derived Cells.

Leprosy is a zoonosis in the southern United States involving humans and wild armadillos. The majority of patients presenting with zoonotic strains of Mycobacterium leprae note extensive outdoor activity but only rarely report any history of direct contact with wild armadillos. Whether M. leprae is transmitted to new vertebrate hosts through the environment independently or with the aid of other organisms, e.g., arthropod vectors, is a fundamental question in leprosy transmission. The objectives of this study were to assess the potential for ticks to transmit M. leprae and to test if viable M. leprae can be maintained in tick-derived cells. To evaluate tick transmission, nymphal Amblyomma maculatum ticks were injected with isolated M. leprae. Infection and transmission were assessed by qPCR. Ticks infected as nymphs harbored M. leprae through vertical transmission events (nymph to adult and adult to progeny); and, horizontal transmission of M. leprae to a vertebrate host was observed. Mycobacterium leprae DNA was detected in multiple tick life cycle stages. Likewise, freshly isolated M. leprae (Thai-53) was used to infect a tick-derived cell line, and enumeration and bacterial viability were assessed at individual time points for up to 49 days. Evaluations of the viability of long-term cultured M. leprae (Thai-53 and Br4923) were also assessed in a mouse model. Tick-derived cells were able to maintain viable M. leprae over the 49-day course of infection and M. leprae remained infectious within tick cells for at least 300 days. The results of this study suggest that ticks themselves might serve as a vector for the transmission of M. leprae and that tick cells are suitable for maintenance of viable M. leprae for an extended period of time.

P-188: Carfilzomib, lenalidomide, and dexamethasone followed by salvage autologous stem cell transplant with or without maintenance for relapsed or refractory multiple myeloma

<h3>Background</h3> Salvage high dose chemotherapy followed by autologous stem cell transplantation (HDCT/ASCT) is a treatment option in patients with relapsed and/or refractory multiple myeloma (RRMM) after prolonged remissions with frontline transplantation. The role of salvage HDCT/ASCT following re-induction treatment with state-of-the-art triplet regimens has not been defined. The present analysis therefore aims to investigate the efficacy and toxicity of salvage HDCT/ASCT after carfilzomib (CFZ)/lenalidomide (LEN)/dexamethasone (KRd) re-induction with or without post-transplant maintenance treatment. <h3>Methods</h3> We retrospectively assessed efficacy and toxicity in 44 patients receiving salvage HDCT/ASCT following re-induction with carfilzomib/lenalidomide/dexamethasone (KRd). All patients had received frontline HDCT/ASCT with median time to progression (TTP1) of 2.9 (1.2-13.5) years, allowing for paired comparison of frontline and salvage HDCT/ASCT. Median age at time of re-induction was 58.9 years (range 40-71) and n=38/44 patients (86%) had only 1 prior line of therapy (range 1-3). Sixteen of 44 patients (36%) were LEN pretreated and all patients were CFZ-naive. Maintenance treatment was administered in n=22/44 patients (50%) after frontline HDCT/ASCT and in n=17/44 patients (39%) after salvage HDCT/ASCT. <h3>Results</h3> After a median of 3 re-induction cycles (range 3-9), 25/44 patients (57%) attained at least very good partial response (VGPR), which increased to 34/44 (77%) at best response after salvage HDCT/ASCT. Patients achieving deep remissions during frontline treatment were more likely to re-achieve deep remissions in the salvage setting at each individual timepoint: after (re-)induction (≥VGPR: odds ratio [OR] 6.22; 95% confidence interval [95%-CI] 1.33-29.01; p=0.02), after (salvage) HDCT/ASCT (≥nCR: OR 5.71; 95%-CI 1.44-22.62; p=0.01) and at best response (≥nCR: OR 4.50; 95%-CI 1.12-18.13; p=0.03). After a median follow up of 23.9 months, median progression-free survival (PFS) was 23.3 months from salvage HDCT/ASCT. Patients at least in VGPR at the time of salvage HDCT/ASCT and those receiving maintenance treatment post salvage HDCT/ASCT had significantly superior PFS (hazard ratio [HR] 0.19, p=0.001 and HR 0.20, p=0.009). In patients achieving at least an equal depth of response before salvage HDCT/ASCT as before frontline HDCT/ASCT, PFS after salvage HDCT/ASCT was comparable to the frontline situation (p=0.3). <h3>Conclusion</h3> Despite higher comorbidity scores at salvage HDCT/ASCT, no significant increase in relevant toxicity parameters including infections and intensive care unit admission was observed and no transplant-related mortality occurred after salvage HDCT/ASCT. This is the first report of state-of-the-art triplet re-induction and salvage HDCT/ASCT for RRMM after frontline transplantation. Deep remissions achieved with KRd translate into prolonged PFS following salvage HDCT/ASCT and are enhanced by maintenance treatment.

Using multiband multi-echo imaging to improve the robustness and repeatability of co-activation pattern analysis for dynamic functional connectivity

Emerging evidence has shown that functional connectivity is dynamic and changes over the course of a scan. Furthermore, connectivity patterns can arise from short periods of co-activation on the order of seconds. Recently, a dynamic co-activation patterns (CAPs) analysis was introduced to examine the co-activation of voxels resulting from individual timepoints. The goal of this study was to apply CAPs analysis on resting state fMRI data collected using an advanced multiband multi-echo (MBME) sequence, in comparison with a multiband (MB) sequence with a single echo. Data from 28 healthy control subjects were examined. Subjects underwent two resting state scans, one MBME and one MB, and 19 subjects returned within two weeks for a repeat scan session. Data preprocessing included advanced denoising namely multi-echo independent component analysis (ME-ICA) for the MBME data and an ICA-based strategy for Automatic Removal of Motion Artifacts (ICA-AROMA) for the MB data. The CAPs analysis was conducted using the newly published TbCAPs toolbox. CAPs were extracted using both seed-based and seed-free approaches. Timepoints were clustered using k-means clustering. The following metrics were compared between MBME and MB datasets: mean activation in each CAP, the spatial correlation and mean squared error (MSE) between each timepoint and the centroid CAP it was assigned to, within-dataset variance across timepoints assigned to the same CAP, and the between-session spatial correlation of each CAP. Co-activation was heightened for MBME data for the majority of CAPs. Spatial correlation and MSE between each timepoint and its assigned centroid CAP were higher and lower respectively for MBME data. The within-dataset variance was also lower for MBME data. Finally, the between-session spatial correlation was higher for MBME data. Overall, our findings suggest that the advanced MBME sequence is a promising avenue for the measurement of dynamic co-activation patterns by increasing the robustness and reproducibility of the CAPs.