Subsequent Time Points Research Articles

Clodronate detection and effects on markers of bone resorption are prolonged following a single administration to horses.

Clodronate is a potent antiresorptive agent labelled for use in horses over 4 years of age, for the treatment of navicular syndrome. Concerns regarding the extra-label use of clodronate in equine athletes, such as racehorses, have been raised as inhibition of osteoclast activity by clodronate has been postulated to interfere with normal bone healing, which is imperative to the repair of microfractures. The paucity of data describing the long-term pharmacokinetics of clodronate and effects on biomarkers of bone resorption necessitates further study. (1) To determine clodronate concentrations in blood and urine over a 6-month period in horses undergoing treadmill exercise and (2) to assess the effects of clodronate on protein biomarkers of bone remodelling in this same group of horses. Randomised controlled experimental study. Seven exercised Thoroughbred horses received a single im administration of 1.8mg/kg clodronate and four horses received an equivalent volume of saline. Blood and urine samples were collected prior to, during and for 182 days post drug administration for drug concentration determination using liquid chromatography-tandem mass spectrometry, and determination of protein biomarker (CTX-1 and TRAcP5B) concentrations. Clodronate was detectable in blood for 14-175 days and for up to 175 days in urine. For some horses, concentrations were nondetectable at one time point but detectable at a subsequent time point. The terminal serum half-life ranged from 1.80 to 283.9 days. CTX-1 concentrations were significantly higher, relative to baseline, in both treated and control groups while concentrations of TRAcP5B were significantly lower in the treated group. Relatively small number of horses studied. Based on assessment of protein biomarkers, clodronate appears to influence osteoclasts at label doses. Furthermore, results of this study support racing regulations that preclude horses administered bisphosphonates for medical reasons, from racing for a prolonged period of time.

Efficacy of bone graft materials in extraction sockets for implants in maxillary posteriors- An original research

Introduction: The aim of this study was to compare the effects of hydroxyapatite (HA), deproteinized bovine bone (DPB), human-derived allogenic bone (HALG), and calcium sulfate (CAP) graft biomaterials placed post extraction for future implant therapy in maxillary 1st molar area­ placed by guided tissue regeneration. Material and methods: We conducted a retrospective study. Thirty-two subjects were divided into four groups: DPB, HALG, HA, and CAP. Alveolar bone width at specific implant sites were assessed using sagittal and cross‐sectional CBCT images prior grafting and at three subsequent time points. Results: The vertical and horizontal dimensions did not significantly differ between bone grafts at any time point. In addition, there were no statistically significant differences in graft remodeling rates between grafts Conclusion: Deproteinized bovine bone bone blocks showed equivalent volumetric shrinkage rates as man-derived allogenic bone (HALG), and calcium sulfate (CAP) graft biomaterials when used for treating circumscribed bone defects. Therefore, it is not necessary to over‐contour the ridge in the maxillary molars.

Home Oral Care Domiciliary Protocol for the Management of Dental Erosion in Rugby Players: A Randomized Clinical Trial.

People performing regular physical activity are at high risk of dental erosion especially in cases of high sport drinks intake. Biomimetic hydroxyapatite-based oral hygiene products, like toothpastes and mouthwashes, have been investigated in recent years for their remineralizing activity on the teeth. The aim of the present study was to evaluate the efficacy of two different oral hygiene protocols, respectively consisting of the combination of a hydroxyapatite-based toothpaste plus mouthwash (Trial group) or toothpaste alone (Control Group). At baseline (T0), as well as at 15 days (T1), 30 days (T2) and 90 days (T3), the following clinical indexes were assessed: Basic Erosive Wear Examination (BEWE), Schiff Air Index (SAI), Visual Analogue Scale (VAS), Plaque Index (PI) and Bleeding Index (BI). In general, for all the indexes assessed, a progressive intragroup reduction was noticed from the baseline to the subsequent timepoints, with no intergroup differences. Accordingly, the use of the hydroxyapatite-based toothpaste, alone or in combination with the mouthwash containing hydroxyapatite as well, is an effective method for the domiciliary management of dental erosion in physically active individuals like rugby players.

Longitudinal Testing of Leptospira Antibodies in Horses Located near a Leptospirosis Outbreak in Alpacas.

Simple SummaryThe objective of this study was to look at antibodies in repeated blood samples from horses kept near, or on, a farm where Leptospirosis was diagnosed in a herd of alpacas, resulting in kidney disease and abortion in the alpacas. Blood samples from horses in New Zealand have previously shown approximately 25% have antibodies to Leptospira, although there are few reports of clinical disease. Seven of twelve horses had positive antibody results during the current study, and two horses had high concentrations of antibodies in their blood together with evidence of leptospires in their urine. These results suggest the two horses could have been actively infected with Leptospira, and potentially be at risk of transmitting the disease to humans and other animals on the property. It was not able to be determined if there was a direct association between the positive horses in this study and the outbreak in alpacas. Potentially, there could have been a common exposure for both horses and alpacas, or one group may have infected the other. The potential risk of horses shedding leptospires that could infect humans, or other species, should not be overlooked in New Zealand.The objectives of this study were to determine if horses located near an outbreak of leptospirosis in alpacas had Leptospira titres indicative of a previous or current infection and, if so, to determine the magnitude in change of titres over time. Further, the objective was to determine if horses with high titre results were shedding Leptospira in their urine. Blood samples were collected from twelve horses located on or next to the farm with the outbreak in alpacas, on day zero and at four subsequent time points (two, four, six and nine weeks). The microscopic agglutination test was used to test sera for five serovars endemic in New Zealand: Ballum, Copenhageni, Hardjo, Pomona and Tarassovi. A reciprocal MAT titre cut-off of ≥1:100 was used to determine positive horses. Seven out of twelve horses (58%) were positive to at least one serovar during one of the time points. Two horses recorded titres of ≥1600, one for both Pomona and Copenhageni and the other for Hardjo, and these two horses were both PCR positive for Leptospira in their urine samples. For five out of seven horses, the titres either remained the same or changed by one dilution across the sampling time points. The study confirmed endemic exposure to five endemic Leptospira serovars in New Zealand in a group of horses located near a confirmed leptospirosis outbreak in alpacas.

Examining the effects of quality talk discussions on 4th- and 5th-grade students’ high-level comprehension of text

Given the rapid pace of technological change, access to unlimited information, and diverse forms of complex text, the importance and demand for enhanced literacy skills is greater than ever. Accordingly, researchers have begun developing integrated, multifaceted interventions that dynamically support enhanced literacy competence. The purpose of this year-long quasi-experimental study was to compare the effects of a multifaceted, rigorous discussion intensive literacy intervention called Quality Talk (QT) to a comparison intervention. Fourth- and fifth-grade students (QT treatment, n = 133; comparison, n = 155) from two public schools participated in a district-wide literacy program with half also participating in QT within their language arts class. Spanning baseline and two subsequent time points, findings revealed that, on average, students evidenced statistically significant increases on one form of basic-level comprehension performance over time with no statistically significant difference between QT and comparison classrooms. Given that treatment and comparison classrooms engaged in a district-wide literacy initiative with supplemental daily literacy instruction, these results are not altogether unexpected. However, despite the enhanced literacy instruction across all classes, from Time 2 to Time 3, growth in QT students’ high-level comprehension, as measured via written argumentation essay performance, was statistically significantly greater than their comparison peers’ growth. This study informs the future of education research and practice regarding the feasibility and utility of relevant and rigorous multifaceted literacy interventions focused upon small-group discussion.

Longitudinal associations among peer pressure, moral disengagement and cyberbullying perpetration in adolescents

Peer pressure is considered one of the top reasons adolescents participate in various risk behaviors, but the mechanism of peer pressure and adolescents' cyberbullying perpetration is unclear. The current study examined the longitudinal associations between peer pressure and adolescents' cyberbullying perpetration across three years, taking into account moral disengagement as a potential mediator and family socioeconomic status and gender as moderators of the associations. A sample of 2407 Chinese adolescents (Mage at baseline = 12.75 years) completed measurements of peer pressure, cyberbullying perpetration, moral disengagement, and family socioeconomic status at 3-time points with 1-year intervals. The results showed that peer pressure directly predicted subsequent cyberbullying perpetration. Cyberbullying perpetration at time 1 significantly predicted peer pressure and moral disengagement at time 2 only. Moral disengagement played a mediating role between peer pressure and cyberbullying perpetration across time. The relation between peer pressure and moral disengagement was more robust for adolescents with low family socioeconomic status than those with high family socioeconomic status. Compared to boys, girls who experienced high peer pressure at previous time points were more likely to have high peer pressure at subsequent time points. These findings provide a new scientific basis for the intervention of adolescents' cyberbullying perpetration.

Long-Term Longitudinal Analysis of Neutralizing Antibody Response to Three Vaccine Doses in a Real-Life Setting of Previously SARS-CoV-2 Infected Healthcare Workers: A Model for Predicting Response to Further Vaccine Doses.

We report the time course of neutralizing antibody (NtAb) response, as measured by authentic virus neutralization, in healthcare workers (HCWs) with a mild or asymptomatic SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection diagnosed at the onset of the pandemic, with no reinfection throughout and after a three-dose schedule of the BNT162b2 mRNA vaccine with an overall follow-up of almost two years since infection. Forty-eight HCWs (median age 47 years, all immunocompetent) were evaluated: 29 (60.4%) were asymptomatic. NtAb serum was titrated at eight subsequent time points: T1 and T2 were after natural infection, T3 on the day of the first vaccine dose, T4 on the day of the second dose, T5, T6, and T7 were between the second and third dose, and T8 followed the third dose by a median of 34 days. NtAb titers at all postvaccination time points (T4 to T8) were significantly higher than all those at prevaccination time points (T1 to T3). The highest NtAb increase was following the first vaccine dose while subsequent doses did not further boost NtAb titers. However, the third vaccine dose appeared to revive waning immunity. NtAb levels were positively correlated at most time points suggesting an important role for immunogenetics.

Changes in Onchocerciasis Ov16 IgG4 Rapid Diagnostic Test Results Over One-Month Follow-up: Lessons for Reading Timeframe and Decision-Making.

ABSTRACT.The SD Bioline® IgG4 rapid diagnostic test (RDT) detects IgG4 antibodies induced by the Onchocerca volvulus-specific antigen Ov16. We evaluated the stability of the RDT results over 1 month, at different time points after completion of each assay, using eluted dried blood spots collected in central Cameroon. Agreement coefficients regarding positivity between 30 minutes and 24 hours, 1, 2, 3, and 4 weeks were, 96.4%, 93.4%, 93.3%, 93.2%, and 93.2%, respectively. Between 30 minutes and 24 hours, 3.6% of the 15,444 tests showed inconsistent results with 81.2% of these tests changing from negative to positive, increasing O. volvulus antibody prevalence from 23.9% to 26.2% (P < 0.0001). This change from negative to positive outcome was confirmed at the subsequent timepoints. Depending on the desired accuracy of prevalence estimates, reading time may have to be redefined more strictly.

Reciprocal associations between intuitive eating and positive body image components: A multi-wave, cross-lagged study

Intuitive eating is an adaptive style of eating that has gained substantial research attention. However, possible predictors and outcomes of intuitive eating are poorly understood, as prospective study designs addressing this are missing. Since theoretical research indicates that positive body image might enhance – and be enhanced by – intuitive eating, the present study tested for possible reciprocal associations between three components of positive body image (body appreciation, functionality appreciation, and body image flexibility) and intuitive eating. Adult women (n = 3039) were invited to complete study measures at baseline (T1), four (T2), and eight month (T3) follow-up. Cross-lagged panel analyses were computed to test for possible reciprocal relationships between intuitive eating and positive body image components. Results showed that intuitive eating and both body appreciation and functionality appreciation were reciprocally related. Higher intuitive eating levels at T1 predicted greater increases in these two positive body image components at T2 (and vice versa). Similarly, higher intuitive eating levels at T2 predicted greater increases in these two positive body image components at T3 (and vice versa). Only unidirectional effects were observed between intuitive eating and body image flexibility: higher intuitive eating levels predicted greater increases in body image flexibility at the subsequent time-point. Findings suggest that intuitive eating and certain components of positive body image might serve to enhance each other over time. Intervention strategies designed to cultivate intuitive eating may also result in concomitant improvements in certain indices of positive body image.

Preterm sepsis is associated with acute lung injury as measured by pulmonary severity score.

Sepsis related acute lung injury (ALI) is established in adults but has not been investigated in premature infants. Herein, we used pulmonary severity score (PSS) trajectories and C-reactive protein (CRP) to examine the relation between sepsis and ALI in premature infants. This retrospective study identified 211 sepsis and 123 rule out (RO) events in 443 infants born <31 weeks and <1500 grams. The PSS was calculated prior to, at the time of, and up to 1 week after each event. Initial and peak CRP values were collected for each event. PSS significantly increased at 0 h from baseline (-72h) and remained increased at all subsequent time points (all p < 0.002) in sepsis events. Mean PSS in sepsis episodes were also higher compared to RO events at +24 h, +48 h, +72 h, and +168 h (all p < 0.004). A positive correlation was noted between peak CRP values in sepsis events and PSS at 0 h, +24 h, +48 h, and +72 h. The temporal PSS trends and correlation with CRP levels observed in sepsis but not in RO events supports the hypothesis that neonatal sepsis is associated with ALI and contributes to the accumulating evidence that neonatal ARDS occurs. To evaluate pulmonary severity scores and c-reactive protein values over time to establish an association between preterm neonatal sepsis and acute lung injury (ALI). Though sepsis is well established as the most common indirect cause of ALI leading to acute respiratory distress syndrome (ARDS) in adults and pediatrics, this phenomenon remains undefined in neonates. This study validates the proposal by the Neonatal ARDS Project that ARDS also occurs in neonates by demonstrating acute and sustained changes in markers of pulmonary injury temporally related to a diagnosis of neonatal sepsis in preterm infants.

Moderate-intensity aerobic exercise vs desmopressin in adolescent males with mild hemophilia A: a randomized trial

AbstractPersons with mild hemophilia A (HA) may use intranasal desmopressin prior to sports participation. Desmopressin is expensive and can cause vomiting, headache, palpitation, and occasionally seizures. Our group has previously documented a 2.3-fold increase in factor VIII activity (FVIII:C) in adolescents with mild HA after moderate-intensity aerobic exercise. Herein, we report principal findings of a randomized trial of intranasal desmopressin vs a standardized, moderate-intensity aerobic exercise regimen in adolescents with mild HA. Our primary objective was to compare the change in FVIII:C associated with these 2 interventions. We also examined changes in hemostatic parameters arising from their sequential administration. The study was conducted simultaneously at the Hospital for Sick Children, Canada, and Nationwide Children's Hospital, USA. Thirty-two eligible male adolescents (mean age ± standard deviation: 16.1 ± 2.6 years) with mild HA (mean baseline FVIII:C: 27.9% ± 18.4%) were randomized to 1 of 4 study arms (desmopressin followed by exercise, desmopressin alone, exercise followed by desmopressin, and exercise alone). Blood work was obtained at baseline and at 3 subsequent time-points. Participants randomized to exercise cycled on an ergometer for approximately 12 minutes, with the final 3 minutes at 85% of their predicted maximum heart rate. Standard weight-based dosing of desmopressin was used. Mean immediate increase in FVIII:C was 1.7-fold with exercise compared with 1.9-fold with desmopressin (noninferiority, P = .04). Exercise-induced improvement in hemostatic parameters including FVIII:C was brief compared with more sustained improvements seen with desmopressin. More than 60% of participants randomized to receive both exercise and desmopressin achieved normal (>50%) FVIII:C, 75 and 135 minutes into the study protocol.

Comparative Outcomes of Standard Perioperative Eye Drops, Intravitreal Triamcinolone Acetonide-Moxifloxacin, and Intracameral Dexamethasone-Moxifloxacin-Ketorolac in Cataract Surgery.

Background Since the advent of cataract surgery, topical eye drops have been the mainstay of postoperative prophylaxis and treatment. Due to factors such as high expenses and poor patient compliance, there has been a growing interest and acceptance of “dropless” or “less drops” alternatives. The purpose of this study is to compare the effectiveness of intravitreal triamcinolone acetonide-moxifloxacin and intracameral dexamethasone-moxifloxacin-ketorolac to a standard eye drop regimen in controlling postoperative inflammation, corneal edema, and intraocular pressure (IOP) among cataract patients. Methods A retrospective longitudinal comparative study among 619 consecutive eyes receiving either a standard eye drop regimen, intraoperative triamcinolone acetonide-moxifloxacin, or dexamethasone-moxifloxacin-ketorolac was performed between October 2016 and December 2020. Primary endpoints at postoperative day one (POD1), week one (POW1), and month one (POM1) included corneal edema, anterior chamber inflammation (ACI), and IOP. Results Throughout the postoperative time points, there were no significant differences in corneal edema between intravitreal triamcinolone acetonide-moxifloxacin versus the standard eye drop therapy (OR [95% CI]: 1.09 [0.82, 1.45], P=0.54) and intracameral dexamethasone-moxifloxacin-ketorolac versus the standard eye drop treatment (OR [95% CI]: 1.22 [0.89, 1.67], P=0.22). The postoperative ACI severity was lower in the dexamethasone-moxifloxacin-ketorolac group than in the triamcinolone acetonide-moxifloxacin group by 35% on postoperative day 1 (P=0.01). The differences at subsequent postoperative time points were not statistically significant (P=0.27 and P=1.00 for POW1 and POM1, respectively). IOP at POM1 follow-up visit was statistically significantly higher for the triamcinolone acetonide-moxifloxacin group (mean (±SD): 15.64 (4.26)) than the dexamethasone-moxifloxacin-ketorolac (mean (±SD): 14.16 (4.02)) (P < 0.01). There was no statistical difference in rates of CME (P=0.16), and there were no cases of endophthalmitis. Conclusions Intravitreal triamcinolone acetonide-moxifloxacin and intracameral dexamethasone-moxifloxacin-ketorolac demonstrate similar levels of efficacy to a standard eye drop regimen after cataract surgery. This study reinforces them as viable alternatives to traditional postoperative drops.

Corneal densitometry after allogeneic small-incision intrastromal lenticule implantation for hyperopia correction

PurposeTo evaluate corneal densitometry after allogeneic corneal small-incision intrastromal lenticule implantation (SILI) for hyperopia.MethodsA retrospective study. Thirty-one hyperopic eyes of 24 patients who underwent SILI were enrolled in this study. Examinations took place preoperatively and 1 week, 1 month, 3 months, and 6 months postoperatively. Corneal densitometry (CD) from different concentric radial zones (0–2, 2–6, and 6–10 mm annulus) and layers (anterior, central, and posterior) were obtained using Scheimpflug imaging. The association between CD changes and the uncorrected distance visual acuity (UDVA), spherical equivalent (SE), central corneal thickness (CCT) and K value were examined.ResultsNo serious intraoperative complications occurred during SILI. The mean total CD increased postoperatively compared to preoperatively (P < 0.01). However, no significant differences were found among the four subsequent follow-up time points (P > 0.05). At 6 months postoperatively, the CD values showed an increase of 2.71 ± 2.52, 2.23 ± 2.25, and 1.87 ± 2.46 at the 0–2, 2–6, and 6–10 mm annuli, respectively (all at P < 0.01). The anterior 120 μm displayed the highest densitometry before and after surgery (all at P < 0.01). No significant increase was found within the posterior 60 μm of the cornea (P > 0.05). No correlation was found between the CD and relevant parameters(all at P > 0.05).ConclusionsSILI resulted in an increase in CD within the surgically altered area, however such change has no significant correlation with visual outcomes.

Maternal posttraumatic stress predicts Mother-Child Symptom Flare-Ups over Time.

Although concurrent associations between parent and child posttraumatic stress symptoms (PTSS) have been well-documented, few longitudinal studies have examined bidirectional influences by modeling the effects of both parent and child PTSS simultaneously over time. The current study examines patterns of PTSS in children and their mothers beginning in preschool and continuing through elementary school age (ages 4-9 years) in a large, heterogeneous sample (N = 331 mother-child dyads). Mothers reported on their own and their child's posttraumatic stress symptoms. A random intercept cross-lagged panel model (RI-CLPM) was used to examine associations between symptoms across six time points. Results indicated that maternal and child symptoms were associated with each other at concurrent time points and tended to fluctuate in a synchronized manner relative to their overall mean symptom levels. Longitudinal cross-lagged paths were significant from mother to child, but non-significant from child to mother, suggesting that mothers' symptom fluctuation at one time point predicted significant fluctuation in children's symptoms at the subsequent time point. The concurrent co-variation of maternal and child symptoms and the predictive nature of maternal symptom flare-ups have important implications for both maternal and child mental health interventions and underscore the importance of attending to mothers' symptomatology early in treatment.

Change in Score for Neonatal Acute Physiology-II Measurements for Prediction of Mortality in Severely Septic Preterm Neonates.

To study the discriminatory ability of the change (delta) in the Score for Neonatal Acute Physiology-II (SNAP-II) for 14-d mortality in preterm neonates with severe sepsis. Consecutively born neonates of < 34-wk gestation during the 1-y study period in a tertiary care neonatal unit were included. SNAP-II was recorded at the onset of severe sepsis (T0) and serially at 24 (T1), 48 (T2), and 72 (T3) h. Delta scores (Δ SNAP-II) were derived from the difference between the SNAP-II at baseline and each one of the subsequent time points. Seventy-one preterm neonates were enrolled. Baseline characteristics were similar in survivors (n = 53) and nonsurvivors (n = 18). Median SNAP-II at all the four time points were significantly higher in nonsurvivors (p < 0.001). Delta SNAP-II (T0-T2) was significantly different between nonsurvivors and survivors (mean difference: -14.7; 95% CI: -29, -0.9; p = 0.02), while the difference was not significant between T0-T1 and T0-T3. Initial SNAP-II had a significantly better discriminating ability than Δ SNAP-II at various time points (AUC, 95% CI: 0.59, 0.41-0.75 for T0-T1; 0.70, 0.50-0.87 for T0-T2; and 0.64; 0.38-0.89 for T0-T3). Delta SNAP-II does not have a better discriminatory ability for mortality by 14 d in preterm neonates with severe sepsis.

Abstract 3294: In vivo delivery of a novel CD3-targeted lentiviral vector generates CD19 CAR-T cells in two different humanized mouse models and results in complete B cell depletion

Abstract Introduction: Chimeric antigen receptor therapies (CAR-T) are highly effective against hematologic malignancies but require a lymphodepleting chemotherapy regimen and are faced with many challenges including manufacturing time, scalability, and cost of production due to the need for ex vivo culturing of cells and complex chain of custody requirements. In vivo delivery of self-inactivating lentiviral vectors (LV) encoding for CAR-T transgenes represents a promising strategy to improve the time to treatment, scalability, and cost of current CAR-T therapies. Methods: Lentiviral vectors encoding a CD19 CAR with a synthetic driver element were manufactured in a chemically defined cell substrate that incorporates a modified envelope designed to target and activate CD3+ T cells. Two different humanized mouse models were utilized. In a PBMC humanized mouse model, NSG MHC Class I/II knock-out mice (DKO) were injected with 1E7 human PBMC and followed one day later with 2E7 TU of LV encoding for CD19 CAR. In parallel, CD34+ humanized NSG SGM3 mice were also administered 2E7 TU LV encoding CD19 CAR. Flow cytometry of peripheral blood samples was evaluated at various time points for the presence of CAR+ cells and CD20+ B cells. Additionally, tissue samples were examined by histopathology and PCR for vector copy numbers. Results: The NSG SGM3 humanized CD34+ mouse model exhibited efficient chimerism of human CD45+ hematopoietic cells (&amp;gt;50% of live cells in peripheral blood). Apart from CD15+ neutrophils, all major human immune cell components were well represented in peripheral blood including CD14+ monocytes, CD20+ B cells, and CD3+ lymphocytes. At study initiation, the T cell compartment in the SGM3 mice exhibited skewing towards CD4+ T cells. Injection of CD19 CAR-LV resulted in a significant reduction of CD20+ B cells as early as 5 days post-injection. CD3+ CAR+ cells were detected in peripheral blood by day 5 with evidence of CAR+ cell expansion at subsequent time points. Loss of CD20+ B cells was stable throughout the observation period with some mice exhibiting a complete elimination of B cells. Similarly, the PBMC humanized NSG DKO mice injected with CD19 CAR-LV also showed evidence of CAR+ cells in peripheral blood. Conclusions: CD3-directed self-inactivating lentiviral vectors can efficiently deliver an integrating CAR gene into T lymphocytes following in vivo administration. These in vivo generated CD19 CAR T cells expand systemically and effectively eliminate pre-existing B cells. These data show that the targeting of CD3 through in vivo delivery can produce functional CAR T cells and represents an innovative therapeutic opportunity to potentially overcome current manufacturing times, scalability, and cost challenges facing cell therapies. Citation Format: Frederic Vigant, Ani Kundu, Dongming Zhang, Wei Zhang, Ewa Jaruga-Killeen, Michelle Andraza, Gregory Schreiber, Alissa Kerner, Junyi Zhang, John Henkelman, Renata Soares, Ramya Yarlagadda, Gregory I. Frost, Sid P. Kerkar. In vivo delivery of a novel CD3-targeted lentiviral vector generates CD19 CAR-T cells in two different humanized mouse models and results in complete B cell depletion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3294.

Abstract 5748: Longitudinal evaluation of ctDNA molecular response for monitoring clinical benefit and investigating treatment related impacts in metastatic colorectal cancer patients treated with different drug regimens

Abstract Introduction: The patient-centric liquid biopsy approach to detect changes in ctDNA provides an early indication of treatment response to therapies and is an emerging tool to aid clinicians in treatment decision making. We investigated this approach in the mCRC palliative treatment setting by exploring the potential clinical utility of the validated Guardant Health Molecular Response (MR) algorithm. Methods: Longitudinal plasma samples (70) were collected from 14 patients with mCRC and treated using chemotherapy alone or combined with one or more targeting agents. All patients were clinically stable or had clinical benefit over the course of plasma collection. 6 patients had radiological response by RECISTv1.1 and 10 had tumor RAS/RAF mutation status. Baseline and longitudinal plasma samples (27-276 days post treatment) were tested by GuardantOMNI® 500-gene liquid biopsy assay. Selection of qualifying alterations and generation of MR scores were pursued using the Guardant Health MR algorithm. Results: Thirteen patients were evaluable for MR by having somatic alterations at each timepoint that exceeded the molecule threshold required for reliable MR score calculation. Mean variant allele fraction (mVAF) of all plasma samples outside the 4-10 week on-treatment window trended in the same direction as the early on-treatment plasma samples when compared to baseline. Eleven patients experienced a consistent reduction in mVAF compared to baseline. One outlier showed a mVAF increase at the earliest on-treatment timepoint, followed by molecular clearance at all subsequent timepoints. GuardantOMNI® detected a frameshift APC alteration at the baseline of this patient, which may have limited the tumor response to the chemotherapy. The second outlier patient was originally diagnosed as RAS/RAF wild-type and treated with anti-EGFR and anti-PD-L1. MR scores for this patient across all timepoints reflected an increase in mVAF compared to baseline. Notably, GuardantOMNI® detected a low level KRAS alteration in the baseline plasma sample of this patient, indicating this patient’s disease had elements of KRAS alteration that were not detected by tissue-based testing. All 6 patients with RECIST 1.1 information had partial responses (PR) and 5 showed a decrease in the MR score. The one patient whose MR score did not align with radiographic assessment was the mis-genotyped KRAS mutation-positive patient, who is under further investigation. Conclusions: We demonstrate that ctDNA analysis of plasma samples taken at early timepoints (4-10 weeks) after treatment initiation are sufficient to support MR assessments and highlight the advantage of the patient-centric liquid biopsy approach over genetic testing of diagnostic tumor samples in detecting potential resistance mutations prior to therapy. Citation Format: Neil R. Smith, Jean-Christophe Pignon, Scott A. Shell, Arialle Yablonovitch, Juergen Scheuenpflug, Zheng Feng. Longitudinal evaluation of ctDNA molecular response for monitoring clinical benefit and investigating treatment related impacts in metastatic colorectal cancer patients treated with different drug regimens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5748.

Biweekly fluctuations of neuropsychiatric symptoms according to the Neuropsychiatric Inventory: Erratic symptoms or scores?

ObjectivesThis study investigates the stability of neuropsychiatric symptoms (NPS) assessed biweekly using the Neuropsychiatric Inventory (NPI) in a memory clinic population during a 6 week period.MethodsTwenty‐three spousal caregivers (mean [SD] age = 69.7 [8.8], 82.6% female) of 23 patients (43.5% had dementia) completed all assessments. The NPI was assessed four times during 6 weeks. We examined whether NPI domains were present during all four assessments, studied within‐person variation for each NPI domain, and calculated Spearman's correlations between subsequent time‐points. Furthermore, we associated repeated NPI assessments with repeated measures of caregiver burden to examine the clinical impact of changes in NPI scores over time.ResultsThe course of NPS was highly irregular according to the NPI, with only 35.8% of the NPI domains that were present at baseline persisted during all 6 weeks. We observed large within‐person variation in the presence of individual NPI domains (61.3%, range 37.5%–83.9%) and inconsistent correlations between NPI assessments (e.g., range r s = 0.20–0.57 for agitation, range r s = 0.29–0.59 for anxiety). Higher NPI total scores were related to higher caregiver burden (r s = 0.60, p < 0.001), but changes in NPI total scores were unrelated to changes in caregiver burden (r s = 0.16, p = 0.20).ConclusionsWe observed strong fluctuations in NPI scores within very short time windows raising the question whether this represents erratic symptoms and/or scores. Further studies are needed to investigate the origins of these fluctuations.

Abstract 5916: Tumor-informed patient-specific panel outperforms tumor-naïve and tumor-informed fixed panel for circulating tumor DNA (ctDNA)-based postoperative monitoring of non-small cell lung cancer (NSCLC)

Abstract Background: Patient-specific flexible gene panels designed based on whole-exome sequencing (WES) of resected tumor tissues is a promising strategy for ctDNA-based detection of molecular residual disease (MRD) in early-stage NSCLC. Flexible gene panels could potentially overcome the limitations of fixed panels by incorporating more unique genomic regions that might be absent in fixed panels; however, no study has reported a head-to-head comparison of these two approaches in postoperative disease monitoring. In this study, we investigated the clinical utility of a novel Patient-specific pROgnostic and Potential tHErapeutic marker Tracking (PROPHET) tumor-informed ctDNA assay. Using the same set of longitudinal blood samples, we further compared the performance of PROPHET assay with tumor-informed (TI) and tumor-naïve (TN) fixed panels for predicting MRD and prognosis in surgical NSCLC patients. Methods: Fifty-three patients with stage I-III resected NSCLC from the MEDAL study (NCT03634826) with adequate samples and median follow-up of 647 days were analyzed. Matched surgical tumor tissue and blood samples collected at various time points, including before surgery (baseline), 3-days (B) and 1-month (C) postoperative time points before any adjuvant therapy and subsequent follow-up time points (F) were analyzed. PROPHET assay involved four major steps: identify somatic mutations using WES, customized design of a patient-specific panel consisting of 50 single nucleotide variants, ultra-deep unique molecular-identifier-based next-generation sequencing (UMI-NGS) of serial blood samples using the patient-specific panel, and MRD risk prediction. Fixed panel assay of serial blood samples was performed using UMI-NGS with 168 gene panel spanning 273 kb of human genome. Results: At 1-month post-surgery, PROPHET assay accurately predicted MRD-positive cases among relapsed patients (50%, 13/26), whereas all disease-free patients were MRD-negative (100%, 21/21). Three-year prognostication with PROPHET assay at B+C yielded higher sensitivity (59% vs 26% vs 22%), negative predictive value (66% vs 51% vs 50%), and hazard ratio (7.15, 95%CI [3.2-15.9] vs 4.48 [1.9-10.9] vs 5.58 [2.1-14.7]) as compared with TI and TN fixed panel assays. Disease monitoring using PROPHET assay at B/C/F accurately predicted the MRD risk in 70% (21/30) of relapsed patients at a median lead time of 318 days (range: 20-751), whereas TI assay predicted 43% (13/30) at 282 days (range 20-716) and TN assay predicted 37% (11/30) at 282 days (range: 20-634). Conclusion: Patient-specific tumor-informed ctDNA-based postoperative monitoring enables risk stratification at early postoperative settings better than fixed panel, which paves an alternative strategy in the individualized management of surgical NSCLC patients. Citation Format: Kezhong Chen, Haifeng Shen, Shuailai Wu, Pengfei Zhu, Chenyang Wang, Analyn Lizaso, Guannan Kang, Yang Wang, Juan Lv, Shuai Fang, Wenjun Wu, Fujun Qiu, Yuan Sun, Qiang Lu, Heng Zhao, Shannon Chuai, Fan Yang, Zhihong Zhang. Tumor-informed patient-specific panel outperforms tumor-naïve and tumor-informed fixed panel for circulating tumor DNA (ctDNA)-based postoperative monitoring of non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5916.

Abstract LB515: Cardiovascular risk assessed by aptamer-based proteomics is increased in early breast cancer

Abstract Background: Cancer patients with a high risk for cardiovascular (CV) disease may be susceptible to cardiotoxic injury during cancer therapy. Accordingly, CV risk assessment may help in identifying candidates for preventive cardioprotective treatment. Since existing CV risk scores may lack the sensitivity and granularity to reflect the changes in CV risk that is associated with early cancer, we hypothesized that a CV risk score based on aptamer-based proteomics would permit discrimination of CV risk between patients with early breast cancer and age-, sex- and risk factor-matched healthy subjects. Moreover, we hypothesized that CV risk as assessed by aptamer-based proteomics first increases during and subsequently decreases after anthracycline-containing chemotherapy. Methods: We included 120 women with early breast cancer participating in the 2x2 factorial, randomized, placebo-controlled Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA) trial who were assigned to candesartan vs placebo and metoprolol vs placebo. Blood samples were obtained serially at: Visit 1 (ie, post-surgery but prior to epirubicin), following the first cycle of epirubicin (Visit 2), after the completion of epirubicin therapy (Visit 3), following adjuvant therapy (Visit 4), and 1-2 years after completion of adjuvant and blinded therapy (Visit 5). Age-, sex-, and risk factor-matched subjects (n = 500) from the Fenland study served as controls. We used highly multiplexed modified aptamer-based proteomics to measure ~5000 plasma proteins. A validated 27-protein CV risk model (CVD) that provides information on absolute risk of myocardial infarction, stroke, heart failure or mortality over a 4-year period was used as the dependent variable. Results: The CVD risk probability was significantly higher at Visit 1 than in the age-, sex- and risk-factor matched control group (p &amp;lt; 0.001). The CVD risk probability increased significantly from baseline to completion of epirubicin therapy (p &amp;lt; 0.001) and dropped below baseline levels for subsequent timepoints after the completion of epirubicin treatment. The mean CVD risk increased from 15.9% at Visit 2 to 24.6% at Visit 3, resulting in the percentage of subjects in the medium-high risk bin increasing from 9% at Visit 2 to 28% at Visit 3. The CVD risk distribution at the end of study was similar to the initial distribution at baseline and Visit 2. Conclusion: Using a novel CVD risk proteomics model, we observed that (1) The CVD risk of patients with early breast cancer is increased compared to age-, sex- and risk factor-matched individuals from the general population; (2) CVD risk increases during adjuvant epirubicin-containing chemotherapy, and (3) after completed adjuvant cancer therapy CVD risk returns to pre-chemotherapy level. Use of the CVD risk score may represent a novel tool to identify and monitor cancer patients who may benefit from preventive cardioprotective therapy. Citation Format: Torbjørn Omland, Jessica Chadwick, Ragnhild Røysland, Geeta Gulati, David Astling, Siri L. Heck, Victoria Vinje, Rachel Ostroff, Peter Ganz, Jürgen Geisler, Steve Williams. Cardiovascular risk assessed by aptamer-based proteomics is increased in early breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB515.