Study Time Points Research Articles

Efficacy and safety of pentoxifylline combination therapy in major depressive disorder: a randomized, double-blind, placebo-controlled clinical trial.

In this randomized, double-blind, placebo-controlled clinical trial, we assessed the efficacy and safety of pentoxifylline combination therapy with sertraline in treatment of major depressive disorder (MDD). A total of 56 patients with MDD were assigned into two parallel groups to receive sertraline (100 mg/day) plus placebo or sertraline (100 mg/day) plus pentoxifylline (400 mg three times daily) for six weeks. Patients were evaluated with the Hamilton rating scale for depression (HAM-D) at baseline and weeks 2, 4 and 6. The sertraline plus pentoxifylline group demonstrated greater improvement in HAM-D scores from baseline to all three study time points (P = 0.013, 0.007 and 0.016 for week 2, 4 and 6, respectively). Response to treatment rate was also significantly higher in the sertraline plus pentoxifylline group compared to the sertraline plus placebo group at week 4 [57.1 vs. 21.4%, P = 0.013] and the study endpoint [96.4 vs. 57.1%, P = 0.001]. However, the remission rate, time to remission and time to treatment response did not show any significant difference between trial groups. Our findings support the efficacy and safety of pentoxifylline combination therapy in patients with MDD.

Stakeholder Perspectives on Engaging With Cerebral Palsy Research Studies After Onset of COVID-19 in the United States

ObjectiveTo investigate the effect of the coronavirus disease 2019 (COVID-19) pandemic on perspectives toward participation in cerebral palsy (CP) research. DesignAn online survey with questions relating to the comfort levels of research participation was filled out by people who had CP or had a child with CP. SettingThe online survey was administered through Research Electronic Data Capture platform. ParticipantsA total of 233 (n=233) individuals with CP (42.5%; n=99) or with a child with CP (57.1%; n=133) consented and at least partially completed the online survey (n=210 complete; n=23 partially complete). All participants resided in the United States. InterventionsNot applicable. Main Outcome MeasuresReadiness to participate was analyzed in the context of the time point for research participation during COVID-19 and whether or not the study offered direct benefits to participants. ResultsParticipants were consistently willing to participate sooner in studies that offered direct benefit than in those that did not. Adults responding for themselves had sooner time points for studies without direct benefit compared with parents answering for a child (P=.030). Gross Motor Function Classification System level, but not age or CP type, affected the time point for studies without direct benefit (P=.017). Personal values influenced selected time point for studies without direct benefit (P=.007), whereas environmental factors affected the time point for studies with direct benefit (P=.002). Local COVID-19 incidence rates were not associated with time points for either research type; however, respondents expected precautions to be taken if they chose to participate. ConclusionsAs the pandemic evolves, researchers should consider the perspectives of potential participants as well as ethical and safety factors when reinitiating in-person CP research.

Cockroach-induced IL9, IL13, and IL31 expression and the development of allergic asthma in urban children

Cockroach-induced IL9, IL13, and IL31 expression and the development of allergic asthma in urban children

The Effect of Chronic Alcohol Intoxication on the Daily Rhythm of Some Micromorphometric Parameters of Rat Hepatocytes

The effect of chronic alcohol intoxication on the daily rhythm of micromorphometric parameters characterizing the morphological and functional state of the liver is studied on 80 male Wistar rats of 6 months age, divided into 2 equal groups. The first group served as control; rats of the second group (experiment) were kept under similar conditions but got as a drink a 15% ethanol solution ad libitum instead of water. After three weeks of the experiment, animals were euthanized consistently at four-time points during the day. The pathomorphological study of the liver was carried out, the daily dynamics of the nucleus and cell (by area and nuclear-cytoplasmic ratio (NCR)), ploidy of mononuclear hepatocytes, and the proportion of binuclear hepatocytes were measured. The reliability of circadian rhythm (CR) was determined by cosinor analysis. The study indicates complex changes in the organization of rhythmostasis in the experiment. The chrono-destructive effect of experimental alcohol intoxication on the CR of the cell and NCR, as well as the chronomodulating effect to the CR of the nucleus are established. The effect of ethanol on the CR of ploidy and the number of binuclear hepatocytes, as well as on the nature of their variation at the studied time points is established. An increase in the ploidy of hepatocytes and an in the number of binuclear cells is revealed, which indicates the beginning of the deployment of adaptive-compensatory reactions in the organ.

A101 OPTIMIZING MATERNAL AND NEONATAL OUTCOMES IN IBD: TIGHT CONTROL MANAGEMENT OF IBD DURING PREGNANCY – PILOT STUDY

Abstract Background Managing inflammatory bowel disease (IBD) during pregnancy is challenging as pregnancy-related symptoms may overlap with symptoms of active IBD. Fecal calprotectin (FCP) is an optimal non-invasive measure of assessing disease activity during pregnancy. However, regular FCP during pregnancy may be impractical due to collection techniques. Rather, a home point-of care rapid lateral assay FCP test such as IBDoc® and a self-reported clinical disease activity program (IBD Dashboard) may be beneficial in routine monitoring of IBD activity during pregnancy. Aims To assess whether tight control of objective IBD disease activity using a point-of-care FCP (IBDoc®) monitoring is concordant with self-reported clinical symptoms (IBD Dashboard) in pregnant women with IBD. Methods Pregnant patients, aged ≥18 years, with IBD (Crohn’s Disease (CD) or Ulcerative colitis (UC)), in the 1st trimester (<13 weeks) with a singleton pregnancy were identified and enrolled. Patients were required to have access to a smartphone and internet to use the IBDoc® and IBD Dashboard. Patients completed a IBDoc® FCP and IBD Dashboard assessment at three study time points, 1) screening/baseline in 1st trimester, 2) 2nd trimester (14 to 18 weeks), and 3) 3rd trimester (28 to 32 weeks). Clinical disease activity was assessed by the modified HBI (Harvey Bradshaw Index) for CD and partial Mayo Index (pMayo) for UC. Elevated FCP (≥250 µg/g), mHBI ≥5 or pMayo ≥2 triggered an intervention to investigate or optimize therapy if required. A 5-point Likert scale questionnaire assessed patient satisfaction and feasibility of the IBDoc® and IBD Dashboard. Median values with interquartile ranges (IQR) were calculated for all continuous variables using SPSS. Results 29 patients (17 CD, 12 UC) were included. Median mHBI and pMayo were 2.0 (IQR 2.0) and 0.5 (IQR 1.25) respectively. A total of 17.6% (3/17) of CD patients, and 25.0% (3/12) of UC patients had active clinical disease. Median IBDoc® FCP was 73 µg/g (IQR 343) in the CD group and 267 µg/g (IQR 677) in the UC group. At baseline, disease activity was categorized into four groups: 1) clinical remission (CR) and normal FCP (n=16, no treatment Δ, 100% stayed in CR); 2) clinical disease and elevated FCP (n=5, treatment Δ in all five patients, 80% stayed in CR, 20% had a clinical flare); 3) clinical remission and elevated FCP (n=5, treatment Δ in three patients, 100% stayed in CR); 4) clinical disease and normal FCP (n=1, no treatment Δ, 100% stayed in CR). Median IBDoc® and IBD Dashboard feasibility scores were 5.0 (IQR 1.0). Conclusions A combination of both clinical scores and objective disease markers may better predict disease relapse compared to either clinical scores or objective markers in isolation. A home point-of-care FCP test is feasible among pregnant patients with IBD. Funding Agencies None

A168 HEALTH-RELATED QUALITY OF LIFE IN WOMEN WITH INFLAMMATORY BOWEL DISEASE: FROM PRECONCEPTION TO POSTPARTUM

Abstract Background Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), impacts health-related quality of life (HRQoL). In pregnancy and postpartum, distinguishing IBD-specific symptoms is challenging. The extent to which pregnancy and disease activity affects HRQoL in IBD patients remains unknown. Aims To assess women with and without IBD at pre-, intra-, and postpartum timepoints, and examine the impact of pregnancy, IBD type, and disease activity on IBD-related HRQoL. Methods Preconception (PC) and pregnant women aged ≥18 years with and without IBD completed surveys at various timepoints from PC to 12 months postpartum (PP). The Short IBD Questionnaire (SIBDQ) is a validated survey that assesses HRQoL in IBD patients and covers bowel, emotional, systemic, and social domains; a higher score indicates a better HRQoL. Participants completed SIBDQ and modified Harvey Bradshaw Index (mHBI) for CD or partial Mayo score (pMayo) for UC. Clinically active disease was defined as mHBI ≥5 or pMayo ≥2; objectively active disease was defined as C-reactive protein (CRP) ≥8.0mg/L or fecal calprotectin (FC) ≥250mg/kg. Continuous variables were analyzed by the t-test whereas categorical variables were assessed by the chi-squared test, with p<0.05 suggestive of statistical significance. Results 61 patients with IBD (36 UC, 25 CD) and 12 healthy controls were included. In IBD patients, SIBDQ was positively associated with income during PC, but not once patients became pregnant. No association was found with education level. There were no significant differences in mean SIBDQ between study timepoints. SIBDQ was significantly lower in IBD patients with clinically active disease at all trimesters of pregnancy and all PP timepoints, but not at PC. SIBDQ was significantly lower in patients with high CRP during trimester 1 (T1), but not later in pregnancy. Generally, SIBDQ was lower in patients with higher FC; SIBDQ bowel scores were significantly lower in patients with high FC at T2, T3, and PP6. During PC, SIBDQ was significantly higher in UC patients than CD patients; this difference was lost in pregnancy. During PP, SIBDQ bowel and social scores were significantly lower in UC patients than CD patients at 6 months. Compared to healthy controls, IBD patients had significantly lower SIBDQ at PC, T1, and T2; they also had significantly lower SIBDQ bowel scores in early PP, which resolved by 12 months. In IBD patients, no association was found between PP SIBDQ scores and breastfeeding or delivery method. Conclusions Women with IBD experience worse HRQoL in early pregnancy, and worse bowel-related HRQoL postpartum. UC patients have better PC HRQoL but suffer worse postpartum bowel-related HRQoL than CD patients. Overall, SIBDQ correlates well with clinical and biochemical disease activity during pregnancy and postpartum. Funding Agencies Women and Children’s Health Research Institute (WCHRI), Centre of Excellence for Gastrointestinal Inflammation and Immunity Research (CEGIIR), University of Alberta Faculty of Medicine

Potential Antiviral Target for SARS-CoV-2: A Key Early Responsive Kinase during Viral Entry

Currently, there is no effective antiviral medication for coronavirus disease 2019 (COVID-19) and the knowledge on the potential therapeutic target is in great need. Guided by a time-course transmi...

Effect of a Low-Glycemic Load Diet Intervention on Maternal and Pregnancy Outcomes in Obese Pregnant Women.

The increased prevalence of obese, pregnant women who have a higher risk of glucose intolerance warrants the need for nutritional interventions to improve maternal glucose homeostasis. In this study, the effect of a low-glycemic load (GL) (n = 28) was compared to a high-GL (n = 34) dietary intervention during the second half of pregnancy in obese women (body mass index (BMI) > 30 or a body fat >35%). Anthropometric and metabolic parameters were assessed at baseline (20 week) and at 28 and 34 weeks gestation. For the primary outcome 3h-glucose-iAUC (3h-incremental area under the curve), mean between-group differences were non-significant at every study timepoint (p = 0.6, 0.3, and 0.8 at 20, 28, and 34 weeks, respectively) and also assessing the mean change over the study period (p = 0.6). Furthermore, there was no statistically significant difference between the two intervention groups for any of the other examined outcomes (p ≥ 0.07). In the pooled cohort, there was no significant effect of dietary GL on any metabolic or anthropometric outcome (p ≥ 0.2). A post hoc analysis comparing the study women to a cohort of overweight or obese pregnant women who received only routine care showed that the non-study women were more likely to gain excess weight (p = 0.046) and to deliver large-for-gestational-age (LGA) (p = 0.01) or macrosomic (p = 0.006) infants. Thus, a low-GL diet consumed during the last half of pregnancy did not improve pregnancy outcomes in obese women, but in comparison to non-study women, dietary counseling reduced the risk of adverse outcomes.

Physical Activity Improves Mental Health in Children and Adolescents Irrespective of the Diagnosis of Attention Deficit Hyperactivity Disorder (ADHD)-A Multi-Wave Analysis Using Data from the KiGGS Study.

Physical activity (PA) may have positive effects on mental health in children and adolescents. This post hoc study aimed to further investigate the relationship between different frequency levels of PA and general mental health as well as specific hyperactivity/inattention symptoms in children and adolescents. Methods: The analyses were based on data drawn from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) study, a regularly conducted large-scale, epidemiological investigation of somatic and mental health of children and adolescents in Germany. Parents were asked about their children’s attention deficit hyperactivity disorder (ADHD) records and answered questionnaires concerning any mental health problem behavior of the children and adolescents using the Strengths and Difficulties Questionnaire (SDQ). The overall problem score as well as the hyperactivity/inattention symptoms subscale (SDQ-H/I) were entered as outcomes in a regression model controlling for parental socio-economic status and participants’ sex, age, and body mass index (BMI). Cross-sectional analyses were conducted at three time points of the KiGGS study (baseline, wave 1, and wave 2) using general linear models (GLM). This was performed for different age groups (4–5, 6–9, 10–17 years). Results: Significant negative relationships were found between PA and general mental health problems. For the relationship between PA and SDQ-H/I, different patterns emerged at the three time points. There was no interaction between PA frequency levels and diagnosis of ADHD (ADHD vs. non-ADHD controls) regarding the SDQ total score. Conclusion: This study underlines the importance of a high frequency level of PA for a good mental health status among children and adolescents, irrespective of the diagnosis of ADHD.

Impact of COVID-19 Lockdown on Body Weight, Eating Habits, and Physical Activity of Jordanian Children and Adolescents.

The lockdown for the COVID-19 pandemic affects lifestyle patterns globally and impacts children and adolescents. This study aims to assess the effect of the lockdown on body weight, eating habits, and physical activity of Jordanian youth (children and adolescents). A cross-sectional study was conducted on a sample of 477 Jordanian children and adolescents aged 6-17 y. The study tool was a structured validated questionnaire. It comprised 4 parts, including a general description of the study purpose, sociodemographic and anthropometric data, physical activity data, and food intake pattern. Questions were reported before and during lockdown. Changes in outcomes over the 2 study time points were evaluated. After the lockdown period, the mean body weight and body mass index for age Z-scores (BAZ) showed a significant increase (P < 0.001) compared with before the lockdown period. More than 50% of the subjects reported that they spent more than 3 h in front of the screen during the lockdown. The percent of subjects who watched TV for more than 3h was increased. Moreover, physical inactivity was increased significantly during the lockdown. All food groups consumption was significantly increased during the lockdown compared to before the lockdown. COVID-19 lockdown period was characterized by an increase in the use of screen-based devices, lower physical activity, uncontrolled food intake, and weight gain.

Abstract PS8-39: Evidence for reproductive control of liver size with implications for risk of liver metastases in postpartum breast cancer patients

Abstract Women diagnosed with breast cancer within 10 years of a completed pregnancy are 2~3x more likely to develop liver metastases than never-pregnant (nulliparous) patients, even after controlling for prognostic variables (Goddard 2017). This finding suggests a unique biology in the postpartum liver, a putative pre-metastatic niche, which makes postpartum patients more susceptible to liver metastases. In rodent models, we previously reported increased liver size, hepatocyte proliferation, and anabolic metabolism during pregnancy and lactation. Within one week post-weaning, the rodent liver returned to its pre-pregnant size via a coordinated cell death and tissue remodeling process we call liver involution (Goddard 2017). We find that this process of involution supports overt liver metastasis using two different mammary tumor cell lines. In women, a liver-breast interaction during pregnancy and weaning, as occurs in rodents, has not been described. To investigate the human liver with pregnancy and weaning, we conducted a prospective, non-interventional clinical trial in healthy pregnant women. 47/77 women completed the pregnancy study visits and 17/47 completed post-wean visits. Participants underwent magnetic resonance imaging (MRI) of their livers, provided blood samples, and completed body metric analyses at each study time point. The majority of women (~70%) had increased liver size and evidence of increased liver function at third trimester compared to first trimester, with liver size returning to pre-pregnancy levels with weaning. In this cohort, the increase in liver size exceeded levels expected if the metabolic demands associated with increased body weight during pregnancy were the primary mediator. Intriguingly, primary bile acid and bile acid synthetic enzyme concentrations correlated with liver size increase during pregnancy. Women whose liver growth did not follow the most often observed pattern of increase with pregnancy and decrease postpartum had unchanged bile acid levels, were more likely to have gestational hypertension, and did not have expected increases in liver glucose production during pregnancy. Combined, this study provides the first description of human liver size increase with pregnancy, and return to pre-pregnant baseline size after weaning, with evidence that women who do not experience these liver changes may be metabolically distinct. Furthermore, these data are consistent with the hypothesis that reproductive alterations to the liver, in particular weaning-induced involution, contributes to the increased risk for liver metastases in women diagnosed with breast cancer postpartum. Reference: Goddard, E. T., Hill, R. C., Nemkov, T., D'Alessandro, A., Hansen, K. C., Maller, O., Mongoue-Tchokote, S., Mori, M., Partridge, A. H., Borges, V. F., &amp; Schedin, P. (2017, Feb). The Rodent Liver Undergoes Weaning-Induced Involution and Supports Breast Cancer Metastasis. Cancer Discov, 7(2), 177-187. https://doi.org/10.1158/2159-8290.CD-16-0822 Citation Format: Alexandra Quackenbush, Erica Goddard, Claire Dorfman, Kimberly Vesco, Jonathan Purnell, Pepper Schedin. Evidence for reproductive control of liver size with implications for risk of liver metastases in postpartum breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-39.

A Systematic Review and Scoping Analysis of Smoking Cessation after a Urological Cancer Diagnosis

Smoking cessation after a urologic cancer diagnosis significantly benefits patients. It is not well known how often patients quit after diagnosis or how urologists intervene to support patients' smoking cessation efforts. To examine rates of smoking cessation after diagnosis among patients with urologic cancers and to assess how often patients are given advice and support to quit smoking in the urology setting. Following the PRISMA guidelines, a systematic review was conducted of the available studies on smoking cessation after a urologic cancer diagnosis during April 2020 by a trained medical librarian using the MEDLINE, PsycInfo, Embase, and Cochrane CENTRAL databases. Studies were included based on three independent reviews and if they met a priori inclusion/exclusion criteria. In total, 2568 records were identified, 31 of which were included for final analysis. Four studies (patient n=587) reported outcomes related to the prospective implementation of a smoking cessation program with patient-level quit rates ranging from 3.2% to 47.3%. Twenty one studies reported outcomes of passive (no directed, active intervention) smoking cessation after the diagnosis of a urologic cancer (patient n=3669) with widely varying quit rates. In general, the quality of included studies was poor. There was no standardization of the measurement or timing of outcomes and few studies included validated survey instruments or biochemical confirmation of cessation. Seventeen studies included data on whether patients received advice to quit smoking after diagnosis. The proportion of patients in each study who were told to quit ranged from 2.8-78.3%. There are few smoking cessation interventions that have been prospectively implemented and reported in the urology literature and studies on quit rates after diagnosis are limited. The paucity of quality data and lack of smoking cessation interventions being used in routine urologic oncology care underscores the need for more rigorous study and implementation of evidence-based practices in this area.

Correlations Between Retinal Optical Coherence Tomography and Histopathology in Preclinical Safety Assessment of Ocular Therapies.

Twelve studies that involved intravitreal or subretinal test article administration in multiple laboratory animal species and employed both OCT and histopathologic assessment were identified. These data were compared to determine the degree of correlation for each identified abnormality. Severity of observed OCT and histopathological changes ranged from minimal to severe, with moderate and severe changes having a higher rate of agreement between the 2 techniques. Changes to well-defined structures, including the retinal blood vessels, optic nerve, and retinal pigment epithelium, also showed a strong correlation. There was a strong correlation between OCT and histopathology in both intravitreal and subretinal injection studies, demonstrating the value of collaboration between the study ophthalmologist and pathologist and offering translatable means to monitor pharmacological or toxicological effects in preclinical toxicological studies.

702 Postpartum depression screening during the COVID-19 pandemic

To compare postpartum depression screening rates during the COVID-19 pandemic with matched controls and determine if delivery during the pandemic is associated with increased postpartum (PP) Edinburgh Postnatal Depression Scale (EPDS) scores. At a tertiary care center directly affected by the COVID-19 pandemic, we conducted a retrospective cohort study of EPDS use and results for all women delivering in April 2019 and 2020. Women with incomplete prenatal care or delivery records were excluded. Outcomes were the proportion of women screened, median PP EPDS scores, and rates of screen positivity (score ≥ 10). Student t, Fisher exact, and Chi-squared tests were used for bivariate analyses as appropriate. Logistic regression models predicting PP visit attendance and study timepoint were created for significant factors. Patient demographics did not differ pre- vs peri-pandemic (Table 1), though black women were less likely to have PP visits overall (P<0.01). Patients delivering pre-pandemic were more likely to have diagnoses of anxiety/ depression (P<0.01), to have NICU admissions (P=0.03), and to have more prenatal visits (9.52 v 8.62, P<0.01). During the pandemic, patients were less likely to have PP visits (P<0.01) or to have PP EDPS scores from visits (P<0.01), especially virtual visits. However, there was no significant difference in EPDS scores or screen positive rates across timepoints (Table 2). In our model of pre-/post- pandemic care timing, not having an EPDS PP (P<0.01), not needing NICU care (P<0.01), having fewer prenatal visits (P<0.01), and not having anxiety/ depression (P=0.01) were significant independent predictors of having received care in the peri-pandemic period. Black race (P<0.01) and receiving care during COVID predicted not having a PP visit. The COVID-19 pandemic has adversely affected depression screening, possibly due to new logistic barriers that may exacerbate pre-existing health disparities. Quality improvement efforts should work to optimize the screening process as care models continue to shift.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

925 Implementation of postpartum home blood pressure monitoring to reduce readmissions for hypertensive disorders of pregnancy

Postpartum readmissions due to hypertensive disorders of pregnancy (HDP) comprise over 50% of our monthly obstetrical readmissions. We sought to implement an evidence-based postpartum home blood pressure monitoring system to reduce postpartum readmissions due to HDP. This quality improvement initiative enrolled postpartum women with HDP or chronic hypertension. To enroll they also had to be English speaking and have access to text messaging. We utilized University of Pennsylvania’s Heart Safe Motherhood automated text-based platform which allowed providers to remotely monitor blood pressure and titrate medications for patients from discharge through 14 days post discharge. Our primary outcome measure was postpartum readmission due to HDP. We aimed to reduce preventable readmission rates due to HDP by 50%. In the four months following implementation (April 1– July 31, 2020) our overall 30-day readmission rate decreased from a baseline of 2.4% prior to implementation to 1.8% following implementation. The percentage of readmissions secondary to hypertension decreased by 24% between the two study timepoints (62.2% pre-implementation vs. 38.1% post-implementation, p=0.08; Figure 1). The majority of women readmitted were participating in home blood pressure monitoring at the time of their readmission (N= 13; 62%) and women with hypertensive disorders of pregnancy were most commonly readmitted due to worsening disease, such as gestational hypertension with subsequent development of preeclampsia with severe features (N=6; 75%). During the four months following implementation of a home blood pressure monitoring system, postpartum readmissions due to HDP were reduced by over a third. Although not statistically significant, this has a clinically significant impact on both patient and system levels. Additionally, the majority of the women readmitted were participating in home blood pressure monitoring suggesting that heightened surveillance and improved postpartum communication may identify at risk women triaging them for more urgent evaluation.

Drought-mitigating Pseudomonas putida Strain Modulates Polyamine Catabolism in Arabidopsis thaliana

Plant growth-promoting rhizobacteria often play a significant role in alleviating drought stress in plants by colonizing the rhizosphere through myriad mechanisms. We have previously reported that the drought-mitigating rhizobacterium, Pseudomonas putida GAP-P45, modulates polyamine biosynthetic gene expression and cellular accumulation of polyamines (putrescine, spermidine, and spermine) in water-stressed Arabidopsis thaliana (Sen et al. in Plant Physiol Biochem 129:180–188, 2018). In continuation, here, we report the effect of the aforementioned strain on the expression of polyamine catabolic genes (CuAO1-3, PAO1-5), activities of catabolic enzymes (copper amine oxidase and polyamine oxidase), and accumulation of catabolic by-product, γ-amino butyric acid (GABA) in water-stressed A. thaliana. Similar to the previously reported increase in polyamine biosynthesis and accumulation, P. putida GAP-P45 inoculation under water stress led to significant upregulation of most polyamine catabolic genes at most time points of study. GAP-P45 inoculation of water-stressed A. thaliana increased mostly copper amine oxidase activity in the plants, while polyamine oxidase activity showed either similar or slightly increased levels as compared to the non-inoculated, water-stressed seedlings. The accumulation of GABA in A. thaliana was differentially impacted under these conditions. We conclude that P. putida GAP-P45 tightly regulates polyamine metabolism at least at the transcriptional level under water stress. Taken together with our previous study, the data obtained from the current study point towards GAP-P45 mediated enhanced putrescine turnover and a possible feedback inhibition of polyamine back-conversion due to net accumulation of free putrescine in A. thaliana under water stress.

Increased T-cell receptor repertoire diversity to predict better overall survival in gastrointestinal malignancies.

474 Background: Severe treatment-induced lymphopenia is a poor prognostic factor for multiple solid malignancies. Emerging data suggests that increased TCR repertoire is associated with improved survival. We hypothesized that increased TCR repertoire following severe treatment-induced lymphopenia would be associated with better survival after accounting for known prognostic factors. Methods: Patients within a prospective cohort were retrospectively analyzed for severe (grade 4) lymphopenia during radiotherapy (RT) at a single institution between 2007-2016. Peripheral blood samples were collected weekly. TCR repertoire at 3 time points were evaluated: pre-RT, during or immediately post-RT at absolute lymphocyte count (ALC) nadir, and ~2 months post-RT. Peripheral blood was analyzed via multiparametric flow cytometry. TCR beta sequencing was performed on immunoSEQ platform from Adaptive Biotechnologies. A Gini diversity index reflecting TCR repertoire was calculated as well as percentage change between ALC nadir and ALC 2 months post-RT. Primary endpoint was overall survival (OS). Cox modeling and Kaplan Meier estimates were used for survival analyses. Results: 109 patients were enrolled. 20 patients were evaluable with complete data. Median follow up was 40 months. Primary malignancy was pancreatic adenocarcinoma in 40%, gastric adenocarcinoma in 30%, and cholangiocarcinoma in 30%. Clinical stage was I-II in 29%, III in 50%, and IV in 21%. 80% underwent chemotherapy (CTX) pre-RT and none received CTX post-RT. 80% had concurrent CTX during RT. Median RT dose was 56 Gy. Among those with pathology available (n = 12), 17% had a pathologic complete response (pCR) and 83% had R0 resection. Median ALC at each of the three study timepoints was 1.26 k/ul, 0.32 k/ul, and 1.02 k/ul, respectively. 4 (20%) patients had increased TCR repertoire as defined by the change in Gini diversity index while 16 (80%) had decreased TCR repertoire post-RT. There were no significant differences in baseline characteristics between the two cohorts. On univariable analysis, increased TCR repertoire from ALC nadir to 2 months post-RT significantly correlated with better OS (HR = 0.20 [95% CI 0.04-0.93]; p = 0.041). Other variables including ECOG, stage, RT dose, CTX use, pCR, R0 resection, baseline WBC, and ALC at three study time points did not correlate with OS. Patients with increased vs decreased TCR repertoire post-RT had a 3-year OS of 75% vs 22%, respectively (log rank p = 0.026). Conclusions: Increased TCR repertoire post-RT was an independent prognostic factor for better OS in our cohort of GI malignancies. Our findings provide biologic insight and refine the association between ALC and cancer outcomes. TCR repertoire warrants further study as a predictive and prognostic biomarker in GI malignancies. Therapeutic approaches to limit severe lymphopenia are ongoing and should include TCR assessment.

Patient-reported outcomes in those consuming medical cannabis: a prospective longitudinal observational study in chronic pain patients.

We investigated patients with chronic pain seeking medical cannabis. We assessed their demographics, patterns of cannabis use, and the long-term effectiveness of cannabis on their pain and functional domains. This observational study enrolled patients between 8 September 2015 and 31 July 2018 from community-based cannabis clinics in Ontario, Canada. In addition to collecting demographic information, the primary outcomes studied were pain intensity and pain-related interference scores assessed at baseline, three, six, and 12 months. Using validated questionnaires, we also assessed anxiety, depression, quality of life (QoL), general health symptoms, neuropathic pain, self-reported opioid consumption, and adverse events. Of the 1,000 patients consented, 757 (76%) participated at one or more of the study time points. At six and 12 months, 230 (30.4%) and 104 (13.7%) of participants were followed up, respectively. Most participants were female (62%), Caucasian (91%), and sought cannabis for pain relief (88%). Time was a significant factor associated with improvement in pain intensity (P < 0.001), pain-related interference scores (P < 0.001), QoL (P < 0.001), and general health symptoms (P < 0.001). Female sex was significantly associated with worse outcomes than male sex including pain intensity (P < 0.001) and pain-related interference (P < 0.001). The proportion of individuals who reported using opioids decreased by half, from 40.8% at baseline to 23.9% at 12 months. Despite significant challenges to collecting long-term observational data on patients who attempted a trial of cannabis products, approximately one-third of patients in the cohort remained on medical cannabis for six months. In this cohort, pain intensity and pain-related interference scores were reduced and QoL and general health symptoms scores were improved compared with baseline.

Nebulized Magnesium Sulfate for Treatment of Persistent Pulmonary Hypertension of Newborn: A Pilot Randomized Controlled Trial.

ObjectivesTo investigate the effectiveness of nebulized magnesium sulfate in treating persistent pulmonary hypertension of newborn (PPHN).MethodsTwenty-eight mechanically ventilated term neonates with severe PPHN were randomized into two groups: NebMag group (n = 14), who receiving nebulized isotonic magnesium (1024 mg/h), and IVMag group (n = 14), who received intravenous magnesium (200 mg/kg over 30 min, followed by 50 mg/kg/h). The study time frame was 24 h. Outcome measures were the changes in oxygenation index (OI), mean arterial blood pressure (MABP), vasoactive inotropic score (VIS), and serum magnesium level.ResultsBaseline demographic, ventilatory, and hemodynamic characteristics were comparable between the two groups. At the end of the study, the OI decreased by 44.3% in the NebMag group compared with 35.3% in the IVMag group (mean difference −3.14; 95%CI −5.08, −1.19; p 0.003). The NebMag group had a higher MABP (mean difference 2.29 mmHg; 95% CI 1.80, 2.77; p 0.000) and lower VIS (mean difference −14.64; 95% CI −16.52, −12.77; p 0.000) at the 24-h study time point. The increase in serum magnesium level, measured at 12-h study time point, was lower in the NebMag group (mean difference −2.26 mmol/L; 95% CI −2.58, −1.96; p 0.000).ConclusionNebulized magnesium sulfate may be an effective therapeutic modality for neonates with severe PPHN on mechanical ventilation, but this should be confirmed by larger studies.Retrospectively registered at www.clinicaltrials.gov (identifier: NCT04328636).

Longitudinal Evolution of Pulmonary Artery Wall Shear Stress in a Swine Model of Pulmonary Artery Stenosis and Stent Interventions.

Branch pulmonary artery stenosis (PAS) commonly occurs in congenital heart disease and it has previously been hypothesized that in branch PAS the pulmonary arteries (PAs) remodel their lumen diameter to maintain constant wall shear stress (WSS). We quantified the longitudinal progression of PA WSS in a swine model of unilateral PAS and two different intervention time courses to test this hypothesis. To quantify WSS in the entire pulmonary tree we used 4D Flow MRI for the large-proximal PAs and a structured tree model for the small-distal PAs. Our results only partially supported the hypothesis that in branch PAS the PAs remodel their lumen diameter to maintain WSS homeostasis. Proximal PA WSS was similar between groups at the final study time-point but WSS of mid-sized (5mm to 500μm) PA segments was found to be different between the sham and LPAS groups. This suggests that WSS homeostasis may only be achieved for the large-proximal PAs. Additionally, our results do not show WSS homeostasis being achieved over shorter periods of time suggesting that any potential WSS dependent changes in PA lumen diameter were a long-term remodeling response rather than a short-term vasodilation response. Future studies should confirm if these findings hold true in humans and investigate the impacts of WSS at different levels of the pulmonary tree on growth.