Publications by authors named "Cathy Liu"

24 Publications

  • Page 1 of 1

Effect of Exclusion Diets on Symptom Severity and the Gut Microbiota in Patients with Irritable Bowel Syndrome.

Clin Gastroenterol Hepatol 2021 May 19. Epub 2021 May 19.

G Oppenheimer Center for Neurobiology of Stress and Resilience; Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, United States,. Electronic address:

Background & Aims: Altered fecal microbiota have been reported in IBS, although studies vary which could be due to dietary effects. Many IBS patients may eliminate certain foods because of their symptoms, which in turn may alter fecal microbiota diversity and composition. This study aims were to determine if dietary patterns were associated with IBS, symptoms, and fecal microbiota differences reported in IBS.

Methods: 346 IBS participants and 170 healthy controls (HCs) completed a Diet Checklist reflecting the diet(s) consumed most frequently. An exclusion diet was defined as a diet that eliminated food components by choice. Within this group, a gluten-free, dairy-free, or low FODMAP diet was further defined as restrictive as they are often implicated to reduce symptoms. Stool samples were obtained from 171 IBS patients and 98 HCs for 16S rRNA gene sequencing and microbial composition analysis.

Results: Having IBS symptoms was associated with consuming a restrictive diet (27.17% of IBS patients vs 7.65% of HCs; OR 3.25; 95% CI 1.66-6.75; p-value 0.006). IBS participants on an exclusion or restrictive diet reported more severe IBS symptoms (p=0.042 and p=0.029 respectively). The composition of the microbiota in IBS patients varied depending on the diet consumed. IBS participants on an exclusion diet had a greater abundance of Lachnospira and a lower abundance of Eubacterium (q-values<0.05) and those on a restrictive diet had a lower abundance of Lactobacillus (q-value <0.05).

Conclusions: Restrictive diets are likely consumed more by IBS patients than HCs to reduce GI symptom severity. Dietary patterns influence the composition of fecal microbiota and may explain some of the differences between IBS and HCs.
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http://dx.doi.org/10.1016/j.cgh.2021.05.027DOI Listing
May 2021

Caesarean section rates: applying the modified ten-group Robson classification in an Australian tertiary hospital.

J Obstet Gynaecol 2021 May 2:1-6. Epub 2021 May 2.

Department of Obstetrics and Gynaecology, The Royal Brisbane and Women's Hospital, Brisbane, Australia.

The aim of this study was to determine the main contributors to caesarean section (CS) rates at an Australian tertiary hospital. We conducted a retrospective review of women who delivered in an Australian tertiary hospital between 2014 and 2017. Women were allocated according to a modified Robson Ten-Group Classification System and CS indications were collected in nulliparous women and women with previous CS. The largest contributor to the 35.7% overall CS rate was women with a term cephalic infant and a previous CS (31.5% relative CS rate) and the most common indication was repeat CS. The group CS rate in nulliparous women with a cephalic term infant was higher when labour was induced compared to occurring spontaneously (36.6% and 18.1% respectively). The primary CS indication for these women was labour dystocia and maternal request was the most common CS indication for nulliparous women with a pre-labour CS.IMPACT STATEMENT Significantly increasing caesarean section (CS) rates continue to prompt concern due to the associated neonatal and maternal risks. The World Health Organisation have endorsed the Robson Ten-Group Classification System to identify and analyse CS rate contributors. We have used the modified Robson Ten-Group Classification System to identify that women with cephalic term infants who are nulliparous or who have had a previous CS are the largest contributors to overall CS rates. CS rates were higher in these nulliparous women if labour was induced compared to occurring spontaneously and the primary CS indication was labour dystocia. In nulliparous women with a CS prior to labour the most common CS indication was maternal request. Majority of women with a previous CS elected for a repeat CS. Future efforts should focus on minimising repeat CS in multiparous women and primary CS in nulliparous women. This may be achieved by redefining the definition of labour dystocia, exploring maternal request CS reasoning and critically evaluating induction timing and indication. Appropriately promoting a trial of labour in women with a previous CS in suitable candidates may reduce repeat CS incidence.
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http://dx.doi.org/10.1080/01443615.2021.1873923DOI Listing
May 2021

Late-in-Life Neurodegeneration after Chronic Sleep Loss in Young Adult Mice.

Sleep 2021 Mar 26. Epub 2021 Mar 26.

Department of Medicine, Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania, USA.

Chronic short sleep (CSS) is prevalent in modern societies and has been proposed as a risk factor for Alzheimer's disease (AD). In support, short-term sleep loss acutely increases levels of amyloid β (Aβ) and tau in wild type (WT) mice and humans, and sleep disturbances predict cognitive decline in older adults. We have shown that CSS induces injury to and loss of locus coeruleus neurons (LCn), neurons with heightened susceptibility in AD. Yet whether CSS during young adulthood drives lasting Aβ and/or tau changes and/or neural injury later in life in the absence of genetic risk for AD has not been established. Here we examined the impact of CSS exposure in young adult WT mice on late-in-life Aβ and tau changes and neural responses in two AD-vulnerable neuronal groups, LCn and hippocampal CA1 neurons. Twelve months following CSS exposure, CSS-exposed mice evidenced reductions in CA1 neuron counts and volume, spatial memory deficits, CA1 glial activation, and loss of LCn. Aβ42 and hyperphosphorylated tau were increased in the CA1; however, amyloid plaques and tau tangles were not observed. Collectively the findings demonstrate that CSS exposure in the young adult mouse imparts late-in-life neurodegeneration and persistent derangements in amyloid and tau homeostasis. These findings occur in the absence of a genetic predisposition to neurodegeneration and demonstrate for the first time that CSS can induce lasting, significant neural injury consistent with some, but not all, features of late onset AD.
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http://dx.doi.org/10.1093/sleep/zsab057DOI Listing
March 2021

Does the length of second stage of labour or second stage caesarean section in nulliparous women increase the risk of preterm birth in subsequent pregnancies?

J Perinat Med 2021 Feb 14;49(2):159-165. Epub 2020 Sep 14.

Department of Obstetrics & Gynaecology, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.

Objectives: This study aimed to investigate the role of prolonged second stage of labour and second stage caesarean section on the risk of spontaneous preterm birth (sPTB) in a subsequent pregnancy.

Methods: This was a retrospective cohort study of nulliparous women with two consecutive singleton deliveries between 2014 and 2017 at a tertiary centre. In the vaginal delivery cohort, subsequent pregnancy outcomes for women with a prolonged second stage (>2 h) were compared with those with a normal second stage (≤2 h). In the caesarean delivery cohort, women with a first stage or a second stage were compared with the vaginal delivery cohort. The primary outcome was subsequent sPTB.

Results: A total of 821 women met inclusion criteria, of which 74.8% (614/821) delivered vaginally and 25.2% (207/821) delivered by caesarean section. There was no association between a prolonged second stage in the index pregnancy and subsequent sPTB (aOR 0.70, 95% CI 0.13-3.83, p=0.7). The risk of subsequent sPTB was threefold for those with a second stage caesarean section; however this did not reach statistical significance.

Conclusions: A prolonged second stage of labour in the index pregnancy is not associated with an increased risk of subsequent sPTB. A second stage caesarean section in the index pregnancy may be associated with an increased risk of subsequent sPTB, however there was no statistically significant difference. These findings are important for counseling and suggest that the effects of these factors are not clinically significant to justify additional interventions in the subsequent pregnancy.
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http://dx.doi.org/10.1515/jpm-2020-0269DOI Listing
February 2021

The Role of Resilience in Irritable Bowel Syndrome, Other Chronic Gastrointestinal Conditions, and the General Population.

Clin Gastroenterol Hepatol 2020 Aug 21. Epub 2020 Aug 21.

G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Disease, David Geffen School of Medicine at UCLA, Los Angeles, California. Electronic address:

Background & Aims: Resilience is the ability to adapt positively to stress and adversity. It is a potential therapeutic target as it is reduced in irritable bowel syndrome (IBS) compared to healthy controls and associated with worse symptom severity and poorer quality of life. The aim of this study was to examine if these findings are generalizable by comparing resilience between IBS versus the general population and other chronic gastrointestinal (GI) conditions.

Methods: Participants in the general population completed an online survey containing questionnaires measuring demographics, diagnosis of IBS and other GI conditions, symptom severity, psychological symptoms, resilience, and early adverse life events (EALs). IBS was defined as having a physician diagnosis of IBS and/or meeting Rome criteria without co-morbid GI disease. All others were included in the general population group. The chronic GI conditions group included those with inflammatory bowel disease, celiac disease and/or microscopic colitis.

Results: Resilience was lower in IBS (n = 820) than the general population (n = 1026; p < 0.001) and associated with worse IBS symptom severity (p < 0.05). Global mental health affected resilience differently in IBS compared to the general population (all p's < 0.05). EALs were associated with decreased ability to bounce back from adversity in both IBS and the general population (p < 0.001). Resilience scores were similar in IBS and other chronic GI conditions that present with similar symptoms.

Conclusions: Resilience is lower compared to the general U.S. population but does not appear to be specific to IBS as it is comparable to other chronic GI conditions. Low resilience negatively affects symptom severity and mental health and thus, may serve as a novel therapeutic target.
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http://dx.doi.org/10.1016/j.cgh.2020.08.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897330PMC
August 2020

Postmenopausal women with irritable bowel syndrome (IBS) have more severe symptoms than premenopausal women with IBS.

Neurogastroenterol Motil 2020 10 29;32(10):e13913. Epub 2020 May 29.

Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

Background: Although irritable bowel syndrome (IBS) is more common in women, little is known about the role of hormonal changes and menopause in IBS. This study aimed to evaluate for differences in gastrointestinal (GI) and psychological symptoms between pre- and postmenopausal women with IBS compared to age-matched men with IBS.

Methods: Patients with Rome-positive IBS were identified. Premenopausal women were <45 years of age with regular menses. Postmenopausal women were ≥45 years without menses for at least 1 year. Younger men were <45 years, and older men were ≥45 years. Questionnaires measured severity of IBS symptoms, somatic symptoms, health-related quality of life (HRQOL), and psychological symptoms. Multivariable linear or logistic regressions evaluating relationships between age and sex were performed.

Key Results: 190 premenopausal women (mean age 30.25 years), 52 postmenopausal women (mean age 54.38 years), 190 men <45 years (mean age 30.45 years), and 52 men ≥45 years (mean age 53.37 years) were included. Postmenopausal IBS women had greater severity of IBS symptoms (P = .003) and worse physical HRQOL (P = .048) compared to premenopausal women. No differences were observed between age-matched older and younger IBS men. Constipation increased with age for both sexes but was the principal IBS subtype in women only.

Conclusions And Inferences: Postmenopausal women with IBS have more severe IBS symptoms than premenopausal women, while no comparable age-related changes were seen in IBS men. The modulatory effect of female sex hormones on brain-gut interactions which affect visceral perception and GI function likely contributes to these findings.
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http://dx.doi.org/10.1111/nmo.13913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529855PMC
October 2020

Prediction of time of delivery using cervical length measurement in women with threatened preterm labor.

J Matern Fetal Neonatal Med 2021 Aug 1;34(16):2649-2654. Epub 2019 Oct 1.

Department of Obstetrics and Gynaecology, Royal Brisbane and Women's Hospital, Brisbane, Australia.

Objective: To evaluate the use of transvaginal (TV) sonographic cervical length (CL) measurement alone in predicting time of delivery in women who present in threatened preterm labor.

Methods: A retrospective cohort study at Royal Brisbane and Women's Hospital of all women who presented between 22 weeks and 0 days and 35 weeks and six-day gestation in threatened preterm labor and were admitted for ongoing management including a TV sonographic CL measure. The accuracy of CL for predicting time of delivery was compared between women with a short cervix (CL  < 25 mm) and those with a normal cervix (CL ≥25 mm). The predictive accuracy of CL for spontaneous preterm delivery was analyzed with different outcome-specific thresholds.

Results: One hundred and forty-six women with threatened preterm labor met the inclusion criteria; of which 74 (50.7%) had a short cervix and 72 (49.3%) had a normal cervix. The group with short cervix were more likely to deliver prematurely before 37-week gestation, as well as a shorter time interval between initial presentation and delivery and delivery within 14 days from presentation ( = .0002,  = .0001, and  = .0001, respectively). Similarly, with respect to the area under the receiver operator characteristic curves, CL measurement was found to be significant for time of delivery before or after 37 weeks ( < .0001), preterm delivery before 34 ( =  .0003) and 31 ( <  .0001) weeks; and preterm delivery within 14 days from presentation ( < .0001). Cervical length measurement has a high negative predictive value ranging from 94.9 to 97.1% depending on the different CL threshold used.

Conclusions: Cervical length measurement at the time of presentation was significantly associated with the risk of preterm delivery in women presenting with threatened preterm labor and a short cervix. Cervical length measurement was also helpful in predicting time of delivery within 14 days from presentation. The negative predictive value and predictive accuracy of CL as a single measure were of significance.
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http://dx.doi.org/10.1080/14767058.2019.1670798DOI Listing
August 2021

An In Vitro Human Segmentation Clock Model Derived from Embryonic Stem Cells.

Cell Rep 2019 08;28(9):2247-2255.e5

Morgridge Institute for Research, Madison, WI 53715, USA; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Molecular, Cellular, & Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93117, USA. Electronic address:

Defects in somitogenesis result in vertebral malformations at birth known as spondylocostal dysostosis (SCDO). Somites are formed with a species-specific periodicity controlled by the "segmentation clock," which comprises a group of oscillatory genes in the presomitic mesoderm. Here, we report that a segmentation clock model derived from human embryonic stem cells shows many hallmarks of the mammalian segmentation clock in vivo, including a dependence on the NOTCH and WNT signaling pathways. The gene expression oscillations are highly synchronized, displaying a periodicity specific to the human clock. Introduction of a point of mutation into HES7, a specific mutation previously associated with clinical SCDO, eliminated clock gene oscillations, successfully reproducing the defects in the segmentation clock. Thus, we provide a model for studying the previously inaccessible human segmentation clock to better understand the mechanisms contributing to congenital skeletal defects.
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http://dx.doi.org/10.1016/j.celrep.2019.07.090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814198PMC
August 2019

The risk of preterm delivery and pregnancy outcomes in women with asymptomatic short cervix: a retrospective cohort study.

J Matern Fetal Neonatal Med 2021 Jun 6;34(11):1747-1753. Epub 2019 Aug 6.

Discipline of Obstetrics and Gynaecology, Faculty of Medicine, University of Queensland, Herston, Australia.

Objective: Routine cervical length measurement in asymptomatic pregnant women to prevent preterm birth has not been universally adopted due to poor predictive accuracy. The purpose of our study was to evaluate the risk of preterm delivery and pregnancy outcomes in women with asymptomatic short cervix and examine the implications of gestational age at presentation on these outcomes.

Study Design: This was a retrospective cohort study of women with singleton pregnancies who presented prior to or at 32 + 0 weeks with an asymptomatic short cervix (≤25 mm) between April 2014 to March 2018 at a single tertiary maternity center. Women with cervical length ≤25 mm were grouped into four cohorts according to gestational age at presentation: Obstetric outcomes were compared between the cohorts and the general cohort of women delivering during the same period. Outcomes were compared using Mann-Whitney , chi-square tests, and logistic regression. Survival analysis was carried out to compare the probability of delivery for each subgroup.

Results: The rate of spontaneous preterm birth <37 weeks was highest in the cohort presenting at 25 + 0-27 + 6 weeks, and lowest in the first cohort presenting at <22 + 0 (60.0 versus 22.2%,  < .05). When compared with the general cohort, the rate of spontaneous preterm birth at <37-week gestation was significantly higher in the asymptomatic short cervix cohort (40.4 versus 8.7%,  < .001), with a 7.1-fold increase in the relative risk of spontaneous PTB.

Conclusions: In asymptomatic women, cervical shortening showed significant increase in the risk of preterm birth. Our study findings suggest that routine cervical screening may be helpful in predicting risk of preterm birth even in women who are considered low-risk for preterm birth.
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http://dx.doi.org/10.1080/14767058.2019.1647163DOI Listing
June 2021

The efficacy of quantitative fetal fibronectin in predicting spontaneous preterm birth in symptomatic women: A retrospective cohort study.

Aust N Z J Obstet Gynaecol 2019 10 6;59(5):656-661. Epub 2019 Feb 6.

Centre for Advanced Prenatal Care, The Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.

Background: Recent data suggest that quantitative measurements of fetal fibronectin can be used accurately to predict increased risk of preterm birth.

Aim: The purpose of this study was to demonstrate that the quantification of fetal fibronectin improves diagnostic accuracy in women who present with symptoms suggestive of threatened preterm labour (TPL) using a quantitative fetal fibronectin (qfFN) bedside analyser.

Study Design: This was a retrospective cohort study of pregnant women who presented between 22 and 32  weeks gestation with symptoms of TPL who had qfFN measured using the Rapid fFN Q10 system. The ability to predict spontaneous preterm birth (sPTB) within 48 h, 14 days and <34 weeks gestation at qfFN thresholds of 10, 50 and 200 ng/mL was assessed.

Results: The overall rate of sPTB <34 weeks was 4.1% (n = 373). For deliveries within 48 h, within 14 days and <34 weeks, a qfFN threshold of 200 ng/mL had positive predictive values of 26.7%, 42.9% and 46.7%, respectively, when compared to patients with qfFN values of 0-9 ng/mL. The corresponding relative risks were 68.5, 53.8 and 38.0, respectively CONCLUSION: Quantitative fetal fibronectin testing with thresholds of 10, 50 and 200 ng/mL allows for more accurate prediction of preterm birth in symptomatic women. This higher degree of discrimination allows for more directed interventions for high-risk patients and reduces the cost and burden of unnecessary treatment for low-risk patients.
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http://dx.doi.org/10.1111/ajo.12947DOI Listing
October 2019

Risk and Protective Factors Related to Early Adverse Life Events in Irritable Bowel Syndrome.

J Clin Gastroenterol 2020 01;54(1):63-69

Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, G. Oppenheimer Center for Neurobiology of Stress and Resilience, University of California, Los Angeles.

Background: Irritable bowel syndrome (IBS) is a stress-sensitive disorder of brain-gut interactions associated with a higher prevalence of early adverse life events (EALs). However, it is incompletely understood how trauma severity or disclosure influence the risk of developing IBS or symptom severity.

Aims: To determine whether (1) IBS patients report a greater number of EALs compared with healthy controls; (2) trauma severity and first age of EAL increase the odds of IBS; (3) confiding in others reduces the odds of IBS; (4) the number, trauma severity, and first age of EAL are associated with symptom severity; (5) sex differences exist.

Methods: In total, 197 IBS patients (72% women, mean age=30.28 y) and 165 healthy controls (59% women, mean age=30.77 y) completed the Childhood Traumatic Events Scale, measuring severity of EALs and degree of confiding in others. Regression analyses were used to predict IBS status from EALs and association between gastrointestinal symptoms and EALs.

Results: A greater number of EALs [odds ratio (OR)=1.36, 95% confidence interval (CI), 1.14-1.62; P<0.001] and higher perceived trauma severity (OR=1.13, 95% CI, 1.08-1.19; P<0.001) were associated with increased odds of IBS. Confiding in others decreased the odds of having IBS (OR=0.83, 95% CI, 0.72-0.96; P=0.012). The first age of EAL was not predictive of IBS. No sex differences were found.

Conclusions: Assessing the traumatic severity of EALs and amount of confiding in others is important as they can affect the risk of having IBS. Our findings emphasize early intervention to improve health outcomes in individuals with EALs.
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http://dx.doi.org/10.1097/MCG.0000000000001153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802286PMC
January 2020

Natural Killer-Derived Exosomal miR-186 Inhibits Neuroblastoma Growth and Immune Escape Mechanisms.

Cancer Res 2019 03 12;79(6):1151-1164. Epub 2018 Dec 12.

Children's Center for Cancer and Blood Diseases and Divisions of Hematology, Oncology, Blood and Marrow Transplantation, Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, USC-Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.

In neuroblastoma, the interplay between immune cells of the tumor microenvironment and cancer cells contributes to immune escape mechanisms and drug resistance. In this study, we show that natural killer (NK) cell-derived exosomes carrying the tumor suppressor microRNA (miR)-186 exhibit cytotoxicity against MYCN-amplified neuroblastoma cell lines. The cytotoxic potential of these exosomes was partly dependent upon expression of miR-186. miR-186 was downregulated in high-risk neuroblastoma patients, and its low expression represented a poor prognostic factor that directly correlated with NK activation markers (i.e., NKG2D and DNAM-1). Expression of MYCN, AURKA, TGFBR1, and TGFBR2 was directly inhibited by miR-186. Targeted delivery of miR-186 to MYCN-amplified neuroblastoma or NK cells resulted in inhibition of neuroblastoma tumorigenic potential and prevented the TGFβ1-dependent inhibition of NK cells. Altogether, these data support the investigation of a miR-186-containing nanoparticle formulation to prevent tumor growth and TGFβ1-dependent immune escape in high-risk neuroblastoma patients as well as the inclusion of -derived NK exosomes as a potential therapeutic option alongside NK cell-based immunotherapy. These findings highlight the therapeutic potential of NK cell-derived exosomes containing the tumor suppressor miR-186 that inhibits growth, spreading, and TGFβ-dependent immune escape mechanisms in neuroblastoma.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428417PMC
March 2019

Examining driver injury severity in intersection-related crashes using cluster analysis and hierarchical Bayesian models.

Accid Anal Prev 2018 Nov 15;120:139-151. Epub 2018 Aug 15.

Civil and Environmental Engineering, Carnegie Mellon University, Pittsburgh, PA, 15213-3890, United States. Electronic address:

Traffic crashes are more likely to occur at intersections where the traffic environment is complicated. In this study, a hybrid approach combining cluster analysis and hierarchical Bayesian models is developed to examine driver injury severity patterns in intersection-related crashes based on two-year crash data in New Mexico. Three clusters are defined by K-means cluster analysis based on weather and roadway environmental conditions in order to reveal drivers' risk compensation instability under diverse external environment. Hierarchical Bayesian random intercept models are developed for each of the three clusters as well as the whole dataset to identify the contributing factors on multilevel driver injury outcomes: property damage only (Level I), complaint of injury and visible injury (Level II), and incapacitating injury and fatality (Level III). Model comparison with an ordinary multinomial logistic model omitting crash data hierarchical features and cross-level interactions verifies the suitability and effectiveness of the proposed hybrid approach. Results show that a number of crash-level variables (time period, weather, light condition, area, and road grade), vehicle/driver-level variables (traffic controls, vehicle action, vehicle type, seatbelt used, driver age, drug/alcohol impaired, and driver age) along with some cross-level interactions (i.e., left turn and night, drug and dark) impose significantly influence driver injury severity. This study provides insightful understandings of the effects of these variables on driver injury severity in intersection-related crashes and beneficial references for developing effective countermeasures for severe crash prevention.
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http://dx.doi.org/10.1016/j.aap.2018.08.009DOI Listing
November 2018

Obstetric and perinatal outcomes in pregnancies with isolated foetal congenital heart abnormalities.

J Matern Fetal Neonatal Med 2019 Sep 3;32(18):2985-2992. Epub 2018 Apr 3.

a Mater Research Institute, University of Queensland , Brisbane , Australia.

To determine obstetric, intrapartum, and perinatal outcomes for pregnancies with isolated foetal congenital heart defects (CHDs). This was a retrospective cohort study of women that delivered an infant with an isolated major CHD between January 2010 and April 2017 at a major Australian perinatal centre. The study cohort was compared with a cohort of women with infants without CHD. Cardiac abnormalities were broadly subdivided into the following five categories using the International Classification of Diseases Tenth Revision (ICD-10) as a guide - transposition of the great arteries (TGA), septal defects, right heart lesions (RHL), left heart lesions (LHL), and "other". Demographic characteristics and obstetric, intrapartum, and perinatal outcomes were compared between the two cohorts. The final study cohort comprised of 342 infants with isolated CHD and 68,911 controls. Of the infants with CHD, 20.4% (70/342) had transposition of the great vessels, 23% (79/342) had septal lesions, 14.6% (50/342) had right sided lesions, 23.3% (80/342) left sided, and 18.4% (63/342) categorised as "other". Women with foetal CHD had a higher BMI and had higher rates of cardiac disease, diabetes mellitus, and hypertension, be smokers and consume alcohol compared to controls. The CHD cohort had lower odds of spontaneous vaginal delivery (SVD) (OR 0.73, 95%CI 0.58-0.90) and higher odds of caesarean for nonreassuring foetal status (aOR 1.65, 95%CI 1.07-2.55), birth weight <5th (aOR 3.44, 95%CI 2.38-4.98) and <10th (aOR 2.49, 95%CI 1.82-3.40) centiles, neonatal intensive care unit (NICU) admission (aOR 109.14, 95%CI 74.44-160.02), severe respiratory distress (aOR 2.90, 95%CI 2.33-3.76), 5 minutes Apgar score <7 (aOR 2.48, 95%CI 1.46-4.20), severe acidosis (aOR 1.80, 95%CI 1.14-2.85), stillbirth (aOR 4.09, 95%CI 1.62-10.33), neonatal death (aOR 24.30, 95%CI 13.24-44.61), and overall perinatal death (aOR 13.42, 95%CI 8.08-22.30). Infants with TGA had the lowest overall risk of complications whilst infants with RHL, LHL, and "others" had the highest risk of adverse outcomes, particularly death. Infants with CHD have overall worse obstetric and perinatal outcomes compared with controls. Infants with TGA have the best perinatal outcomes of all the CHD subcategories.
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http://dx.doi.org/10.1080/14767058.2018.1453799DOI Listing
September 2019

Expression of Five Neuroblastoma Genes in Bone Marrow or Blood of Patients with Relapsed/Refractory Neuroblastoma Provides a New Biomarker for Disease and Prognosis.

Clin Cancer Res 2017 Sep 30;23(18):5374-5383. Epub 2017 May 30.

Department of Pediatrics, Keck School of Medicine, University of Southern California, Children's Center for Cancer and Blood Diseases, Los Angeles, California.

We determined whether quantifying neuroblastoma-associated mRNAs (NB-mRNAs) in bone marrow and blood improves assessment of disease and prediction of disease progression in patients with relapsed/refractory neuroblastoma. mRNA for CHGA, DCX, DDC, PHOX2B, and TH was quantified in bone marrow and blood from 101 patients concurrently with clinical disease evaluations. Correlation between NB-mRNA (delta cycle threshold, Δ, for the geometric mean of genes from the TaqMan Low Density Array NB5 assay) and morphologically defined tumor cell percentage in bone marrow, I-meta-iodobenzylguanidine (MIBG) Curie score, and CT/MRI-defined tumor longest diameter was determined. Time-dependent covariate Cox regression was used to analyze the relationship between Δ and progression-free survival (PFS). NB-mRNA was detectable in 83% of bone marrow (185/223) and 63% (89/142) of blood specimens, and their Δ values were correlated (Spearman = 0.67, < 0.0001), although bone marrow was 7.9 ± 0.5 stronger than blood When bone marrow morphology, MIBG, or CT/MRI were positive, NB-mRNA was detected in 99% (99/100), 88% (100/113), and 81% (82/101) of bone marrow samples. When all three were negative, NB-mRNA was detected in 55% (11/20) of bone marrow samples. Bone marrow NB-mRNA correlated with bone marrow morphology or MIBG positivity ( < 0.0001 and = 0.007). Bone marrow and blood Δ values correlated with PFS ( < 0.001; = 0.001) even when bone marrow was morphologically negative ( = 0.001; = 0.014). Multivariate analysis showed that bone marrow and blood Δ values were associated with PFS independently of clinical disease and gene status ( < 0.001; = 0.055). This five-gene NB5 assay for NB-mRNA improves definition of disease status and correlates independently with PFS in relapsed/refractory neuroblastoma. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2647DOI Listing
September 2017

Hospital and Health Plan Partnerships: The Affordable Care Act's Impact on Promoting Health and Wellness.

Am Health Drug Benefits 2016 Jul;9(5):269-78

Graduate student, College of Pharmacy, Mercer University.

Background: The Affordable Care Act (ACA) healthcare reforms, centered on achieving the Centers for Medicare & Medicaid Services (CMS) Triple Aim goals of improving patient care quality and satisfaction, improving population health, and reducing costs, have led to increasing partnerships between hospitals and insurance companies and the implementation of employee wellness programs. Hospitals and insurance companies have opted to partner to distribute the risk and resources and increase coordination of care.

Objective: To examine the ACA's impact on the health and wellness programs that have resulted from the joint ventures of hospitals and health plans based on the published literature.

Method: We conducted a review of the literature to identify successful mergers and best practices of health and wellness programs. Articles published between January 2007 and January 2015 were compiled from various search engines, using the search terms "corporate," "health and wellness program," "health plan," "insurance plan," "hospital," "joint venture," and "vertical merger." Publications that described consolidations or wellness programs not tied to health insurance plans were excluded. Noteworthy characteristics of these programs were summarized and tabulated.

Results: A total of 44 eligible articles were included in the analysis. The findings showed that despite rising healthcare costs, joint ventures prevent hospitals from trading-off quality and services for cost reductions. Administrators believed that partnering would allow the companies to meet ACA standards for improving clinical outcomes at reduced costs. Before the implementation of the ACA, some employers had wellness programs, but these were not standardized and did not need to produce measurable results. The ACA encouraged improvement of employee wellness programs by providing funding for expanded health services and by mandating quality care. Successful workplace health and wellness programs have varying components, but all include monetary incentives and documented outcomes.

Conclusion: The concurrent growth of hospital health plans (especially those emerging from vertical mergers and partnerships) and wellness programs in the United States provides a unique opportunity for employees and patient populations to promote wellness and achieve the Triple Aim goals as initiated by CMS.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007056PMC
July 2016

Pain and Interoception Imaging Network (PAIN): A multimodal, multisite, brain-imaging repository for chronic somatic and visceral pain disorders.

Neuroimage 2016 Jan 19;124(Pt B):1232-1237. Epub 2015 Apr 19.

Oppenheimer Family Center for the Neurobiology of Stress at UCLA, Los Angeles, CA, USA; Department of Medicine at UCLA, Los Angeles, CA, USA; Department of Physiology at UCLA, Los Angeles, CA, USA; Department of Psychiatry at UCLA, Los Angeles, CA, USA; Pain and Interoception Network (PAIN) at UCLA, Los Angeles, CA 90095, USA. Electronic address:

The Pain and Interoception Imaging Network (PAIN) repository (painrepository.org) is a newly created NIH (NIDA/NCCAM) funded neuroimaging data repository that aims to accelerate scientific discovery regarding brain mechanisms in pain and to provide more rapid benefits to pain patients through the harmonization of efforts and data sharing. The PAIN Repository consists of two components, an Archived Repository and a Standardized Repository. Similar to other 'open' imaging repositories, neuroimaging researchers can deposit any dataset of chronic pain patients and healthy controls into the Archived Repository. Scans in the Archived Repository can be very diverse in terms of scanning procedures and clinical metadata, complicating the merging of datasets for analyses. The Standardized Repository overcomes these limitations through the use of standardized scanning protocols along with a standardized set of clinical metadata, allowing an unprecedented ability to perform pooled analyses. The Archived Repository currently includes 741 scans and is rapidly growing. The Standardized Repository currently includes 433 scans. Pain conditions currently represented in the PAIN repository include: irritable bowel syndrome, vulvodynia, migraine, chronic back pain, and inflammatory bowel disease. Both the PAIN Archived and Standardized Repositories promise to be important resources in the field of chronic pain research. The enhanced ability of the Standardized Repository to combine imaging, clinical and other biological datasets from multiple sites in particular make it a unique resource for significant scientific discoveries.
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http://dx.doi.org/10.1016/j.neuroimage.2015.04.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627849PMC
January 2016

On being a doctor again.

Authors:
Cathy Liu

Ann Intern Med 2014 Feb;160(4):286-7

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http://dx.doi.org/10.7326/M13-1105DOI Listing
February 2014

Clinical significance of tumor-associated inflammatory cells in metastatic neuroblastoma.

J Clin Oncol 2012 Oct 27;30(28):3525-32. Epub 2012 Aug 27.

Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA.

Purpose: Children diagnosed at age ≥ 18 months with metastatic MYCN-nonamplified neuroblastoma (NBL-NA) are at high risk for disease relapse, whereas those diagnosed at age < 18 months are nearly always cured. In this study, we investigated the hypothesis that expression of genes related to tumor-associated inflammatory cells correlates with the observed differences in survival by age at diagnosis and contributes to a prognostic signature.

Methods: Tumor-associated macrophages (TAMs) in localized and metastatic neuroblastomas (n = 71) were assessed by immunohistochemistry. Expression of 44 genes representing tumor and inflammatory cells was quantified in 133 metastatic NBL-NAs to assess age-dependent expression and to develop a logistic regression model to provide low- and high-risk scores for predicting progression-free survival (PFS). Tumors from high-risk patients enrolled onto two additional studies (n = 91) served as independent validation cohorts.

Results: Metastatic neuroblastomas had higher infiltration of TAMs than locoregional tumors, and metastatic tumors diagnosed in patients at age ≥ 18 months had higher expression of inflammation-related genes than those in patients diagnosed at age < 18 months. Expression of genes representing TAMs (CD33/CD16/IL6R/IL10/FCGR3) contributed to 25% of the accuracy of a novel 14-gene tumor classification score. PFS at 5 years for children diagnosed at age ≥ 18 months with NBL-NA with a low- versus high-risk score was 47% versus 12%, 57% versus 8%, and 50% versus 20% in three independent clinical trials, respectively.

Conclusion: These data suggest that interactions between tumor and inflammatory cells may contribute to the clinical metastatic neuroblastoma phenotype, improve prognostication, and reveal novel therapeutic targets.
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http://dx.doi.org/10.1200/JCO.2011.40.9169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675667PMC
October 2012

Combination immunotherapy with anti-CD20 and anti-HLA-DR monoclonal antibodies induces synergistic anti-lymphoma effects in human lymphoma cell lines.

Leuk Lymphoma 2007 May;48(5):944-56

Department of Internal Medicine, University of California, Davis, CA, USA.

Rituximab is effective in about one half of patients with indolent lymphoma. Even these patients relapse and develop rituximab resistance. To increase potency and circumvent resistance, the anti-lymphoma effects of rituximab, an anti-CD20 MAb(1), combined with chLym-1(2), an anti-HLA-DR MAb, were assessed in human lymphoma cell lines by examining growth inhibition and cell death, apoptosis induction, ADCC(3) and CDC(4). There were additive effects in all assays and synergism in cell lines, such as B35M, which displayed resistance to either MAb alone. In B35M cells, combined rituximab and chLym-1 induced a 27-fold direct reduction in viable cells, whereas equivalent concentrations of rituximab or chLym-1 alone induced only a 1-fold and 10-fold reduction in viable cells, respectively. Because these results occurred at MAb concentrations readily achievable in patients, they suggest that this combination immunotherapy regimen may increase the potency and range of effectiveness of these MAbs in lymphoma patients.
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http://dx.doi.org/10.1080/10428190701272272DOI Listing
May 2007

A limited screen for protein interactions reveals new roles for protein phosphatase 1 in cell cycle control and apoptosis.

J Proteome Res 2007 Mar 3;6(3):1165-75. Epub 2007 Feb 3.

Division Of Hematology/Oncology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, 4650 Sunset Boulevard, Los Angeles, California 90027, USA.

Protein phosphatase 1 (PP1) catalytic subunits typically combine with other proteins that modulate their activity, direct them to distinct substrates, or serve as substrates for PP1. More than 50 PP1-interacting proteins (PIPs) have been identified so far. Given there are approximately 10 000 phosphoproteins in mammals, many PIPs remain to be discovered. We have used arrays containing 100 carefully selected antibodies to identify novel PIPs that are important in cell proliferation and cell survival in murine fetal lung epithelial cells and human A549 lung cancer cells. The antibody arrays identified 31 potential novel PIPs and 11 of 17 well-known PIPs included as controls, suggesting a sensitivity of at least 65%. A majority of the interactions between PP1 and putative PIPs were isoform- or cell type-specific. We confirmed by co-immunoprecipitation that 9 of these proteins associate with PP1: APAF-1, Bax, E-cadherin, HSP-70, Id2, p19Skp1, p53, PCNA, and PTEN. We examined two of these interactions in greater detail in A549 cells. Exposure to nicotine enhanced association of PP1 with Bax (and Bad), but also induced inhibitory phosphorylation of PP1. In addition to p19Skp1, PP1alpha antibodies also coprecipitated cullin 1, suggesting that PP1alpha is associated with the SCF1 complex. This interaction was only detectable during the G1/S transition and S phase. Forced loss of PP1 function decreased the levels of p27Kip1, a well-known SCF1 substrate, suggesting that PP1 may rescue proteins from ubiquitin/proteasome-mediated destruction. Both of these novel interactions are consistent with PP1 facilitating cell cycle arrest and/or apoptosis.
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http://dx.doi.org/10.1021/pr060504hDOI Listing
March 2007

Protein phosphatase 1alpha activity prevents oncogenic transformation.

Mol Carcinog 2006 Sep;45(9):648-56

Division of Hematology/Oncology, Childrens Hospital Los Angeles, The University of Southern California Keck School of Medicine, Los Angeles, 90027, USA.

Cyclin-dependent kinase 2 (Cdk2) phosphorylates Thr320 of protein phosphatase 1alpha (PP1alpha) in late G(1), thereby inhibiting its activity. Phosphorylation-resistant PP1alphaT320A, acting as a constitutively active (CA) mutant, causes a late G(1) arrest by preventing the phosphorylation and inactivation of the retinoblastoma protein (pRb). Both PP1alpha-mediated G(1) arrest and PP1alpha phosphorylation in late G(1) require the presence of pRb, indicating that PP1alpha is a crucial regulator of the pRb pathway, which is almost invariably mutated in human cancer. These findings prompted us to investigate whether PP1alpha interferes with oncogenic transformation. The ability of NIH 3T3 cells to form foci after transformation with ras/cyclin D1 was significantly inhibited by co-transfection with PP1alphaT320A, but not PP1alpha. Likewise, cells expressing PP1alphaT320A or PP1alphaT320A fused to green fluorescent protein (GFP) were unable to form colonies in soft agar, regardless of whether PP1alpha constructs were co-transfected with ras/cyclin D1 or transfected into stably transformed cells. Overexpressed wild-type (Wt) PP1alpha and GFP-PP1alpha were phosphorylated in Thr320, most likely explaining its lack of effect. Expression of GFP-PP1alphaT320A was associated with caspase-cleaved pRb in Western blots (WB) and morphological signs of cell death. These findings demonstrate that PP1alpha activity can override oncogenic signaling by causing cell-cycle arrest and/or apoptosis rather than restoring contact inhibition or anchorage dependence.
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http://dx.doi.org/10.1002/mc.20191DOI Listing
September 2006

Antilymphoma effects of anti-HLA-DR and CD20 monoclonal antibodies (Lym-1 and Rituximab) on human lymphoma cells.

Cancer Biother Radiopharm 2004 Oct;19(5):545-61

Department of Internal Medicine, University of California-Davis, Davis, CA, USA.

Aim: Anti-HLA-DR and anti-CD20 monoclonal antibodies (MAbs) have been effective for immunotherapy and radioimmunotherapy in non-Hodgkin's lymphoma (NHL). The aim of our study was to compare the antilymphoma effects of Lym-1 and rituximab in human lymphoma cell lines, using assays of viability, apoptosis, antibody-dependent cellular cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC), under conditions relevant to the clinic.

Methods: To characterize response relationships at varied concentrations of Lym-1 and rituximab, growth inhibition and cell death were assayed over 96 hours in four NHL cell lines derived from Burkitt's or large-cell lymphoma patients. Untreated cells and cells treated with an mLym-1 isotype-matched MAb were used as negative controls for direct assays. Western blot was used to detect apoptosis through the activation of caspase-3 and cleavage of poly (ADP-ribase) polymerase (PARP). The indirect cytotoxicity of Lym-1 and rituximab was assayed at varied concentrations, using ADCC activity in the presence of purified peripheral blood leukocytes and CDC activity in the presence of human donor serum.

Results: Lym-1 and rituximab showed significant direct and indirect antilymphoma effects. Lym-1 had a substantial, and statistically greater, effect than rituximab over longer intervals of time. In Raji and B35M cells, Lym-1 induced potent growth inhibition reflected by 90% and 94% reductions in viable cells, respectively, whereas rituximab induced 63% and 56% reductions. Concurrently, Lym-1 increased nonviable cells by 372% and 153% in these cells, respectively, whereas rituximab induced 139% and 43% increases. Lym-1-induced apoptosis was greater than that of rituximab in all cell lines tested. Lym-1, both the chimeric form and the mouse parent, mediate ADCC more effectively, in the presence of a total peripheral blood leukocyte (PBL) population, than does rituximab, although the results for CDC activity were mixed.

Conclusions: In conclusion, Lym-1 had more potent direct and indirect cytotoxic effects than rituximab in lymphoma cells under conditions achievable in patients. Because the HLA-DR target antigen of Lym-1 is enriched on most B-cell lymphomas, these results support its complementary use in patients as an alternative to CD20 for monoimmunotherapy and for combination immunotherapy with rituximab, because the HLA-DR and CD20 antigens are physically and functionally coupled on human B cells.
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http://dx.doi.org/10.1089/cbr.2004.19.545DOI Listing
October 2004

Protein phosphatase 1alpha is required for murine lung growth and morphogenesis.

Dev Dyn 2004 Apr;229(4):791-801

Division of Hematology/Oncology, Department of Pediatrics, Childrens Hospital Los Angeles, University of Southern California School of Medicine, Los Angeles, California, USA.

Protein phosphatase 1 (PP1) plays important roles in cell cycle control and apoptosis, two processes that impinge on morphogenesis and differentiation. Following the precedent set by other molecules regulating the cell cycle and apoptosis, we hypothesized that PP1 may have context-specific roles in development. Therefore, we have studied the spatial and temporal expression of PP1alpha during murine lung development and determined the consequences of loss of PP1alpha function on branching morphogenesis. By using an immunohistochemical approach, we show here that PP1alpha was expressed throughout the epithelium and mesenchyme upon the emergence of the lung primordium on embryonic day 10, with immunostaining exclusively extranuclear. During the late pseudoglandular stage, PP1alpha was predominantly expressed in the distal lung epithelium, whereas the mesenchyme contained very little or no PP1alpha protein. Peri- and postnatally, PP1alpha immunostaining was mostly nuclear in apparently differentiated cells, as judged by colocalization with well-known markers for lung differentiation. Exposure of fetal lung explants to antisense oligodeoxynucleotides against PP1alpha, resulted in decreased overall size of the cultured lung, a defect in forming new airways, lack of expression of surfactant protein C, and histologic signs of poor differentiation. These data suggest that PP1alpha is required for branching morphogenesis and differentiation.
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http://dx.doi.org/10.1002/dvdy.10497DOI Listing
April 2004
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