Publications by authors named "David Bogumil"

26 Publications

  • Page 1 of 1

Marijuana use and perinatal outcomes in obstetric patients at a safety net hospital.

Eur J Obstet Gynecol Reprod Biol 2021 Nov 16;266:36-41. Epub 2021 Sep 16.

Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Objective: To characterize the association between antepartum marijuana exposure and maternal and neonatal outcomes at our institution.

Study Design: Retrospective chart review identified an obstetric cohort of singleton gestations. Women with self-reported marijuana use were compared with non-users. Demographic characteristics, risk factors, and maternal-fetal outcomes were evaluated. Associations between outcomes and marijuana use were assessed with regression analysis.

Results: Of 2792 deliveries, 5.4% reported marijuana use. Compared to non-users, marijuana users entered prenatal care later, were younger, non-Hispanic, and used other illicit substances. Marijuana users had a higher rate of cesarean delivery (p = 0.01). After adjusting for confounders, marijuana use remained associated with 4.1-fold risk of delivering a small for gestational age (SGA) infant and 2.89-fold risk of neonatal oxygen use.

Conclusion: At a safety net hospital, antepartum marijuana use is significantly associated with cesarean delivery, SGA and supplemental oxygen use at birth. Healthcare disparities associated with marijuana use make this a population of critical interest.
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http://dx.doi.org/10.1016/j.ejogrb.2021.09.015DOI Listing
November 2021

Association of Genetic Risk Score With NAFLD in An Ethnically Diverse Cohort.

Hepatol Commun 2021 10 18;5(10):1689-1703. Epub 2021 Jun 18.

Department of Preventive Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA.

Most genetic studies of nonalcoholic fatty liver disease (NAFLD) have been conducted in Whites. In this large and ethnically diverse cohort, we assessed the transportability of previously identified genetic variants for NAFLD, built a genetic risk score (GRS), and examined its association with NAFLD risk in multiple ethnic groups. Thirty previously identified genome-wide association studies (GWAS) variants (P < 5 × 10 ) and 17 other variants associated with NAFLD were examined in a nested case-control study of NAFLD (1,448 cases/8,444 controls) in this multi-ethnic cohort study. We then built a GRS using 11 independent single-nucleotide polymorphisms from these prior studies and examined its association with NAFLD by cirrhosis status across multiple ethnic groups. Of the 30 GWAS SNPs, 20 (67%) were replicated (P < 0.05) in the pooled multi-ethnic population. The highest percentage of replication was seen in Latinos (43%), followed by Japanese Americans (37%), Whites (17%), and Native Hawaiians and African Americans (≤10%). Several genetic variants, including those in PNPLA3 (patatin-like phospholipase domain containing 3), HSD17B13 (hydroxysteroid 17-beta dehydrogenase 13), TM6SF2 (transmembrane 6 superfamily member 2), GATAD2A (GATA zinc finger domain containing 2A), GCKR (glucokinase regulator), SUGP1 (SURP and G-patch domain containing 1), MBOAT7 (membrane bound O-acyltransferase domain containing 7), TRIB1 (tribbles pseudokinase 1), SAMM50 (sorting and assembly machinery component), and ERLIN1 (ER lipid raft associated 1)-CHUK (component of inhibitor of nuclear factor kappa B kinase complex)-CWF19L1 (CWF19 like cell cycle control factor 1) gene cluster, were replicated in at least two ethnic groups. An 11-SNP weighted GRS was associated with NAFLD risk in the multi-ethnic population (odds ratio [OR] per SD increase = 1.41; 95% confidence interval [CI] = 1.32-1.50), as well as in each ethnic group (OR ranged from 1.30 in African Americans to 1.52 in Latinos). The GRS-NAFLD association was stronger for NAFLD with cirrhosis (OR = 1.67; 95% CI = 1.46-1.92) compared to NAFLD without cirrhosis (OR = 1.37; 95% CI = 1.28-1.46) (P = 0.003). Conclusion: In this ethnically diverse cohort, we replicated several key genetic variants for NAFLD and showed the utility of GRS based on the risk alleles for NAFLD risk stratification in multiple ethnic groups.
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http://dx.doi.org/10.1002/hep4.1751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485887PMC
October 2021

Genome-wide association study of pancreatic fat: The Multiethnic Cohort Adiposity Phenotype Study.

PLoS One 2021 30;16(7):e0249615. Epub 2021 Jul 30.

University of Hawaii Cancer Center, University of Hawaii at Mānoa, Honolulu, Hawaii, United States of America.

Several studies have found associations between higher pancreatic fat content and adverse health outcomes, such as diabetes and the metabolic syndrome, but investigations into the genetic contributions to pancreatic fat are limited. This genome-wide association study, comprised of 804 participants with MRI-assessed pancreatic fat measurements, was conducted in the ethnically diverse Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS). Two genetic variants reaching genome-wide significance, rs73449607 on chromosome 13q21.2 (Beta = -0.67, P = 4.50x10-8) and rs7996760 on chromosome 6q14 (Beta = -0.90, P = 4.91x10-8) were associated with percent pancreatic fat on the log scale. Rs73449607 was most common in the African American population (13%) and rs79967607 was most common in the European American population (6%). Rs73449607 was also associated with lower risk of type 2 diabetes (OR = 0.95, 95% CI = 0.89-1.00, P = 0.047) in the Population Architecture Genomics and Epidemiology (PAGE) Study and the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM), which included substantial numbers of non-European ancestry participants (53,102 cases and 193,679 controls). Rs73449607 is located in an intergenic region between GSX1 and PLUTO, and rs79967607 is in intron 1 of EPM2A. PLUTO, a lncRNA, regulates transcription of an adjacent gene, PDX1, that controls beta-cell function in the mature pancreas, and EPM2A encodes the protein laforin, which plays a critical role in regulating glycogen production. If validated, these variants may suggest a genetic component for pancreatic fat and a common etiologic link between pancreatic fat and type 2 diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249615PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323875PMC
October 2021

The association between ambient air pollutants and pancreatic cancer in the Multiethnic Cohort Study.

Environ Res 2021 11 30;202:111608. Epub 2021 Jun 30.

Department of Preventive Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA. Electronic address:

Background: Prior studies examining the association between ambient air pollutants and pancreatic cancer have been conducted in racially/ethnically homogeneous samples and have produced mixed results, with some studies supporting evidence of an association with fine particulate matter.

Methods: To further investigate these findings, we estimated exposure levels of particulate matter (PM, PM) and oxides of nitrogen (NO, and NO) using kriging interpolation for 100,527 men and women from the Multiethnic Cohort Study, residing largely in Los Angeles County from 1993 through 2013. We measured the association between these air pollutants and incident pancreatic cancer using Cox proportional hazards models with time-varying pollutant measures, with adjustment for confounding factors.

Results: A total of 821 incident pancreatic cancer and 1,660,488 person-years accumulated over the study period, with an average follow-up time of over 16 years. PM (per 10 μg/m) was associated with incident pancreatic cancer (hazard ratio [HR] = 1.61; 95% CI, 1.09, 2.37). This PM -association was strongest among Latinos (HR = 3.59; 95% CI, 1.60, 8.06) and ever smokers (HR = 1.76; 95% CI, 1.05, 2.94). There was no association for PM (HR = 1.12; 95% CI, 0.94, 1.32, per 10 μg/m), NO (HR = 1.14; 95% CI, 0.88, 1.48, per 50 ppb), or NO (HR = 1.14; 95% CI, 0.85, 1.54, per 20 ppb).

Conclusions: Our findings support prior research identifying an association between fine particulate matter, PM, and pancreatic cancer. Although not statistically heterogeneous, this association was most notable among Latinos and smokers. Future studies are needed to replicate these results in an urban setting and in a racially/ethnically diverse population.
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http://dx.doi.org/10.1016/j.envres.2021.111608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8578294PMC
November 2021

Red meat consumption, cooking mutagens, NAT1/2 genotypes and pancreatic cancer risk in two ethnically diverse prospective cohorts.

Int J Cancer 2021 Apr 12. Epub 2021 Apr 12.

Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

There is limited evidence on the association between red meat consumption and pancreatic cancer among ethnic minorities. We assessed this relationship in two large prospective cohorts: the Multiethnic Cohort Study (MEC) and the Southern Community Cohort Study (SCCS). Demographic, dietary and other risk factor data were collected at cohort entry. Red meat intake was assessed using cohort-specific validated food frequency questionnaires. Incident pancreatic cancer cases were identified via linkages to state cancer registries. Cox regression was used to calculate relative risks (RRs) and 95% confidence intervals (CIs) for the association of red meat intake with pancreatic cancer risk in each cohort. We performed additional analyses to evaluate cooking methods, mutagens and effect modification by NAT1/2 genotypes. From a total of 184 542 (MEC) and 66 793 (SCCS) at-risk participants, we identified 1618 (MEC) and 266 (SCCS) incident pancreatic cancer cases. Red meat consumption was associated with pancreatic cancer risk in the MEC (RR 1.18, 95% CI 1.02-1.37) and with borderline statistical significance in the SCCS (RR 1.31, 95% CI 0.93-1.86). This association was significant in African Americans (RR 1.49, 95% CI 1.06-2.11) and Latinos (RR 1.44, 95% CI 1.02-2.04) in the MEC, and among African Americans (RR 1.55, 95% CI 1.03-2.33) in the SCCS. NAT2 genotypes appeared to modify the relationship between red meat and pancreatic cancer in the MEC (p = 0.03). Our findings suggest that the associations for red meat may be strongest in African Americans and Latinos. The mechanisms underlying the increased risk for these populations should be further investigated.
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http://dx.doi.org/10.1002/ijc.33598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8594451PMC
April 2021

Replication and Genetic Risk Score Analysis for Pancreatic Cancer in a Diverse Multiethnic Population.

Cancer Epidemiol Biomarkers Prev 2020 12 21;29(12):2686-2692. Epub 2020 Sep 21.

Department of Preventive Medicine, Keck School of Medicine of University of Southern California, Los Angeles, California.

Background: Genome-wide association studies (GWAS) have identified several SNPs associated with pancreatic cancer. No studies yet have attempted to replicate these SNPs in US minority populations. We aimed to replicate the associations of 31 GWAS-identified SNPs with pancreatic cancer and build and test a polygenic risk score (PRS) for pancreatic cancer in an ethnically diverse population.

Methods: We evaluated 31 risk variants in the Multiethnic Cohort and the Southern Community Cohort Study. We included 691 pancreatic ductal adenocarcinoma (PDAC) cases and 13,778 controls from African-American, Japanese-American, Latino, Native Hawaiian, and white participants. We tested the association between each SNP and PDAC, established a PRS using the 31 SNPs, and tested the association between the score and PDAC risk.

Results: Eleven of the 31 SNPs were replicated in the multiethnic sample. The PRS was associated with PDAC risk [OR top vs. middle quintile = 2.25 (95% confidence interval, 1.73-2.92)]. Notably, the PRS was associated with PDAC risk in all ethnic groups except Native Hawaiian (OR per risk allele ranged from 1.33 in Native Hawaiians to 1.91 in African Americans; heterogeneity = 0.12).

Conclusions: This is the first study to replicate 11 of the 31 GWAS-identified risk variants for pancreatic cancer in multiethnic populations, including African Americans, Japanese Americans, and Latinos. Our results also suggest a potential utility of PRS with GWAS-identified risk variants for the identification of individuals at increased risk for PDAC across multiple ethnic groups.

Impact: PRS can potentially be used to stratify pancreatic cancer risk across multiple ethnic groups.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710597PMC
December 2020

Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer.

Nat Commun 2020 06 24;11(1):3175. Epub 2020 Jun 24.

Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, 464-8681, Japan.

Pancreatic cancer is the fourth leading cause of cancer-related deaths in Japan. To identify risk loci, we perform a meta-analysis of three genome-wide association studies comprising 2,039 pancreatic cancer patients and 32,592 controls in the Japanese population. Here, we identify 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P < 5.0 × 10), of which 16p12.3 has not been reported in the Western population. The lead single nucleotide polymorphism (SNP) at 16p12.3 is rs78193826 (odds ratio = 1.46, 95% confidence interval = 1.29-1.66, P = 4.28 × 10), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant. Associations between selected GP2 gene variants and pancreatic cancer are replicated in 10,822 additional cases and controls of East Asian origin. Functional analyses using cell lines provide supporting evidence of the effect of rs78193826 on KRAS activity. These findings suggest that GP2 gene variants are probably associated with pancreatic cancer susceptibility in populations of East Asian ancestry.
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http://dx.doi.org/10.1038/s41467-020-16711-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314803PMC
June 2020

Incident testicular cancer in relation to using marijuana and smoking tobacco: A systematic review and meta-analysis of epidemiologic studies.

Urol Oncol 2020 07 12;38(7):642.e1-642.e9. Epub 2020 May 12.

Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA; Department of Obstetrics and Gynecology, Keck School of Medicine of USC, Los Angeles, CA. Electronic address:

Background: Recent epidemiologic studies identified credible associations between marijuana smoking and risk of nonseminomatous testicular germ cell tumors (TGCTs), but did not distinguish exposure to cannabinoid compounds from exposure to other constituents of smoke.

Methods: We implemented a systematic review of scholarly literature followed by random effects meta-analysis to quantitatively synthesize published data relating incident TGCT to each of 2 exposure histories: ever using marijuana, and ever smoking tobacco.

Results: We identified four epidemiologic studies of marijuana use and 12 of tobacco smoking. Summary data concur with earlier reports of a specific association of marijuana use with nonseminoma, summary odds ratio [sOR] = 1.71 (95% confidence interval [CI] 1.12-2.60), and identify a positive association, sOR = 1.18 (95% CI 1.05-1.33), between tobacco smoking and all TGCT.

Conclusions: Available data accord with positive associations between incident TGCT and each exposure, implicating both cannabinoid compounds and other constituents of smoke. Etiologic interpretation awaits epidemiologic studies that assess associations between tobacco smoking and nonseminomatous TGCT, investigating not only these exposures but also both co-use of tobacco and marijuana and smoke-free sources of cannabinoids, while adequately evaluating potential confounding among all of these exposures.
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http://dx.doi.org/10.1016/j.urolonc.2020.03.013DOI Listing
July 2020

A Systematic Review of the Efficacy of Preclinical Models of Lung Cancer Drugs.

Front Oncol 2020 23;10:591. Epub 2020 Apr 23.

Department of Medical Oncology, Norris Comprehensive Cancer Center, Los Angeles, CA, United States.

Preclinical cell models are the mainstay in the early stages of drug development. We sought to explore the preclinical data that differentiated successful from failed therapeutic agents in lung cancer. One hundred thirty-four failed lung cancer drugs and twenty seven successful lung cancer drugs were identified. Preclinical data were evaluated. The independent variable for cell model experiments was the half maximal inhibitory concentration (IC50), and for murine model experiments was tumor growth inhibition (TGI). A logistic regression was performed on quartiles (Q) of IC50s and TGIs. We compared odds of approval among drugs defined by IC50 and TGI quartile. Compared to drugs with preclinical cell experiments in highest IC50 quartile (Q4, IC50 345.01-100,000 nM), those in Q3 differed little, but those in the lower two quartiles had better odds of being approved. However, there was no significant monotonic trend identified (P-trend 0.4). For preclinical murine models, TGI values ranged from -0.3119 to 1.0000, with a tendency for approved drugs to demonstrate poorer inhibition than failed drugs. Analyses comparing success of drugs according to TGI quartile produced interval estimates too wide to be statistically meaningful, although all point estimates accord with drugs in Q2-Q4 (TGI 0.5576-0.7600, 0.7601-0.9364, 0.9365-1.0000) having lower odds of success than those in Q1 (-0.3119-0.5575). There does not appear to be a significant linear trend between preclinical success and drug approval, and therefore published preclinical data does not predict success of therapeutics in lung cancer. Newer models with predictive power would be beneficial to drug development efforts.
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http://dx.doi.org/10.3389/fonc.2020.00591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190806PMC
April 2020

Reply to: Comment on "Comparing the two-finger versus two-thumb technique for single person infant CPR: A systematic review and meta-analysis".

Resuscitation 2020 05 24;150:196. Epub 2020 Mar 24.

Department of Preventive Medicine, Keck School of Medicine, University of Southern California, United States.

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http://dx.doi.org/10.1016/j.resuscitation.2020.02.041DOI Listing
May 2020

Comparing the two-finger versus two-thumb technique for single person infant CPR: A systematic review and meta-analysis.

Resuscitation 2020 03 20;148:161-172. Epub 2020 Jan 20.

Department of Preventive Medicine, Keck School of Medicine, University of Southern California, United States.

Introduction: Current guidelines recommend that single person cardiopulmonary resuscitation (CPR) on an infant should be performed with two-fingers just below the inter-mammillary line with the hand clenched, while two-person CPR should be performed with two-thumbs with the hands encircling the chest. Those recommendations are based on literature that demonstrates higher quality chest compressions with the two-thumb technique, with concerns that this technique may compromise ventilation parameters when performed by the single rescuer. The purpose of this study is to compare the two compression techniques' performance during CPR using both compression and ventilation parameters.

Methods: We performed a systematic review and meta-analysis of literature identified through a search of PubMed and One-Search comparing the quality of chest compressions and ventilation parameters between the two-thumb and two-finger techniques (Prospero registration # CRD42018087672).

Results: We identified 20 manuscripts examining single person infant CPR that met study criteria, with 16 that included data suitable for meta-analysis. All of the studies included in the analysis were performed on a standardized manikin. Overall, the two-thumb technique resulted in a mean difference of 5.61 mm greater compression depth compared to the two-finger technique, with 36.91% more compressions of adequate depth per national guidelines. Interestingly, ventilation parameters did not differ between the two techniques.

Conclusion: While recognizing that the results of this review may differ from actual clinical experience due to the lack of fidelity between manikins and actual human infants, this systematic review with meta-analysis demonstrates that when CPR is performed on a simulated infant manikin by a single rescuer, the two-thumb technique with hands encircling the chest improves chest compression quality and does not appear to compromise ventilation.
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http://dx.doi.org/10.1016/j.resuscitation.2019.12.039DOI Listing
March 2020

Unravelling plasmidome distribution and interaction with its hosting microbiome.

Environ Microbiol 2020 01 15;22(1):32-44. Epub 2019 Dec 15.

Faculty of Natural Sciences, Department of Life Sciences, The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, P.O.B. 653 Beer-Sheva, Building 41, Room 228, Beer-Sheva, Israel.

Horizontal gene transfer via plasmids plays a pivotal role in microbial evolution. The forces that shape plasmidomes functionality and distribution in natural environments are insufficiently understood. Here, we present a comparative study of plasmidomes across adjacent microbial environments present in different individual rumen microbiomes. Our findings show that the rumen plasmidome displays enormous unknown functional potential currently unannotated in available databases. Nevertheless, this unknown functionality is conserved and shared with published rat gut plasmidome data. Moreover, the rumen plasmidome is highly diverse compared with the microbiome that hosts these plasmids, across both similar and different rumen habitats. Our analysis demonstrates that its structure is shaped more by stochasticity than selection. Nevertheless, the plasmidome is an active partner in its intricate relationship with the host microbiome with both interacting with and responding to their environment.
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http://dx.doi.org/10.1111/1462-2920.14813DOI Listing
January 2020

FEAST: fast expectation-maximization for microbial source tracking.

Nat Methods 2019 07 10;16(7):627-632. Epub 2019 Jun 10.

Department of Computer Science, University of California Los Angeles, Los Angeles, CA, USA.

A major challenge of analyzing the compositional structure of microbiome data is identifying its potential origins. Here, we introduce fast expectation-maximization microbial source tracking (FEAST), a ready-to-use scalable framework that can simultaneously estimate the contribution of thousands of potential source environments in a timely manner, thereby helping unravel the origins of complex microbial communities ( https://github.com/cozygene/FEAST ). The information gained from FEAST may provide insight into quantifying contamination, tracking the formation of developing microbial communities, as well as distinguishing and characterizing bacteria-related health conditions.
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http://dx.doi.org/10.1038/s41592-019-0431-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8535041PMC
July 2019

High-Quality Diets Are Associated With Reduced Risk of Hepatocellular Carcinoma and Chronic Liver Disease: The Multiethnic Cohort.

Hepatol Commun 2019 Mar 31;3(3):437-447. Epub 2019 Jan 31.

Department of Preventive Medicine, Keck School of Medicine University of Southern California Los Angeles CA.

Hepatocellular carcinoma (HCC) and chronic liver disease (CLD) are major sources of morbidity and mortality globally. Both HCC incidence and CLD mortality are known to vary by race. There is limited research on the association between dietary measures and these outcomes in a diverse population. We prospectively investigated the associations between four diet quality index (DQI) scores (Healthy Eating Index-2010, Alternative Healthy Eating Index-2010, Alternate Mediterranean Diet [aMED], and Dietary Approaches to Stop Hypertension), HCC incidence, and CLD mortality in the Multiethnic Cohort. We analyzed data from 169,806 African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites, aged 45 to 75 years. DQI scores were calculated by using a validated food frequency questionnaire administered at baseline. During an average 17 years of follow-up, 603 incident cases of HCC and 753 CLD deaths were identified among study participants. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for each DQI were estimated using Cox regression. Higher aMED scores, reflecting favorable adherence to a healthful diet, were associated with a lower risk of HCC (quintile [Q]5 versus Q1 HR, 0.68; 95% CI, 0.51-0.90; trend, = 0.02). In racial/ethnic-specific analyses, there was no significant heterogeneity across groups (interaction, = 0.32); however, the association only remained statistically significant among Latinos (Q4 versus Q1 HR, 0.47; 95% CI, 0.29-0.79; trend, = 0.006). All DQI measures were inversely associated with CLD mortality, with no significant heterogeneity by race/ethnicity. Higher aMED scores were associated with a lower risk of HCC. A higher score of any DQI was associated with a lower risk of CLD mortality. These results suggest that better diet quality may reduce HCC incidence and CLD mortality.
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http://dx.doi.org/10.1002/hep4.1313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396362PMC
March 2019

Man-made microbial resistances in built environments.

Nat Commun 2019 02 27;10(1):968. Epub 2019 Feb 27.

Institute of Environmental Biotechnology, Graz University of Technology, Petersgasse 12/I, Graz, 8010, Austria.

Antimicrobial resistance is a serious threat to global public health, but little is known about the effects of microbial control on the microbiota and its associated resistome. Here we compare the microbiota present on surfaces of clinical settings with other built environments. Using state-of-the-art metagenomics approaches and genome and plasmid reconstruction, we show that increased confinement and cleaning is associated with a loss of microbial diversity and a shift from Gram-positive bacteria, such as Actinobacteria and Firmicutes, to Gram-negative such as Proteobacteria. Moreover, the microbiome of highly maintained built environments has a different resistome when compared to other built environments, as well as a higher diversity in resistance genes. Our results highlight that the loss of microbial diversity correlates with an increase in resistance, and the need for implementing strategies to restore bacterial diversity in certain built environments.
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http://dx.doi.org/10.1038/s41467-019-08864-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393488PMC
February 2019

A proteomics approach for the identification of species-specific immunogenic proteins in the Mycobacterium abscessus complex.

Microbes Infect 2019 Apr - May;21(3-4):154-162. Epub 2018 Nov 13.

Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University, Universitaetsstr. 1, 40225, Duesseldorf, Germany.

The Mycobacterium abscessus complex can cause fatal pulmonary disease, especially in cystic fibrosis patients. Diagnosing M. abscessus complex pulmonary disease is challenging. Immunologic assays specific for M. abscessus are not available. In this study seven clinical M. abscessus complex strains and the M. abscessus reference strain ATCC19977 were used to find species-specific proteins for their use in immune assays. Six strains showed rough and smooth colony morphotypes simultaneously, two strains only showed rough mophotypes, resulting in 14 separate isolates. Clinical isolates were submitted to whole genome sequencing. Proteomic analysis was performed on bacterial lysates and culture supernatant of all 14 isolates. Species-specificity for M. abscessus complex was determined by a BLAST search for proteins present in all supernatants. Species-specific proteins underwent in silico B- and T-cell epitope prediction. All clinical strains were found to be M. abscessus ssp. abscessus. Mutations in MAB_4099c as a likely genetic basis of the rough morphotype were found in six out of seven clinical isolates. 79 proteins were present in every supernatant, of which 12 are exclusively encoded by all members of M. abscessus complex plus Mycobacterium immunogenum. In silico analyses predicted B- and T-cell epitopes in all of these 12 species-specific proteins.
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http://dx.doi.org/10.1016/j.micinf.2018.10.006DOI Listing
February 2020

Two-thumb-encircling advantageous for lay responder infant CPR: a randomised manikin study.

Arch Dis Child 2019 06 14;104(6):530-534. Epub 2018 Jul 14.

Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

Objective: Paediatric health providers and educators influence infant mortality through advocacy and training within families and communities. This research sought to establish the efficacy and training of two-finger versus two-thumb-encircling techniques for lone responder infant chest compressions with ventilations in initially trained infant caregivers.

Design: This is a randomised, cross-over educational intervention assessed on instrumented manikins using the 2015 guideline measures of quality infant cardiopulmonary resuscitation (CPR). Additional subjective data on the experience were collected through self-reporting.

Setting: Non-healthcare community organisations and secondary school classrooms.

Participants: Fourteen years or older, fluent in English and had not taken infant CPR in the last 5 years.

Interventions: Groups of eight participants were randomised to learn one technique, practised and then tested for 8 min. After a 30 min rest, the group repeated the process using the other technique.

Main Outcome Measures: Mean chest compression depth and rate, compression fraction, and correct hand position; tiredness and pain as reported by the caregiver.

Results: The two-thumb-encircling technique achieved a deeper mean compression depth over the 8 min period (2.0 mm, p<0.01), closer to the minimum recommendation of 40 mm; the two-finger technique achieved higher percentages of compression fraction and complete recoil. Caregivers preferred the two-thumb technique (64%), and of these 70% had long fingernails.

Conclusions: The two-thumb-encircling technique improved compression depth, over an 8 min scenario, and was preferred by caregivers. This adds to the existing literature on the advantages of two-thumb-encircling as a technique for lone and team infant CPR, which counters current guidelines.
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http://dx.doi.org/10.1136/archdischild-2018-314893DOI Listing
June 2019

Pediatric dog bites: a population-based profile.

Inj Prev 2019 08 8;25(4):290-294. Epub 2018 Feb 8.

Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

Background: Previous studies have identified risk factors for dog bites in children, but use data from individual trauma centers, with limited generalizability. This study identifies a population risk profile for pediatric dog bites using the National Trauma Data Bank. We hypothesized that the population at risk was younger boys, that such bites occur at home, are moderately severe, and are on the face or neck.

Methods: For this retrospective cross-sectional study, a sample of 7912 children 17 years old and younger with International Classification of Diseases (ICD)-9 event code E906.0, for dog bites, were identified. Datasets from 2007 to 2014 were used. Data included patient's gender, age, ICD-9 primary and location E-codes, AIS body region and AIS severity.

Results: Most children were 6-12 years old and female, but a similar number fell into the narrower range of 0-2 years old. Injuries in the younger group frequently occurred at home, on the face and head, and with minor severity. Age of the child predicts the location of incident (P<0.001), the severity of injury (P<0.001) and the body region of the injury (P<0.001). Body region of the injury predicted its severity (P<0.001).

Discussion: Younger children are more likely to receive dog bites, and bites incurred are likely of greater severity. Children this young cannot yet be taught how to properly interact with a dog.

Conclusions: Dog bites are a significant source of morbidity for children. Based on the population risk factors profile generated, this study recommends targeting live dog education towards the parents of young children.
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http://dx.doi.org/10.1136/injuryprev-2017-042621DOI Listing
August 2019

Prevalence of nonaccidental trauma among children at American College of Surgeons-verified pediatric trauma centers.

J Trauma Acute Care Surg 2017 11;83(5):862-866

From the Division of Pediatric Surgery (D.D.A.B., N.E.D., J.S.U., R.V.B.), Children's Hospital Los Angeles, Los Angeles, California; Department of Pediatrics and Audrey Hepburn Child Advocacy, Response and Evaluation Services Center (K.K.I.), Children's Hospital Los Angeles, Los Angeles, California; and Keck School of Medicine (J.S.U., R.V.B., K.K.I), University of Southern California, Los Angeles, California.

Background: Child abuse remains a national epidemic that has detrimental effects if unnoticed in the clinical setting. Extreme cases of child abuse, or nonaccidental trauma (NAT), have large financial burdens associated with them due to treatment costs and long-term effects of abuse. Clinicians who have additional training and experience with pediatric trauma are better equipped to detect signs of NAT and have more experience reporting it. This additional training and experience can be measured by using the American College of Surgeons (ACS) Pediatric Trauma verification. It is hypothesized that ACS-verified pediatric trauma centers (vPTCs) have an increased prevalence of NAT because of this additional experience and training relative to non-ACS vPTCs.

Methods: The National Trauma Data Bank, for the years 2007 to 2014, was utilized to compare the prevalence of NAT between ACS vPTCs relative to non-ACS vPTCs to produce both crude and Injury Severity Score adjusted prevalence ratio estimates.

Results: The majority of NAT cases across all hospitals were male (58.3%). The mean age of the NAT cases was 2.3 years with a mean Injury Severity Score (ISS) of 11.1. The most common payment method was Medicaid (64.4%). The prevalence of NAT was 1.82 (1.74-1.90) times higher among ACS vPTCs and 1.81 (1.73-1.90) after adjusting for ISS.

Conclusions: The greater prevalence of NAT at vPTCs likely represents a more accurate measure of NAT among pediatric trauma patients, likely due to more experience and training of clinicians.

Level Of Evidence: Prognostic/Epidemiological, Level II.
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http://dx.doi.org/10.1097/TA.0000000000001629DOI Listing
November 2017

Evolution of Chaperonin Gene Duplication in Stigonematalean Cyanobacteria (Subsection V).

Genome Biol Evol 2017 01;9(1):241-252

Institute of General Microbiology, Christian-Albrechts University of Kiel, Am Botanischen Garten 11, Kiel, Germany.

Chaperonins promote protein folding and are known to play a role in the maintenance of cellular stability under stress conditions. The group I bacterial chaperonin complex comprises GroEL, that forms a barrel-like oligomer, and GroES that forms the lid. In most eubacteria the GroES/GroEL chaperonin is encoded by a single-copy bicistronic operon, whereas in cyanobacteria up to three groES/groEL paralogs have been documented. Here we study the evolution and functional diversification of chaperonin paralogs in the heterocystous, multi-seriate filament forming cyanobacterium Chlorogloeopsis fritschii PCC 6912. The genome of C. fritschii encodes two groES/groEL operons (groESL1, groESL1.2) and a monocistronic groEL gene (groEL2). A phylogenetic reconstruction reveals that the groEL2 duplication is as ancient as cyanobacteria, whereas the groESL1.2 duplication occurred at the ancestor of heterocystous cyanobacteria. A comparison of the groEL paralogs transcription levels under different growth conditions shows that they have adapted distinct transcriptional regulation. Our results reveal that groEL1 and groEL1.2 are upregulated during diazotrophic conditions and the localization of their promoter activity points towards a role in heterocyst differentiation. Furthermore, protein-protein interaction assays suggest that paralogs encoded in the two operons assemble into hybrid complexes. The monocistronic encoded GroEL2 is not forming oligomers nor does it interact with the co-chaperonins. Interaction between GroES1.2 and GroEL1.2 could not be documented, suggesting that the groESL1.2 operon does not encode a functional chaperonin complex. Functional complementation experiments in Escherichia coli show that only GroES1/GroEL1 and GroES1/GroEL1.2 can substitute the native operon. In summary, the evolutionary consequences of chaperonin duplication in cyanobacteria include the retention of groESL1 as a housekeeping gene, subfunctionalization of groESL1.2 and neofunctionalization of the monocistronic groEL2 paralog.
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http://dx.doi.org/10.1093/gbe/evw287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381637PMC
January 2017

Recycler: an algorithm for detecting plasmids from de novo assembly graphs.

Bioinformatics 2017 02;33(4):475-482

Blavatnik School of Computer Science, Tel-Aviv University, Tel Aviv, Israel.

Motivation: Plasmids and other mobile elements are central contributors to microbial evolution and genome innovation. Recently, they have been found to have important roles in antibiotic resistance and in affecting production of metabolites used in industrial and agricultural applications. However, their characterization through deep sequencing remains challenging, in spite of rapid drops in cost and throughput increases for sequencing. Here, we attempt to ameliorate this situation by introducing a new circular element assembly algorithm, leveraging assembly graphs provided by a conventional de novo assembler and alignments of paired-end reads to assemble cyclic sequences likely to be plasmids, phages and other circular elements.

Results: We introduce Recycler, the first tool that can extract complete circular contigs from sequence data of isolate microbial genomes, plasmidome and metagenome sequence data. We show that Recycler greatly increases the number of true plasmids recovered relative to other approaches while remaining highly accurate. We demonstrate this trend via simulations of plasmidomes, comparisons of predictions with reference data for isolate samples, and assessments of annotation accuracy on metagenome data. In addition, we provide validation by DNA amplification of 77 plasmids predicted by Recycler from the different sequenced samples in which Recycler showed mean accuracy of 89% across all data types-isolate, microbiome and plasmidome.

Availability And Implementation: Recycler is available at http://github.com/Shamir-Lab/Recycler.

Contact: [email protected]

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btw651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408804PMC
February 2017

DnaK-Dependent Accelerated Evolutionary Rate in Prokaryotes.

Genome Biol Evol 2016 06 3;8(5):1590-9. Epub 2016 Jun 3.

Institute of General Microbiology, Christian-Albrechts Universtiy of Kiel, Kiel, Germany

Many proteins depend on an interaction with molecular chaperones in order to fold into a functional tertiary structure. Previous studies showed that protein interaction with the GroEL/GroES chaperonine and Hsp90 chaperone can buffer the impact of slightly deleterious mutations in the protein sequence. This capacity of GroEL/GroES to prevent protein misfolding has been shown to accelerate the evolution of its client proteins. Whether other bacterial chaperones have a similar effect on their client proteins is currently unknown. Here, we study the impact of DnaK (Hsp70) chaperone on the evolution of its client proteins. Evolutionary parameters were derived from comparison of the Escherichia coli proteome to 1,808,565 orthologous proteins in 1,149 proteobacterial genomes. Our analysis reveals a significant positive correlation between protein binding frequency with DnaK and evolutionary rate. Proteins with high binding affinity to DnaK evolve on average 4.3-fold faster than proteins in the lowest binding affinity class at the genus resolution. Differences in evolutionary rates of DnaK interactor classes are still significant after adjusting for possible effects caused by protein expression level. Furthermore, we observe an additive effect of DnaK and GroEL chaperones on the evolutionary rates of their common interactors. Finally, we found pronounced similarities in the physicochemical profiles that characterize proteins belonging to DnaK and GroEL interactomes. Our results thus implicate DnaK-mediated folding as a major component in shaping protein evolutionary dynamics in bacteria and supply further evidence for the long-term manifestation of chaperone-mediated folding on genome evolution.
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http://dx.doi.org/10.1093/gbe/evw102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898814PMC
June 2016

Integration of two ancestral chaperone systems into one: the evolution of eukaryotic molecular chaperones in light of eukaryogenesis.

Mol Biol Evol 2014 Feb 4;31(2):410-8. Epub 2013 Nov 4.

Institute of Microbiology, Christian-Albrechts-University of Kiel, Kiel, Germany.

Eukaryotic genomes are mosaics of genes acquired from their prokaryotic ancestors, the eubacterial endosymbiont that gave rise to the mitochondrion and its archaebacterial host. Genomic footprints of the prokaryotic merger at the origin of eukaryotes are still discernable in eukaryotic genomes, where gene expression and function correlate with their prokaryotic ancestry. Molecular chaperones are essential in all domains of life as they assist the functional folding of their substrate proteins and protect the cell against the cytotoxic effects of protein misfolding. Eubacteria and archaebacteria code for slightly different chaperones, comprising distinct protein folding pathways. Here we study the evolution of the eukaryotic protein folding pathways following the endosymbiosis event. A phylogenetic analysis of all 64 chaperones encoded in the Saccharomyces cerevisiae genome revealed 25 chaperones of eubacterial ancestry, 11 of archaebacterial ancestry, 10 of ambiguous prokaryotic ancestry, and 18 that may represent eukaryotic innovations. Several chaperone families (e.g., Hsp90 and Prefoldin) trace their ancestry to only one prokaryote group, while others, such as Hsp40 and Hsp70, are of mixed ancestry, with members contributed from both prokaryotic ancestors. Analysis of the yeast chaperone-substrate interaction network revealed no preference for interaction between chaperones and substrates of the same origin. Our results suggest that the archaebacterial and eubacterial protein folding pathways have been reorganized and integrated into the present eukaryotic pathway. The highly integrated chaperone system of yeast is a manifestation of the central role of chaperone-mediated folding in maintaining cellular fitness. Most likely, both archaebacterial and eubacterial chaperone systems were essential at the very early stages of eukaryogenesis, and the retention of both may have offered new opportunities for expanding the scope of chaperone-mediated folding.
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http://dx.doi.org/10.1093/molbev/mst212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907059PMC
February 2014

Cumulative impact of chaperone-mediated folding on genome evolution.

Biochemistry 2012 Dec 10;51(50):9941-53. Epub 2012 Dec 10.

Institute for Genomic Microbiology, Heinrich-Heine University of Düsseldorf, Düsseldorf, Germany.

Molecular chaperones support protein folding and unfolding along with assembly and translocation of protein complexes. Chaperones have been recognized as important mediators between an organismal genotype and phenotype as well as important maintainers of cellular fitness under environmental conditions that induce high mutational loads. Here we review recent studies revealing that the folding assistance supplied by chaperones is evident in genomic sequences implicating chaperone-mediated folding as an influential factor during protein evolution. Interaction of protein with chaperones ensures a proper folding and function, yet an adaptation to obligatory dependence on such assistance may be irreversible, representing an evolutionary trap. A correlation between the requirement for a chaperone and protein expression level indicates that the evolution of substrate-chaperone interaction is bounded by the required substrate abundance within the cell. Accumulating evidence suggests that the utility of chaperones is governed by a delicate balance between their help in mitigating the risks of protein misfolding and aggregate formation on one hand and the slower rate of protein maturation and the energetic cost of chaperone synthesis on the other.
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http://dx.doi.org/10.1021/bi3013643DOI Listing
December 2012

Chaperones divide yeast proteins into classes of expression level and evolutionary rate.

Genome Biol Evol 2012 14;4(5):618-25. Epub 2012 Mar 14.

Institute of Molecular Evolution, Heinrich-Heine University Düsseldorf, Germany.

It has long been known that many proteins require folding via molecular chaperones for their function. Although it has become apparent that folding imposes constraints on protein sequence evolution, the effects exerted by different chaperone classes are so far unknown. We have analyzed data of protein interaction with the chaperones in Saccharomyces cerevisiae using network methods. The results reveal a distinct community structure within the network that was hitherto undetectable with standard statistical tools. Sixty-four yeast chaperones comprise ten distinct modules that are defined by interaction specificity for their 2,691 interacting proteins. The classes of interacting proteins that are in turn defined by their dedicated chaperone modules are distinguished by various physiochemical protein properties and are characterized by significantly different protein expression levels, codon usage, and amino acid substitution rates. Correlations between substitution rate, codon bias, and gene expression level that have long been known for yeast are apparent at the level of the chaperone-defined modules. This indicates that correlated expression, conservation, and codon bias levels for yeast genes are attributable to previously unrecognized effects of protein folding. Proteome-wide categories of chaperone-substrate specificity uncover novel hubs of functional constraint in protein evolution that are conserved across 20 fungal genomes.
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http://dx.doi.org/10.1093/gbe/evs025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381671PMC
August 2012

Chaperonin-dependent accelerated substitution rates in prokaryotes.

Genome Biol Evol 2010 21;2:602-8. Epub 2010 Jul 21.

Institute of Botany III, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Many proteins require the assistance of molecular chaperones in order to fold efficiently. Chaperones are known to mask the effects of mutations that induce misfolding because they can compensate for the deficiency in spontaneous folding. One of the best studied chaperones is the eubacterial GroEL/GroES system. In Escherichia coli, three classes of proteins have been distinguished based on their degree of dependency on GroEL for folding: 1) those that do not require GroEL, 2) those that require GroEL in a temperature-dependent manner, and 3) those that obligately require GroEL for proper folding. The buffering effects of GroEL have so far been observed in experimental regimens, but their effect on genomes during evolution has not been examined. Using 446 sequenced proteobacterial genomes, we have compared the frequency of amino acid replacements among orthologs of 236 proteins corresponding to the three categories of GroEL dependency determined for E. coli. Evolutionary rates are significantly correlated with GroEL dependency upon folding with GroEL dependency class accounting for up to 84% of the variation in amino acid substitution rates. Greater GroEL dependency entails increased evolutionary rates with GroEL obligatory proteins (Class III) evolving on average up to 15% faster than GroEL partially dependent proteins (Class II) and 35% faster than GroEL-independent proteins (Class I). Moreover, GroEL dependency class correlations are strictly conserved throughout all proteobacteria surveyed, as is a significant correlation between folding class and codon bias. The results suggest that during evolution, GroEL-dependent folding increases evolutionary rate by buffering the deleterious effects of misfolding-related mutations.
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http://dx.doi.org/10.1093/gbe/evq044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296371PMC
December 2010
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