Excess pancreatic cancer risk due to smoking and modifying effect of quitting smoking: The Multiethnic Cohort Study.

PURPOSE: Risk factors for pancreatic cancer include racial/ethnic disparities and smoking. However, risk trajectories by smoking history and race/ethnicity are unknown. We examined the association of smoking with pancreatic cancer by race/ethnicity to generate age-specific incidence estimates by smoking history. METHODS: We modeled pancreatic cancer incidence by race/ethnicity, age, pack-years, and years-quit using an excess relative risk model for 182,011 Multiethnic Cohort participants. We tested heterogeneity of smoking variables and pancreatic cancer by race/ethnicity and predicted incidence by smoking history. RESULTS: We identified 1,831 incident pancreatic cancer cases over an average 19.3 years of follow-up. Associations of pack-years (p interaction by race/ethnicity = 0.41) and years-quit (p interaction = 0.83) with pancreatic cancer did not differ by race/ethnicity. Fifty pack-years smoked was associated with 91% increased risk (95% CI 54%, 127%) relative to never smokers in the combined sample. Every year quit corresponded to 9% decreased excess risk (95% CI 2%, 15%) from pack-years smoked. Differences in baseline pancreatic cancer risk across racial/ethnic groups (p < 0.001) translated to large differences in risk for smokers at older ages across racial/ethnic groups (65-122 cases per 100,000 at age 70). CONCLUSION: Smoking pack-years were positively associated with elevated pancreatic cancer risk. Predicted risk trajectories showed a high impact of smoking cessation at < 65 years. Although we did not identify significant heterogeneity in the association of pack-years or years quit with pancreatic cancer risk, current smoker risk varied greatly by race/ethnicity in later life due to large differences in baseline risk.

FEAST: fast expectation-maximization for microbial source tracking.

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.

Risk of Alzheimer's disease and related dementia by sex and race/ethnicity: The Multiethnic Cohort Study.

INTRODUCTION: Data are limited for comparison of sex- and race/ethnicity-specific risks of Alzheimer's disease and related dementia (ADRD). METHODS: In the population-based Multiethnic Cohort, we estimated the age-standardized diagnostic incidence rate (ASDIR) and relative risk of late-onset ADRD (n = 16,410) among 105,796 participants based on Medicare claims (1999-2014) by sex and race/ethnicity. RESULTS: The ASDIR for ADRD was higher for women (17.0 per 1000 person-years) than for men (15.3) and varied across African Americans (22.9 in women, 21.5 in men), Native Hawaiians (19.3, 19.4), Latinos (16.8, 14.7), Whites (16.4, 15.5), Japanese Americans (14.8, 13.8), and Filipinos (12.5, 9.7). Similar risk patterns were observed for AD. Adjustment for education and cardiometabolic diseases attenuated the differences. Accounting for deaths from competing causes increased the sex difference, while reducing the racial/ethnic differences. Less racial/ethnic disparity was detected among apolipoprotein E (APOE) e4 carriers. DISCUSSION: More research is needed to understand the sex and racial/ethnic differences in ADRD.

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

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 (RRQ4vsQ1 1.18, 95% CI 1.02-1.37) and with borderline statistical significance in the SCCS (RRQ4vsQ1 1.31, 95% CI 0.93-1.86). This association was significant in African Americans (RRQ4vsQ1 1.49, 95% CI 1.06-2.11) and Latinos (RRQ4vsQ1 1.44, 95% CI 1.02-2.04) in the MEC, and among African Americans (RRQ4vsQ1 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 (pinteraction = 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.

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

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 (PM2.5, PM10) and oxides of nitrogen (NOX, and NO2) 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. PM2.5 (per 10 µg/m3) was associated with incident pancreatic cancer (hazard ratio [HR] = 1.61; 95% CI, 1.09, 2.37). This PM2.5 -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 PM10 (HR = 1.12; 95% CI, 0.94, 1.32, per 10 µg/m3), NOx (HR = 1.14; 95% CI, 0.88, 1.48, per 50 ppb), or NO2 (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, PM2.5, 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.

Unravelling plasmidome distribution and interaction with its hosting microbiome.

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.

Pediatric dog bites: a population-based profile.

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.

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

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: imizrahi@bgu.ac.il. Supplementary information: Supplementary data are available at Bioinformatics online.

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

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.

Plasmid-encoded toxin defence mediates mutualistic microbial interactions.

Gut environments harbour dense microbial ecosystems in which plasmids are widely distributed. Plasmids facilitate the exchange of genetic material among microorganisms while enabling the transfer of a diverse array of accessory functions. However, their precise impact on microbial community composition and function remains largely unexplored. Here we identify a prevalent bacterial toxin and a plasmid-encoded resistance mechanism that mediates the interaction between Lactobacilli and Enterococci. This plasmid is widespread across ecosystems, including the rumen and human gut microbiota. Biochemical characterization of the plasmid revealed a defence mechanism against reuterin, a toxin produced by various gut microbes, such as Limosilactobacillus reuteri. Using a targeted metabolomic approach, we find reuterin to be prevalent across rumen ecosystems with impacts on microbial community structure. Enterococcus strains carrying the protective plasmid were isolated and their interactions with L. reuteri, the toxin producer, were studied in vitro. Interestingly, we found that by conferring resistance against reuterin, the plasmid mediates metabolic exchange between the defending and the attacking microbial species, resulting in a beneficial relationship or mutualism. Hence, we reveal here an ecological role for a plasmid-coded defence system in mediating a beneficial interaction.

Risk Factors for Type 2 Diabetes in the Multiethnic Cohort.

OBJECTIVES: In this report, we investigated the association between established risk factors and type 2 diabetes (T2D) across 5 distinct ethnic groups and explored differences according to T2D definition within the Multiethnic Cohort (MEC) Study. METHODS: Using the full MEC, with participants in Hawaii and Los Angeles (N=172,230), we applied Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All participants completed questionnaires asking about demographics, anthropometrics, lifestyle factors, and regular diet. T2D status was determined from self-reported diagnosis/medication and Medicare claims. We assessed the associations between well-established risk factors and T2D in the full cohort, after stratification by ethnic group, according to the T2D definition, and in a biorepository subset. Effect modification by ethnicity was evaluated using Wald's tests. RESULTS: Overall, 46,500 (27%) participants had an incident T2D diagnosis after a mean follow-up of 17.1±6.9 years. All predictors were significantly associated with T2D: overweight (HR=1.74), obesity (HR=2.90), red meat intake (HR=1.15), short (HR=1.04) and long (HR=1.08) sleep duration, and smoking (HR=1.26) predicted a significantly higher T2D incidence, whereas coffee (HR=0.90) and alcohol (HR=0.78) consumption, physical activity (HR=0.89), and diet quality (HR=0.96) were associated with lower T2D incidence. The strength of these associations was similar across ethnic groups with noteworthy disparities for overweight/obesity, physical activity, alcohol intake, coffee consumption, and diet quality. CONCLUSIONS: These findings confirm the importance of known risk factors for T2D across ethnic groups, but small differences were detected that may contribute to disparate incidence rates in some ethnic groups, especially for obesity and physical activity.

Interethnic Differences in Bladder Cancer Incidence and the Association between Type 2 Diabetes and Bladder Cancer in the Multiethnic Cohort Study.

Background: Research on the association between type 2 diabetes (T2D) and bladder cancer (BCA) risk among non-European ancestry populations is sparse to nonexistent, and most prior studies rely on a single baseline assessment of T2D status. Methods: We estimated the T2D-BCA association using the Multiethnic Cohort Study of 185,059 men and women in California and Hawaii. Participants were African American, European American, Japanese American, Latin American, and Native Hawaiian, ages 45-75 years at enrollment (1993-1996). T2D was assessed by self-report at baseline, follow-up surveys, and Medicare claims. Cases were identified using Surveillance, Epidemiology and End Results Program cancer registries through 2016. Associations were estimated by race/ethnicity using Cox proportional hazards regression. Adjusted attributable fractions (AAF) and cumulative absolute risk of bladder cancer were estimated across groups. Results: Over an average 19.7 years of follow-up 1,890 incident bladder cancer cases were diagnosed. Time-varying T2D was associated with bladder cancer in the multiethnic sample (HR = 1.17; 95% confidence interval, 1.05-1.30); however, the HR did not differ by race/ethnicity (P = 0.85). The AAF was 4.2% in the multiethnic sample and largest among Native Hawaiians (9.8%). Absolute risk of bladder cancer among European Americans without T2D was higher than all other groups with T2D. Conclusion: T2D is significantly associated with bladder cancer risk in a multiethnic sample. Significance: Those with T2D have higher incidence of bladder cancer, regardless of racial/ethnic group. Reducing T2D prevalence could substantially lower bladder cancer incidence among Native Hawaiians due to T2D being more common in this group. High absolute risk of bladder cancer among European Americans, regardless of T2D status, indicates that elevated bladder cancer risk in this group may be due to factors other than T2D. Future studies must explore reasons for this difference in incidence.

Association of Obesity and Type 2 Diabetes with Non-Hodgkin Lymphoma: The Multiethnic Cohort.

BACKGROUND: Given the role of the immune system in non-Hodgkin lymphoma (NHL) etiology, obesity and type 2 diabetes (T2D) may impact NHL development. We examined the association of body mass index (BMI) and T2D with NHL in the multiethnic cohort (MEC). METHODS: The MEC recruited >215,000 participants in Hawaii and Los Angeles from five racial/ethnic groups; NHL cases were identified through cancer registry linkages. T2D status, and BMI at age 21 and cohort entry were derived from repeated self-reports; for T2D, Medicare claims were also applied. HRs and 95% confidence intervals (CI) for BMI and T2D as predictors of NHL were determined using Cox regression adjusted for relevant covariates. RESULTS: Among 192,424 participants, 3,472 (1.8%) with NHL and 68,850 (36%) with T2D after 19.2 ± 6.6 years follow-up, no significant association between T2D and NHL (HR, 1.04; 95% CI, 0.96-1.13) was observed. Stratification by BMI at cohort entry showed a significant association of T2D with NHL among individuals with normal weight only (HR, 1.18; 95% CI, 1.03-1.37). In a model with both BMI values plus T2D, only overweight (HR, 1.13; 95% CI, 1.01-1.26) and obesity (HR, 1.25; 95% CI, 0.99-1.59) at age 21 were associated with NHL incidence. Stratification by sex, race/ethnicity, and NHL subtype indicated no differences. CONCLUSIONS: Our findings suggest an association between T2D and NHL incidence in several subgroups but not in the total population and an elevated risk related to early-life BMI. IMPACT: Excess body weight in early life, rather than T2D, may be a predictor of NHL incidence.

Cumulative impact of chaperone-mediated folding on genome evolution.

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.

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

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.

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

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 × 10-8 ) 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 heterogeneity = 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.

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

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.

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

Background: 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. Methods: 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. Results: 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). Conclusion: 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.

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

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.

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

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.