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The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding initial triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing novel targets for effective prevention and therapy. Here, we interrogate the differential molecular mechanisms dependent on cell of origin and pathology subtype that determine immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell of origin dependent-epithelial gene signatures revealed that Nt5e/CD73, a cell surface enzyme that is the pacemaker for extracellular adenosine generation, is one of the top 10% of genes over-expressed in murine tumors arising from ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by Imaging Mass Cytometry and High-Performance Liquid Chromatography. Our data indicate that ductal activation of oncogenic mutant Kras results in loss of PTEN and elevated AKT signaling which ultimately releases CD73 suppression. Delivery of CD73 small molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. Analysis in human PDAC subtypes indicates that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC Squamous and Basal Subtypes, considered to have the highest immunosuppression and worst prognosis. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment which is dependent on ductal cell of origin, linking biology with pathological subtype classification, critical components to personalized approaches for PDAC prevention and immunotherapeutic intervention.Abstract Figure

Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-binding protein that deaminates adenosine(A) to inosine(I). A-to-I editing alters post-transcriptional RNA processing making ADAR1 a critical regulator of gene expression. Consequently, Adar1 has been implicated in organogenesis. To determine the role of Adar1 in pancreatic development and homeostasis, we specifically deleted Adar1 from the murine pancreas (Ptf1aCre/+; Adar1Fl/Fl). The resulting mice had stunted growth likely due to malabsorption associated with exocrine pancreas insufficiency. Analyses of pancreases revealed ductal expansion, heightened interferon-stimulated gene expression and an increased influx of immune cells. In addition, we observed an increased prevalence of CD4+ T and natural killer cells in their splenic tissue. These results indicate an association between loss of pancreatic Adar1 with dysregulation of systemic immunity. Concurrent deletion of Adar1 and Mavs, a signaling protein implicated in the innate immune pathway rescued the degenerative phenotype and resulted in normal pancreatic development. Taken together, our work suggests that the primary function of Adar1 in the pancreas is to prevent aberrant activation of the Mavs-mediated innate immune pathway, thereby maintaining pancreatic homeostasis.Summary statementThis work defines the role of Adar1 in pancreatic development and homeostasis.

In 2018, Vagococcus salmoninarum was isolated from two lots of broodstock "coaster" brook trout (Salvelinus fontinalis) containing ~1,500 fish at the Iron River National Fish Hatchery, at which time it was identified as the causative agent of a chronic coldwater streptococcosis epizootic. Clinical signs included exophthalmia, lethargy, erratic swimming and loss of equilibrium. Female fish experienced disproportionately higher morbidity and mortality than male co-inhabitants, and routinely retained eggs following spawning. The most consistent gross clinical sign was heart pallor and turbid pericardial effusion. An attempted treatment using florfenicol was ineffective at halting the epizootic, which spanned more than a year and resulted in >50% mortality before remaining fish were culled. As there is no previous documentation of V. salmoninarum at this hatchery or in this species, it is still unclear what circumstances led to this epizootic. The inability to treat this chronic disease led to the loss of valuable broodstock, hampering ongoing fishery conservation efforts in the Great Lakes Basin.

Heat waves and high air temperature are associated with increased morbidity and mortality. However, the majority of research conducted on this topic is focused on high income areas of the world. Although heat waves have the most severe impacts on vulnerable populations, relatively few studies have studied their impacts in low and middle income countries (LMICs). The aim of this paper is to review the existing evidence in the literature on the impact of heat on human health in LMICs. We identified peer-reviewed epidemiologic studies published in English between January 1980 and August 2018 investigating potential associations between high ambient temperature or heat waves and mortality or morbidity. We selected studies according to the following criteria: quantitative studies that used primary and/or secondary data and report effect estimates where ambient temperature or heat waves are the main exposure of interest in relation to human morbidity or mortality within LMICs. Of the total 146 studies selected, eighty-two were conducted in China, nine in other countries of East Asia and the Pacific, twelve in South Asia, ten in Sub-Saharan Africa, eight in the Middle East and North Africa, and seven in each of Latin America and Europe. The majority of studies (92.9%) found positive associations between heat and human morbidity/mortality. Additionally, while outcome variables and study design differed greatly, most utilized a time-series study design and examined overall heath related morbidity/mortality impacts in an entire population, although it is notable that the selected studies generally found that the elderly, women, and individuals within the low socioeconomic brackets were the most vulnerable to the effects of high temperature. By highlighting the existing evidence on the impact of extreme heat on health in LMICs, we hope to determine data needs and help direct future studies in addressing this knowledge gap. The focus on LMICs is justified by the lack of studies and data studying the health burden of higher temperatures in these regions even though LMICs have a lower capacity to adapt to high temperatures and thus an increased risk.

Vagococcus salmoninarum was identified as the causative agent of a chronic epizootic in broodstock "coaster" brook trout (Salvelinus fontinalis) at the Iron River National Fish Hatchery. The epizootic spanned more than a year, was unresponsive to multiple florfenicol treatments, and resulted in >50% mortality of the affected fish. The decision was made to cull the remaining fish during spawning, which presented an opportunity to more thoroughly examine V. salmoninarum sampling methods, organ tropism and vertical transmission. A newly developed qPCR targeting the pheS gene was used in concert with bacterial culture to show that V. salmoninarum indeed disproportionately affects females and has a tropism for female reproductive tissues. The study demonstrates that some female reproductive tissues (e.g. ovarian fluid, unfertilized eggs) are also an effective option for non-lethal detection. Despite the widespread presence of V. salmoninarum in ovarian fluid and on egg surfaces, we found no evidence of intra-ova transmission.

Athens, Greece has been in economic and social crises after the 2008 global recession, resulting in an increase in wood burning as a cheaper method of residential heating in the winter. Reducing wood burning emissions is a source-specific method to address air quality degradation, and indirectly climate change, through instituting policies aimed at human health co-benefits. In this work, we investigate and quantify the potential health co-benefits from policies reducing outdoor particulate matter (PM) pollution from residential wood burning by assessing the pollution conditions during the 2015 calendar year in Athens, Greece, emphasizing vulnerable populations. We conducted a systematic literature search to extract data regarding effective improvements to outdoor PM due to wood burning interventions, and get a range of potential ambient PM reduction estimates regarding realistic benefits from different interventions. We applied a health impact assessment methodology and used existing Athens specific data to calculate the preventable daily average non-accidental deaths associated with reducing PM, additionally considering low and high socioeconomic status (SES) groups. We found that the reduction in outdoor PM concentration showed the potential to benefit lower SES groups as much as 13.5 times more than the high SES group, representing an opportunity for policies to improve not only the health of the total population but also improve environmental equity and health disparities.

Background The optimal management of tetralogy of Fallot (TOF) in symptomatic neonates remains unknown. We compared outcomes for those undergoing palliation vs complete repair in the neonatal period. Methods In a retrospective cohort study of symptomatic neonates with TOF who had a neonatal complete repair (group 1, n = 112) or staged repair (group 2, n = 26) from 2000 to 2013, we compared outcomes at 4 time points: neonatal complete repair vs palliation (group 1 vs 2A), neonatal vs later complete repair (group 1 vs 2B), the single vs combined admissions to achieve a complete repair (group 1 vs group 2A + 2B), and cumulative events 2 years after complete repair for both groups. Results Demographics, anatomy, comorbidities, surgical approach, and mortality were similar between groups 1 and 2. Group 1 had a longer duration of cardiopulmonary bypass and deep hypothermic circulatory arrest and more postprocedure cardiac events compared with group 2A; a longer duration of intubation, intensive care, and postprocedure hospital stay compared with groups 2A and 2B; and a longer total hospital stay compared with group 2B. With combined admissions for group 2, there was no difference in the total duration of intensive care, total hospital stay, or reinterventions compared with group 1. Conclusions Both management options result in similar survival; however, early morbidity was greater with neonatal complete repair. The impact of increased neonatal exposures, such as cardiopulmonary bypass, deep hypothermic circulatory arrest, and intensive care, on neurocognitive development requires further study but should be considered when choosing an optimal strategy.

Introduction In-situ interprofessional emergency team training improves participants’ with confidence and knowledge and identifies latent safety threats. This study examined the impact of a structured debrief on an interprofessional perinatal team’s ability to identify latent safety threats and assess competency in managing perinatal emergencies. It was hypothesized that latent safety threats would be reduced and checklist compliance would increase during subsequent in-situ perinatal team training. Methods Two in-situ training sessions were held six months apart. The perinatal emergency response team provided care for a standardized patient with preterm twin gestation. Each session included off-ward delivery and resuscitation of the first infant, transportation to appropriate inpatient units, cesarean delivery, and resuscitation of the second twin. Postpartum hemorrhage ensued, requiring massive transfusion protocol activation. Medical experts assessed team performance with critical action checklists. A structured debrief identified latent safety threats, developed action plans, and reviewed checklist compliance. Checklist compliance rates were analyzed using a z-ratio test. Results The first training session: seven teams (75 staff) completed 75% (292/391) critical action checklist items and identified 34 latent safety threats. Second training session: four teams (45 staff) completed 89% (94/106) critical action checklist items. Ten latent safety threats were mitigated during the second session. Utilizing a z-ratio, a significant difference was detected between the overall checklist compliance rates of the two sessions, z = -3.069, p = .002. Post-hoc power calculation was

Preeclampsia, a serious hypertensive disorder of pregnancy, is characterized by elevated ceramide (CER) content that is responsible for heightened trophoblast cell death rates via apoptosis and autophagy. Whether trophoblast cells undergo necroptosis, a newly characterized form of regulated necrosis, and the potential role of CER in this process remain to be established. Herein, we report that exposure of both JEG3 cells and primary isolated cytotrophoblasts to C16:0 CER in conjunction with a caspase-8 inhibitor (Q-VD-OPh) promoted necroptotic cell death, as evidenced by increased expression and association of receptor-interacting protein kinases RIP1 and RIP3, as well as phosphorylation of mixed lineage kinase domain-like (MLKL) protein. MLKL activation and oligomerization could be abrogated by pretreatment with the necroptosis inhibitor necrostatin-1 (Nec-1). CER+Q-VD-OPH-treated primary trophoblasts displayed striking necrotic morphology along with disrupted fusion processes as evidenced by maintenance of E-cadherin-stained membrane boundaries and reduced glial cell missing-1 expression, but these events were effectively reversed using Nec-1. Of clinical relevance, we established an increased susceptibility to necroptotic cell death in preeclamptic placentae relative to normotensive controls. In preeclampsia, increased necrosome (RIP1/RIP3) protein levels, as well as MLKL activation and oligomerization associated with necrotic cytotrophoblast morphology. In addition, caspase-8 activity was reduced in severe early-onset preeclampsia cases. This study is the first to report that trophoblast cells undergo CER-induced necroptotic cell death, thereby contributing to the increased placental dysfunction and cell death found in preeclampsia.

Objective: To determine whether type and timing of surfactant preparation affect cerebral blood flow (CBF) hemody- namics differently. Study design: Two sites monitoring cerebral hemodynamics during surfactant administration. Beractant (4.0 ml/kg) and poractant (2.5 ml/kg first dose, 1.25 ml/kg subsequent doses) were administered according to the manufacturer. CBF velocity (CBFv) was assessed before and after the first (Site A) and second (Site B) doses of beractant and poractant. Results: At Site A, 10 infants (birth weight 690 ± 133 g) were studied. CBFv decreased 28.9 ± 5.1% following the first dose of surfactant; there were no differences between beractant and poractant. At Site B, 16 infants (birth weight 896 ± 311 g) were studied. CBFv increased 47.4 ± 35.7% after the second dose of beractant and did not change after the second dose of poractant. Conclusion: This is a preliminary report of two related trials examining CBFv responses to beractant and poractant. CBFv decreased similarly after the first dose of beractant and poractant. CBFv increased after the second dose of beractant, but not after poractant. Cerebral hemodynamic responses between the first and second doses may be due to differences in quantities of airway fluid, while second dose differences between beractant and poractant may be due to differences in dose-volume.

This paper presents the results of the first two surveys conducted using the innovative NERD (Norms Evolving in Response to Dilemmas) platform. The structure, results, and analysis of the first two NERD surveys on genomics and human health and salmon genomics are compared. This comparison demonstrates that NERD is a cost-effective and efficient public consultation and experimental tool that has provided insight on public acceptance of new technologies such as genomics.

This study examined the factor structure and psychometric properties of the Beck Depression Inventory-II (BDI-II; A. T. Beck, Steer, & Brown, 1996) in samples of high-school adolescents (N=414; 210 boys and 204 girls, ages 14-18 years). Confirmatory factor analyses provided satisfactory fit estimates for the two- and three-factor oblique solutions reported frequently in the extant literature. The solution to a general factor with domain-specific somatic and cognitive-affective factors was examined as an alternative model to previously established models for the current high-school sample data. Results provided stronger support for the general factor model. Estimates of internal consistency for scores on this instrument were high (coefficient alpha=.92, average interitem correlation=.35). The mean BDI-II total score for the nonclinical samples (M=12.50, SD=10.50) was compared with the mean scores reported for various adolescent normative samples in the extant literature. The BDI-II total score correlated moderately and significantly with scores on self-report measures of hopelessness (r=.63), anxiety (r=.53), and suicide-related behaviors (r=.57), providing support of adequate correlates for the BDI-II. Estimates of known-groups validity were evaluated using data from a small sample of 167 clinical adolescent inpatients. Specific study findings, limitations, and recommendations are discussed.

National stakeholders in health system improvement and patient safety including accreditation bodies have requested health professional educational programs to include multiple interprofessional experiences through didactic and experiential opportunities. Clinical and population health faculty at the University of South Carolina redesigned and expanded an introductory interprofessional course to include more than 500 students from public health, social work, medicine, pharmacy, and nursing. Students participated in 3 live class meetings and completed required online coursework to explore concepts related to social determinants of health and health disparities, health system improvement, patient safety, cultural competency, and ethics to address interprofessional education core competencies. Course modifications and expanded student enrollment improved understanding of key health concepts and appreciation of interprofessional collaboration.

Objective: The study was performed to determine the sensitivity of nuchal thickness measurements for the detection of congenital heart defects (CHD) and to develop an algorithm for estimating patient-specific risk of CHD. Study Design: Nuchal thickness measurements (expressed as multiples of the median) were obtained in 3003 midtrimester fetuses in which postnatal evaluation of the heart was available. The sensitivity and false-positive rate of nuchal thickness threshold values for detecting CHD were used to calculate the area under the receiver operating characteristics curve. Stepwise logistic regression analysis was used to determine the significant predictors of heart defect among nuchal thickness and epidemiologic risk factors. Individual risk of CHD was calculated on the basis of background population risk of major CHD (estimated at 4.4 of 1000) and the product of the likelihood ratios of the significant risk factors from the logistic regression. Results: There were 95 cases of confirmed CHD. Nuchal thickness was statistically significant for the prediction of CHD with an area under the curve=0.58, P =.01. Nuchal thickness and prior child with CHD were the only significant predictors among the multiple risk factors for this disorder. Patient-specific risk estimates for CHD based on these two "markers" were calculated. It was accurate and improved the prediction of CHD, area under the curve=0.63, P Conclusion: Midtrimester nuchal thickness measurement significantly detected postnatally confirmed CHD in chromosomally normal fetuses. We report for the first time a method for estimating individual patient risk of CHD. (Am J Obstet Gynecol 2002;187:1250-3.)

While studies have investigated the physical demands of dance in terms of cardiorespiratory fitness, there are no recent comparisons of cardiorespiratory response to exercise among professional dancers of different genres. Our purpose was to: 1. develop a cardiorespiratory profile of professional dancers; 2. investigate differences in peak and recovery heart rate (HR) between professional modern and ballet dancers using an accelerated 3-minute step test; 3. demonstrate the relationship between cardiorespiratory variables; and 4. investigate the effects of company and work variables on the dancers' cardiorespiratory profiles. We hypothesized greater cardiorespiratory fitness in modern dancers than in ballet dancers, due to the nature of their repertory. Furthermore, we hypothesized that company profiles would reflect differences in work variables. Two hundred and eleven dancers (mean age 24.6 ± 4.7) from nine companies (two modern and seven ballet) performed a 3-minute step test. Demographics, height, mass, blood pressure (BP), smoking history, and resting peak and recovery HR were recorded. Body mass index (BMI) and fitness category were calculated. Independent t-tests were used to compare differences in demographics and cardiorespiratory variables due to genre, MANOVA were conducted to compare differences due to company, and correlations were calculated to determine the relationships between cardiorespiratory variables (p < 0.05). Modern dancers demonstrated higher mass and BMI, lower BP, lower resting HR and HR recovery, and a higher percentage were categorized as "fit" compared to ballet dancers (p < 0.03). There were differences between companies in age, experience, BMI, BP, resting, peak, and recovery HR, and fitness category (p < 0.001). The differences in cardiorespiratory fitness levels that may be related to rigor of repertory, rehearsal and performance seasons, or off-season exercise training are discussed. Results support the need for comprehensive physical fitness screening to identify dancers who could benefit from aerobic conditioning to enhance overall performance preparedness and to minimize fatigue effects.

The molecular components of mammalian circadian clocks are elusive. We have isolated a human gene termed RIGUI that encodes a bHLH/PAS protein 44% homologous to Drosophila period. The highly conserved mouse homolog (m-rigui) is expressed in a circadian pattern in the suprachiasmatic nucleus (SCN), the master regulator of circadian clocks in mammals. Circadian expression in the SCN continues in constant darkness, and a shift in the light/dark cycle evokes a proportional shift of m-rigui expression in the SCN. m-rigui transcripts also appear in a periodic pattern in Purkinje neurons, pars tuberalis, and retina, but with a timing of oscillation different from that seen in the SCN. Sequence homology and circadian patterns of expression suggest that RIGUI is a mammalian ortholog of the Drosophila period gene, raising the possibility that a regulator of circadian clocks is conserved.

A polymorphic CAG repeat was identified in the human alpha 1A voltage-dependent calcium channel subunit. To test the hypothesis that expansion of this CAG repeat could be the cause of an inherited progressive ataxia, we genotyped a large number of unrelated controls and ataxia patients. Eight unrelated patients with late onset ataxia had alleles with larger repeat numbers (21-27) compared to the number of repeats (4-16) in 475 non-ataxia individuals. Analysis of the repeat length in families of the affected individuals revealed that the expansion segregated with the phenotype in every patient. We identified six isoforms of the human alpha 1A calcium channel subunit. The CAG repeat is within the open reading frame and is predicted to encode glutamine in three of the isoforms. We conclude that a small polyglutamine expansion in the human alpha 1A calcium channel is most likely the cause of a newly classified autosomal dominant spinocerebellar ataxia, SCA6.

Many are supportive of approaches that incorporate lay citizens into policy making and risk management decisions. However, a great deal of learning must first take place about how citizen engagement for controversial topics is best accomplished. Online risk communication efforts are increasing in popularity but there is little empirical evidence accrued to demonstrate the effectiveness of such methods. The intention of our overall study is to create a powerful method for in-depth two-way communication with the public and expert communities about complex and sensitive issues at the heart of stem cell (SC) research. The fundamental objective is to raise awareness of SC science with lay citizens by fostering more holistic or “all things considered” ethical judgments. Our risk communication study demonstrates that lay citizens are both interested in, and capable of learning about, complex scientific issues provided the right tools are used to convey information and assess understanding. Our results show that it is worth the time and effort for SC researchers to continue posting podcasts and FAQ’s about their work for non-expert communities to view. In addition, despite having increased our participants’ risk perceptions about induced pluripotent stem (iPS) cell research, almost all were very supportive of this type of research in Canada by the end of the survey. In other words, participants understood that this research did in fact pose some risks and learned a great deal about both the risks and benefits of iPS cell research, and still thought this research was worthwhile to pursue.

Based on my case study of a metropolitan clinic in Southern Ontario, I argue that Ontario midwives are able to meet the needs of religiously and culturally diverse populations. A sizeable majority of study participants embraced diverse religious or spiritual practices and stated that these were complimented by midwifery care. While some clients reported a perception that midwives were willing to accept religious or spiritual perspectives as legitimate in the context of birth, others choose midwives because a religious investment in the virtue of modesty motivated them to seek out a female caregiver. I argue that by practicing the core values of Ontario midwifery (informed choice, continuity of care, and choice of birthplace) and being willing to accept multiple knowledge systems as valid, Ontario midwives enable women to direct the course of their care according to religious or spiritual beliefs and practices.

Purpose. The activity, pharmacokinetics, pharmacodynamics, efficacy, safety, and formulary considerations of dalbavancin are reviewed. Summary. Dalbavancin is a novel second-generation lipoglycopeptide antimicrobial with unique pharmacokinetics and excellent activity against resistant gram-positive pathogens, including methicillin-resistant Staphylococcus aureus. Available only in i.v. form, it exhibits excellent tissue penetration, particularly in the skin, and a long half-life that allows once-weekly administration. Clinically relevant drug interactions involving dalbavancin have not been identified. While sharing a similar mechanism of action and spectrum of activity with other glycopeptides, dalbavancin has demonstrated in vitro and in vivo bactericidal potency superior to that of vancomycin, teicoplanin, and other commonly used antimicrobials. Clinical trials indicate that dalbavancin is efficacious for skin and soft-tissue infections and catheter-related bloodstream infections. Dalbavancin appears to be noninferior to linezolid and superior to vancomycin. Adverse events are mild to moderate and include pyrexia, headache, and nausea. Conclusion. Dalbavancin has enhanced activity against gram-positive bacteria and unique pharmacokinetics compared with existing drugs in its class. It appears to be safe and efficacious for use against common infections, including complicated skin infections and catheter-related bloodstream infections.

Background & Aims The histopathology of nonalcoholic fatty liver disease (NAFLD) is similar to that of alcoholic liver disease. Colonic bacteria are a source of many metabolic products, including ethanol and other volatile organic compounds (VOC) that may have toxic effects on the human host after intestinal absorption and delivery to the liver via the portal vein. Recent data suggest that the composition of the gut microbiota in obese human beings is different from that of healthy-weight individuals. The aim of this study was to compare the colonic microbiome and VOC metabolome of obese NAFLD patients (n = 30) with healthy controls (n = 30). Methods Multitag pyrosequencing was used to characterize the fecal microbiota. Fecal VOC profiles were measured by gas chromatography–mass spectrometry. Results There were statistically significant differences in liver biochemistry and metabolic parameters in NAFLD. Deep sequencing of the fecal microbiome revealed over-representation of Lactobacillus species and selected members of phylum Firmicutes (Lachnospiraceae; genera, Dorea , Robinsoniella , and Roseburia ) in NAFLD patients, which was statistically significant. One member of phylum Firmicutes was under-represented significantly in the fecal microbiome of NAFLD patients (Ruminococcaceae; genus, Oscillibacter ). Fecal VOC profiles of the 2 patient groups were different, with a significant increase in fecal ester compounds observed in NAFLD patients. Conclusions A significant increase in fecal ester VOC is associated with compositional shifts in the microbiome of obese NAFLD patients. These novel bacterial metabolomic and metagenomic factors are implicated in the etiology and complications of obesity.

We have identified and mapped 61 novel and previously described chromosome 17 and X genes, using a human placental cDNA library. These genes were isolated using a gene identification and mapping strategy based on reciprocal probing of arrayed chromosome specific cosmid and cDNA libraries. This strategy scans gridded cosmids for nuclear genes and isolates the expressed sequence by a cosmid to cDNA filter hybridization. Inherent to this approach is the advantage of identifying the corresponding genomic cosmid clone of a particular cDNA. The genomic and cDNA reagents can be used for fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) based mapping to resolve map positions of cDNAs belonging to gene families and those associated with multiple chromosomes. The downstream utility of reagents generated by the reciprocal probing methods is demonstrated in our studies.

In the prefatory Advertisement to an early story, ‘A Calculus at Heaven’ (1944), Norman Mailer wrote: ‘I think its tone gives away the peculiar megalomania of a young writer who is determined to become an important writer.’ (26) Although the choice of subject—the war between the Americans and Japanese in the Pacific—is an obvious one for 1942, Mailer is not, like his predecessors, simply protesting against the organisation of war that propels men helplessly toward their death. Unlike Hemingway, who depicts violence as the manifestation of an incomprehensible force, Mailer believed it to be individually satisfying: ‘life and death and violent action were the fundamentals, and he would find no lie there.’ (47) Unlike the characters in John Dos Passos’ novel, USA, who are deterministically manipulated by destructive social forces, Mailer attempts to show that his characters are being shaped, as they approach death, by forces within themselves.