Geopolitical Analysis of Terror in Selected U.S. Countries

Throughout the world media reports of airplanes crashing into the Twin Towers in New York City and the Pentagon in Washington D.C made the front page of every paper almost instantly after September 11, 2001. This unprecedented media event led to the generation of certain key questions in the ways in which the media reports on terrorism. This research is concerned with the ways in which the U.S media has responded to the 9- 11 terrorist attacks through time and space. In examining how U.S based media responds to terrorist attacks we can begin to understand if this response is helpful or detrimental in adding to terrorism. The purpose of this research is to examine the change in the amount and spatial distribution of terror coverage in the United States

Dynamic distribution modelling of the swamp tigertail dragonflySynthemis eustalacta(Odonata: Anisoptera: Synthemistidae) over a 20‐year bushfire regime

Intensity and severity of bushfires in Australia have increased over the past few decades due to climate change, threatening habitat loss for numerous species. Although the impact of bushfires on vertebrates is well-documented, the corresponding effects on insect taxa are rarely examined, although they are responsible for key ecosystem functions and services. Understanding the effects of bushfire seasons on insect distributions could elucidate long-term impacts and patterns of ecosystem recovery. Here, the authors investigated the effects of recent bushfires, land-cover change, and climatic variables on the distribution of a common and endemic dragonfly, the swamp tigertail (Synthemis eustalacta) (Burmeister, 1839), which inhabits forests that have recently undergone severe burning. The authors used a temporally dynamic species distribution modelling approach that incorporated 20 years of community-science data on dragonfly occurrence and predictors based on fire, land cover, and climate to make yearly predictions of suitability. The authors also compared this to an approach that combines multiple temporally static models that use annual data. The authors found that for both approaches, fire-specific variables had negligible importance for the models, while the percentage of tree and non-vegetative cover were most important. The authors also found that the dynamic model outperformed the static ones, based on cross-validation omission rate. Model predictions indicated temporal variation in area and spatial arrangement of suitable habitat, but no patterns of habitat expansion, contraction, or shifting. These results highlight not only the efficacy of dynamic modelling to capture spatiotemporal variables such as vegetation cover for an endemic insect species, but also provide a novel approach to mapping species distributions with sparse locality records.journal articl

APOBEC-related mutagenesis and neo-peptide hydrophobicity: implications for response to immunotherapy.

Tumor-associated neo-antigens are mutated peptides that allow the immune system to recognize the affected cell as foreign. Cells carrying excessive mutation load often develop mechanisms of tolerance. PD-L1/PD-1 checkpoint immunotherapy is a highly promising approach to overcome these protective signals and induce tumor shrinkage. Yet, the nature of the neo-antigens driving those beneficial responses remains unclear. Here, we show that APOBEC-related mutagenesis - a mechanism at the crossroads between anti-viral immunity and endogenous nucleic acid editing - increases neo-peptide hydrophobicity (a feature of immunogenicity), as demonstrated by in silico computation and in the TCGA pan-cancer cohort, where APOBEC-related mutagenesis was also strongly associated with immune marker expression. Moreover, APOBEC-related mutagenesis correlated with immunotherapy response in a cohort of 99 patients with diverse cancers, and this correlation was independent of the tumor mutation burden (TMB). Combining APOBEC-related mutagenesis estimate and TMB resulted in greater predictive ability than either parameter alone. Based on these results, further investigation of APOBEC-related mutagenesis as a marker of response to anti-cancer checkpoint blockade is warranted

Prevalence of established and emerging biomarkers of immune checkpoint inhibitor response in advanced hepatocellular carcinoma.

The clinical deployment of immune checkpoint inhibitors (ICIs) has created a tandem drive for the identification of biomarkers linked to benefit. Comprehensive genomic profiling was performed to evaluate the frequency of genomic biomarkers of ICI response in 755 patients with advanced hepatocellular carcinoma (HCC). Median age was 62 years' old, 73% were male, 46% had extrahepatic disease, 107 had documented hepatitis C, 96 had hepatitis B and 4 patients were coinfected. Median tumor mutation burden (TMB) was 4 mutations/Mb and only 6 tumors (0.8%) were TMB-high. Out of 542 cases assessed for microsatellite instability (MSI), one (0.2%) was MSI-high and TMB-high. Twenty-seven (4%) patients had POLE/D alterations. One patient had a pathogenic POLE R762W mutation but TMB was 4 mutations/Mb. Forty percent had DNA damage response gene alterations. In a small case series (N=17) exploring the relationship between biomarkers and ICI response, one patient (TMB 15 mutations/Mb, MSI-low) had a sustained complete response to nivolumab lasting > 2 years. Otherwise there were no significant genomic or TMB differences between responders, progressors, and those with stable disease. Overall, markers of genomic instability were infrequent in this cohort. Larger clinically annotated datasets are needed to explore genomic and non-genomic determinants of ICI response in HCC

The 20-Ne(p,n)20-Na Reaction at 120 MeV

This work was supported by the National Science Foundation Grant NSF PHY 81-14339 and by Indiana Universit

Revisiting Epidermal Growth Factor Receptor (EGFR) Amplification as a Target for Anti-EGFR Therapy: Analysis of Cell-Free Circulating Tumor DNA in Patients With Advanced Malignancies.

PurposeTo date, evidence for tissue epidermal growth factor receptor (EGFR) overexpression as a biomarker for anti-EGFR therapies has been weak. We investigated the genomic landscape of EGFR amplification in blood-derived cell-free tumor DNA (cfDNA) across diverse cancers and the role of anti-EGFR therapies in achieving response.MethodsWe assessed EGFR amplification status among 28,584 patients with malignancies evaluated by clinical-grade next-generation sequencing (NGS) of blood-derived cfDNA (54- to 73-gene panel). Furthermore, we curated the clinical characteristics of 1,434 patients at the University of California San Diego who had cfDNA testing by this NGS test.ResultsOverall, EGFR amplification was detected in cfDNA from 8.5% of patients (2,423 of 28,584), most commonly in colorectal (16.3% [458 of 2,807]), non-small-cell lung (9.0% [1,096 of 12,197]), and genitourinary cancers (8.1% [170 of 2,104]). Most patients had genomic coalterations (96.9% [95 of 98]), frequently involving genes affecting other tyrosine kinases (72.4% [71 of 98]), mitogen-activated protein kinase cascades (56.1% [55 of 98]), cell-cycle-associated signals (52.0% [51 of 98]), and the phosphoinositide 3-kinase pathway (35.7% [35 of 98]). EGFR amplification emerged in serial cfDNA after various anticancer therapies (n = 6), including checkpoint inhibitors (n = 4), suggesting a possible role for these amplifications in acquired resistance. Nine evaluable patients with EGFR amplification were treated with anti-EGFR-based regimens; five (55.6%) achieved partial responses, including three patients whose tissue NGS lacked EGFR amplification.ConclusionEGFR amplification was detected in cfDNA among 8.5% of 28,584 diverse cancers. Most patients had coexisting alterations. Responses were observed in five of nine patients who received EGFR inhibitors. Incorporating EGFR inhibitors into the treatment regimens of patients harboring EGFR amplification in cfDNA merits additional study

MHC-I genotype and tumor mutational burden predict response to immunotherapy.

BackgroundImmune checkpoint blockade (ICB) with antibodies inhibiting cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1) (or its ligand (PD-L1)) can stimulate immune responses against cancer and have revolutionized the treatment of tumors. The influence of host germline genetics and its interaction with tumor neoantigens remains poorly defined. We sought to determine the interaction between tumor mutational burden (TMB) and the ability of a patient's major histocompatibility complex class I (MHC-I) to efficiently present mutated driver neoantigens in predicting response ICB.MethodsComprehensive genomic profiling was performed on 83 patients with diverse cancers treated with ICB to determine TMB and human leukocyte antigen-I (HLA-I) genotype. The ability of a patient's MHC-I to efficiently present mutated driver neoantigens (defined by the Patient Harmonic-mean Best Rank (PHBR) score (with lower PHBR indicating more efficient presentation)) was calculated for each patient.ResultsThe median progression-free survival (PFS) for PHBR score < 0.5 vs. ≥ 0.5 was 5.1 vs. 4.4 months (P = 0.04). Using a TMB cutoff of 10 mutations/mb, the stable disease > 6 months/partial response/complete response rate, median PFS, and median overall survival (OS) of TMB high/PHBR high vs. TMB high/PHBR low were 43% vs. 78% (P = 0.049), 5.8 vs. 26.8 months (P = 0.03), and 17.2 months vs. not reached (P = 0.23), respectively. These findings were confirmed in an independent validation cohort of 32 patients.ConclusionsPoor presentation of driver mutation neoantigens by MHC-I may explain why some tumors (even with a high TMB) do not respond to ICB

Screening and Treatment for Subclinical Hypertensive Heart Disease in Emergency Department Patients With Uncontrolled Blood Pressure: A Cost‐effectiveness Analysis

ObjectivesPoorly controlled hypertension (HTN) is extremely prevalent and, if left unchecked, subclinical hypertensive heart disease (SHHD) may ensue leading to conditions such as heart failure. To address this, we designed a multidisciplinary program to detect and treat SHHD in a high‐risk, predominantly African American community. The primary objective of this study was to determine the cost‐effectiveness of our program.MethodsStudy costs associated with identifying and treating patients with SHHD were calculated and a sensitivity analysis was performed comparing the effect of four parameters on cost estimates. These included prevalence of disease, effectiveness of treatment (regression of SHHD, reversal of left ventricular hypertrophy [LVH], or blood pressure [BP] control as separate measures), echocardiogram costs, and participant time/travel costs. The parent study for this analysis was a single‐center, randomized controlled trial comparing cardiac effects of standard and intense (<120/80 mm Hg) BP goals at 1 year in patients with uncontrolled HTN and SHHD. A total of 149 patients (94% African American) were enrolled, 133 (89%) had SHHD, 123 (93%) of whom were randomized, with 88 (72%) completing the study. Patients were clinically evaluated and medically managed over the course of 1 year with repeated echocardiograms. Costs of these interventions were analyzed and, following standard practices, a cost per quality‐adjusted life‐year (QALY) less than $50,000 was defined as cost‐effective.ResultsTotal costs estimates for the program ranged from$117,044 to $119,319. Cost per QALY was dependent on SHHD prevalence and the measure of effectiveness but not input costs. Cost‐effectiveness (cost per QALY less than$50,000) was achieved when SHHD prevalence exceeded 11.1% for regression of SHHD, 4.7% for reversal of LVH, and 2.9% for achievement of BP control.ConclusionsIn this cohort of predominantly African American patients with uncontrolled HTN, SHHD prevalence was high and screening with treatment was cost‐effective across a range of assumptions. These data suggest that multidisciplinary programs such as this can be a cost‐effective mechanism to mitigate the cardiovascular consequences of HTN in emergency department patients with uncontrolled BP.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136283/1/acem13122.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136283/2/acem13122_am.pd

Characteristics of post hoc subgroup analyses of oncology clinical trials: A systematic review

BACKGROUND: Subgroup analyses in clinical trials assess intervention effects on specific patient subgroups, ensuring generalizability. However, they are usually only able to generate hypotheses rather than definitive conclusions. This study examined the prevalence and characteristics of post hoc subgroup analysis in oncology. METHODS: We systematically reviewed published subgroup analyses from 2000 to 2022. We included articles presenting secondary, post hoc, or subgroup analyses of interventional clinical trials in oncology, cancer survivorship, or cancer screening, published separately from the original clinical trial publication. We collected cancer type, year of publication, where and how subgroup analyses were reported, and funding. RESULTS: Out of 16 487 screened publications, 1612 studies were included, primarily subgroup analyses of treatment trials for solid tumors (82%). Medical writers contributed to 31% of articles, and 58% of articles reported conflicts of interest. Subgroup analyses increased significantly over time, with 695 published between 2019 and 2022, compared to 384 from 2000 to 2014. Gastrointestinal tumors (25%) and lymphoid lineage tumors (39%) were the most frequently studied solid and hematological malignancies, respectively. Industry funding and reporting of conflicts of interest increased over time. Subgroup analyses often neglected to indicate their secondary nature in the title. Most authors were from high-income countries, most commonly North America (45%). CONCLUSIONS: This study demonstrates the rapidly growing use of post hoc subgroup analysis of oncology clinical trials, revealing that the majority are supported by pharmaceutical companies, and they frequently fail to indicate their secondary nature in the title. Given the known methodological limitations of subgroup analyses, caution is recommended among authors, readers, and reviewers when conducting and interpreting these studies