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Introduction Tobacco consumption and radon exposure are considered the first and second most common causes of lung cancer, respectively. The aim of this study was to analyze both whether selected genetic polymorphisms in loci that are in DNA repair pathways, are related to non-small-cell lung cancer (NSCLC) and whether they may modulate the association between residential radon exposure and lung cancer in both smokers and never smokers. Methods A multicentre, hospital-based, case–control study with 826 cases and 1201 controls was designed in a radon-prone area. Genotyping was determined in whole blood and residential radon exposure was measured in participants’ dwellings. Results Attending to tobacco exposure, the variant in the gene NBN (rs1805794) was associated with lung cancer in never smokers (OR 2.72; 95%1.44–5.2) and heavy smokers (OR 3.04; 95%CI 1.21–7.69). The polymorphism with the highest lung cancer association was OGG1 (rs125701), showing an OR of 8.04 (95%CI 1.64–58.29) for its homozygous variant genotype in heavy smokers. Attending to indoor radon exposure (>200 Bq/m3), rs1452584, for its homozygous variant genotype, showed the highest association (OR 3.04 (95%CI 1.15–8.48). Conclusion The genes analyzed seem to have no association with the fully adjusted model, but they might modulate lung cancer association when different categories of tobacco consumption are considered (i.e. heavy smokers). This association may similarly be elevated for those individuals having high indoor radon exposures, though at a minor extent.

Heroin intake decreases markedly during proestrus in normally cycling female rats; however, it is not known whether estradiol, progesterone, or both hormones are responsible for these decreases in heroin intake. The purpose of the present study was to examine the roles of estradiol and progesterone in heroin intake by artificially inducing a proestrus state in ovariectomized rats. To this end, ovariectomized female rats were implanted with intravenous catheters and trained to self-administer heroin (0.0075 mg/kg/infusion) on a fixed ratio (FR1) schedule of reinforcement. After 1 week of training, rats were tested at weekly intervals with estradiol (0.005 mg, sc) or vehicle 22 hr before a test session and progesterone (0.125 mg, sc) or vehicle 0.5 hr before a test session to artificially mimic the naturally occurring hormone concentrations characteristic of late proestrus. Administration of estradiol 22 hr prior to testing and progesterone 0.5 hr prior to testing significantly reduced heroin intake relative to the previous training day and vehicle control. It is interesting that this same effect was observed when only estradiol, but not progesterone, was administered. These data suggest that estradiol but not progesterone is responsible for the proestrus-induced decreases in heroin intake previously reported in normally cycling female rats. These findings differ from those reported previously with stimulants and suggest that estrogen-based pharmacotherapies may be of value to women with opioid use disorder. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Lung cancer's radiomic phenotype may potentially inform clinical decision-making with respect to radical radiotherapy. At present there are no validated biomarkers available for the individualisation of radical radiotherapy in lung cancer and the mortality rate of this disease remains the highest of all other solid tumours. MEDLINE was searched using the terms 'radiomics' and 'lung cancer' according to the Preferred Reporting Items for Systematic Reviews and Met-Analyses (PRISMA) guidance. Radiomics studies were defined as those manuscripts describing the extraction and analysis of at least 10 quantifiable imaging features. Only those studies assessing disease control, survival or toxicity outcomes for patients with lung cancer following radical radiotherapy ± chemotherapy were included. Study titles and abstracts were reviewed by two independent reviewers. The Radiomics Quality Score was applied to the full text of included papers. Of 244 returned results, 44 studies met the eligibility criteria for inclusion. End points frequently reported were local (17%), regional (17%) and distant control (31%), overall survival (79%) and pulmonary toxicity (4%). Imaging features strongly associated with clinical outcomes include texture features belonging to the subclasses Gray level run length matrix, Gray level co-occurrence matrix and kurtosis. The median cohort size for model development was 100 (15-645); in the 11 studies with external validation in a separate independent population, the median cohort size was 84 (21-295). The median number of imaging features extracted was 184 (10-6538). The median Radiomics Quality Score was 11% (0-47). Patient-reported outcomes were not incorporated within any studies identified. No studies externally validated a radiomics signature in a registered prospective study. Imaging-derived indices attained through radiomic analyses could equip thoracic oncologists with biomarkers for treatment response, patterns of failure, normal tissue toxicity and survival in lung cancer. Based on routine scans, their non-invasive nature and cost-effectiveness are major advantages over conventional pathological assessment. Improved tools are required for the appraisal of radiomics studies, as significant barriers to clinical implementation remain, such as standardisation of input scan data, quality of reporting and external validation of signatures in randomised, interventional clinical trials.

Microbeam radiotherapy (MRT) is the delivery of spatially fractionated beams that have the potential to offer significant improvements in the therapeutic ratio due to the delivery of micron-sized high dose and dose rate beams. They build on longstanding clinical experience of GRID radiotherapy and more recently lattice-based approaches. Here we briefly overview the preclinical evidence for MRT efficacy and highlight the challenges for bringing this to clinical utility. The biological mechanisms underpinning MRT efficacy are still unclear, but involve vascular, bystander, stem cell and potentially immune responses. There is probably significant overlap in the mechanisms underpinning MRT responses and FLASH radiotherapy that needs to be further defined. (c) 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Background Tumor-based classification of human glioma portends patient prognosis, but considerable unexplained survival variability remains. Host factors (eg, age) also strongly influence survival times, partly reflecting a compromised immune system. How blood epigenetic measures of immune characteristics and age augment molecular classifications in glioma survival has not been investigated. We assess the prognostic impact of immune cell fractions and epigenetic age in archived blood across glioma molecular subtypes for the first time. Methods We evaluated immune cell fractions and epigenetic age in archived blood from the University of California San Francisco Adult Glioma Study, which included a training set of 197 patients with IDH-wild type, 1p19q intact, TERT wild type (IDH/1p19q/TERT-WT) glioma, an evaluation set of 350 patients with other subtypes of glioma, and 454 patients without glioma. Results IDH/1p19q/TERT-WT patients had lower lymphocyte fractions (CD4+ T, CD8+ T, natural killer, and B cells) and higher neutrophil fractions than people without glioma. Recursive partitioning analysis delineated 4 statistically significantly different survival groups for patients with IDH/1p19q/TERT-WT based on an interaction between chronological age and 2 blood immune factors, CD4+ T cells, and neutrophils. Median overall survival ranged from 0.76 years (95% confidence interval = 0.55-0.99) for the worst survival group (n = 28) to 9.72 years (95% confidence interval = 6.18 to not available) for the best (n = 33). The recursive partitioning analysis also statistically significantly delineated 4 risk groups in patients with other glioma subtypes. Conclusions The delineation of different survival groups in the training and evaluation sets based on an interaction between chronological age and blood immune characteristics suggests that common host immune factors among different glioma types may affect survival. The ability of DNA methylation-based markers of immune status to capture diverse, clinically relevant information may facilitate noninvasive, personalized patient evaluation in the neuro-oncology clinic.

The Interior Exploration using Seismic Investigations, Geodesy and Heat Transport (InSight) mission touched down in Elysium Planitia on 26 November 2018, becoming NASA’s eighth successful entry, de...

Purpose The recent implementation of MR-Linacs has highlighted theranostic opportunities of contrast agents in both imaging and radiotherapy. There is a lack of data exploring the potential of superparamagnetic iron oxide nanoparticles (SPIONs) as radiosensitisers. Through preclinical 225 kVp exposures, this study aimed to characterise the uptake and radiobiological effects of SPIONs in tumour cell models in vitro and to provide proof-of-principle application in a xenograft tumour model. Methods SPIONs were also characterised to determine their hydrodynamic radius using dynamic light scattering and uptake was measured using ICP-MS in 6 cancer cell lines; H460, MiaPaCa2, DU145, MCF7, U87 and HEPG2. The impact of SPIONs on radiobiological response was determined by measuring DNA damage using 53BP1 immunofluorescence and cell survival. Sensitisation Enhancement Ratios (SERs) were compared with the predicted Dose Enhancement Ratios (DEFs) based on physical absorption estimations. In vivo efficacy was demonstrated using a subcutaneous H460 xenograft tumour model in SCID mice by following intra-tumoural injection of SPIONs. Results The hydrodynamic radius was found to be between 110 and 130 nm, with evidence of being monodisperse in nature. SPIONs significantly increased DNA damage in all cell lines with the exception of U87 cells at a dose of 1 Gy, 1 h post-irradiation. Levels of DNA damage correlated with the cell survival, in which all cell lines except U87 cells showed an increased sensitivity (P P Conclusions SPIONs showed radiosensitising effects in 5 out of 6 cancer cell lines. No correlation was found between the cell-specific uptake of SPIONs into the cells and DNA damage levels. The in vivo study found a significant decrease in the tumour growth rate.

Objective This study aimed to examine associations of changes in leptin and adiponectin concentrations from birth to age 12 years with adolescent adiposity and cardiometabolic risk in the Health Outcomes and Measures of Environment (HOME) Study, a prospective birth cohort (Cincinnati, Ohio; N = 166). Methods Adiposity and cardiometabolic risk factors were assessed at age 12 years using anthropometry, dual-energy x-ray absorptiometry, and fasting serum biomarkers. Cardiometabolic risk scores were calculated by summing age- and sex- standardized z scores for individual cardiometabolic risk factors. Results Most serum adipocytokine concentrations at birth were not associated with adiposity or cardiometabolic risk outcomes. Leptin and adiponectin concentrations at age 12 years were associated with all outcomes in the expected direction. Adolescents with increasing (β: 4.2; 95% CI: 3.2 to 5.2) and stable (β: 2.2; 95% CI: 1.2 to 3.2) leptin concentrations from birth to age 12 years had higher cardiometabolic risk scores than adolescents with decreasing concentrations (reference group). Adolescents with increasing (e.g., fat mass index = β: -1.04; 95% CI: -1.27 to -0.80) and stable (β: 0.66; 95% CI: -0.92 to -0.40) adiponectin/leptin ratios had more favorable adiposity outcomes than adolescents with decreasing ratios. Conclusions In this cohort, changes in leptin concentrations and adiponectin/leptin ratios over childhood were associated with adiposity and cardiometabolic risk scores, indicating that adipocytokine concentrations are potential biomarkers for predicting excess adiposity and cardiometabolic risk in adolescence.

BackgroundTo reduce lung cancer burden in the US, a better understanding of biological mechanisms in early disease development could provide new opportunities for risk stratification.MethodsIn a nested case-control study, we measured blood leukocyte DNA methylation levels in pre-diagnostic samples collected from 430 men and women in the 1989 CLUE II cohort. Median time from blood drawn to diagnosis was 14 years for all participants. We compared DNA methylation levels by case/control status to identify novel genomic regions, both single CpG sites and differentially methylated regions (DMRs), while controlling for known DNA methylation changes associated with smoking using a previously described pack-years based smoking methylation score. Stratification analyses were conducted by time from blood draw to diagnosis, histology, and smoking status.ResultsWe identified sixteen single CpG sites and forty DMRs significantly associated with lung cancer risk (q < 0.05). The identified genomic regions were associated with genes including H19, HOXA4, RUNX3, BRICD5, PLXNB2, and RP13. For the single CpG sites, the strongest association was noted for cg09736286 in the DIABLO gene (OR [for 1 SD] = 2.99, 95% CI: 1.95-4.59, P-value = 4.81 × 10−7). For the DMRs, we found that CpG sites in the HOXA4 region were hypermethylated in cases compared to controls.ConclusionThe single CpG sites and DMRs that we identified represented significant measurable differences in lung cancer risk, providing new insights into the biological processes of early lung cancer development and potential biomarkers for lung cancer risk stratification.

INTRODUCTION: The aim of this study is to characterize health related quality of life (HRQOL) in Japanese patients after bladder cancer surgery and to perform cross-cultural comparison between Japanese and American patients. METHODS: Firstly, we cross-sectionally assessed HRQOL of 371 patients in Japan using the Bladder Cancer Index (BCI-Japanese). HRQOL of the four groups of patients (native bladder without intravesical therapy, native bladder with intravesical therapy, cystectomy with ileal conduit, and cystectomy with neobladder) were assessed. Secondly, we compared the Japanese with the American cohort (n = 315) from the original BCI paper. After adjusting for age and gender, the differences in each BCI subdomain score was analyzed. RESULTS: Among Japanese patients, the urinary domain function score was significantly lower among the cystectomy with neobladder group, compared to the cystectomy with ileal conduit group (p

Structured AbstractBackgroundPancreatic cancer is projected to become the second leading cause of cancer-related death by 2030 in the United States. DNA methylation (DNAm) age may reflect age-related variations in the biological changes and abnormalities related to cancer development.MethodWe conducted a pooled analysis using prediagnostic blood samples of pancreatic cancer cases and matched controls selected from the Nurses’ Health Study (NHS), the Physician’s Health Study (PHS), and the Health Professionals Follow-up Study (HPFS). We used three DNAm aging clocks (Hannum, Horvath, and PhenoAge) to estimate subjects’ DNAm age, epigenetic age acceleration (AA) and intrinsic epigenetic age acceleration (IEAA) metrics. We performed conditional logistic regression and multivariable Cox proportional hazard regression to examine associations between six AA and IEAA metrics and risk of pancreatic cancer and survival, respectively.ResultsA total of 393 incidence pancreatic cancer cases and 431 matched controls from the NHS, PHS, and HPFS cohorts were included in this analysis. The medians of all three epigenetic AA and three IEAA metrics were consistently above zero (indicating accelerated age) among cases, while they were below zero (indicating decelerated age) among the matched controls. Comparing participants in the highest quartile of age acceleration metrics, the pancreatic cancer risks were significantly increased by 67% to 83% for Hannum and PhenoAge AA or IEAA metrics with minimal of 7- to 9-years accelerated ages. Except for Hovarth AA and IEAA metrics, there were significant dose-response trends, such that higher age accelerations were associated with higher pancreatic cancer risk, but the relationships were nonlinear. Stratified analyses showed heterogeneous associations, varying by participants’ characteristics and by epigenetic AA or IEAA metrics. As time to diagnosis increased, the ORs of pancreatic cancer for the Hannum AA and Horvath AA or IEAA metrics trended upwards, while the ORs for the PhenoAge AA or IEAA and Hannum IEAA metrics trended downward. Overall, we observed no significant association between pancreatic cancer survival and any of the prediagnostic epigenetic AA or IEAA metrics.ConclusionOur results indicate DNAm age acceleration is associated with an increased risk of pancreatic cancer in a nonlinear, dose-response manner. Epigenetic IEAA metrics may be a useful addition to current methods for pancreatic cancer risk prediction.

Heroin intake decreases during the proestrus phase of the estrous cycle in female rats. Circulating concentrations of both estradiol and progesterone peak during proestrus, and it is not known which of these hormones, or their combination, are responsible for these effects. The purpose of this study was to determine the effects of estradiol, progesterone, and their combination on heroin self-administration in female rats. In Experiment 1, the estrous cycle of intact female rats was tracked daily. If a rat was in proestrus, either the estrogen-receptor antagonist, raloxifene, the progesterone-receptor antagonist, mifepristone, or their combination was administered 30 minutes prior to a heroin self-administration session. In this experiment, raloxifene, but not mifepristone, significantly blocked proestrus-associated decreases in heroin intake. In Experiment 2, separate groups of ovariectomized female rats were treated chronically with exogenous estradiol, progesterone, estradiol + progesterone, or vehicle, and heroin intake was examined over a 100-fold dose range. In this experiment, estrogen-treated rats self-administered less heroin than any other group and significantly less heroin than rats treated with progesterone. These data suggest that (1) estradiol but not progesterone is responsible for proestrus-associated decreases in heroin intake and (2) estradiol decreases heroin intake relative to progesterone. These data differ from those reported previously with stimulants and suggest that estrogen-based pharmacotherapies may be of value to women with opioid use disorder.

Per- and polyfluoroalkyl substances (PFAS) exposure may increase adiposity and obesity risk in children. However, no studies have extended these findings into adolescence or identified periods of heightened susceptibility. We estimated associations of repeated pre- and postnatal serum PFAS concentrations with adolescent adiposity and risk of overweight/obesity. We studied 212 mother–offspring pairs from the HOME Study. We quantified serum concentrations of four PFAS in mothers at ~16 week gestation and their children at birth and ages 3, 8, and 12 years. We assessed adiposity at 12 years using anthropometry and dual-energy X-ray absorptiometry. Using multiple informant models, we estimated covariate-adjusted associations of an interquartile range (IQR) increase in log(2)-transformed PFAS for each time period with adiposity measures and tested differences in these associations. Serum perfluorooctanoate (PFOA) and perfluorohexane sulfonate (PFHxS) concentrations during pregnancy were associated with modest increases in central adiposity and risk of overweight/obesity, but there was no consistent pattern for postnatal concentrations. We observed nonlinear associations between PFOA in pregnancy and some measures of adiposity. Overall, we observed a pattern of modest positive associations of gestational PFOA and PFHxS concentrations with central adiposity and the risk of obesity in adolescents, while no pattern was observed for postnatal PFAS concentrations.

Background/objectives Gestational exposure to perfluoroalkyl substances (PFAS), a ubiquitous class of persistent endocrine disrupting chemicals, is associated with increased risk of obesity and cardiometabolic disease. However, it is unclear if gestational PFAS exposure is associated with adiposity trajectories related to adult obesity and cardiometabolic health. Subjects/methods We measured perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononaoic acid, and perfluorohexanesulfonic acid (PFHxS) concentrations in maternal serum collected between 16 weeks gestation and delivery in a cohort of 345 mother-child pairs in Cincinnati, OH (enrolled 2003-06). From age 4 weeks to 12 years, we measured weight and length or height up to eight times and calculated child body mass index (BMI) (1865 repeated measures). Using covariate-adjusted linear mixed models and splines to account for repeated BMI measures and nonlinear BMI patterns, respectively, we estimated the age/magnitude of infancy BMI zenith (~1 year) and childhood BMI nadir (~5 years), BMI accrual from 8 to 12 years, and BMI at age 12 years by PFAS terciles. Results BMI trajectories varied by PFOA concentrations (age × PFOA interaction p value = 0.03). Children born to women with higher PFOA concentrations had lower infancy and early childhood BMI, earlier BMI nadir, accelerating BMI gains in mid-childhood and adolescence, and higher BMI at age 12 years. Some of these associations were non-monotonic. PFOS and PFHxS were not associated with alterations in BMI trajectories, but were monotonically associated with lower BMI across infancy, childhood, and adolescence. Compared to children in the first PFOS tercile, those in the second (β: -0.83; 95% confidence interval (CI): -2.11, 0.51 kg/m2), and third (β: -1.41; 95% CI: -2.65, -0.14 kg/m2) had lower BMI at age 12 years. Conclusions These results suggest that gestational PFOA exposure may be associated with BMI trajectories related to adult obesity and cardiometabolic disease, while PFOS and PFHxS exposure is associated with lower BMI in the first 12 years of life.

Background Though bladder cancer has been the subject of many well-powered genome-wide association studies, the mechanisms involving bladder-cancer-associated single nucleotide polymorphisms (SNPs) remain largely unknown. This study focuses on rs798766, rs401681, rs2294008, and rs8102137, which have been associated with bladder cancer and are also cis-acting methylation quantitative loci (mQTL). Methods Among 412 bladder cancer cases and 424 controls from the Women’s Health Initiative (WHI), we assessed whether the effects of these SNPs on bladder cancer are mediated through proximal DNA methylation changes in pre-diagnostic blood at mQTL-associated CpG sites, which we refer to as natural indirect effects (NIEs). We used a multiple-mediator mediation model for each of the four mQTL adjusted for matching variables and potential confounders, including race/ethnicity, smoking status, and pack-years of smoking. Results While not statistically significant, our results suggest that substantial proportions of the modest effects of rs401681 (ORNIE = 1.05, 95% confidence interval (CI) = 0.89 to 1.25; NIE percent = 98.5%) and rs2294008 (ORNIE = 1.10, 95% CI = 0.90 to 1.33; NIE percent = 77.6%) on bladder cancer risk are mediated through differential DNA methylation at nearby mQTL-associated CpG sites. The suggestive results indicate that rs2294008 may affect bladder cancer risk through a set of genes in the lymphocyte antigen 6 family, which involves genes that bind to and modulate nicotinic acetylcholine receptors. There was no suggestive evidence supporting mediation for rs8102137 and rs798766. Conclusions Though larger studies are necessary, the methylation changes associated with rs401681 and rs2294008 at mQTL-associated CpG sites may be relevant for bladder carcinogenesis, and this study demonstrates how multi-omic data can be integrated to help understand the downstream effects of genetics variants.

Size distributions of giant aerosol particles (dry radius larger than 0.5 μm, sometimes referred to as coarse-mode aerosol particles) are not well characterized in the atmosphere. Measurements are problematic for these particles because they (i) occur in low concentrations, (ii) have difficulty in passing through air inlets, (iii) may be dry or deliquesced particles, and (iv) if sampled by impaction, typically require labor-intensive methods. In this study, a simple, high-volume impaction system called the Giant Nucleus Impactor (GNI), based on free-stream exposure of polycarbonate slides from aircraft, is described along with an automated optical microscope–based system for analysis of the impacted particles. The impaction slides are analyzed in a humidity-controlled chamber (typically 90% relative humidity) that ensures deliquescence of soluble (typically sea salt) particles. A computer-controlled optical microscope with two digital cameras is used to acquire and analyze images of the aerosol particles. At relative humidities above deliquescence (74% RH for sea salt), such particles will form near-spherical cap solution drops on the polycarbonate slides. The sea-salt mass in each giant aerosol particle is then calculated using simple geometry and published water activity measurements. The system has a sample volume of about 10 L s−1 at aircraft speeds of 105 m s−1. For salt particles, the measurement range is from about 0.7 μm dry radius to at least 16 μm dry radius, with a size-bin resolution of 0.2 μm dry radius. The sizing accuracy was tested using polystyrene latex (PSL) beads of known size.

Background: Pancreatic cancer is projected to become the second most common cause of cancer-related death over the next 5 years. Because inflammation is thought to be a common trajectory for disease initiation, we sought to prospectively characterize immune profiles using DNA methylation markers and examine DNA methylation levels previously linked to inflammation biomarkers to evaluate whether these immune markers play a key role in pancreatic cancer. Methods: In a nested case–control study pooling three U.S. prospective cohort studies, DNA methylation was measured in prediagnostic leukocytes of incident pancreatic cancer cases and matched controls using the Illumina MethylationEPIC array. Differentially methylated regions were used to predict immune cell types, and CpGs previously associated with inflammatory biomarkers were selected for the analysis. DNA methylation data from a retrospective case–control study conducted in Spain (PanGenEU) was used for independent replication. Results: Immune cell proportions and ratio of cell proportions were not associated with pancreatic cancer risk in the nested case–control study. Methylation extent of CpGs residing in or near gene MNDA was significantly associated with pancreatic cancer risk in the nested case–control study and replicated in PanGenEU. Methylation level of a promoter CpG of gene PIM-1 was associated with survival in both studies. Conclusions: Using a targeted approach, we identified several CpGs that may play a role in pancreatic carcinogenesis in two large, independent studies with distinct study designs. Impact: These findings could provide insight into critical pathways that may help identify new markers of early disease and survival.

The National Cancer Institute's Radiation Research Program, in collaboration with the Radiosurgery Society, hosted a workshop called Understanding High-Dose, Ultra-High Dose Rate and Spatially Fractionated Radiotherapy on August 20 and 21, 2018 to bring together experts in experimental and clinical experience in these and related fields. Critically, the overall aims were to understand the biological underpinning of these emerging techniques and the technical/physical parameters that must be further defined to drive clinical practice through innovative biologically based clinical trials.

Asbestos describes a group of naturally occurring fibrous silicate mineral compounds that have been associated with a number of respiratory maladies, including mesothelioma and lung cancer. In addition, based primarily on epidemiologic studies, asbestos has been implicated as a risk factor for laryngeal and pharyngeal squamous cell carcinoma (SCC). The main objective of this work was to strengthen existing evidence via empirical demonstration of persistent asbestos fibers embedded in the tissue surrounding laryngeal and pharyngeal SCC, thus providing a more definitive biological link between exposure and disease. Six human papillomavirus (HPV)-negative laryngeal (n = 4) and pharyngeal (n = 2) SCC cases with a history working in an asbestos-exposed occupation were selected from a large population-based case-control study of head and neck cancer. A laryngeal SCC case with no history of occupational asbestos exposure was included as a control. Tissue cores were obtained from adjacent nonneoplastic tissue in tumor blocks from the initial primary tumor resection, and mineral fiber analysis was performed using a scanning electron microscope equipped with an energy dispersive X-ray analyzer (EDXA). Chrysotile asbestos fiber bundles were identified in 3/6 of evaluated cases with a history of occupational asbestos exposure. All three cases had tumors originating in the larynx. In addition, a wollastonite fiber of unclear significance was identified one of the HPV-negative pharyngeal SCC cases. No mineral fibers were identified in adjacent tissue of the case without occupational exposure. The presence of asbestos fibers in the epithelial tissue surrounding laryngeal SCC in cases with a history of occupational asbestos exposure adds a key line of physical evidence implicating asbestos as an etiologic factor.

Persons suffering from opioid use disorder (OUD) experience long-lasting dysphoric symptoms well into extended periods of withdrawal. This protracted withdrawal syndrome is notably characterized by heightened anxiety and hyperkatifeia. Here we investigated if an exacerbated withdrawal model of acute morphine dependence results in lasting behavioral adaptation 6 weeks into forced abstinence in C57BL/6J mice. We found that our exacerbated morphine withdrawal paradigm produced distinct alterations in behavior in elevated-plus maze (EPM), open field, and social interaction tests in male and female mice. Following protracted withdrawal male mice showed enhanced exploration of the open arms of the EPM, reduced latency to enter the corner of the OF, and a social interaction deficit. In contrast, female mice showed enhanced thigmotaxis in the OF. Both sexes showed that protracted withdrawal enhanced locomotor behavior in response to subsequent morphine challenge, albeit at different doses. These findings will be relevant for future investigation examining the neural mechanisms underlying these behaviors, and will aid in uncovering physiological sex differences in response to opioid withdrawal.

High dietary glycaemic index (GI) and glycaemic load (GL) may increase cancer risk. However, limited information was available on GI and/or GL and head and neck cancer (HNC) risk. We conducted a pooled analysis on 8 case-control studies (4081 HNC cases; 7407 controls) from the International Head and Neck Cancer Epidemiology (INHANCE) consortium. We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) of HNC, and its subsites, from fixed- or mixed-effects logistic models including centre-specific quartiles of GI or GL. GI, but not GL, had a weak positive association with HNC (ORQ4 vs. Q1 = 1.16; 95% CI = 1.02–1.31). In subsites, we found a positive association between GI and laryngeal cancer (ORQ4 vs. Q1 = 1.60; 95% CI = 1.30–1.96) and an inverse association between GL and oropharyngeal cancer (ORQ4 vs. Q1 = 0.78; 95% CI = 0.63–0.97). This pooled analysis indicates a modest positive association between GI and HNC, mainly driven by laryngeal cancer.

In this short essay, we reflect on the innovation-related studies that have appeared in Manufacturing & Service Operations Management (M&SOM) in its first 20 years of publication and consider the future work that M&SOM could publish in this domain. Innovation management can be defined broadly enough to encompass the efforts of organizations to effectively design and develop novel solutions to existing or new needs. Several different approaches and thematic lenses have emerged in the academic community to address diverse questions in innovation management; however, the work published in M&SOM has a narrow focus. This gap reveals an opportunity for the M&SOM community, which may be addressed in part by improvements in the review process of the journal. We also suggest some specific innovation topics that the researchers in the community might tackle.

Prostate cancer (PCa) is the most common non-cutaneous cancer in men and a notable cause of cancer mortality when it metastasises. The unfolded protein response (UPR) can be cytoprotective but when acutely activated can lead to cell death. In this study, we sought to enhance the acute activation of the UPR using radiation and ONC201, an UPR activator. Treating PCa cells with ONC201 quickly increased the expression of all the key regulators of the UPR and reduced the oxidative phosphorylation, with cell death occurring 72 h later. We exploited this time lag to sensitize prostate cancer cells to radiation through short-term treatment with ONC201. To understand how priming occurred, we performed RNA-Seq analysis and found that ONC201 suppressed the expression of cell cycle and DNA repair factors. In conclusion, we have shown that ONC201 can prime enhanced radiation response.

Radical radiotherapy, often in combination with hormone ablation, is a safe and effective treatment option for localised or locally-advanced prostate cancer. However, up to 30% of patients with locally advanced PCa will go on to develop biochemical failure, within 5 years, following initial radiotherapy. Improving radiotherapy response is clinically important since patients exhibiting biochemical failure develop castrate-resistant metastatic disease for which there is no curative therapy and median survival is 8&ndash, 18 months. The aim of this research was to determine if loss of PTEN (highly prevalent in advanced prostate cancer) is a novel therapeutic target in the treatment of advanced prostate cancer. Previous work has demonstrated PTEN-deficient cells are sensitised to inhibitors of ATM, a key regulator in the response to DSBs. Here, we have shown the role of PTEN in cellular response to IR was both complex and context-dependent. Secondly, we have confirmed ATM inhibition in PTEN-depleted cell models, enhances ionising radiation-induced cell killing with minimal toxicity to normal prostate RWPE-1 cells. Furthermore, combined treatment significantly inhibited PTEN-deficient tumour growth compared to PTEN-expressing counterparts, with minimal toxicity observed. We have further shown PTEN loss is accompanied by increased endogenous levels of ROS and DNA damage. Taken together, these findings provide pre-clinical data for future clinical evaluation of ATM inhibitors as a neoadjuvant/adjuvant in combination with radiation therapy in prostate cancer patients harbouring PTEN mutations.

BackgroundLigaments work to stabilize the human knee joint and prevent excessive movement. Whilst ligaments are known to decline in structure and function with aging, there has been no systematic effort to study changes in gross mechanical properties in the four major human knee ligaments due to osteoarthritis (OA). This study aims to collate material properties for the anterior (ACL) and posterior (PCL) cruciate ligaments, medial (MCL) and lateral (LCL) collateral ligaments. Our cadaveric samples come from a diverse demographic from which the effects of aging and OA on bone and cartilage material properties have already been quantified. Therefore, by combining our previous bone and cartilage data with the new ligament data from this study we are facilitating subject-specific whole-joint modelling studies.MethodsThe demographics of the collected cadaveric knee joints were diverse with age range between 31 to 88 years old, and OA International Cartilage Repair Society grade 0 to 4. Twelve cadaveric human knee joints were dissected, and bone-ligament-bone specimens were extracted for mechanical loading to failure. Ligament material properties were determined from the load-extension curves, namely: linear and ultimate (failure) stress and strain, secant modulus, tangent modulus, and stiffness.ResultsThere were significant negative correlations between age and ACL linear force (p=0.01), stress (p=0.03) and extension (p=0.05), ACL failure force (p=0.02), stress (p=0.02) and extension (p=0.02), PCL secant (p=0.02) and tangent (p=0.02) modulus, and LCL stiffness (p=0.05). Significant negative correlations were also found between OA grades and ACL linear force (p=0.05), stress (p=0.02), extension (p=0.01) and strain (p=0.03), and LCL failure stress (p=0.05). However, changes in age or OA grade did not show a statistically significant correlation with the MCL tensile parameters. Trends showed that almost all the tensile parameters of the ACL and PCLs decreased with increasing age and progression of OA. Due to small sample size, the combined effect of age and presence of OA could not be statistically derived.ConclusionsThis research is the first to correlate changes in tensile properties of the four major human knee ligaments to aging and OA. The current ligament study when combined with our previous findings on bone and cartilage for the same twelve knee cadavers, supports conceptualization of OA as a whole-joint disease that impairs the integrity of many peri-articular tissues within the knee. The subject-specific data pool consisting of the material properties of the four major knee ligaments, subchondral and trabecular bones and articular cartilage will aid reconstruction and graft replacements and advance knee joint finite element models, whilst knowledge of aged or diseased mechanics may direct future therapeutic interventions.

The neutrophil dexamethasone methylation index (NDMI) is an algorithm-based biomarker to assess individuals’ exposures to dexamethasone, a synthetic glucocorticoid commonly administered for inflammation. Cortisol is the main endogenous glucocorticoid that controls vital processes including the immune response and lipid and carbohydrate metabolism. Variations in the NDMI score reflect individuals’ sensitivities of exposures to both exogenous and endogenous glucocorticoids, and this biomarker was trained using elastic net regression on Illumina’s most recent DNA methylation beadarray, the EPIC array, which contains 850,000 cytosine-guanine (CpG) sites. While technology for microarray research continues to advance over time, researchers are capable of conducting more comprehensive epigenome-wide association studies (EWAS). However, many studies are still run and archived using Illumina’s historical 450K platform with approximately 450,000 CpGs, and there are fewer published databases using the 850K EPIC array. To evaluate the cross-platform bioinformatic comparability, we performed elastic net regression modeling using predictors available in the 450K to train the NDMI. Among the 135 pre-surgery glioma cases from the UCSF Immune Profiles Study (IPS), NDMI scores between the 450K and 850K model were strongly correlated (r = 0.99, p < 0.0001). In the 311 controls from the UCSF Adult Glioma Study (AGS), similar correlations were observed (r = 0.96, p < 0.0001). We observe that NDMI remains a robust tool using historical 450K data and conclude that this algorithmic tool is capable of detecting the variations in individuals’ responses to dexamethasone.

Radiation exposures at ultra-high dose rates (UHDR) at several orders of magnitude greater than in current clinical radiotherapy have been shown to manifest differential radiobiological responses compared to conventional dose rates (CONV). This has led to studies investigating the application of UHDR for therapeutic advantage (FLASH-RT) which have gained significant interest since the initial discovery in 2014 that demonstrated reduced lung toxicity with equivalent levels of tumour control compared with conventional dose-rate radiotherapy. Many subsequent studies have demonstrated the potential protective role of FLASH-RT in normal tissues, yet the underlying molecular and cellular mechanisms of the FLASH effect remain to be fully elucidated. Here, we summarise the current evidence of the FLASH effect and review FLASH-RT studies performed in preclinical models of normal tissue response. To critically examine the underlying biological mechanisms of responses to UHDR radiation exposures, we evaluate in vitro studies performed with normal and tumour cells. Differential responses to UHDR vs CONV irradiation recurrently involve reduced inflammatory processes and differential expression of pro- and anti-inflammatory genes. In addition, frequently reduced levels of DNA damage or misrepair products are seen after UHDR irradiation. So far, it is not clear what signal elicits these differential responses, but there are indications for involvement of reactive species. Different susceptibility to FLASH effects observed between normal and tumour cells may result from altered metabolic and detoxification pathways and/or repair pathways used by tumour cells. We summarize the current theories that may explain the FLASH effect and highlight important research questions which are key to a better mechanistic understanding and, thus, the future implementation of FLASH-RT in the clinic. This article is protected by copyright. All rights reserved.

BackgroundMillions of primary school students across the United States are about to return to in-person learning. Amidst circulation of the highly infectious Delta variant, there is danger that without the appropriate safety precautions, substantial amount of school-based spread of COVID-19 may occur.MethodsWe used an extended Susceptible-Infected-Recovered computational model to estimate the number of new infections during 1 semester among a student population under different assumptions about mask usage, routine testing, and levels of incoming protection. Our analysis considers three levels of incoming protection (30%, 40%, or 50%; denoted as “low”, “mid”, or “high”). Universal mask usage decreases infectivity by 50%, and weekly testing may occur among 50% of the student population; positive tests prompt quarantine until recovery, with compliance contingent on symptom status.ResultsWithout masking and testing, more than 75% of susceptible students become get infected within three months in all settings. With masking, this values decreases to 50% for “low” incoming protection settings (“mid”=35%, “high”=24%). Testing half the masked population (“testing”) further drops infections to 22% (16%, 13%).ConclusionWithout interventions in place, the vast majority of susceptible students will become infected through the semester. Universal masking can reduce student infections by 26-78%, and biweekly testing along with masking reduces infections by another 50%. To prevent new infections in the community, limit school absences, and maintain in-person learning, interventions such as masking and testing must be implemented widely, especially among elementary school settings in which children are not yet eligible for the vaccine.

DNA methylation is an epigenetic phenomenon that can alter and control gene expression. Because methylation plays a key role in cell differentiation, methylation markers have been identified that are unique to a given cell type; these markers are stable and can be measured in tissue or whole blood. The article by Katzke and colleagues, published in this issue, uses methylation markers to estimate proportions of immune cell subtypes in peripheral blood samples that were collected prior to diagnosis, thus allowing them to directly examine associations with pancreatic cancer risk. Given that immune-cell counts cannot be measured from archived blood, and that retrospective case–control studies rely on blood that is collected after cancer diagnosis, few studies have been able to examine the role of the systemic immune response in cancer risk. Measurement of DNA methylation in peripheral blood, primarily through development of whole-genome approaches, has also opened new doors to examining cancer etiology. See related article by Katzke et al., p. 2179

Heroin intake decreases significantly during proestrus in normally cycling female rats, and this effect is mediated by endogenous estradiol but not endogenous progesterone. The purpose of this study was to determine whether chronic administration of exogenous estradiol decreases intake of the semi-synthetic opioid, heroin, and the fully synthetic opioid, remifentanil, in intact female rats. Normally cycling female rats were implanted with intravenous catheters and trained to self-administer heroin on a fixed ratio (FR1) schedule of reinforcement. Rats were treated chronically with daily administration of either a low dose of estradiol (0.5 mcg, sc), a high dose of estradiol (5.0 mcg, sc), or vehicle (peanut oil, sc). After two weeks of heroin self-administration training, dose-effect curves were determined for both heroin and remifentanil. Chronic administration of estradiol non-significantly decreased heroin intake and significantly decreased remifentanil intake. Estradiol-induced decreases in remifentanil intake were dose-dependent, characterized by large effect sizes, and greatest in rats treated with the high dose of estradiol. These data indicate that chronic estradiol administration decreases opioid intake in intact female rats with medium to large effect sizes across opioids. These findings suggest that estrogen-based pharmacotherapies may represent a novel treatment approach for women with opioid use disorder.

Importance: Vaccination against SARS-CoV-2 has the potential to significantly reduce transmission and COVID-19 morbidity and mortality. The relative importance of vaccination strategies and nonpharmaceutical interventions (NPIs) is not well understood. Objective: To assess the association of simulated COVID-19 vaccine efficacy and coverage scenarios with and without NPIs with infections, hospitalizations, and deaths. Design, Setting, and Participants: An established agent-based decision analytical model was used to simulate COVID-19 transmission and progression from March 24, 2020, to September 23, 2021. The model simulated COVID-19 spread in North Carolina, a US state of 10.5 million people. A network of 1 017 720 agents was constructed from US Census data to represent the statewide population. Exposures: Scenarios of vaccine efficacy (50% and 90%), vaccine coverage (25%, 50%, and 75% at the end of a 6-month distribution period), and NPIs (reduced mobility, school closings, and use of face masks) maintained and removed during vaccine distribution. Main Outcomes and Measures: Risks of infection from the start of vaccine distribution and risk differences comparing scenarios. Outcome means and SDs were calculated across replications. Results: In the worst-case vaccination scenario (50% efficacy, 25% coverage), a mean (SD) of 2 231 134 (117 867) new infections occurred after vaccination began with NPIs removed, and a mean (SD) of 799 949 (60 279) new infections occurred with NPIs maintained during 11 months. In contrast, in the best-case scenario (90% efficacy, 75% coverage), a mean (SD) of 527 409 (40 637) new infections occurred with NPIs removed and a mean (SD) of 450 575 (32 716) new infections occurred with NPIs maintained. With NPIs removed, lower efficacy (50%) and higher coverage (75%) reduced infection risk by a greater magnitude than higher efficacy (90%) and lower coverage (25%) compared with the worst-case scenario (mean [SD] absolute risk reduction, 13% [1%] and 8% [1%], respectively). Conclusions and Relevance: Simulation outcomes suggest that removing NPIs while vaccines are distributed may result in substantial increases in infections, hospitalizations, and deaths. Furthermore, as NPIs are removed, higher vaccination coverage with less efficacious vaccines can contribute to a larger reduction in risk of SARS-CoV-2 infection compared with more efficacious vaccines at lower coverage. These findings highlight the need for well-resourced and coordinated efforts to achieve high vaccine coverage and continued adherence to NPIs before many prepandemic activities can be resumed.

Diagnostic and therapeutic priorities vary for the 8 types of infection reviewed.

• We conducted a Swiss survey on patterns of practice during COVID-19 pandemic. • Dedicated IT solutions were implemented in all radiation-oncology departments. • Upfront endocrine treatments for breast and prostate cancer were privileged. • Use of hypofractionation for breast, rectal cancer and palliation was increased.

Objective Adipocytokines are markers of fetal metabolism, but their association with childhood growth is unclear. This study examined associations of neonatal adipocytokines with longitudinal childhood adiposity measures in a prospective cohort of pregnant women and their children. Methods We measured leptin and adiponectin concentrations at delivery and children’s body mass index (BMI) z-scores between ages 4 weeks and 8 years. We estimated differences in BMI z-scores and rates of BMI z-score change by leptin (N = 257) and adiponectin (N = 271) terciles. Results Children in the middle (mean difference: 0.2; 95% CI: −0.1, 0.4) and highest (0.4; 95% CI: 0.1, 0.6) leptin terciles had greater BMI z-scores than children in the lowest tercile. Associations were null after adjustment for birthweight z-score. Children in the lowest adiponectin tercile had greater gains in BMI z-score (change per year: 0.10; 95% CI: 0.08, 0.13) than children in the middle (0.07; 95% CI: 0.04, 0.09) and highest terciles (0.04; 95% CI: −0.01, 0.05) (adiponectin x age interaction P < 0.001). Conclusions Lower adiponectin levels were associated with increased rates of BMI gains in the first 8 years of life. While leptin was positively associated with BMI, this association may be confounded by birthweight.

Mouse models are essential tools in cancer research that have been used to understand the genetic basis of tumorigenesis, cancer progression and to test the efficacies of anticancer treatments including radiotherapy. They have played a critical role in our understanding of radiotherapy response in tumours and normal tissues and continue to evolve to better recapitulate the underlying biology of humans. In addition, recent developments in small animal irradiators have significantly improved in vivo irradiation techniques, allowing previously unimaginable experimental approaches to be explored in the laboratory. The combination of contemporary mouse models with small animal irradiators represents a major step forward for the radiobiology field in being able to much more accurately replicate clinical exposure scenarios. As radiobiology studies become ever more sophisticated in reflecting developments in the clinic, it is increasingly important to understand the basis and potential limitations of extrapolating data from mice to humans. This review provides an overview of mouse models and small animal radiotherapy platforms currently being used as advanced radiobiological research tools towards improving the translational power of preclinical studies.

BACKGROUND: A few papers have considered reproducibility of a posteriori dietary patterns across populations, as well as pattern associations with head and neck cancer risk when multiple populations are available. METHODS: We used individual-level pooled data from seven case-control studies (3844 cases; 6824 controls) participating in the International Head and Neck Cancer Epidemiology consortium. We simultaneously derived shared and study-specific a posteriori patterns with a novel approach called multi-study factor analysis applied to 23 nutrients. We derived odds ratios (ORs) and 95% confidence intervals (CIs) for cancers of the oral cavity and pharynx combined, and larynx, from logistic regression models. RESULTS: We identified three shared patterns that were reproducible across studies (75% variance explained): the Antioxidant vitamins and fiber (OR = 0.57, 95% CI = 0.41, 0.78, highest versus lowest score quintile) and the Fats (OR = 0.80, 95% CI = 0.67, 0.95) patterns were inversely associated with oral and pharyngeal cancer risk. The Animal products and cereals (OR = 1.5, 95% CI = 1.1, 2.1) and the Fats (OR = 1.8, 95% CI = 1.4, 2.3) patterns were positively associated with laryngeal cancer risk, whereas a linear inverse trend in laryngeal cancer risk was evident for the Antioxidant vitamins and fiber pattern. We also identified four additional study-specific patterns, one for each of the four US studies examined. We named them all as Dairy products and breakfast cereals, and two were associated with oral and pharyngeal cancer risk. CONCLUSION: Multi-study factor analysis provides insight into pattern reproducibility and supports previous evidence on cross-country reproducibility of dietary patterns and on their association with head and neck cancer risk. See video abstract at, http://links.lww.com/EDE/B430.

BackgroundExamining inflammation-related DNA methylation alterations in blood could help elucidate the role of inflammation in lung cancer etiology and aid discovery of factors that are key to lung cancer development and progression. In a nested case-control study, we estimated the neutrophil-to-lymphocyte ratio using a validated index, methylation-derived NLR (mdNLR), and quantified DNA methylation levels at loci previously linked with circulating concentrations of C-reactive protein (CRP). We examined associations between these measures and lung cancer risk, and among the cases, lung cancer survival, using pre-diagnostic blood samples of cases (median of 14 years before diagnosis) and controls in the CLUE I/II cohorts. Our analyses controlled for self-reported smoking and methylation-predicted cumulative smoking in order to better focus our examinations on the DNA methylation marks that are informative of the immune response profile.ResultsUsing conditional logistic regression and further adjusting for BMI, batch effects, and a smoking-based methylation score, we observed a 47% increased risk of non-small cell lung cancer (NSCLC) for one standard deviation increase in mdNLR (n = 150 pairs; OR: 1.47 [1.08, 2.02]) and found the estimated CRP Scores to be inversely associated with risk of NSCLC risk after additionally adjusting for methylation-predicted pack-years (n = 150 pairs; Score 1 OR: 0.57 [0.40, 0.81]; Score 2 OR: 0.62 [0.45, 0.84]; Score 3 OR: 0.65 [0.44, 0.95]). Using Cox proportional-hazards models and adjusting age, sex, smoking status, methylation-predicted pack-years, BMI, batch effect, and stage, we observed a 27% increased risk of dying from lung cancer for one standard deviation increase in mdNLR (n = 145 deaths in 205 cases; HR: 1.27 [1.08, 1.50]). A 50% increased risk of dying from lung cancer for one standard deviation increase in mdNLR was observed for NSCLC cases (n = 103 deaths in 149 cases; HR: 1.50 [1.19, 1.89]).ConclusionsA better understanding of inflammation-associated methylation-based biomarkers in lung cancer development could provide insight into critical pathways that may help identify new markers of early disease and survival.

Background Between 1962 and 1971, the US Air Force sprayed Agent Orange across Vietnam, exposing many soldiers to this dioxin-containing herbicide. Several negative health outcomes have been linked to Agent Orange exposure, but data is lacking on the effects this chemical has on the genome. Therefore, we sought to characterize the impact of Agent Orange exposure on DNA methylation in the whole blood and adipose tissue of veterans enrolled in the Air Force Health Study (AFHS). Methods We received adipose tissue (n = 37) and whole blood (n = 42) from veterans in the AFHS. Study participants were grouped as having low, moderate, or high TCDD body burden based on their previously measured serum levels of dioxin. DNA methylation was assessed using the Illumina 450 K platform. Results Epigenome-wide analysis indicated that there were no FDR-significantly methylated CpGs in either tissue with TCDD burden. However, 3 CpGs in the adipose tissue (contained within SLC9A3, LYNX1, and TNRC18) were marginally significantly (q PTPRN2) was marginally significantly (q SLC9A3, among other regions in adipose tissue, to be significantly differentially methylated with higher TCDD burden. Comparing whole blood data to a study of dioxin exposed adults from Alabama identified a CpG within the gene SMO that was hypomethylated with dioxin exposure in both studies. Conclusion We found limited evidence of dioxin associated DNA methylation in adipose tissue and whole blood in this pilot study of Vietnam War veterans. Nevertheless, loci in the genes of SLC9A3 in adipose tissue, and PTPRN2 and SMO in whole blood, should be included in future exposure analyses.

Author(s): Johnson, Karl T; Palakshappa, Deepak; Basu, Sanjay; Seligman, Hilary; Berkowitz, Seth A | Abstract: ObjectiveTo improve food insecurity interventions, we sought to better understand the hypothesized bidirectional relationship between food insecurity and health care expenditures.Data sourceNationally representative sample of the civilian noninstitutionalized population of the United States (2016-2017 Medical Expenditure Panel Survey [MEPS]).Study designIn a retrospective longitudinal cohort, we conducted two sets of analyses: (a) two-part models to examine the association between food insecurity in 2016 and health care expenditures in 2017; and (b) logistic regression models to examine the association between health care expenditures in 2016 and food insecurity in 2017. We adjusted for demographic and socioeconomic variables as well as 2016 health care expenditures and food insecurity.Data collectionHealth care expenditures, food insecurity, and medical condition data from 10n886 adults who were included in 2016-2017 MEPS.Principal findingsFood insecurity in 2016, compared with being food secure, was associated with both a higher odds of having any health care expenditures in 2017 (OR 1.29, 95% CI: 1.04 to 1.60) and greater total expenditures ($1738.88 greater, 95% CI: $354.10 to $3123.57), which represents approximately 25% greater expenditures. Greater 2016 health care expenditures were associated with slightly higher odds of being food insecure in 2017 (OR 1.007 per $1000 in expenditures, 95% CI: 1.002 to 1.012, Pn=0.01). Exploratory analyses suggested that poor health status may underlie the relationship between food insecurity and health care expenditures.ConclusionsA bidirectional relationship exists between food insecurity and health care expenditures, but the strength of either direction appears unequal. Higher health care expenditures are associated with a slightly greater risk of being food insecure (adjusted for baseline food insecurity status) but being food insecure is associated with substantially greater subsequent health care expenditures (adjusted for baseline health care expenditures). Interventions to address food insecurity and poor health may be helpful to break this cycle.

Background Per- and polyfluoroalkyl substances (PFAS) may adversely influence cardiometabolic risk. However, few studies have examined if the timing of early life PFAS exposure modifies their relation to cardiometabolic risk. We examined the influence of gestational and childhood PFAS exposure on adolescents’ cardiometabolic risk. Methods We quantified concentrations of four PFAS (perfluorooctanoate [PFOA], perfluorooctane sulfonate [PFOS], perfluorononanoate [PFNA], and perfluorohexane sulfonate [PFHxS]) in sera collected during pregnancy, at birth, and at ages 3, 8, and 12 years from 221 mother–child pairs in the HOME Study (enrolled 2003–06, Cincinnati, Ohio). We measured cardiometabolic risk factors using physical examinations, fasting serum biomarkers, and dual-energy X-ray absorptiometry scans at age 12 years. Cardiometabolic risk summary scores were calculated by summing age- and sex-standardized z-scores for individual cardiometabolic risk factors. We used multiple informant models to estimate covariate-adjusted associations of serum PFAS concentrations (log2-transformed) at each visit with cardiometabolic risk scores and their individual components, and tested for differences in associations across visits. Results The associations of serum PFOA concentrations with cardiometabolic risk scores differed across visits (P for heterogeneity = 0.03). Gestational and cord serum PFOA concentrations were positively associated with cardiometabolic risk scores (βs and 95% confidence intervals [95% CIs]: gestational 0.8 [0.0, 1.6]; cord 0.9 [-0.1, 1.9] per interquartile range increase). These positive associations were primarily driven by homeostatic model assessment for insulin resistance index (β = 0.3 [0.1, 0.5]) and adiponectin to leptin ratio (β = -0.5 [-1.0, 0.0]). Other individual cardiometabolic risk factors associated with gestational PFOA included insulin and waist circumference. Gestational and cord PFHxS were also associated with higher cardiometabolic risk scores (βs: gestational 0.9 [0.2, 1.6]; cord 0.9 [0.1, 1.7]). Conclusion In this cohort of children with higher gestational PFOA exposure, fetal exposure to PFOA and PFHxS was associated with unfavorable cardiometabolic risk in adolescence.

Key Points Question What is the association of COVID-19 vaccine efficacy and coverage scenarios with and without nonpharmaceutical interventions (NPIs) with SARS-CoV-2 infections, hospitalizations, and deaths? Findings A decision analytical model of North Carolina found that removing NPIs while vaccines were distributed resulted in substantial increases in infections, hospitalizations, and deaths. Furthermore, as NPIs were removed, higher vaccination coverage with less efficacious vaccines contributed to a larger reduction in risk of infection compared with more efficacious vaccines at lower coverage. Meaning These findings highlight the need for high COVID-19 vaccine coverage and continued adherence to NPIs before safely resuming many prepandemic activities., Importance Vaccination against SARS-CoV-2 has the potential to significantly reduce transmission and COVID-19 morbidity and mortality. The relative importance of vaccination strategies and nonpharmaceutical interventions (NPIs) is not well understood. Objective To assess the association of simulated COVID-19 vaccine efficacy and coverage scenarios with and without NPIs with infections, hospitalizations, and deaths. Design, Setting, and Participants An established agent-based decision analytical model was used to simulate COVID-19 transmission and progression from March 24, 2020, to September 23, 2021. The model simulated COVID-19 spread in North Carolina, a US state of 10.5 million people. A network of 1 017 720 agents was constructed from US Census data to represent the statewide population. Exposures Scenarios of vaccine efficacy (50% and 90%), vaccine coverage (25%, 50%, and 75% at the end of a 6-month distribution period), and NPIs (reduced mobility, school closings, and use of face masks) maintained and removed during vaccine distribution. Main Outcomes and Measures Risks of infection from the start of vaccine distribution and risk differences comparing scenarios. Outcome means and SDs were calculated across replications. Results In the worst-case vaccination scenario (50% efficacy, 25% coverage), a mean (SD) of 2 231 134 (117 867) new infections occurred after vaccination began with NPIs removed, and a mean (SD) of 799 949 (60 279) new infections occurred with NPIs maintained during 11 months. In contrast, in the best-case scenario (90% efficacy, 75% coverage), a mean (SD) of 527 409 (40 637) new infections occurred with NPIs removed and a mean (SD) of 450 575 (32 716) new infections occurred with NPIs maintained. With NPIs removed, lower efficacy (50%) and higher coverage (75%) reduced infection risk by a greater magnitude than higher efficacy (90%) and lower coverage (25%) compared with the worst-case scenario (mean [SD] absolute risk reduction, 13% [1%] and 8% [1%], respectively). Conclusions and Relevance Simulation outcomes suggest that removing NPIs while vaccines are distributed may result in substantial increases in infections, hospitalizations, and deaths. Furthermore, as NPIs are removed, higher vaccination coverage with less efficacious vaccines can contribute to a larger reduction in risk of SARS-CoV-2 infection compared with more efficacious vaccines at lower coverage. These findings highlight the need for well-resourced and coordinated efforts to achieve high vaccine coverage and continued adherence to NPIs before many prepandemic activities can be resumed., This decision analytical study assesses the association of simulated COVID-19 vaccine efficacy and coverage scenarios with and without nonpharmaceutical interventions with infections, hospitalizations, and deaths.

Introduction Active-case finding (ACF) programs have an important role in addressing case detection gaps and halting tuberculosis (TB) transmission. Evidence is limited on the cost-effectiveness of ACF interventions, particularly on how their value is impacted by different operational, epidemiological and patient care-seeking patterns. Methods We evaluated the costs and cost-effectiveness of a combined facility and community-based ACF intervention in Zambia that utilized mobile chest X-ray with computer-aided reading/interpretation software and laboratory-based Xpert MTB/RIF testing. Programmatic costs (in 2018 US dollars) were assessed from the health system perspective using prospectively collected cost and operational data. Cost-effectiveness of the ACF intervention was assessed as the incremental cost per TB death averted over a five-year time horizon using a multi-stage Markov state-transition model reflecting patient symptom-associated care-seeking and TB care under ACF compared to passive care. Results Over 18 months of field operations, the ACF intervention costed $435 to diagnose and initiate treatment for one person with TB. After accounting for patient symptom-associated care-seeking patterns in Zambia, we estimate that this one-time ACF intervention would incrementally diagnose 407 (7,207 versus 6,800) TB patients and avert 502 (611 versus 1,113) TB-associated deaths compared to the status quo (passive case finding), at an incremental cost of $2,284 per death averted over the next five-year period. HIV/TB mortality rate, patient symptom-associated care-seeking probabilities in the absence of ACF, and the costs of ACF patient screening were key drivers of cost-effectiveness. Conclusions A one-time comprehensive ACF intervention simultaneously operating in public health clinics and corresponding catchment communities can have important medium-term impact on case-finding and be cost-effective in Zambia. The value of such interventions increases if targeted to populations with high HIV/TB mortality, substantial barriers (both behavioral and physical) to care-seeking exist, and when ACF interventions can optimize screening by achieving operational efficiency.

Background The aim of this study was to investigate the relationship between high-risk genotypes of Human Papilloma Virus (HPV) and cancer of different subsites of the oral cavity. Material and methods A pooled analysis of five studies included on the International Head and Neck Cancer Epidemiology (INHANCE) Consortium was conducted. HPV 16 and HPV 18 were considered. Adjusted odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) for HPV and each oral cavity subsites were simultaneously estimated using multinomial logistic regression models. Results The analysis included 1157 cases and 3272 controls. This study showed a slightly higher prevalence of HPV infection among oral cancer cases than controls. In particular, an increased risk of other and not otherwise specified (NOS) sites within the oral cavity, oral tongue, palate and floor of mouth cancer was observed for overall HPV16 positivity (OR = 1.66, 95 % CI: 1.01−2.72; OR = 1.97, 95 % CI: 1.36−2.85; OR = 2.48, 95 % CI: 1.50−4.11; OR = 2.71, 95 % CI: 1.06−6.95, respectively). In particular, HPV16E7 was related to cancer of floor of mouth, oral cavity NOS and palate (OR = 2.71, 95 % CI: 1.06−6.95; OR = 3.32, 95 % CI:1.53−7.19; OR = 3.34, 95 % CI:1.38−8.06). Results were inconsistent for HPV18 due to low prevalence of infection. Conclusion Our study suggests that HPV16 infection may increase the risk of developing floor of mouth, gum, tongue, and palate cancers. Clinical relevance Subjects with HPV infection have a higher risk of cancer from all sites of the oral cavity.

Background: White blood cell (WBC) DNA may contain methylation patterns that are associated with subsequent breast cancer risk. Using a high-throughput array and samples collected, on average, 1.3 years prior to diagnosis, a case–cohort analysis nested in the prospective Sister Study identified 250 individual CpG sites that were differentially methylated between breast cancer cases and noncases. We examined five of the top 40 CpG sites in a case–control study nested in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) Cohort. Methods: We investigated the associations between prediagnostic WBC DNA methylation in 297 breast cancer cases and 297 frequency-matched controls. Two WBC DNA specimens from each participant were used: a proximate sample collected 1 to 2.9 years and a distant sample collected 4.2–7.3 years prior to diagnosis in cases or the comparable timepoints in controls. WBC DNA methylation level was measured using targeted bisulfite amplification sequencing. We used logistic regression to obtain ORs and 95% confidence intervals (CI). Results: A one-unit increase in percent methylation in ERCC1 in proximate WBC DNA was associated with increased breast cancer risk (adjusted OR = 1.29; 95% CI, 1.06–1.57). However, a one-unit increase in percent methylation in ERCC1 in distant WBC DNA was inversely associated with breast cancer risk (adjusted OR = 0.83; 95% CI, 0.69–0.98). None of the other ORs met the threshold for statistical significance. Conclusions: There was no convincing pattern between percent methylation in the five CpG sites and breast cancer risk. Impact: The link between prediagnostic WBC DNA methylation marks and breast cancer, if any, is poorly understood.

Machine learning approaches—which seek to predict outcomes or classify patient features by recognizing patterns in large datasets—are increasingly applied to clinical epidemiology research on diabetes. Given its novelty and emergence in fields outside of biomedical research, machine learning terminology, techniques, and research findings may be unfamiliar to diabetes researchers. Our aim was to present the use of machine learning approaches in an approachable way, drawing from clinical epidemiological research in diabetes published from 1 Jan 2017 to 1 June 2020. Machine learning approaches using tree-based learners—which produce decision trees to help guide clinical interventions—frequently have higher sensitivity and specificity than traditional regression models for risk prediction. Machine learning approaches using neural networking and “deep learning” can be applied to medical image data, particularly for the identification and staging of diabetic retinopathy and skin ulcers. Among the machine learning approaches reviewed, researchers identified new strategies to develop standard datasets for rigorous comparisons across older and newer approaches, methods to illustrate how a machine learner was treating underlying data, and approaches to improve the transparency of the machine learning process. Machine learning approaches have the potential to improve risk stratification and outcome prediction for clinical epidemiology applications. Achieving this potential would be facilitated by use of universal open-source datasets for fair comparisons. More work remains in the application of strategies to communicate how the machine learners are generating their predictions.

An increasing body of evidence implicates high levels of selenium intake in the development of diabetes, although prospective studies remain sparse. We conducted a nested case-control study of 622 diabetes incident cases and 622-age, sex, and follow-up time-matched controls in the prospective Jinchang cohort of 48,001 participants with a median of 5.8 years of follow-up. Inductively coupled plasma mass spectrometry (ICP-MS) was used to measure all 622 case-control pairs' baseline serum levels of selenium (Se), which were then categorized into quartiles based on the frequency distribution among the controls. Multivariable adjusted conditional logistic regression and restricted cubic splines (RCS) models were applied to evaluate independent odds ratios (OR) as estimates for relative risks (RR) of diabetes according to quartiles (Q) of selenium levels. Compared to the lowest quartile (Q1 as reference), significantly greater diabetes risks (with 95% confidence interval) were observed in Q3 (OR = 1.62, 1.17–2.35) and Q4 (OR = 1.79, 1.21–2.64). Sub-analyses showed these increased risks of diabetes by serum levels of Se. appeared to differ by sex, age, BMI status, history of hypertension, and dyslipidemia. Further, application of RSC models showed that serum Se levels between 95 and 120 μg/L were significantly and positively associated with diabetes risk whereas no apparent relation exists when Se levels were under 95 μg/L in this cohort population.

Lineage-specific DNA methylation marks differentiate leukocyte cell types while individual biological aging mechanisms impact other methylation alterations. Human glioma incidence and survival times have been shown to be associated with aberrant immune profiles and have a strong dependency on age. Here we developed a single epigenetic analysis framework to evaluate both immune cell fractions and epigenetic age in peripheral blood. We examined these measures in archived blood from 197 triple-negative glioma patients (TNG; IDH wildtype, 1p19q intact and TERT wildtype) and 312 frequency-matched controls from the SF Bay Area Adult Glioma Study (AGS). Significant differences were observed with TNG cases having lower CD4 and CD8 T cell, natural killer, and B cell fractions, and higher neutrophil fractions than controls. TNG cases were significantly older than controls in two of three epigenetic age estimates; however, there was no difference in epigenetic age acceleration once immune cell proportions were considered. For the TNG cases, we augmented results from several machine learning methods to delineate risk groups of TNG patients with significantly different overall survival. We compared survival models built by recursive partitioning, random forest, and elastic net methods. The final model was chosen by repeated bootstrap sampling via the Brier score loss function and validated in an independent set of 72 IDH-mutant only or TERT-mutant only glioma patients also from the AGS. The final model indicated important interactions between immune cell fractions (including CD4 and CD8 T cells and neutrophils) and treatment, age, and dexamethasone status when adjusted for the main effects of epigenetic age, glioblastoma status, and the neutrophil-to-lymphocyte ratio. The capacity of immunomethylomics to capture diverse, clinically relevant information and the simplicity of its implementation make this a powerful tool for personalized patient evaluation in the neuro-oncology clinic.