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Background: Human epidermal growth factor receptor-2 (HER-2) and tumor-associated glycoprotein 72 (TAG-72) have proven to be excellent molecular targets for cancer imaging and therapy. Trastuzumab, which binds to HER-2, is effective in the treatment of disseminated intraperitoneal disease when labeled with (213)Bi or (212)Pb. (213)Bi-humanized CC49 monoclonal antibody (HuCC49DeltaCH2), which binds to TAG-72, inhibits the growth of subcutaneous xenografts. A next logical step to improve therapeutic benefit would be to target tumors with both molecules simultaneously.Methods: Athymic mice bearing intraperitoneal human colon carcinoma xenografts were treated with a combination of trastuzumab and HuCC49DeltaCH2 labeled with (213)Bi administered through an intraperitoneal route. The sequence of administration also was examined.Results: Before combining the 2 monoclonal antibodies, the effective doses of (213)Bi-CC49DeltaCH2 and (213)Bi-trastuzumab for the treatment of peritoneal disease were determined to be 500 muCi for each labeled antibody. Treatment with (213)Bi-HuCC49DeltaCH2 resulted in a median survival of 45 days and was comparable to the median survival achieved with (213)Bi-trastuzumab. Each combination provided greater therapeutic efficacy than either of the agents given alone. However, the greatest therapeutic benefit was achieved when (213)Bi-HuCC49DeltaCH2 and (213)Bi-trastuzumab were coinjected, and a median survival of 147 days was obtained.Conclusions: Dual targeting of 2 distinct molecules in tumors such as TAG-72 and HER-2 with alpha-particle radiation resulted in an enhanced, additive, therapeutic benefit. The authors also observed that this radioimmunotherapeutic strategy was well tolerated. [ABSTRACT FROM AUTHOR]

The Legume Inflammation Feeding Experiment is, to our knowledge, the first randomized crossover feeding trial testing the effects of a legume-enriched, low-glycemic index (GI) diet among men characterized for colorectal adenomas and insulin resistance (IR) status. This study was designed to test the effects of a legume-enriched diet compared with a healthy American (HA) diet under weight-stable conditions. The primary objective was to assess effects on C-reactive protein (CRP) and C-peptide levels. The secondary objective was to assess changes by IR status or history of adenomas. A total of 64 men who completed a colonoscopy within the previous 2 y consumed 2 diets in random order each for 4 wk separated by a washout period. The diets were a legume-enriched (250 g/d), low-GI (GI 38) diet and a high-GI (GI 69) HA diet. We measured fasting glucose, insulin, C-peptide, CRP, and soluble tumor necrosis factor-alpha receptors I and II (sTNFRI/II) at the beginning and end of the diet periods. Participants who consumed both the legume and HA diets had favorably improved CRP (-20.2 and -18.3%) and sTNFRI (-3.7 and -4.4%) concentrations, respectively. The sTNFRII concentrations declined marginally during the legume diet period (-3.8%; P = 0.060) and significantly during the HA diet period (-5.1%; P < 0.001). Fasting glucose increased significantly during both the legume (+1.8%) and HA (-2.2%) diet periods. Only the changes in glucose differed between the diet periods. Serum C-peptide and plasma insulin levels did not change in participants consuming either diet. Healthful dietary changes can improve biomarkers of IR and inflammation. [ABSTRACT FROM AUTHOR]

The signal produced by fluorescence in situ hybridization (FISH) often is inconsistent among cells and sensitivity is low. Small DNA targets on the chromatin are difficult to detect. We report here an improved nick translation procedure for Texas red and Alexa Fluor 488 direct labeling of FISH probes. Brighter probes can be obtained by adding excess DNA polymerase I. Using such probes, a 30&ThickSpace;kb yeast transgene, and the rp1 , rp3 and zein multigene clusters were clearly detected. [ABSTRACT FROM AUTHOR]

Context: High-dose chemotherapy poses considerable challenges to emesis management. Although prior studies suggest that acupuncture may reduce nausea and emesis, it is unclear whether such benefit comes from the nonspecific effects of attention and clinician-patient interaction.Objective: To compare the effectiveness of electroacupuncture vs minimal needling and mock electrical stimulation or antiemetic medications alone in controlling emesis among patients undergoing a highly emetogenic chemotherapy regimen.Design: Three-arm, parallel-group, randomized controlled trial conducted from March 1996 to December 1997, with a 5-day study period and a 9-day follow-up.Setting: Oncology center at a university medical center.Patients: One hundred four women (mean age, 46 years) with high-risk breast cancer.Interventions: Patients were randomly assigned to receive low-frequency electroacupuncture at classic antiemetic acupuncture points once daily for 5 days (n = 37); minimal needling at control points with mock electrostimulation on the same schedule (n = 33); or no adjunct needling (n = 34). All patients received concurrent triple antiemetic pharmacotherapy and high-dose chemotherapy (cyclophosphamide, cisplatin, and carmustine).Main Outcome Measures: Total number of emesis episodes occurring during the 5-day study period and the proportion of emesis-free days, compared among the 3 groups.Results: The number of emesis episodes occurring during the 5 days was lower for patients receiving electroacupuncture compared with those receiving minimal needling or pharmacotherapy alone (median number of episodes, 5, 10, and 15, respectively; P<.001). The electroacupuncture group had fewer episodes of emesis than the minimal needling group (P<.001), whereas the minimal needling group had fewer episodes of emesis than the antiemetic pharmacotherapy alone group (P =.01). The differences among groups were not significant during the 9-day follow-up period (P =.18).Conclusions: In this study of patients with breast cancer receiving high-dose chemotherapy, adjunct electroacupuncture was more effective in controlling emesis than minimal needling or antiemetic pharmacotherapy alone, although the observed effect had limited duration. JAMA. 2000;284:2755-2761. [ABSTRACT FROM AUTHOR]

Thailand is among countries with the highest global incidence and mortality rates of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). While viral hepatitis and liver fluke infections have been associated with HCC and iCCA, respectively, other environmental risk factors, overall risk factor commonality and combinatorial roles, and effects on survival have not been systematically examined. We conducted a TIGER-LC consortium-based population study covering all high-incidence areas of both malignancies across Thailand: 837 HCC, 1474 iCCA, and 1112 controls (2011-2019) were comprehensively queried on lifelong environmental exposures, lifestyle, and medical history. Multivariate logistic regression and Cox proportional hazards analyses were used to evaluate risk factors and associated survival patterns. Our models identified shared risk factors between HCC and iCCA, such as viral hepatitis infection, liver fluke infection, and diabetes, including novel and shared associations of agricultural pesticide exposure (OR range of 1.50; 95% CI: 1.06-2.11 to 2.91; 95% CI: 1.82-4.63) along with vulnerable sources of drinking water. Most patients had multiple risk factors, magnifying their risk considerably. Patients with lower risk levels had better survival in both HCC (HR 0.78; 95% CI: 0.64-0.96) and iCCA (HR 0.84; 95% CI: 0.70-0.99). Risk factor co-exposures and their common associations with HCC and iCCA in Thailand emphasize the importance for future prevention and control measures, especially in its large agricultural sector. The observed mortality patterns suggest ways to stratify patients for anticipated survivorship and develop plans to support medical care of longer-term survivors, including behavioral changes to reduce exposures., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

We consider the problem of combining multiple biomarkers to improve the diagnostic accuracy of detecting a disease when only group-tested data on the disease status are available. There are several challenges in addressing this problem, including unavailable individual disease statuses, differential misclassification depending on group size and number of diseased individuals in the group, and extensive computation due to a large number of possible combinations of multiple biomarkers. To tackle these issues, we propose a pairwise model fitting approach to estimating the distribution of the optimal linear combination of biomarkers and its diagnostic accuracy under the assumption of a multivariate normal distribution. The approach is evaluated in simulation studies and applied to data on chlamydia detection and COVID-19 diagnosis., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Statistics in Medicine published by John Wiley & Sons Ltd.)

Objective: In the United States, cancer mortality rates continue to decline, yet geographic and racial disparities persist and are particularly evident in the Delta region, characterized by high economic distress and disease burden. We examined cancer mortality patterns by demographic groups across geographic region (Delta vs non-Delta) and investigated the influence of macro-level social determinants of health (SDoH) in cancer death., Study Design and Methods: This observational study included cancer death records of individuals aged ≥20 years from 2018 to 2021 in the United States. County-level characteristics were ascertained through the linkage of multiple national administrative and community surveys. We estimated age-standardized mortality rates (ASR) and rate ratios. We calculated the adjusted relative risks by county-level SDoH (geographic region, rurality, household income, income inequality, health insurance, and education) and other factors using age-adjusted multivariate quasi-Poisson regression., Results: In 2018-2021, approximately 2.4 million cancer deaths occurred in the United States. We observed important declines in the Black-White disparities, from 16.6% in 2018 (ASR = 289.9 vs 248.6 per 100,000) to 12.1% in 2021 (281.1 vs 250.8) in the Delta region and from 15.9% (254.9 vs 219.9) to 10.7% (240.6 vs 217.3) in the non-Delta region, though Black men in the Delta region remained the highest rate (ASR 2021  = 346.9 per 100,000). County-level analyses provided strong evidence of geographic inequality and the role of SDoH, particularly education and income inequality., Conclusions: Unfavorable SDoH are associated with increased cancer death risk. Region-specific health policies and interventions in the Delta region are essential to advance cancer health equity., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Abstract: Compared with the general population, hematopoietic cell transplantation (HCT) survivors are at elevated risk for developing solid subsequent neoplasms (SNs). The Center for International Blood and Marrow Transplant Research (CIBMTR) is a key resource for quantifying solid SN incidence following HCT, but the completeness of SN ascertainment is uncertain. Within a cohort of 18 450 CIBMTR patients linked to the California Cancer Registry (CCR), we evaluated the completeness of solid SN data reported to the CIBMTR from 1991 to 2018 to understand the implications of using CIBMTR data alone or combined with CCR data to quantify the burden of solid SNs after HCT. We estimated the cumulative incidence of developing a solid SN, accounting for the competing risk of death. Within the cohort, solid SNs were reported among 724 patients; 15.6% of these patients had an SN reported by CIBMTR only, 36.9% by CCR only, and 47.5% by both. The corresponding cumulative incidence of developing a solid SN at 10 years following a first HCT was 4.0% (95% confidence interval [CI], 3.5-4.4) according to CIBMTR data only, 5.3% (95% CI, 4.9-5.9) according to CCR data only, and 6.3% (95% CI, 5.7-6.8) according to both sources combined. The patterns were similar for allogeneic and autologous HCT recipients. Linking detailed HCT information from CIBMTR with comprehensive SN data from cancer registries provides an opportunity to optimize SN ascertainment for informing follow-up care practices and evaluating risk factors in the growing population of HCT survivors., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Background: It is important to understand the impact of the COVID-19 pandemic on cancer death rates in 2020 in the US. We estimated whether there were larger-than-expected changes in cancer mortality rates from March to December 2020 after accounting for temporal and seasonal patterns using data from January 2011 to February 2020 by cancer type and age., Methods: We obtained death counts and underlying causes of death by cancer type, month/year (2011-2020), and age group from the National Center for Health Statistics and population estimates from the US Census Bureau. Poisson regression was used to test for significant changes in cancer death rates from March to December 2020 compared with prior years., Results: After accounting for temporal trends and seasonal patterns, total cancer death rates were significantly lower than expected during March to December 2020 among 55- to 64-year-olds and ≥75-year-olds, but not in other age groups. Cancer death rates were 2% lower than expected from March to June among 55- to 64-year-olds and 2% to 3% lower from March to July and December among ≥75-year-olds. Among ≥75-year-olds, colorectal cancer death rates were lower from March to June [rate ratios (RR) = 0.94-0.96; P < 0.05]; however, lung cancer death rates were 5% lower across each month (all RRs = 0.95; P < 0.05)., Conclusions: In the US, cancer death rates based on the underlying cause of death were broadly similar to expected rates from March to December 2020. However, cancer death rates were lower than expected among 55- to 64-year-olds and ≥75-year-olds, likely due to COVID-19 as a competing cause of death., Impact: Cancer mortality rates from 2020 should be interpreted with caution., (©2024 American Association for Cancer Research.)

Properly assessing the effects of environmental chemical exposures on disease risk remains a challenging problem in environmental epidemiology. Various analytic approaches have been proposed, but there are few papers that have compared the performance of different statistical methods on a single dataset. In this paper, we compare different regression-based approaches for estimating interactions between chemical mixture components using data from a case-control study on non-Hodgkin's lymphoma. An analytic challenge is the high percentage of exposures that are below the limit of detection (LOD). Using imputation for LOD, we compare different Bayesian shrinkage prior approaches including an approach that incorporates the hierarchical principle where interactions are only included when main effects exist. Further, we develop an approach where main and interactive effects are represented by a series of distinct latent functions. We also fit the Bayesian kernel machine regression to these data. All of these approaches show little evidence of an interaction among the chemical mixtures when measurements below the LOD were imputed. The imputation approach makes very strong assumptions about the relationship between exposure and disease risk for measurements below the LOD. As an alternative, we show the results of an analysis where we model the exposure relationship with two parameters per mixture component; one characterizing the effect of being below the LOD and the other being a linear effect above the LOD. In this later analysis, we identify numerous strong interactions that were not identified in the analyses with imputation. This case study demonstrated the importance of developing new approaches for mixtures when the proportions of exposure measurements below the LOD are high.

Background: Reducing cigarettes per day may lower the risk of lung cancer compared with continuing to smoke at the same intensity. Other changes in smoking behaviors, such as increasing cigarette consumption or quitting for a period and relapsing, may also affect lung cancer risk., Methods: We examined changes in smoking status and cigarettes per day among 24 613 Finnish male smokers aged 50-69 years who participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Longitudinal data on smoking were collected during study follow-up visits 3 times a year (approximately every 4 months) between 1985 and 1993. Incident lung cancer patients through 2012 were identified by the Finnish Cancer Registry. Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression., Results: Compared with smoking 20 cigarettes per day continuously across the intervention period, reducing an average of 5 cigarettes per day per year while smoking was associated with a 20% lower risk of lung cancer (95% CI = 0.71 to 0.90). A substantially lower risk of lung cancer was also observed when participants smoked at 50% (RR = 0.72, 95% CI = 0.57 to 0.90) and 10% (RR = 0.55, 95% CI = 0.36 to 0.83) of study visits, relative to smoked at 100% of study visits., Conclusions: Smokers may lower their risk of lung cancer by reducing smoking intensity (cigarettes per day while smoking) and the time they smoke. However, quitting smoking completely is the most effective way for smokers to reduce their risk of lung cancer., (Published by Oxford University Press 2024.)

Background: Identifying the impact of environmental mixtures on human health is an important topic. However, such studies face challenges when exposure measurements lie below limit of detection (LOD). While various approaches for accommodating a single exposure subject to LOD have been used, their impact on mixture analysis has not been thoroughly investigated. Our study aims to understand the impact of five popular LOD accommodation approaches on mixture analysis results with multiple exposures subject to LOD, including omitting subjects with any exposures below LOD (complete case analysis); single imputations by LOD/ 2 , and by estimates from a censored accelerated failure time (AFT) model; and multiple imputation (MI) with or without truncation based on LOD., Methods: In extensive simulation studies with high-dimensional and highly correlated exposures and a continuous health outcome, we examined the performance of each LOD approach on three mixture analysis methods: elastic net regression, weighted quantile sum regression (WQS) and Bayesian kernel machine regression (BKMR). We further analyzed data from the National Health and Nutrition Examination Survey (NHANES) on how persistent organic pollutants (POPs) influenced leukocyte telomere length (LTL)., Results: Complete case analysis was inefficient and could result in severe bias for some mixture methods. Imputation by LOD/ 2 showed unstable performance across mixture methods. Conventional MI was associated with consistent mild biases, which can be reduced by using a truncated distribution for imputation. Estimating censored values by AFT models had a minimal impact on the results. In the NHANES analysis, imputation by LOD/ 2 , truncated MI and censored AFT models performed similarly, with a positive overall effect of POPs on LTL while PCB126, PCB169 and furan 2,3,4,7,8-pncdf being the most important exposures., Conclusions: Our study favored using truncated MI and censored AFT models to accommodate values below LOD for the stability of downstream mixture analysis., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Per- and polyfluoroalkyl substances (PFAS) are widespread and environmentally persistent chemicals with immunotoxic properties. Children are prenatally exposed through maternal transfer of PFAS to cord blood, but no studies have investigated the relationship with childhood leukemia., Methods: We measured maternal serum levels of 19 PFAS in first-trimester samples collected in 1986-2010 and evaluated associations with acute lymphoblastic leukemia in full-term offspring (aged younger than 15 years) for 400 cases and 400 controls in the Finnish Maternity Cohort, matched on sample year, mother's age, gestational age, birth order, and child's sex. We analyzed continuous and categorical exposures, estimating odds ratios (ORs) and 95% confidence intervals (CIs) via conditional logistic regression adjusted for maternal smoking and correlated PFAS (ρ ≥ ±0.3). We also stratified by calendar period, mean diagnosis age, and the child's sex., Results: N-methyl-perfluorooctane sulfonamidoacetic acid was associated with acute lymphoblastic leukemia in continuous models (per each doubling in levels: ORperlog2 = 1.22, 95% CI = 1.07 to 1.39), with a positive exposure-response across categories (OR>90th percentile = 2.52, 95% CI = 1.33 to 4.78; Ptrend = .01). Although we found no relationship with perfluorooctane sulfonic acid overall, an association was observed in samples collected in 1986-1995, when levels were highest (median = 17.9 µg/L; ORperlog2 = 4.01, 95% CI = 1.62 to 9.93). A positive association with perfluorononanoic acid was suggested among first births (Pinteraction = .06). The N-methyl-perfluorooctane sulfonamidoacetic acid association was mainly limited to children diagnosed before age 5 years (Pinteraction = .02). We found no consistent patterns of association with other PFAS or differences by sex., Conclusions: These novel data offer evidence of a relationship between some PFAS and risk of the most common childhood cancer worldwide, including associations with the highest levels of perfluorooctanesulfonic acid and with a precursor, N-methyl-perfluorooctane sulfonamidoacetic acid., (Published by Oxford University Press 2023.)

Human exposure to per- and polyfluoroalkyl substances (PFAS) occurs globally through contaminated food, dust, and drinking water. Studies of PFAS and thyroid cancer have been limited. We conducted a nested case-control study of prediagnostic serum levels of 19 PFAS and papillary thyroid cancer (400 cases, 400 controls) in the Finnish Maternity Cohort (pregnancies 1986-2010; follow-up through 2016), individually matched on sample year and age. We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for log 2 transformed and categorical exposures, overall and stratified by calendar period, birth cohort, and median age at diagnosis. We adjusted for other PFAS with Spearman correlation rho = 0.3-0.6. Seven PFAS, including perfluoroctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), N-ethyl-perfluorooctane sulfonamidoacetic acid (EtFOSAA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluorohexane sulfonic acid (PFHxS) were detected in >50% of women. These PFAS were not associated with risk of thyroid cancer, except for PFHxS, which was inversely associated (OR log 2  = 0.82, 95% CI: 0.70-0.97). We observed suggestive but imprecise increased risks associated with PFOA, PFOS, and EtFOSAA for those diagnosed at ages <40 years, whereas associations were null or inverse among those diagnosed at 40+ years (P-interaction: .02, .08, .13, respectively). There was little evidence of other interactions. These results show no clear association between PFAS and papillary thyroid cancer risk. Future work would benefit from evaluation of these relationships among those with higher exposure levels and during periods of early development when the thyroid gland may be more susceptible to environmental harms., (© 2023 UICC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

When extracting medical record data to form a retrospective cohort, investigators typically focus on a pre-specified study window, and select subjects who had hospital visits during that study window. However, such data extraction may suffer from an informative observation process, since sicker patients may have hospital visits more frequently. For example, Consecutive Pregnancy Study is a retrospective cohort study of women with multiple pregnancies in 23 Utah hospitals from 2003 to 2010, where the interest is to understand the risk factors of recurrent pregnancy outcomes, such as preterm birth. The observation process is informative in the sense that, women with adverse pregnancy outcomes may be less likely/willing/able to endure subsequent pregnancies. We proposed a three-part joint model with shared random effects structure to address this analytic complication. Particularly, a first-order transition model is used to model the longitudinal binary outcome; a gamma regression model is assumed for the inter-pregnancy intervals; a continuation ratio model specifies the probability of continuing with more births in the future. We note that the latter two parts give rise to a parametric cure-rate survival model. The performance of the proposed method was examined in extensive simulation studies, with both correctly and mis-specified models. The analyses of Consecutive Pregnancy Study data further demonstrate the inadequacies of fitting the transition model alone ignoring the informative observation process., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Twin gestations have greater nutritional demands than singleton gestations, yet dietary intakes of women with twin gestations have not been well described., Methods: In a prospective, multi-site US study of 148 women with dichorionic twin gestations (2012-2013), we examined longitudinal changes in diet across pregnancy. Women completed a food frequency questionnaire during each trimester of pregnancy. We examined changes in means of total energy and energy-adjusted dietary components using linear mixed effects models., Results: Mean energy intake (95% CI) across the three trimesters was 2010 kcal/day (1846, 2175), 2177 kcal/day (2005, 2349), 2253 kcal/day (2056, 2450), respectively (P = 0.01), whereas the Healthy Eating Index-2010 was 63.9 (62.1, 65.6), 64.5 (62.6, 66.3), 63.2 (61.1, 65.3), respectively (P = 0.53)., Discussion: Women with twin gestations moderately increased total energy as pregnancy progressed, though dietary composition and quality remained unchanged. These findings highlight aspects of nutritional intake that may need to be improved among women carrying twins., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Atrazine is a common agricultural herbicide in the United States. Few epidemiologic studies have evaluated cancer risks. Previous analyses within the Agricultural Health Study (AHS) have found some evidence of associations with cancer at some sites., Objective: We updated exposure information, incident cases, and follow-up time to assess the associations between atrazine use and cancer at specific sites in the AHS., Methods: Information about lifetime pesticide use was reported at enrollment (1993-1997) and follow-up (1999-2005). Among 53,562 pesticide applicators in North Carolina and Iowa, we identified 8,915 incident cases through cancer registry linkages through 2014 (North Carolina)/2017 (Iowa). We used Poisson regression to evaluate the association between ever/never and intensity-weighted lifetime days of atrazine use and incident cancer risk controlling for several confounders. We also evaluated lagged exposures and age-stratified risk., Results: Approximately 71.2% of applicators reported ever using atrazine, which was associated with lung cancer [ rate ratios  ( RR ) = 1.24 ; 95% confidence interval (CI): 1.04, 1.46]. Aggressive prostate cancer risk was increased in the highest quartile ( RR Q 4 = 1.20 ; 95% CI: 0.95, 1.52; p -trend = 0.19 ), particularly among those < 60 years old ( RR Q 4 = 3.04 ; 95% CI: 1.61, 5.75; p -trend < 0.001 ; p -interaction = 0.04 ). Among applicators < 50 years of age, ever-atrazine use was associated with non-Hodgkin lymphoma (NHL) ( RR = 2.43 ; 95% CI: 1.10, 5.38; p -interaction = 0.60 ). For soft tissue sarcoma, there was an elevated risk in the highest tertile of exposure ( RR T 3 : 2.54; 95% CI: 0.97, 6.62; p -trend = 0.31 ). In analyses with exposure lagged by 25 years, there was an elevated risk of pharyngeal ( RR T 3 = 3.04 ; 95% CI: 1.45, 6.36; p -trend = 0.07 ) and kidney ( RR Q 4 = 1.62 ; 95% CI: 1.15, 2.29; p -trend < 0.005 ) cancers., Discussion: We observed suggestive associations with some malignancies in overall, age-specific, and lagged analyses. Associations with aggressive prostate cancer and NHL were apparent among those diagnosed at younger ages and with cancers of the pharynx and kidney, and soft tissue sarcomas were observed in lagged analyses. Further work is needed to confirm these observed associations and elucidate potential underlying mechanisms. https://doi.org/10.1289/EHP13684.

Assessing outcomes following hematopoietic cell transplantation (HCT) poses challenges due to the necessity for systematic and often prolonged patient follow-up. Linking the HCT database of the Center for International Blood and Marrow Transplant Research (CIBMTR) with cancer registry data may improve long-term outcome ascertainment, but the reliability of mortality data in death certificates from cancer registries among HCT recipients remains unknown. We compared the classification of vital status and primary cause of death (COD), as well as the length of follow-up between the CIBMTR and California Cancer Registry (CCR) to assess the possibility of supplementing the CIBMTR with cancer registry data. This retrospective study leveraged a linked CIBMTR-CCR dataset. We included patients who were California residents at the time of HCT and received a first allogeneic (allo) or autologous (auto) HCT for a hematologic malignancy diagnosed during 1991-2016. Follow-up was through 2018. We analyzed 18,450 patients (alloHCT, n = 8232; autoHCT, n = 10,218). The Vital status agreement was 97.7% for alloHCT and 97.2% for autoHCT. Unknown COD was higher in CIBMTR (12.9%) than in CCR (1.6%). After excluding patients with unknown COD information, the overall agreement of primary COD (cancer versus noncancer) was 53.7% for alloHCT and 83.2% for autoHCT. This agreement was lower within the first 100 days post-HCT (alloHCT, 31.0%; autoHCT, 54.6%). Compared with CIBMTR, deaths due to cancer were higher in CCR (alloHCT, 90.0%; autoHCT, 90.1% versus alloHCT, 47.3%; autoHCT, 82.5% in CIBMTR). CIBMTR reports more frequently noncancer-related deaths, including graft-versus-host disease and infections. The cumulative incidence of cancer-specific mortality at 20 years differed, particularly for alloHCT (CCR, 53.7%; CIBMTR, 27.6%). The median follow-up among alive patients was longer in CCR (alloHCT, 6.0 years; autoHCT, 4.7 years) than in CIBMTR (alloHCT, 5.0 years; autoHCT, 3.8 years). Our findings highlight the completeness of vital status data in CIBMTR but reveal substantial disagreement in primary COD. Consequently, caution is required when interpreting HCT studies that use only death certificates to estimate cause-specific mortality outcomes. Improving the accuracy of COD registration and follow-up completeness by developing communication pathways between cancer registries and hospital-based cohorts may enhance our understanding of late effects and long-term outcomes among HCT survivors., (Copyright © 2023. Published by Elsevier Inc.)

Disease incidence data in a national-based cohort study would ideally be obtained through a national disease registry. Unfortunately, no such registry currently exists in the United States. Instead, the results from individual state registries need to be combined to ascertain certain disease diagnoses in the United States. The National Cancer Institute has initiated a program to assemble all state registries to provide a complete assessment of all cancers in the United States. Unfortunately, not all registries have agreed to participate. In this article, we develop an imputation-based approach that uses self-reported cancer diagnosis from longitudinally collected questionnaires to impute cancer incidence not covered by the combined registry. We propose a two-step procedure, where in the first step a mover-stayer model is used to impute a participant's registry coverage status when it is only reported at the time of the questionnaires given at 10-year intervals and the time of the last-alive vital status and death. In the second step, we propose a semiparametric working model, fit using an imputed coverage area sample identified from the mover-stayer model, to impute registry-based survival outcomes for participants in areas not covered by the registry. The simulation studies show the approach performs well as compared with alternative ad hoc approaches for dealing with this problem. We illustrate the methodology with an analysis that links the United States Radiologic Technologists study cohort with the combined registry that includes 32 of the 50 states., (Published by Oxford University Press 2022.)

Understanding the relationships between exposure and disease incidence is an important problem in environmental epidemiology. Typically, a large number of these exposures are measured, and it is found either that a few exposures transmit risk or that each exposure transmits a small amount of risk, but, taken together, these may pose a substantial disease risk. Further, these exposure effects can be nonlinear. We develop a latent functional approach, which assumes that the individual effect of each exposure can be characterized as one of a series of unobserved functions, where the number of latent functions is less than or equal to the number of exposures. We propose Bayesian methodology to fit models with a large number of exposures and show that existing Bayesian group LASSO approaches are a special case of the proposed model. An efficient Markov chain Monte Carlo sampling algorithm is developed for carrying out Bayesian inference. The deviance information criterion is used to choose an appropriate number of nonlinear latent functions. We demonstrate the good properties of the approach using simulation studies. Further, we show that complex exposure relationships can be represented with only a few latent functional curves. The proposed methodology is illustrated with an analysis of the effect of cumulative pesticide exposure on cancer risk in a large cohort of farmers., (© 2023 John Wiley & Sons, Ltd.)

Introduction: Sample handling can influence biomarker measurement and introduce variability when combining data from multiple studies or study sites. To inform the development of blood collection protocols within a multisite cohort study, we directly quantified concentrations of 54 biomarkers in blood samples subjected to different handling conditions. Materials and Methods: We obtained serum, lithium heparin plasma, and EDTA plasma from 20 adult volunteers. Tubes of chilled whole blood were either centrifuged and processed within 2 hours of collection (the "reference standard") or were stored with cool packs for 24 or 48 hours; centrifuged before and/or after this delay; or collected in tubes with/without gel separators. We used linear mixed models with random intercepts to estimate geometric mean concentrations and relative percent differences across the conditions. Results: Compared to the reference standard tubes, concentrations of many biomarkers changed after processing delays, but changes were often small. In serum, we observed large differences for B vitamers, glutamic acid (37% and 73% increases with 24- and 48-hour delays, respectively), glycine (12% and 23% increases), serine (16% and 27% increases), and acetoacetate (-19% and -26% decreases). Centrifugation timing and separator tube use did not affect concentrations of most biomarkers. Conclusion: Sample handling should be consistent across samples within an analysis. The length of processing delays should be recorded and accounted for when this is not feasible.

Covariance estimation for multiple groups is a key feature for drawing inference from a heterogeneous population. One should seek to share information about common features in the dependence structures across the various groups. In this paper, we introduce a novel approach for estimating the covariance matrices for multiple groups using a hierarchical latent factor model that shrinks the factor loadings across groups toward a global value. Using a sparse spike and slab model on these loading coefficients allows for a sparse formulation of our model. Parameter estimation is accomplished through a Markov chain Monte Carlo scheme, and a model selection approach is used to select the number of factors to use. We validate our model through extensive simulation studies. Finally, we apply our methodology to the NICHD Consecutive Pregnancies Study to estimate the correlations between birth weights and gestational ages of three consecutive birth within four different subgroups (underweight, normal, overweight, and obese) of women., (© 2023 John Wiley & Sons Ltd.)

Researchers in biology and medicine have increasingly focused on characterizing circadian rhythms and their potential impact on disease. Understanding circadian variation in metabolomics, the study of chemical processes involving metabolites may provide insight into important aspects of biological mechanism. Of scientific importance is developing a statistical rigorous approach for characterizing different types of 24-hour patterns among high dimensional longitudinal metabolites. We develop a latent class approach to incorporate variation in 24-hour patterns across metabolites where profiles are modeled with finite mixtures of distinct shape-invariant circadian curves that themselves incorporate variation in amplitude and phase across metabolites. An efficient Markov chain Monte Carlo sampling is used to carry out Bayesian posterior computation. When the model was fit separately by individual to the data from a small group of participants, two distinct 24-hour rhythms were identified, with one being sinusoidal and the other being more complex with multiple peaks. Interestingly, the latent pattern associated with circadian variation (simple sinusoidal curve) had a similar phase across the three participants, while the more complex latent pattern reflecting diurnal variation differed across individual. The results suggested that this modeling framework can be used to separate 24-hour rhythms into an endogenous circadian and one or more exogenous diurnal patterns in describing human metabolism., (© 2023 John Wiley & Sons Ltd.)

Background: Objective markers of ultraprocessed foods (UPF) may improve the assessment of UPF intake and provide insight into how UPF influences health., Objectives: To identify metabolites that differed between dietary patterns (DPs) high in or void of UPF according to Nova classification., Methods: In a randomized, crossover, controlled-feeding trial (clinicaltrials.govNCT03407053), 20 domiciled healthy participants (mean ± standard deviation: age 31 ± 7 y, body mass index [kg/m 2 ] 22 ± 11.6) consumed ad libitum a UPF-DP (80% UPF) and an unprocessed DP (UN-DP; 0% UPF) for 2 wk each. Metabolites were measured using liquid chromatography with tandem mass spectrometry in ethylenediaminetetraacetic acid plasma, collected at week 2 and 24-h, and spot urine, collected at weeks 1 and 2, of each DP. Linear mixed models, adjusted for energy intake, were used to identify metabolites that differed between DPs., Results: After multiple comparisons correction, 257 out of 993 plasma and 606 out of 1279 24-h urine metabolites differed between UPF-DP and UN-DP. Overall, 21 known and 9 unknown metabolites differed between DPs across all time points and biospecimen types. Six metabolites were higher (4-hydroxy-L-glutamic acid, N-acetylaminooctanoic acid, 2-methoxyhydroquinone sulfate, 4-ethylphenylsulfate, 4-vinylphenol sulfate, and acesulfame) and 14 were lower following the UPF-DP; pimelic acid, was lower in plasma but higher in urine following the UPF-DP., Conclusions: Consuming a DP high in, compared with 1 void of, UPF has a measurable impact on the short-term human metabolome. Observed differential metabolites could serve as candidate biomarkers of UPF intake or metabolic response in larger samples with varying UPF-DPs. This trial was registered at clinicaltrials.gov as NCT03407053 and NCT03878108., (Published by Elsevier Inc.)

Saturated fatty acids (SFAs) during pregnancy are associated with disrupted metabolic programming among offspring at birth and later growth. We examined plasma phospholipid SFAs in early pregnancy and fetal growth throughout pregnancy. We enrolled 321 pregnant women from the NICHD Fetal Growth Studies-Singleton Cohort at gestational weeks 8-13. Ultrasonogram schedules were randomly assigned to capture weekly fetal growth. We measured plasma phospholipid SFAs at early pregnancy using blood samples and modeled fetal growth trajectories across tertiles of SFAs with cubic splines using linear mixed models after full adjustment. We then compared pairwise weekly fetal growth biometrics referencing the lowest tertile in each SFA using the Wald test. We found that even-chain and very long even-chain SFAs were inversely associated, whereas odd-chain SFAs were positively associated with fetal weight and size. Compared with the lowest tertile, the highest tertile of pentadecanoic acid (15:0) had a greater fetal weight and size, starting from week 13 until late pregnancy (at week 39: 3429.89 vs. 3269.08 g for estimated fetal weight; 328.14 vs. 323.00 mm for head circumference). Our findings could inspire future interventions using an alternative high-fat diet rich in odd-chain SFAs for optimal fetal growth.

Poa pratensis, commonly known as Kentucky bluegrass, is a popular cool-season grass species used as turf in lawns and recreation areas globally. Despite its substantial economic value, a reference genome had not previously been assembled due to the genome's relatively large size and biological complexity that includes apomixis, polyploidy, and interspecific hybridization. We report here a fortuitous de novo assembly and annotation of a P. pratensis genome. Instead of sequencing the genome of a C4 grass, we accidentally sampled and sequenced tissue from a weedy P. pratensis whose stolon was intertwined with that of the C4 grass. The draft assembly consists of 6.09 Gbp with an N50 scaffold length of 65.1 Mbp, and a total of 118 scaffolds, generated using PacBio long reads and Bionano optical map technology. We annotated 256K gene models and found 58% of the genome to be composed of transposable elements. To demonstrate the applicability of the reference genome, we evaluated population structure and estimated genetic diversity in P. pratensis collected from three North American prairies, two in Manitoba, Canada and one in Colorado, USA. Our results support previous studies that found high genetic diversity and population structure within the species. The reference genome and annotation will be an important resource for turfgrass breeding and study of bluegrasses., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)

Purpose: The physical properties of protons lower doses to surrounding normal tissues compared with photons, potentially reducing acute and long-term adverse effects, including subsequent cancers. The magnitude of benefit is uncertain, however, and currently based largely on modeling studies. Despite the paucity of directly comparative data, the number of proton centers and patients are expanding exponentially. Direct studies of the potential risks and benefits are needed in children, who have the highest risk of radiation-related subsequent cancers. The Pediatric Proton and Photon Therapy Comparison Cohort aims to meet this need., Methods and Materials: We are developing a record-linkage cohort of 10,000 proton and 10,000 photon therapy patients treated from 2007 to 2022 in the United States and Canada for pediatric central nervous system tumors, sarcomas, Hodgkin lymphoma, or neuroblastoma, the pediatric tumors most frequently treated with protons. Exposure assessment will be based on state-of-the-art dosimetry facilitated by collection of electronic radiation records for all eligible patients. Subsequent cancers and mortality will be ascertained by linkage to state and provincial cancer registries in the United States and Canada, respectively. The primary analysis will examine subsequent cancer risk after proton therapy compared with photon therapy, adjusting for potential confounders and accounting for competing risks., Results: For the primary aim comparing overall subsequent cancer rates between proton and photon therapy, we estimated that with 10,000 patients in each treatment group there would be 80% power to detect a relative risk of 0.8 assuming a cumulative incidence of subsequent cancers of 2.5% by 15 years after diagnosis. To date, 9 institutions have joined the cohort and initiated data collection; additional centers will be added in the coming year(s)., Conclusions: Our findings will affect clinical practice for pediatric patients with cancer by providing the first large-scale systematic comparison of the risk of subsequent cancers from proton compared with photon therapy., Competing Interests: Matthew M. Mille reports sponsored travel to scientific meetings. Daniel J. Indelicato received a grant from the National Cancer Institute within the past 36 months for participation on the National Cancer Institute Pediatric Clinical Institutional Review Board. Joshua D. Palmer received research grants from Varian Medical Systems, The Kroger Company, Genentech, and the National Institutes of Health, consultant fees from Huron Consulting, a speaker honorarium from Varian Medical Systems, and travel support from Novocure and Varian Medical Systems, and is a Novocure Advisory Board member. Sujith Baliga received a speaker honorarium from Varian Medical Center. Matthew M. Poppe received a speaker honorarium and travel support from Mevion and is an investor in PEEL Therapeutics. Derek S. Tsang is a consultant for Back Alley Film Productions, MD lawyers and received meeting registration support from Mevion Medical Systems. Torunn I. Yock received in-kind research support from MIM Software, Inc. No other disclosures were reported.

Oral bacteria play important roles in human health and disease. Oral samples collected using ethanol-containing mouthwash are widely used for oral microbiome studies. However, ethanol is flammable and not ideal for transportation/storage in large quantities, and some individuals may avoid ethanol due to the burning sensation or due to various personal, medical, religious, and/or cultural factors. Here, we compared ethanol-free and ethanol-containing mouthwashes using multiple microbiome metrics and assessed the stability of the mouthwash samples stored up to 10 days before processing. Forty volunteers provided oral wash samples collected using ethanol-free and ethanol-containing mouthwashes. From each sample, one aliquot was immediately frozen, one was stored at 4°C for 5 days and frozen, while the third aliquot was stored for 5 days at 4°C and 5 days at ambient temperature to mimic shipping delays and then frozen. DNA was extracted, the 16S rRNA gene V4 region was amplified and sequenced, and bioinformatic processing was performed using QIIME 2. Microbiome metrics measured in the two mouthwash types were very similar, with intraclass correlation coefficients (ICCs) for alpha and beta diversity metrics greater than 0.85. Relative abundances of some taxa were significantly different, but ICCs of the top four most abundant phyla and genera were high (> 0.75) for the comparability of the mouthwashes. Stability during delayed processing was also high for both mouthwashes based on alpha and beta diversity measures and relative abundances of the top four phyla and genera (ICCs ≥ 0.90). These results demonstrate ethanol-free mouthwash performs similarly to ethanol-containing mouthwash for microbial analyses, and both mouthwashes are stable for at least 10 days without freezing prior to laboratory processing. Ethanol-free mouthwash is suitable for collecting and shipping oral wash samples, and these results have important implications for planning future epidemiologic studies of the oral microbiome., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: The gut microbiome is plausibly associated with colorectal cancer risk; however, previous studies mostly investigated this association cross-sectionally. We investigated cross-sectional and prospective associations of the rectal tissue microbiome with adenoma recurrence in the Polyp Prevention Trial (PPT)., Methods: PPT is a 4-year randomized clinical trial of the effect of a dietary intervention on adenoma recurrence among community members. We extracted DNA from rectal biopsies at baseline, end of year 1, and end of year 4 among 455 individuals and sequenced the V4 region of the 16S rRNA gene. At each timepoint, we investigated associations of alpha diversity, beta diversity, and presence and relative abundance of select taxa with adenoma recurrence using multivariable logistic regression., Results: Variation in beta diversity was primarily explained by subject and minimally by year of collection or time between biopsy and colonoscopy. Cross-sectionally, year 4 alpha diversity was strongly, inversely associated with adenoma prevalence [ORQ3 vs. Q1 Shannon index = 0.40 (95% confidence interval, CI: 0.21-0.76)]. Prospective alpha diversity associations (i.e., baseline/year 1 alpha diversity with adenoma recurrence 3-4 years later) were weak or null, as were cross-sectional and prospective beta diversity-adenoma associations. Bacteroides abundance was more strongly, positively associated with adenoma prevalence cross-sectionally than prospectively., Conclusions: Rectal tissue microbiome profiles may be associated with prevalent adenomas, with little evidence supporting prospective associations., Impact: Additional prospective studies, with serial fecal and tissue samples, to explore microbiome-colorectal cancer associations are needed. Eventually, it may be possible to use microbiome characteristics as intervenable risk factors or screening tools., (©2022 American Association for Cancer Research.)

Objective: The objective of the study was to determine whether adding longitudinal measures of fundal height (FH) to the standard cross-sectional FH to trigger third trimester ultrasound estimated fetal weight (EFW) would improve small for gestational age (SGA) prediction., Study Design: We developed a longitudinal FH calculator in a secondary analysis of a prospective cohort study of 1,939 nonobese pregnant women who underwent serial FH evaluations at 12 U.S. clinical sites. We evaluated cross-sectional FH measurement ≤ -3 cm at visit 3 (mean: 32.0 ± 1.6 weeks) versus the addition of longitudinal FH up to and including visit 3 to trigger an ultrasound to diagnose SGA defined as birth weight <10th percentile. If the FH cut points were not met, the SGA screen was classified as negative. If FH cut points were met and EFW was <10th percentile, the SGA screen was considered positive. If EFW was ≥10th percentile, the SGA screen was also considered negative. Sensitivity, specificity, and positive predictive value (PPV) and negative predictive value (NPV) were computed., Results: In a comparison of methods, 5.8% of women were classified as at risk of SGA by both cross-sectional and longitudinal classification methods; cross-sectional FH identified an additional 4.0%, and longitudinal fundal height identified a separate, additional 4.5%.Using cross-sectional FH as an ultrasound trigger, EFW had a PPV and NPV for SGA of 69 and 92%, respectively. After adding longitudinal FH, PPV increased to 74%, whereas NPV of 92% remained unchanged; however, the number of women who underwent triggered EFW decreased from 9.7 to 5.7%., Conclusion: An innovative approach for calculating longitudinal FH to the standard cross-sectional FH improved identification of SGA birth weight, while simultaneously reducing the number of triggered ultrasounds. As an essentially free-of-charge screening test, our novel method has potential to decrease costs as well as perinatal morbidity and mortality (through better prediction of SGA)., Key Points: · We have developed an innovative calculator for fundal height trajectory.. · Longitudinal fundal height improves detection of SGA.. · As a low cost screening test, the fundal height calculator may decrease costs and morbidity through better prediction of SGA.., Competing Interests: D.A.W. has been a consultant for Parsagen, for which she received no compensation. She was formerly Professor of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine at University of California, Irvine during time of data collection. She is currently Senior Client Partner at Korn Ferry, Los Angeles, California. At the time of manuscript development, S.J.P. was a postdoctoral fellow at NICHD, and she is currently an employee of Pfizer, Inc, Collegeville, PA. The other authors did not report any potential conflicts of interest., (Thieme. All rights reserved.)

Procedures to arrest metaphase chromosomes are used for determining chromosome numbers, chromosomal aberrations, and natural chromosome variation, as well as chromosome sorting. Here is described a technique of nitrous oxide gas treatment of freshly harvested root tips that is highly effective at producing an excellent mitotic index together with well-spread chromosomes. The details of the treatment and equipment used are provided. The metaphase spreads can be used directly for determining chromosome numbers or for in situ hybridization to reveal chromosomal features., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The role of immunological responses to exposed bacteria on disease incidence is increasingly under investigation. With many bacterial species, and many potential antibody reactions to a particular species, the large number of assays required for this type of discovery can make it prohibitively expensive. We propose a two-phase group testing design to more efficiently screen numerous antibody effects in a case-control setting., Methods: Phase 1 uses group testing to select antibodies that are differentially expressed between cases and controls. The selected antibodies go on to Phase 2 individual testing., Results: We evaluate the two-phase group testing design through simulations and example data and find that it substantially reduces the number of assays required relative to standard case-control and group testing designs, while maintaining similar statistical properties., Conclusion: The proposed two-phase group testing design can dramatically reduce the number of assays required, while providing comparable results to a case-control design., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Characterizing the sleep-wake cycle in adolescents is an important prerequisite to better understand the association of abnormal sleep patterns with subsequent clinical and behavioral outcomes. The aim of this research was to develop hidden Markov models (HMM) that incorporate both objective (actigraphy) and subjective (sleep log) measures to estimate the sleep-wake cycle using data from the NEXT longitudinal study, a large population-based cohort study. The model was estimated with a negative binomial distribution for the activity counts (1-minute epochs) to account for overdispersion relative to a Poisson process. Furthermore, self-reported measures were dichotomized (for each one-minute interval) and subject to misclassification. We assumed that the unobserved sleep-wake cycle follows a two-state Markov chain with transitional probabilities varying according to a circadian rhythm. Maximum-likelihood estimation using a backward-forward algorithm was applied to fit the longitudinal data on a subject by subject basis. The algorithm was used to reconstruct the sleep-wake cycle from sequences of self-reported sleep and activity data. Furthermore, we conduct simulations to examine the properties of this approach under different observational patterns including both complete and partially observed measurements on each individual., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 Informa UK Limited, trading as Taylor & Francis Group.)

Follow-up of US cohort members for incident cancer is time-consuming, is costly, and often results in underascertainment when the traditional methods of self-reporting and/or medical record validation are used. We conducted one of the first large-scale investigations to assess the feasibility, methods, and benefits of linking participants in the US Radiologic Technologists (USRT) Study (n = 146,022) with the majority of US state or regional cancer registries. Follow-up of this cohort has relied primarily on questionnaires (mailed approximately every 10 years) and linkage with the National Death Index. We compared the level of agreement and completeness of questionnaire/death-certificate-based information with that of registry-based (43 registries) incident cancer follow-up in the USRT cohort. Using registry-identified first primary cancers from 1999-2012 as the gold standard, the overall sensitivity was 46.5% for self-reports only and 63.0% for both self-reports and death certificates. Among the 37.0% false-negative reports, 27.8% were due to dropout, while 9.2% were due to misreporting. The USRT cancer reporting patterns differed by cancer type. Our study indicates that linkage to state cancer registries would greatly improve completeness and accuracy of cancer follow-up in comparison with questionnaire self-reporting. These findings support ongoing development of a national US virtual pooled registry with which to streamline cohort linkages., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2022.)

Background: Multistate models can be effectively used to characterise the natural history of cancer. Inference from such models has previously been useful for setting screening policies., Methods: We introduce the basic elements of multistate models and the challenges of applying these models to cancer data. Through simulation studies, we examine (1) the impact of assuming time-homogeneous Markov transition intensities when the intensities depend on the time since entry to the current state (i.e., the process is time-inhomogenous semi-Markov) and (2) the effect on precancer risk estimation when observation times depend on an unmodelled intermediate disease state., Results: In the settings we examined, we found that misspecifying a time-inhomogenous semi-Markov process as a time-homogeneous Markov process resulted in biased estimates of the mean sojourn times. When screen-detection of the intermediate disease leads to more frequent future screening assessments, there was minimal bias induced compared to when screen-detection of the intermediate disease leads to less frequent screening., Conclusions: Multistate models are useful for estimating parameters governing the process dynamics in cancer such as transition rates, sojourn time distributions, and absolute and relative risks. As with most statistical models, to avoid incorrect inference, care should be given to use the appropriate specifications and assumptions., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Dinophysis spp. can produce diarrhetic shellfish toxins (DST) including okadaic acid and dinophysistoxins, and some strains can also produce non-diarrheic pectenotoxins. Although DSTs are of human health concern and have motivated environmental monitoring programs in many locations, these monitoring programs often have temporal data gaps (e.g., days without measurements). This paper presents a model for the historical time-series, on a daily basis, of DST-producing toxigenic Dinophysis in 8 monitored locations in western Andalucía over 2015-2020, incorporating measurements of algae counts and DST levels. We fitted a bivariate hidden Markov Model (HMM) incorporating an autoregressive correlation among the observed DST measurements to account for environmental persistence of DST. We then reconstruct the maximum-likelihood profile of algae presence in the water column at daily intervals using the Viterbi algorithm. Using historical monitoring data from Andalucía, the model estimated that potentially toxigenic Dinophysis algae is present at greater than or equal to 250 cells/L between < 1% and >10% of the year depending on the site and year. The historical time-series reconstruction enabled by this method may facilitate future investigations into temporal dynamics of toxigenic Dinophysis blooms., Competing Interests: Declarations Conlict of Interest None declared.

The chr12q24.13 locus encoding OAS1-OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-λ1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454 -A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)